1

ICH Q8, 9 & 10 and the Impact on the QP

ICH Q8, 9 & 10 and the Impact on the QP

Peter H. GoughDavid Begg Associates

phg@david-begg-associates.com

2

A New Approach to RegulationA New Approach to Regulation

� Approach to the regulation of pharmaceuticals is undergoing a paradigm shift

� Led by the American Food and Drug Administration (FDA)

� Started with Process Analytical Technology (PAT) and 21st Century GMP initiatives.

� These changes will directly impact on many aspects of quality management and the QP.

� Approach to the regulation of pharmaceuticals is undergoing a paradigm shift

� Led by the American Food and Drug Administration (FDA)

� Started with Process Analytical Technology (PAT) and 21st Century GMP initiatives.

� These changes will directly impact on many aspects of quality management and the QP.

3

2001 - FDA’s Concerns2001 - FDA’s Concerns

� Current State of Pharmaceutical Manufacturing:

� Many product formulations and processes

derived empirically

� Too little knowledge on fundamental

mechanisms impacting product quality

� Very low efficiency and high cost

� Industry hesitant or afraid to use new technologies

� Current State of Pharmaceutical Manufacturing:

� Many product formulations and processes

derived empirically

� Too little knowledge on fundamental

mechanisms impacting product quality

� Very low efficiency and high cost

� Industry hesitant or afraid to use new technologies

4

2001 - FDA’s Concerns2001 - FDA’s Concerns

FDA’s CONCLUSION:

� Current approach likely to beinadequate to meet future needs

� FDA unable to deliver on their statutory

inspection obligations

� Need to encourage greater emphasis on science and risk-based approaches

FDA’s CONCLUSION:

� Current approach likely to beinadequate to meet future needs

� FDA unable to deliver on their statutory

inspection obligations

� Need to encourage greater emphasis on science and risk-based approaches

5

FDA Initiatives since 2001FDA Initiatives since 2001

PATcGMP

Critical P

ath

“Desired State”

ICH GMP activities

6

Process Analytical Technology (PAT)Process Analytical Technology (PAT)

� Not just testing but a philosophy of

� Control in-process rather than end-product testing

� Minimises risks of poor quality

� Not just testing but a philosophy of

� Control in-process rather than end-product testing

� Minimises risks of poor quality

7

PAT Approach – Quality by DesignPAT Approach – Quality by Design

� Identify the parameters that are criticalto product quality

� Statistically designed experiments

� Measure these parameters

� Control these parameters

� Feed back

� Feed forward

� Identify the parameters that are criticalto product quality

� Statistically designed experiments

� Measure these parameters

� Control these parameters

� Feed back

� Feed forward

8

Paradigm ShiftParadigm Shift

� Current paradigm:� Current paradigm:

Starting Materials

Variable

Processing parameters

Fixed

Product

Variable

9

Paradigm ShiftParadigm Shift

� PAT paradigm:� PAT paradigm:

Starting Materials

Variable

Processing parameters

Variable

Product

Fixed

10

ICHICH

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals

for Human Use (ICH)

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals

for Human Use (ICH)

11

ICH ParticipantsICH Participants

Q Q uality

S S afety

E E fficacy

M M ultidisciplinary

Expert WorkingGroups (EWGs)

12

ICH GMP GuidanceICH GMP Guidance

� EU, Japan and ‘observers’ joined USA to define a new paradigm at an ICH GMP Workshop in Brussels, July 2003

� Three guidance documents:

� Q8, on Pharmaceutical Development

� Q9, on Quality Risk Management

� Q10, on Pharmaceutical Quality Systems

� EU, Japan and ‘observers’ joined USA to define a new paradigm at an ICH GMP Workshop in Brussels, July 2003

� Three guidance documents:

� Q8, on Pharmaceutical Development

� Q9, on Quality Risk Management

� Q10, on Pharmaceutical Quality Systems

13

Flexible Regulatory ApproachFlexible Regulatory Approach

� Regulators evaluate risk, based on:

� Product and process design (Q8)

� Measures to evaluate and manage risks (Q9)

� Quality system implementation (Q10)

� Regulators determine risk and modify level of oversight accordingly for:

� Submissions

� Post-approval change review

� GMP inspections

� Result:

� Removal of barriers to continuous improvement

� Efficient use of resources by industry and regulators

� Regulators evaluate risk, based on:

� Product and process design (Q8)

� Measures to evaluate and manage risks (Q9)

� Quality system implementation (Q10)

� Regulators determine risk and modify level of oversight accordingly for:

� Submissions

� Post-approval change review

� GMP inspections

� Result:

