INTRODUCTION TO ICH Q8 & Q9 GUIDELINES

K. S. BABUHead - Corporate Regulatory Affairs

Watson Pharma., IndiaNovember 29, 2007

2

FOREWORD

EMPHASIS

Interpretation of guidance documents

Regulatory relevance & applications

Bonus: Q10 guideline, due to its relevance

3

WHAT ARE THESE GUIDELINES ABOUT?

Q8: - “Pharmaceutical Development” (“Implemented”)

- Contents of 3.2.P.2 Section of Module 3, CTD

Q8 – Annexure (“Draft stage”)

- Provides further clarification to Q8 concepts

- Links ‘’QbD’’ & “PAT” (FDA), & ‘’QRM’’ (EU), “FEMA”

Q9: - “Quality Risk Management” (“Implemented”)

Q10: - “Pharmaceutical Quality System” (“Draft stage”)

4

REGULATORY STATUS OF ICH Q 8

Reached Step 5 – Regulatory Implementation

EU:

Transmission to CHMP and to Interested Parties in December 2004. Issued as EMEA/CHMP/167068/2004-ICH. Deadline for comments : June 2005. Final approval by CHMP: November 2005. Date for coming into operation: May 2006.

MHLW:

Adopted on September 1, 2006, PFSB/ELD Notification N° 0901001

FDA:

Published in the Federal Register, Vol. 71, No 98, May 22, 2006

5

REGULATORY STATUS OF ICH Q 8 - Annexure

Reached Step 3 in Nov. 2007:

- Regulatory Consultation & Discussion

- Draft Guideline

EU / MHLW / FDA: TO BE NOTIFIED

6

REGULATORY STATUS OF ICH Q 9

Reached Step 5 – Regulatory Implementation

EU: Published on the EMEA website

MHLW: Adopted on September 1, 2006, PFSB/ELD Notification n° 0901004

FDA: Published in the Federal Register, Vol. 71, No 106, pages 32105-32106, June 2, 2006

7

REGULATORY STATUS OF ICH Q 10

Reached Step 3 in May 2007:- Regulatory Consultation & Discussion- Draft Guideline

EU: Transmission to CHMP and to Interested Parties May 2007. Issued as EMEA/CHMP/ICH/214732/2007. Deadline for comments: November 2007.

MHLW: Released for consultation 13th July 2007, PFSB/ELD, deadline for comments 1st October 2007

FDA: Published in the Federal Register July 13, 2007, Volume 72, No. 134, pages 38604-38605. Deadline for comments October 11, 2007.

8

BRIEF NOTE ON ICH Q10 : P.Q.S.

• Based on ISO concepts

• Includes applicable GMP regulations

• Compliments ICH Q8 and ICH Q9

• Acts as a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle.

• Content is currently specified by regional GMP requirements

• Not intended to create any new expectations beyond current regulatory requirements

• Consequently, the content of ICH Q10 that is additional to current GMP requirements is optional

9

Q8: OVERVIEW

Talks about Pharmaceutical Dev. section in regulatory submissions Suggested Contents for 3.2.P.2 of CTD Quality Module 3:

3.2.P.2.1 Components of drug product (drug substance/ excipients) 3.2.P.2.2 Formulation Dev. 3.2.P.2.3 Manufacturing Process Development 3.2.P.2.4 Container Closure System 3.2.P.2.5 Microbiological Attributes 3.2.P.2.6 Compatibility

There is “much more” than meeting the filing requirements or CTD check-list

10

Q8: OVERVIEW (contd.)

Greater understanding of the product / process & variables

Science- and risk-based submissions

Wider regulatory “flexibility”

Q8 Annexure & “Q R M” (ICH Q9)

11

Q8: Related EU Directives and Guidelines

2003/63/EC, Annex I, 3.2.2.2 – Pharmaceutical Development

CPMP/QWP/155/96 Guideline on Development Pharmaceuticsuideline on Development Pharmaceutics

NTA Volume 2B - Common Technical Document

Note for guidance on development pharmaceuticsNote for guidance on development pharmaceutics (EMEA/CHMP/167068/2004)

Link to EU Directives:http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev1.htm

12

Q8: Objectives of Pharmaceutical Dev. Section

UNDERSTANDING: Provide a comprehensive understating of the product and manufacturing process for reviewers and inspectors

EVIDENCE: Establish evidence that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use

ASSURANCE: Provide scientific discussion to support that –the design / process will consistently deliver a quality product

SYSTEMATIC ASSESSMENT:Testing during developmental stage – Extensive & Different from routine

Critical parameters of the formulation and process which can influence batch reproducibility, medicinal product performance and medicinal product quality shall be identified and described.

