4-2 inspections gmp standards

7/27/2019 4-2 Inspections GMP Standards

http://slidepdf.com/reader/full/4-2-inspections-gmp-standards 1/47

Required GMP Standards

and Inspections

Alain Kupferman

Workshop on WHO prequalification requirements for reproductive health medicines,

Jakarta, October 2009




Jakarta, October 20092 |

Drug

meetingrequirements

Equipment Personnel

MethodsPremisesDefinition of conditions under

which drugs are manufactured,

packed, tested, held

State of Control:a drug firm is considered

to be operating in a state of

control when it can guarantee

a finished drug product

for which quality, strength and

purity has been assured

throughout production andthat the product is compliant

with its registration

STATE OF CONTROL





ELEMENTS OF COMPLIANCE

EQUIPMENT COMPONENTS PERSONNEL FACILITIES PROCESS

QUALIFICATION ANALYSIS TRAINING QUALIFICATIONDEVELOPMENT

VALIDATION

PRODUCT

APPROVAL BY

AUTHORITIES





S E L F -I N S P

E C T I ON

I N S P E C T I ON

MONITORING OF COMPLIANCE





DEFINITIONS

Compliance

The state of conformity of a regulated party (including a corporation, institution,individual or other legal entity) or a product with a legislative or regulatoryrequirement.

Compliance Monitoring Actions planned to maintain regular surveillance in order to evaluate compliancewith applicable requirements of the National Regulatory Authority (NRA) and itsassociated Regulations.

This includes a wide variety of fact gathering and assessment activities such asinspections, market surveys and a product sampling program.

Compliance Verification Actions taken to verify compliance in response to information regarding known or suspected non-compliance with the applicable requirements of the NRA and itsassociated Regulations.This includes actions such as information gathering either off-site or via on-sitevisits.





DEFINITIONS

Enforcement

Actions that may be taken to induce, encourage or compel compliance with the NRAand its associated Regulations.

Inspection

On-site monitoring and assessment against the applicable requirements of the NRA

and its associated Regulations.

Inspections are routinely conducted on a predetermined cycle or as required to assess

compliance.

Inspector

Any person designated as an inspector for the purpose of the enforcement of the NRA

Investigation

Actions taken to gather evidence to support a case referral for potential judicial

determination regarding specific violations of the NRA and its associated regulations.





REASONS FOR INSPECTION

• Regular schedule based on general GMP’s

• Pre-approval inspections

• Submission of a variation

• Submission of an NDA

• New products and/or manufacturing changes• Site changes

• For cause inspections

• Recalls or significant complaint

• Past inspection history





• Focus on Risk and Quality Systems

• Doctrine of Liability for Executives

• Process Analytical Technology

TRENDS





FOCUS ON QUALITY SYSTEMS & RISK

Quality Systems Inspection Program

Assess Firm's State of Control

Systems Approach (6 systems)

Executive ManagementExpected to Establish Effective Procedures and Controls toEnsure:

Timely Investigations

Supportable Decisions Are Documented





The idea underlying this approach is that

deficiencies in one systemwill affect all other systems as well.

FDA Systems Approach (6 systems)Quality System

Facilities System

Equipment System

Materials System

Production System

Packaging & Labeling System

FOCUS ON QUALITY SYSTEMS





“Risk Based Pharmaceutical cGMP Initiative” Goals

(GMPs for 21st Century)the most up-to-date concepts of risk management and quality systems approaches

should be incorporated while continuing to ensure product quality (PAT);

the latest scientific advances in pharmaceutical manufacturing and technology

should be encouraged;

the submission review program and the inspection program should operate in acoordinated and synergistic manner;

regulation and manufacturing standards should be applied consistently;

management of the program encourages innovation in the pharmaceutical

manufacturing sector; and

FDA resources should be used most effectively and efficiently to address the most

significant health risks

FDA FOCUS ON QUALITY SYSTEMS & RISK





•Increased number of pharmaceutical products and a greater role of

medicines in health care

•Decreased frequency of FDA (NRA) manufacturing inspections as a result of

fewer resources available for pharmaceutical manufacturing inspections

• FDA’s (NRA’s) accumulation of experience with, and lessons learned from,

various approaches to the regulation of product quality

•Advances in the pharmaceutical sciences and manufacturing technologies

•Application of biotechnology in drug discovery and manufacturing

•Advances in the science and management of quality

•Globalization of the pharmaceutical industry

WHY A NEW FOCUS ?





