Pre-Approval

Inspection Readiness

Presented by

Pepe Rodriguez-Perez PhD

Business Excellence Consulting Inc BEC Spain SL

wwwcalidadprcom email pepecalidadprcom

2

Agenda

US FDA Structure and Authority

Generic Drug Approval Process

ndash The PreApproval Inspection (PAI)

Pharmaceutical development

ndash QBD

ndash Process Validations

FDA Quality System Inspection Elements

Pre-Inspection Activities the Value of a Mock Audit

Interaction with FDA Inspectors

Data Integrity

3

FDA Overview US Department of Health amp Human Services

US Food and Drug Administration Centers for

ndash Food Safety and Nutrition (CFSAN)

ndash Drug Evaluation and Research (CDER)

ndash Biologics Evaluation and Research (CBER)

ndash Devices and Radiological Health (CDRH)

ndash Center for Veterinary Medicine (CVM)

ndash Center for Tobacco Products (CTP)

ndash Office of Regulatory Affairs (ORA HQ)

ndash Field Regions (SER SWR PAR NER CER) raquo District Offices

San Juan District Office (SJN-DO)

ndash SJN MRP PON USVI

14000

3

FDA Overview US Department of Health amp Human Services

US Food and Drug Administration Centers for

ndash Food Safety and Nutrition (CFSAN)

ndash Drug Evaluation and Research (CDER)

ndash Biologics Evaluation and Research (CBER)

ndash Devices and Radiological Health (CDRH)

ndash Center for Veterinary Medicine (CVM)

ndash Center for Tobacco Products (CTP)

ndash Office of Regulatory Affairs (ORA HQ)

ndash Field Regions (SER SWR PAR NER CER) raquo District Offices

San Juan District Office (SJN-DO)

ndash SJN MRP PON USVI

14000

4

FDA Mission To ensure that

ndash Foods are safe wholesome and sanitary

ndash Human and veterinary drugs biological products

and medical devices are safe and effective

ndash Cosmetics are safe

ndash Electronic products that emit radiation are safe

Authority for Inspections

United States of America

ndash Federal Food Drugs amp

Cosmetic Act

ndash The FDA is responsible for

protecting the public health by

assuring the safety efficacy and

security of human and veterinary

drugs biological products

medical devices our nationrsquos

food supply cosmetics and

products that emit radiation 5

6

FDA Laws Overview

1906 ndash Congress enacted Food and Drug Act

1938- Federal Food Drug and Cosmetic Act

ndash To ensure that food are safe and produced under sanitary conditions

ndash Drugs and device are safe and effectives for their intended use

ndash Cosmetics are safe and made from appropriate ingredients

ndash Labeling and packaging is truthful

1963 - Fist version of GMP for Drugs

1978 cGMP for Drugs 21 CFR 211

1987 Guideline on General Principles of Process Validation

1997 ndash FDA Modernization Act (FDAMA) Fine-tuning FDA laws

1997- Electronic Records (21 CFR Part 11)

2013 ndash Combination Products

Generic Drugs The use of bioequivalence as the basis for approving generic

copies of drug products was established by the ldquoDrug Price

Competition and Patent Term Restoration Act of 1984rdquo also

known as the Waxman-Hatch Act

This Act expedites the availability of less costly generic drugs by

permitting the FDA to approve applications to market generic

versions of brand-name drugs without conducting costly and

duplicative clinical trials At the same time the brand-name

companies can apply for up to five additional years patent

protection for the new medicines they developed to make up for

time lost while their products were going through the FDArsquos

approval process Brand-name drugs are subject to the same

bioequivalence tests as generics upon reformulation 7

Authority for Inspections

United States of America

ndash Federal Food Drugs amp

Cosmetic Act

ndash The FDA is responsible for

protecting the public health by

assuring the safety efficacy and

security of human and veterinary

drugs biological products

medical devices our nationrsquos

food supply cosmetics and

products that emit radiation 5

6

FDA Laws Overview

1906 ndash Congress enacted Food and Drug Act

1938- Federal Food Drug and Cosmetic Act

ndash To ensure that food are safe and produced under sanitary conditions

ndash Drugs and device are safe and effectives for their intended use

ndash Cosmetics are safe and made from appropriate ingredients

ndash Labeling and packaging is truthful

1963 - Fist version of GMP for Drugs

1978 cGMP for Drugs 21 CFR 211

1987 Guideline on General Principles of Process Validation

1997 ndash FDA Modernization Act (FDAMA) Fine-tuning FDA laws

1997- Electronic Records (21 CFR Part 11)