� Removal of barriers to continuous improvement

� Efficient use of resources by industry and regulators

14

ICH Quality GMP Related Activities - Current StatusICH Quality GMP Related Activities - Current Status

Q8 – Pharmaceutical Development� Approved by ICH in November 2005

� Implemented in EU, Japan and USA during 2006

� Q8(R1) at Step 3 of ICH process

Q9 – Quality Risk Management� Approved by ICH in November 2005

� Implemented in Japan & USA during 2006 but not yet in EU

Q10 – Pharmaceutical Quality Systems� Draft formally issued for comment

� Expect final ICH approval in Spring of 2008

Q8 – Pharmaceutical Development� Approved by ICH in November 2005

� Implemented in EU, Japan and USA during 2006

� Q8(R1) at Step 3 of ICH process

Q9 – Quality Risk Management� Approved by ICH in November 2005

� Implemented in Japan & USA during 2006 but not yet in EU

Q10 – Pharmaceutical Quality Systems� Draft formally issued for comment

� Expect final ICH approval in Spring of 2008

15

ICH Q8

“Pharmaceutical

Development”

ICH Q8

“Pharmaceutical

Development”

16

Q8 seeks to DeliverQ8 seeks to Deliver

� Product quality and performance achieved and assured by design of effective manufacturing processes

� Product specifications based on mechanistic understanding of how formulation and process factors impact product performance

� An ability to affect continuous improvement and continuous "real time" assurance of quality

� Product quality and performance achieved and assured by design of effective manufacturing processes

� Product specifications based on mechanistic understanding of how formulation and process factors impact product performance

� An ability to affect continuous improvement and continuous "real time" assurance of quality

17

Q8 Key ConceptsQ8 Key Concepts

� Q8 is the way that PAT concepts can be integrated with the Regulatory process

� Information from pharmaceutical development studies is a basis for risk management (using Q9)

� Identify critical parameters, which carry the risk

� This assessment helps define the ‘design space’

� Q8 is the way that PAT concepts can be integrated with the Regulatory process

� Information from pharmaceutical development studies is a basis for risk management (using Q9)

� Identify critical parameters, which carry the risk

� This assessment helps define the ‘design space’

18

Design SpaceDesign Space

� Design space is the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality .

� Design space is the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality .

19

Knowledge Space

Design SpaceDesign Space

� The batch process settings are NOT registered and, hence, moving them within the Design Space is NOT a change

� The batch process settings are NOT registered and, hence, moving them within the Design Space is NOT a change

Design Space

Batch process settings

20

Design SpaceDesign Space

� Design space is the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality .

� Design space is the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality .

21

n-Dimensional Design Spacen-Dimensional Design Space

% Moisture

ParticleSize

SurfaceArea

% lubricant

Interaction 1

Interaction 2

Design Space – n-D(Bulk Blend)

Batch process settings

Describing Flavour – Coffee(Flavour Space)

Sweet

Toast

Chocolate

Cinnamon

Tobacco

Peat

22

ICH Q8 (R1)ICH Q8 (R1)

� Received Step 2 approval 1 Nov. 2007

� Hoped to reach Step 4 in June 2008

� ICH Q8 (R1) provides an annex to Q8 guideline.

� This annex elaborates the elements of pharmaceutical development as:

� Target Product Profile

� Critical Quality Attributes (CQA)

� Linking material attributes and process parameters to CQAs by risk assessment

� Design Space

� Control Strategy

� Product lifecycle management and continual improvement

� Received Step 2 approval 1 Nov. 2007

� Hoped to reach Step 4 in June 2008

� ICH Q8 (R1) provides an annex to Q8 guideline.

� This annex elaborates the elements of pharmaceutical development as:

� Target Product Profile

� Critical Quality Attributes (CQA)

� Linking material attributes and process parameters to CQAs by risk assessment

� Design Space

� Control Strategy

� Product lifecycle management and continual improvement

23

ICH Q8 (R1) – Design SpaceICH Q8 (R1) – Design Space

� Concept of ‘Design Space’ is elaborated upon with guidance on:

� Selection of variables

� Defining and describing a design space in a submission

� Unit operation design space(s)

� Relationship of Design Space to scale and equipment

� Design Space versus proven acceptable ranges

� Design Space and edge of failure

� Concept of ‘Design Space’ is elaborated upon with guidance on:

� Selection of variables

� Defining and describing a design space in a submission

� Unit operation design space(s)

� Relationship of Design Space to scale and equipment

� Design Space versus proven acceptable ranges

� Design Space and edge of failure

24

ICH Q8 (R1) – Appendix 1- Overall DevelopmentICH Q8 (R1) – Appendix 1- Overall Development

Systematic, relating mechanistic understanding of input material attributes and process parameters to drug product CQAs

Multivariate experiments to understand product and process

Establishment of design space

PAT tools utilised

Mainly empirical

Developmental research often conducted one variable at a time

QbD Approach‘Minimal’ Approach

25

ICH Q9

“Quality Risk Management”

ICH Q9

“Quality Risk Management”

26

ICH Q9 - Principles of Quality Risk ManagementICH Q9 - Principles of Quality Risk Management

Two primary principles:

1. The evaluation of the risk to quality should be based on scientific knowledgeand ultimately link to the protection of the patient.

2. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.

Two primary principles:

1. The evaluation of the risk to quality should be based on scientific knowledgeand ultimately link to the protection of the patient.

2. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.

27

ICH Q9 –Quality Risk Management Process ICH Q9 –Quality Risk Management Process

28

Risk Management Methodology Risk Management Methodology

Failure Mode Effects Analysis (FMEA)

Failure Mode Effects & Criticality Analysis (FMCEA)

Fault Tree Analysis (FTA)

Hazard Analysis of Critical Control Points (HACCP)

Hazard Operability Analysis (HAZOP)

Risk Ranking and Filtering

Preliminary Hazard Analysis (PHA)

Supporting statistical tools

Failure Mode Effects Analysis (FMEA)

Failure Mode Effects & Criticality Analysis (FMCEA)

Fault Tree Analysis (FTA)

Hazard Analysis of Critical Control Points (HACCP)

Hazard Operability Analysis (HAZOP)

Risk Ranking and Filtering

Preliminary Hazard Analysis (PHA)

Supporting statistical tools Annex I:•Short description•Potential areasof use

29

Q9 - Implementation in EUQ9 - Implementation in EU

� Q9 was fully implemented in USA and Japan in 2006

� NOT yet implemented in EU

� EMEA Q9 Implementation Group consisting of inspectors and regulatory assessors

� EU adoption expected to be as follows:

� Added as Annex 20 of GMP Guide

� Changes to Introduction and Chapter 1 of EU GMP

Guide

� Revisions to some CHMP NfGs

� Q9 was fully implemented in USA and Japan in 2006

� NOT yet implemented in EU

� EMEA Q9 Implementation Group consisting of inspectors and regulatory assessors

� EU adoption expected to be as follows:

� Added as Annex 20 of GMP Guide

� Changes to Introduction and Chapter 1 of EU GMP

Guide

� Revisions to some CHMP NfGs

30

ICH Q10

“Pharmaceutical Quality

Systems”

ICH Q10

“Pharmaceutical Quality

Systems”

31

ICH Q10 – ObjectiveICH Q10 – Objective

� The objective is to describe a model for an effective quality management system for the pharma. industry, referred to as the pharmaceutical quality system, that:

� Ensures the realisation of a quality drug product

� Establishes and maintains a state of control

� Facilitates continual improvement over the product lifecycle

� The objective is to describe a model for an effective quality management system for the pharma. industry, referred to as the pharmaceutical quality system, that:

� Ensures the realisation of a quality drug product

� Establishes and maintains a state of control

� Facilitates continual improvement over the product lifecycle

32

Q10 – IntroductionQ10 – Introduction

Q10 will:

� Augment existing GMPs

� Provide a bridge between different regional regulations

� Complement and facilitate implementation of Q8“Pharmaceutical Development” and Q9 “Quality Risk Management”

Q10 will:

� Augment existing GMPs

� Provide a bridge between different regional regulations

� Complement and facilitate implementation of Q8“Pharmaceutical Development” and Q9 “Quality Risk Management”

33

Q10 –IntroductionQ10 –Introduction

Implementation of Q10 should facilitate:

� Innovation and continual improvement throughout the product lifecycle and

� Strengthen the link between pharmaceutical development and manufacturing organizations.

Implementation of Q10 should facilitate:

� Innovation and continual improvement throughout the product lifecycle and

� Strengthen the link between pharmaceutical development and manufacturing organizations.