RISK ASSESSMENT





RISK ASSESSMENT

RISK ASSESSMENT





RISK ASSESSMENT





RISK ASSESSMENT COMPONENTS

PRODUCT COMPONENT

PROCESS COMPONENT

FACILITY COMPONENT





1. Intrinsic factors

Factors such as sterility, medical gas, and the determination of prescription (Rx)versus over the counter (OTC) are crude methods to distinguish between products

with higher and lower potential for public health consequence should there be a drug

defect.

If there is a quality defect, sterile drugs would have a higher public health

consequence than nonsterile drugs; hence, sterile drugs should be given a higher

weight.Specific products where there is a heightened risk of cross-contamination, such as

sites manufacturing highly sensitizing agents (e.g., penicillin) and at least one other

product using similar processing methods should be taken into account.

2. Past recalls for quality defects / Complaints

Drug recall data provide information on past recalls for quality defects with potentialfor human health hazard.

PRODUCT COMPONENT





Some processes are more complex and more susceptible to problems than

others.

A primary goal of CGMP inspections is to ensure that processing operations

are in a state of control.

Two types of process-related factors were identified for inclusion in the risk-

ranking model:

1. Factors associated with maintaining process control

2. Factors associated with potential vulnerability to product or

environmental contamination

PROCESS COMPONENT

PROCESS COMPONENT





It is important to arrive to a risk-ranking (i.e., from high to low) of the

probability of a loss of a state of control and, independently, the

vulnerability of the process to contamination for a product category and

processing operations associated with that product category.

It is necessary to survey on risks associated with commonly employed

manufacturing operations (e.g., measuring, mixing, compression, and

filling) and for a variety of product categories (e.g., immediate and

modified release solid-oral drugs, sterile liquids, metered dose inhalers,

and active ingredients by chemical and fermentation processes).

PROCESS COMPONENT

PROCESS COMPONENT RISK MANAGEMENT





PROCESS COMPONENT: RISK MANAGEMENT

ICH Q9

FACILITY COMPONENT





The facility component of the US FDA risk ranking model includes 4factors:

1. History of violation (e.g., CGMP deficiencies have higher weights)

2. History of inspection (e.g., no prior inspection, newly registered/

licensed or no CGMP inspection in the past 2 years have higher

weights than those with recent CGMP inspection)

3. Estimated volume of production output (surrogate for exposure,

e.g., higher volume and production output, higher weights)

4. Type of establishment (e.g., manufacturer, repacker, contract lab)

FACILITY COMPONENT

MANAGEMENT CONTROLS





MANAGEMENT CONTROLS

Strict Liability Requires Diligence & Management Controls to:

• Prevent Violations• Detect Problems When They Occur

• Correct Root Cause Issues

Indiv iduals Corporations Act Through

Can Be Held AccountableIndiv iduals

The FD&C Act

“…dispenses with the conventional requirement for criminal conduct -- awarenessof some wrongdoing.“

“…a positive duty to seek out and remedy violations when they occur … and …, a

duty to implement measures that wil ensure that violations will not occur.”“…and permits conviction of responsible corporate officials, who … have thepower to prevent or correct violations”

PROCESS ANALYTICAL TECHNOLOGY





PAT is considered to be a system for

•designing ,

•analyzing, and

•controlling manufacturingthrough timely measurements (i.e. during processing)

of critical quality and performance attributes of raw and in-

process materials and processes with the goal of ensuring final

product quality.”

PROCESS ANALYTICAL TECHNOLOGYPAT






1. PAT Tools

2. Process Understanding

3. Risk-Based Approach

4. Integrated Systems Approach

5. Real Time Release







1. PAT Tools

•Multivariate data acquisition and analysis tools

•Modern process analyzers or process analytical chemistry tools

•Process and endpoint monitoring and control tools

•Continuous improvement and knowledge management tools

2. Process Understanding

A process is generally considered well understood when

•all critical sources of variability are identified and explained;

•variability is managed by the process; and,

•product quality attributes can be accurately and reliably predicted over the ranges

of acceptance criteria established for materials used, process parameters, and

manufacturing environmental and other conditions.

The ability to predict reflects a high degree of process understanding.