2013 ndash Combination Products

Generic Drugs The use of bioequivalence as the basis for approving generic

copies of drug products was established by the ldquoDrug Price

Competition and Patent Term Restoration Act of 1984rdquo also

known as the Waxman-Hatch Act

This Act expedites the availability of less costly generic drugs by

permitting the FDA to approve applications to market generic

versions of brand-name drugs without conducting costly and

duplicative clinical trials At the same time the brand-name

companies can apply for up to five additional years patent

protection for the new medicines they developed to make up for

time lost while their products were going through the FDArsquos

approval process Brand-name drugs are subject to the same

bioequivalence tests as generics upon reformulation 7

6

FDA Laws Overview

1906 ndash Congress enacted Food and Drug Act

1938- Federal Food Drug and Cosmetic Act

ndash To ensure that food are safe and produced under sanitary conditions

ndash Drugs and device are safe and effectives for their intended use

ndash Cosmetics are safe and made from appropriate ingredients

ndash Labeling and packaging is truthful

1963 - Fist version of GMP for Drugs

1978 cGMP for Drugs 21 CFR 211

1987 Guideline on General Principles of Process Validation

1997 ndash FDA Modernization Act (FDAMA) Fine-tuning FDA laws

1997- Electronic Records (21 CFR Part 11)