13

Q8: IMPORTANT CONSIDERATIONS

3.2.P.2.1.1 Drug Substance:

- Key physicochemical characteristics of the drug substance

(e.g. solubility, water content, particle size distribution), which are variable and critical for the quality of the product and which can influence the performance of the drug product

- Compatibility of drug substance with the excipients- For combination products, the compatibility of the drug

substances with each other- Polymorphism issues

14

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.1.2 Excipients:

- Choice of excipients (in particular relative to their respective functions) & their concentration (with justification)

- Their characteristics that may influence the drug product performance

- Compatibility of excipients with other excipients, where relevant

- Justification for their inclusion, in some cases (e.g. preservatives, anti-oxidants) accompanied by experimental data

- Safety of the excipients, where relevant

15

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.2.1 Formulation Development:

- Differences between clinical formulations and current formulation

- Summary describing the development of the formulation including identification of critical attributes to the quality of the drug product

- The choice of drug product components (drug substance, excipients, container closure system etc.,) and the manufacturing process

- Results of comparative in vitro studies (dissolution) and in vivo studies (bio-equivalence), when appropriate

- Any special design features of the drug product (tablet score line,over fill etc.,)

16

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.2.2 Overages:

- Use of an overage of a drug substance to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged

- A justification of any overage on grounds of safety and efficacy

- Information on amount of overage, reason for the overage and the justification for the amount of overage.

17

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.2.3 Physicochemical and Biological parameters:

- The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed

- The selection of dissolution testing should be discussed.

18

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.3 – Manufacturing Process Development

- Basis for process improvement, process validation, continuous process verification and process control requirements.

- The selection, the control, and any improvement of the manufacturing process.

- Appropriateness of the equipment used for the intended product.

- For the sterile products, appropriate method of sterilization and the primary packaging material selection should be discussed.

19

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.3 – Manufacturing Process Development (contd.)

- Significant difference between the manufacturing process of pivotal batches and intended commercial batches.

- If differences are there, the influence of the difference on product performance, manufacturability and quality to be discussed.

- Experiments of laboratory scale batches should be described.

- Information from scaling up from laboratory through pilot to production scale to justify that scale-up can be achieved without a consequent loss in quality.

20

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.4 – Container Closure System

- Discussion on the suitability of the container closure system used for storage, transportation and use of the product

- This discussion should consider

• choice of the materials for primary packaging

• protection from moisture and light

• compatibility of the materials with the dosage form

• performance of the dose delivery from the device if dosing device is used

• Food grade certification

21

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.5 – Microbiological Attributes

Where appropriate the microbiological attributes of the dosage form should be addressed (according to Ph.Eur.). The discussion should include for example:

• The rationale for performing or not performing microbial limits testing for non-sterile products.

• The selection and effectiveness of preservative systems in products containing antimicrobial preservatives.

• For sterile products, the integrity of the container closure system as it relates to preventing microbial contamination.

The lowest concentration of antimicrobial preservative should be demonstrated to be effective in controlling microorganisms.

22

Q8: IMPORTANT CONSIDERATIONS (contd.)

3.2.P.2.6 – Compatibility

• The compatibility of the drug product with reconstitution diluent(s) should be addressed to provide appropriate labelling information.

• This information should cover the recommended in-use shelf life at the recommended storage temperature.

23

Q8: OVERVIEW (contd.)

Greater understanding of the product / process & variables

Science- and risk-based submissions

Wider regulatory “flexibility”

Q8 Annexure & “Q R M” (ICH Q9)

24

Specific Cases

• Use of one lot of API for Exhibit batches : PSD Profile Optimization

• Impact of age of API used in Exhibit batches

• Blend time optimization

• Switching to alternate sources for Excipients (E.g., Mg.Stearate– Animal grade to Veg. grade)

25

Focus of Q8 Annexure

• Define Target Product Profile

• Identify ‘CQAs’ – Critical Quality Attributes of Product

• Determine QAs of inputs – materials/parameters etc.