34

Q10 - EnablersQ10 - Enablers

� The enablers provide the means for science- and risk-based decisions related to product quality

� Knowledge Management

� Manage knowledge from development through commercialisation to discontinuation

� Quality Risk Management (Q9)

� Proactive approach to managing risks to quality

� The enablers provide the means for science- and risk-based decisions related to product quality

� Knowledge Management

� Manage knowledge from development through commercialisation to discontinuation

� Quality Risk Management (Q9)

� Proactive approach to managing risks to quality

35

The ‘Desired State’The ‘Desired State’

� Product quality and performance achieved by design

� Specifications based on mechanistic understanding of how formulation and process factors impact product performance

� Continuous “real time” assurance of quality

� Product quality and performance achieved by design

� Specifications based on mechanistic understanding of how formulation and process factors impact product performance

� Continuous “real time” assurance of quality

36

Impact on the QP –Data interpretationImpact on the QP –Data interpretation

� Many recent changes place significant focus on data evaluation :

� ICH Q8

� ICH Q9

� Product Quality Reviews

� On-going stability

� QPs must be have good understanding of statistical techniques for data interpretation

� Many recent changes place significant focus on data evaluation :

� ICH Q8

� ICH Q9

� Product Quality Reviews

� On-going stability

� QPs must be have good understanding of statistical techniques for data interpretation

37

Data

Info

rmatio

n

QP

Decisio

n

Knowledge

� QP Decisions:

� Based on knowledge

� Knowledge:

� Derived from combining information sources

� Information:

� Derived from data using statistical analysis

� Data:

� Derived from relevant samples using validated methods

� QP Decisions:

� Based on knowledge

� Knowledge:

� Derived from combining information sources

� Information:

� Derived from data using statistical analysis

� Data:

� Derived from relevant samples using validated methods

Data, Information, Knowledge & QP DecisionsData, Information, Knowledge & QP Decisions

38

Impact on the QP –Batch certificationImpact on the QP –Batch certification

� A QP’s primary legal duty is to certify that product has been made in accordance with the Marketing Authorisation (MA)

� Current MAs have of a defined method of manufacture

� i.e. a fixed process

� Future MAs will define a ‘Design Space’

� A QP’s primary legal duty is to certify that product has been made in accordance with the Marketing Authorisation (MA)

� Current MAs have of a defined method of manufacture

� i.e. a fixed process

� Future MAs will define a ‘Design Space’

39

Impact on the QP –Q8 & Design SpaceImpact on the QP –Q8 & Design Space

� The Design Space may well be a mathematical algorithm that defines an n-dimensional space

� Real-time release

� Changes within the Design Space will not require regulatory submissions

� Who will Authorities hold accountable for ensuring that there is a system for managing changes within the Design Space?

The Qualified Person!

� The Design Space may well be a mathematical algorithm that defines an n-dimensional space

� Real-time release

� Changes within the Design Space will not require regulatory submissions

� Who will Authorities hold accountable for ensuring that there is a system for managing changes within the Design Space?

The Qualified Person!

40

Impact on the QP –Quality Risk Management (Q9)Impact on the QP –Quality Risk Management (Q9)

� A good understanding of Quality Risk Management (QRM) is going to be crucial

� Who will Authorities hold accountable for the QRM process and the final Risk Acceptance decision?

The Qualified Person!

� A good understanding of Quality Risk Management (QRM) is going to be crucial

� Who will Authorities hold accountable for the QRM process and the final Risk Acceptance decision?

The Qualified Person!

41

Impact on the QP –Quality Systems (Q10)Impact on the QP –Quality Systems (Q10)

� Senior management are ultimately responsible for the Quality System

� Who will they delegate the task of developing and implementing the PQS to?

The Qualified Person ?

� Senior management are ultimately responsible for the Quality System

� Who will they delegate the task of developing and implementing the PQS to?

The Qualified Person ?

42

Impact on the QP –Quality Systems (Q10)Impact on the QP –Quality Systems (Q10)

� The QP should NOT have to be the architect of the PQS

� The QP should be the auditor of the PQS

� The QP must monitor and be able to influence the content and implementation of the PQS

� The QP should NOT have to be the architect of the PQS

� The QP should be the auditor of the PQS

� The QP must monitor and be able to influence the content and implementation of the PQS

43

Impact on the QP –SummaryImpact on the QP –Summary

� The new paradigm for pharmaceutical regulation is still developing

� QPs must keep up with the evolving expectations

� ICH Q8, 9 & 10 may be largely written but it is the interpretation over coming years that is going to be

crucial for QPs

� QPs have the opportunity to influence the development of this new approach

� The QP is going to be key to implementing the new paradigm

� The new paradigm for pharmaceutical regulation is still developing

� QPs must keep up with the evolving expectations

� ICH Q8, 9 & 10 may be largely written but it is the interpretation over coming years that is going to be

crucial for QPs

� QPs have the opportunity to influence the development of this new approach

� The QP is going to be key to implementing the new paradigm

44

Impact on the QP –SummaryImpact on the QP –Summary

The future for the QP is going

to be much more interesting

and stimulating than just

reviewing batch records!

The future for the QP is going

to be much more interesting

and stimulating than just

reviewing batch records!

e-mail: phg@david-begg-associates.com

www.david-begg-associates.com