2013 ndash Combination Products

Generic Drugs The use of bioequivalence as the basis for approving generic

copies of drug products was established by the ldquoDrug Price

Competition and Patent Term Restoration Act of 1984rdquo also

known as the Waxman-Hatch Act

This Act expedites the availability of less costly generic drugs by

permitting the FDA to approve applications to market generic

versions of brand-name drugs without conducting costly and

duplicative clinical trials At the same time the brand-name

companies can apply for up to five additional years patent

protection for the new medicines they developed to make up for

time lost while their products were going through the FDArsquos

approval process Brand-name drugs are subject to the same

bioequivalence tests as generics upon reformulation 7

Generic Drugs The use of bioequivalence as the basis for approving generic

copies of drug products was established by the ldquoDrug Price

Competition and Patent Term Restoration Act of 1984rdquo also

known as the Waxman-Hatch Act

This Act expedites the availability of less costly generic drugs by

permitting the FDA to approve applications to market generic

versions of brand-name drugs without conducting costly and

duplicative clinical trials At the same time the brand-name

companies can apply for up to five additional years patent

protection for the new medicines they developed to make up for

time lost while their products were going through the FDArsquos

approval process Brand-name drugs are subject to the same

bioequivalence tests as generics upon reformulation 7

8

9

The FDArsquos Drug Review Process

10

The FDArsquos Drug Review Process

11

NDA vs ANDA Review Process

12

Center for Drug Evaluation amp Research Office of Generic Drugs (OGD) 13

Generic Drug Review Process

Bioequivalence Review Labeling Review Chemistry amp Micro

Review Request for Plant

Inspection

APPLICANT

ANDA

Acceptable amp

Complete

Application Review

N ChemMicro

OK

Labeling

OK

Bioequivalence

OK

PreApproval

Inspection Results

OK

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

N N N

N

Y Y Y

Y

Y

Refuse to Receive Letter

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

9

The FDArsquos Drug Review Process

10

The FDArsquos Drug Review Process

11

NDA vs ANDA Review Process

12

Center for Drug Evaluation amp Research Office of Generic Drugs (OGD) 13

Generic Drug Review Process

Bioequivalence Review Labeling Review Chemistry amp Micro

Review Request for Plant

Inspection

APPLICANT

ANDA

Acceptable amp

Complete

Application Review

N ChemMicro

OK

Labeling

OK

Bioequivalence

OK

PreApproval

Inspection Results

OK

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

N N N

N

Y Y Y

Y

Y

Refuse to Receive Letter

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

The FDArsquos Drug Review Process

10

The FDArsquos Drug Review Process

11

NDA vs ANDA Review Process

12

Center for Drug Evaluation amp Research Office of Generic Drugs (OGD) 13

Generic Drug Review Process

Bioequivalence Review Labeling Review Chemistry amp Micro

Review Request for Plant

Inspection

APPLICANT

ANDA

Acceptable amp

Complete

Application Review

N ChemMicro

OK

Labeling

OK

Bioequivalence

OK

PreApproval

Inspection Results

OK

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

N N N

N

Y Y Y

Y

Y

Refuse to Receive Letter

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

The FDArsquos Drug Review Process

11

NDA vs ANDA Review Process

12

Center for Drug Evaluation amp Research Office of Generic Drugs (OGD) 13

Generic Drug Review Process

Bioequivalence Review Labeling Review Chemistry amp Micro

Review Request for Plant

Inspection

APPLICANT

ANDA

Acceptable amp

Complete

Application Review

N ChemMicro

OK

Labeling

OK

Bioequivalence

OK

PreApproval

Inspection Results

OK

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

N N N

N

Y Y Y

Y

Y

Refuse to Receive Letter

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

NDA vs ANDA Review Process

12

Center for Drug Evaluation amp Research Office of Generic Drugs (OGD) 13

Generic Drug Review Process

Bioequivalence Review Labeling Review Chemistry amp Micro

Review Request for Plant

Inspection

APPLICANT

ANDA

Acceptable amp

Complete

Application Review

N ChemMicro

OK

Labeling

OK

Bioequivalence

OK

PreApproval

Inspection Results

OK

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

N N N

N

Y Y Y

Y

Y

Refuse to Receive Letter

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Center for Drug Evaluation amp Research Office of Generic Drugs (OGD) 13

Generic Drug Review Process

Bioequivalence Review Labeling Review Chemistry amp Micro

Review Request for Plant

Inspection

APPLICANT

ANDA

Acceptable amp

Complete

Application Review

N ChemMicro

OK

Labeling

OK

Bioequivalence

OK

PreApproval

Inspection Results

OK

Not Approvable

Letter

Approval Withheld until

Results Satisfactory

Bio Deficiency Letter

APPROVED ANDA

N N N

N

Y Y Y

Y

Y

Refuse to Receive Letter

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

What is the goal of a

Pre-Approval Inspection

To assure that establishments involved in the

manufacturing testing or other manipulation of

new drug dosage forms and drug substances are

evaluated for

ndash conformance with commitments in the application

ndash site cGMP compliance

ndash data authenticity reliability and accuracy

ndash adequacy of analytical methodologies

14

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

PAI Objectives (Program 7346832)

There are three primary inspectional objectives of

this PAI program These objectives are

1) Readiness for Commercial Manufacturing

2) Conformance to Application

3) Data Integrity Audit

15

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

PAI Objective 1 Readiness for Commercial Manufacturing

Determine whether the establishment has a quality

system that is designed to achieve sufficient control over

the facility and commercial manufacturing operations

a) Manufacturing and laboratory changes deviations and

trends relating to the development of new drug substance

and product manufacturing have been adequately

evaluated

b) A sound and appropriate program for sampling testing

and evaluation of components in-process materials

finished products containers and closures for the purpose

of releasing materials or products has been established

including a robust supplier qualification program

16

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

PAI Objective 1 Readiness for Commercial Manufacturing cont

c) The establishment has sufficient facility and equipment

controls in place to prevent contamination of and by the

application product (or API)

d) Adequate procedures exist for batch release change control

investigating failures deviations complaints and adverse

events and for reporting this information to FDA such as

field alert reporting

e) The feasibility of the proposed commercial process and

manufacturing batch record including instructions

processing parameters and process control measures are

scientifically and objectively justified This objective is

linked to the firmrsquos process validation program

17

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

PAI Objective 2

Conformance to Application

Verify that the formulation manufacturing or

processing methods and analytical (or

examination) methods are consistent with

descriptions contained in the CMC section of the

application for the biobatch (and other pivotal

clinical batches when applicable) the proposed

commercial scale batch and API ndash Observing processing andor testing operations

ndash Compare the biobatch manufacturing process against the

proposed commercial batch record

18

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

PAI Objective 3

Data Integrity Audit

Audit the raw data hardcopy or electronic to

authenticate the data submitted in the CMC

section of the application

Verify that all relevant data (eg stability

biobatch data) were submitted in the CMC section

such that CDER product reviewers can rely on the

submitted data as complete and accurate ndash Laboratory notebooks and associated chromatograms generated

during release testing of biobatch

ndash Failure to include aberrant test results in CMC section

ndash Improper invalidation of OOS results

19

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Investigatorrsquos Role during PAI