Although retrospective process capability data are indicative of a state of control,these alone may be insufficient to gauge or communicate process understanding







3. Risk-Based Approach

Within an established quality system and for a particular manufacturing process,

there is an inverse relationship between the level of process understanding and

the risk of producing a poor quality product

4. Integrated Systems Approach

Development, manufacturing, quality assurance, and information/knowledge

management functions

5. Real Time Release

Real time release is the ability to evaluate and ensure the acceptable quality of

in-process and/or final product based on process analytical data


PROCESS ANALYTICAL TECHNOLOGY d ICH





PROCESS ANALYTICAL TECHNOLOGY and ICH

PROCESS ANALYTICAL TECHNOLOGY d ICH





PROCESS ANALYTICAL TECHNOLOGY and ICH





Error Precursors





FINDINGS FROM INSPECTIONS

Source:MHRA (MCA)






Source:MHRA (MCA)






FINDINGS FROM FDA INSPECTIONS






INSPECTION RESULTS





Buildings and Facilities

•Not of adequate size or capacity for intended activities

•Failure to provide separate or defined areas to prevent contamination, cross-contamination or

mix-ups

•No appropriately cleaned or maintained

•Effectiveness of sanitation has not been established

•Poorly designed air handling systems or not appropriate for intended activities

•Not monitored for temperature or humidity

•Poorly designed water systems

•Poor hygienic zone system

•Use of low quality building fabrics leading to easily damaged walls and doors which become

difficult to clean

• Incorrect airflows and pressure differentials to prevent cross contamination

• Sterile area changing rooms insufficient in size or bqd lqyout

• Goods receipt areas of insufficient size

INSPECTION RESULTS

INSPECTION RESULTS





Equipment

• No or improperly maintained cleaning and usage logs

•No expiration dating of cleaned equipment

•No or inadequate cleaning validation

•Not identified as to use or status•No or insufficient SOP for use

•Not or incorrectly identified in batch record

•Inadequate calibration program

•Preventative maintenance program not in existence or inadequate

INSPECTION RESULTS



INSPECTION RESULTS





Quality Management Systems, Records and Reports

•Incomplete batch and test records:

- Steps not verified

- Laboratory results not included

- Equipment not identified

•Not reviewed or revised periodically

•Inadequate documentation of deviations and OOS •Incomplete or tardy recording and investigation of complaints and incidents

• No regular management review of quality indicators

• Lack of quality improvement / CAPA processes

• Insufficient change control

• Ineffective self -inspection systems

• Recall systems incomplete and untested

• Non-compliance with previous inspection commitments• Inadequate recording of training and effectiveness

•Insufficient documentation of maintenance and calibration activities

INSPECTION RESULTS

INSPECTION RESULTS





Laboratory Controls

•Not based on scientifically sound and appropriate

(specific) specifications

•Test methods not appropriately validated

Standard Operating Procedures (SOP)

• Not in existence.

•Incomplete or not in sufficient detail

•Not followed or deviations not justified

•Not periodically reviewed and updated

INSPECTION RESULTS

INSPECTION RESULTS





Procedures and Process Controls

• Aseptic processing principles not applied or validated:

- Not all aseptic processes are included in challenge studies.

- Product exposed to environment that is not properly controlled.

- Failure to validate aseptic connection.

- Failure to follow SOP.•Investigations following excursions not performed, documented or

are inadequate:

- Do not include other batches associated with failure.

- Are not completed in timely manner.

INSPECTION RESULTS

INSPECTION RESULTS





Procedures and Process Controls

• In-process hold times not validated or incorporated into stability program

•Sterilization procedures not appropriately validated or revalidated•No or inadequate process validation studies or in-process testing

•Inadequate changeover procedures for multi-purpose areas

•No time limits for completion of time-sensitive production phases

INSPECTION RESULTS

INSPECTION RESULTS





Environmental Monitoring

• Not performed during manufacturing operations

•Appropriate limits:

- Not based on trends

- Do not consider nature of the product

•Inadequate monitoring frequencies

•Improper location of sampling devices or monitoring locations not identified

No viable monitoring close to point of fill for aseptic products

Poor handling and positioning of settle plates in critical zonesPoor or no continuous particle monitoring in critical zones

•Inadequate personnel monitoring

•Wash bays, cold stores and water systems not monitored microbiologically

• No monitoring during or following building work

• No assessment of recovery or growth promotion

•Sampling procedures not representative of usage procedures

•Data not linked to manufacturing process •Investigation following excursions are no performed,not documented, or inadequate:

- Are not complete, do not consider impact on product, are not completed in timely manner

•Procedures allow for consecutive out of specification results before taking action

INSPECTION RESULTS

CONCLUSION



Workshop on WHO prequalification requirements for reproductive health medicines,|

CONCLUSION

Adopt the mindset

Be prepared and compliant all the time,

NOT just at the time of the inspection

Conduct at regular intervals

Inspection Readiness Training

Self Audits

Integrate audit program with overall system based GMP program.

4-2 inspections gmp standards

Documents