Assess the following

ndash Quality Systems

ndash Manufacturing Operations

ndash Sampling Plans

ndash Laboratory

ndash Test Methods Validation

ndash Drug Product Specifications

ndash ReprocessingReworking

ndash Standard Operating Procedures

ndash Batch Records 20

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

The Firmrsquos Role

Make records available (as appropriate) to

conduct the pre-approval inspection

ndash Product Development Report

ndash Batch Records and Laboratory Records

ndash ProtocolsSOPs

Assure facility is cGMP compliant and ready for

an FDA inspection

ndash Once an application is submitted to Center the firm

should be considered ready for inspection

21

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Product Development Report

A very useful document for both the firm

and the FDA

The data generated during product

development which defines the drug

product targets the steps in the

manufacturing process where variation is

critical to quality and thereby focuses the

subsequent process validation effort

22

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Product Development Report

API Impurity Profile

ndash How is the API characterized

Excipients

Formulation Wet or Dry Granulation

ndash Solution or Suspension

ndash Sterile - Terminalaseptic conditions

ndash TabletCapsule - ImmediateModified

ReleaseExtended Release

23

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Product Development Report

Describes the development of Processing

Equipment order of addition of ingredients

to the formulation mixing times and

speeds drying time and temperature

nitrogen blankets blending hold times

compression slugging filling polishing

imprinting labeling and packaging

Product Development Report may not be a

formal document

24

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Batch Records

The batch records submitted in the

application must be audited as part of

the inspection to assure

ndash That the proposed production process is the

same process that was used for the

manufacture of the biostability batches

25

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

ReprocessingReworking

cGMP regulations require reprocessing

procedures to be in writing If firm

makes provisions for reprocessing drug

product details must be submitted as

part of the application

ndash Standard Operating Procedures

ndash QA review and approval

26

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

27

Different Responsibilities

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

28

Different Responsibilities

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

29

Different Responsibilities

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

How ICH Q8 Q9 Q10

Guidelines Are Working

Together Throughout The

Product Life Cycle

30

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Nov 2005 amp Nov 2008

ICH Q8 Q9 and Q10

High level guidances

(not prescriptive)

Science and risk-based

Encourages systematic

approaches

Applicable over entire product

lifecycle

Intended to work together to

enhance pharmaceutical product

quality

31

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Pharmaceutical Development -

Q8(R2)

Describes science and risk-based

approaches for pharmaceutical product and

manufacturing process development

Introduced concepts of design space and

flexible regulatory approaches

Introduced concepts of Quality by Design

(QbD) and provided examples of QbD

development approaches and design space 32

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Differing Approaches to

Pharmaceutical Development

33

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Q8(R2) - Example QbD

Approach

Quality Target Product Profile (QTPP)

Determine ldquopotentialrdquo critical quality attributes

Link raw material attributes and process parameters

to CQAs and perform risk assessment

Develop a design space (optional and not required)

Design and implement a control strategy

Manage product lifecycle including continual

improvement

CQArsquos

Product Profile

Risk Assessments

Design Space

Control Strategy

Continual

Improvement34

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Product Lifecycle

concept

Human and veterinary

drugs

Biotech products

Finish products amp APIs

Drug constituent of a

combination product

35

Manage product lifecycle including

continual improvement

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Three-stage approach to process validation

Stage 1 ndash Process Design ndash Building and capturing process knowledge and understanding

ndash Establishing a strategy for process control

Stage 2 ndash Process Qualification ndash Design a facility and qualification of utilities and equipment

ndash Process performance qualification

ndash PPQ protocol

ndash PPQ protocol execution and report

Stage 3 ndash Continued Process Verification

36

Focus on alignment with

lsquoproduct lifecyclersquo

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Manufacturers should

Understand the sources of variation

Detect the presence and degree of variation

Understand the impact of variation on the process and

ultimately on product attributes

Control the variation in a manner commensurate with

the risk it represents to the process and product

37

Process Validation

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

38

Focus on alignment with

lsquoproduct lifecyclersquo

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

39

Focus on alignment with

lsquoproduct lifecyclersquo

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

40

Focus on alignment with

lsquoproduct lifecyclersquo

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

FDA Quality Systems Guidance

for Finished Pharmaceuticals

41 Inspection Readiness BEC

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Inspection Readiness BEC 42

Quality System

Drug Inspection Target Includes the Quality Control Unit and all of its review

and approval duties

ndash Approval of and adherence to Procedures and associated recordkeeping systems

ndash Product Reviews

ndash Complaint Reviews

ndash Failure Evaluations

ndash Change Control

ndash Product Improvement Projects

ndash RejectsReprocessingRework

ndash Stability

ndash Validation

ndash Training

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Inspection Readiness BEC 43

Facilities and Equipment

Inspection Target

Building and Facilities along with

maintenance

Equipment qualification calibration and

maintenance

Water steam compressed gas HVAC

Change control system

Investigate discrepancies

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Inspection Readiness BEC 44

Materials

Inspection Target

Procedures and documentation showing adequate control of finished products in-process materials components containers closures

Qualificationvalidation and security of computerized or automated processes

Change control system

Investigation of Discrepancies

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Inspection Readiness BEC 45

Production System

Drug Inspection Target

Trainingqualification of personnel

Complete batch production documentation

Process validation

Production time limits

In-process testingexamination

Change Control System

Investigation of discrepancies

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Inspection Readiness BEC 46

Packaging and Labeling

Inspection Target

Training

Acceptance operations

Control of materials to prevent mix-ups

Accountability

Packaginglabeling records

Line separation

Line clearance inspection and documentation

Validation of labelingpackaging operations

Investigation of discrepancies

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Inspection Readiness BEC 47

Laboratory Control

Inspection Target

Staffing and training

Adequate equipment calibration and maintenance

Reference standards

Adherence to written procedures

Validationverification analytical methods

Analytical records and raw data

Adherence to OOS procedure and timely completion of investigations

Stability testing program and reserve samples

Change control system

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Before the Inspection

SOP for Inspection Readiness

Strong Internal AuditAssessment function

ndash Continuous assessment using Risk Management

Criteria

ndash Not autopilot auditing

ndash Same auditorhellip

Perform a full-system audit (Mock) at least one

month prior to inspection

ndash Be sure any necessary CA-PA has been originated 48

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Before the Inspection

Educate all your employees on proper inspection

rules and etiquette

Educate your supervisory (all exempt) personnel

on FDA regulations

Inspections and external audits concern to all

employees not only those from Quality Dept

Promote the participation on the internal audit

cadre

Certify internal auditors

49

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Before the Inspection

A few words about Internal Audit

Internal Audits are the most powerful tool to

avoid inspection surprises

If the inspector discovers something why your

internal auditor did not

The same auditor auditing several consecutive

years the same area is not effective

An effective internal audit function is priceless

50

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

During the Inspection

Use your best resources to assist during

inspection

War room

Managing documents

Photographs etc

Opening meeting

Daily wrap up

Close-our meeting

51

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

During the Inspection

Answering Inspectorrsquos Questions

Think before your answer

Answer questions accurately and truthfully

Donrsquot be intimidated or defensive

Know your work and be confident

Be professional

If you donrsquot know the answer it is

acceptable to reply that donrsquot know but you

can find out

52

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

At the end of the Inspection

Do not hesitate to challenge (be polite) the

inspector to explain the basis of citations

Many companies are unwilling to challenge

the inspector out of fear to provoking some

sort of retaliatory response

However FDA may interpret silence as

agreement

Inspection Readiness BEC 53

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Data integrity data manipulation and fraud appears to be increasing

Itrsquos occuring in early stages of drug development (ie clinical studies) during commercial manufacturing and in various FDA regulated products

The FDampC Act is a strict liability statute

FDA takes the position that corporations act through the actions of individuals

Part of an FDA Investigatorrsquos job is to document individual responsibility for violations noted during inspections

54

Data Integrity Information that is accurate complete and truthful

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Data Integrity and Quality

FDA needs to be able to verify the quality and

integrity of the data during inspections

ndash Data needs to meet ALCOA elements of quality

ndash Attributable ndash data are identified with a specific subject and a specific

observer and recorder (Password audit trail and e-signature)

ndash Legible ndash data are readable and understandable by humans (reports tables

and listings)

ndash Contemporaneous - data are recorded at the time they are generated or

observed (Time stamps and time-limited entry)

ndash Original ndash data are recorded for the first time (Source data)

ndash Accurate ndash data are correct (Calculations algorithms analyses)

55

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

56

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

57

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

58

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Train employees on proper data handling

and reporting

Assure the reliability of data reported in

applications and manufacturing records

Emphasize that everyone in the company is

responsible for data integrity 59

What Can Industry Do

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

FDA ONLINE Resources httpwwwfdagov

60

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

FDA ONLINE Resources

wwwfdagovora

61

Gracias

wwwcalidadprcom

wwwbecspainslcom

62

Gracias

wwwcalidadprcom

wwwbecspainslcom

62