• Select appropriate process

• Determine functional relationships between material attributes & process parameters to Product CQAs

• Identify a control strategy

• Propose a “design space”

• Define and describe design space in regulatory submission

26

Focus of Q8 Annexure (contd.)

Defining DESIGN SPACE: Options -

• Ranges of input variables or parameters

• Analysis of historical data can be basis

• Scaling factors

• Multivariate operations

Operation within the design space results in a product that meets the defined quality attributes

Periodic reassessment throughout life-cycle

27

ICH Q 9 (QRM) as part of development

• To design a quality product and its manufacturing process

- to consistently deliver the intended performance of the product

• To enhance knowledge of product performance over a wide range of - material attributes

(e.g. particle size distribution, moisture content, flow properties)

- processing options

- process parameters

28

QRM as part of development (contd.)

• To assess the critical attributes of

- Raw materials

- Solvents

- Active Pharmaceutical Ingredient (API)

- Starting materials

- Excipients

- Packaging materials

• To establish appropriate specifications, identify critical process parameters and establish manufacturing controls

29

QRM as part of development (contd.)

• To decrease variability of quality attributes:

- reduce product and material defects

- reduce manufacturing defects

• To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer

• To make use of the “design space” concept (annexure to ICH Q8)

30

Q9 : QUALITY RISK MANAGEMENT

What is “risk”?

Combination of the probability of occurrence of harm, and the severity of that harm.

“Fact: No process is risk-free”

31

MANAGING RISKS IN A COMPANY …

Company

Strategic risks Operational risks Financial risks Compliance risks

Environmental

Quality / GMP

Regulatory filing

Safety & Efficacy

Competitoradvantage

Companyviability

Shareholderharm

Patientharm

ICH Q9

32

EMEA NOTE ON Q9

33

Q9: Dangers from Absence of Risk Management

- Pharmaceutical products may not be available to patients when needed, e.g. when a product is recalled from a market or where different risk decisions contribute to inefficient manufacturing processes and consequent delays

- May increase the potential for the release of unacceptable product to the market

- Delays may occur during implementation of changes and improvements to processes

- Safe and effective drugs may be discarded or recalled from the market

- Manufacturers may be reluctant to implement new technologies or continuous improvements to products or processes

- Scarce resources may not be optimally allocated

- Lack of appropriate date to evaluate risk most effectively

34

Q9: Purpose & Objectives

• No national guidance documents in this area in any region

• No common understanding of terms, principles and application of risk management

• Development of a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasising an integrated approach to risk management and science

• Deriving common terminology, including a definition of quality, risk, risk management etc

• Defining the principles for how risk management can be effectively applied and consistently integrated into decisions regarding product quality

• Rationalization & Operationalization of the integration of risk management into the decision making process

35

Q9: Purpose & Objectives (contd.)

• Defining criteria on how to apply the risk management process

• Identification of circumstances, if any, when applying risk management principles is not feasible or appropriate

• Defining what principles of risk management apply to industry, regulators or both across the life-cycle of the product

• Establish - how, what & when information is exchanged between & within industry, to the regulators, and to both, throughout the product life cycle

• Emphasize synergies with the pharmaceutical development project

• Defining roles and responsibilities of regulators and industry

• Discuss how risk can be incorporated into resource allocation decisions

36

Q9: Benefits of Quality Risk Management Approach

• Enhancement of patient confidence worldwide in decision making on the quality of pharmaceuticals

• Promotion of more effective use of regulatory and industry resources

• Establishment of a systematic, well-informed and thorough method of decision making which leads to greater transparency and predictability

• Increased knowledge of exposure to risk

• A greater assurance to regulators of a company’s ability to deal with potential risks

• Fostering continuous improvement and quality by design generally leading to enhanced product quality

• Enables right “decision making”

37

Quality Risk Management Process

38

Risk Assessment

3 Stages: Risk identification: what are the hazards? Risk analysis: risk associated with identified hazards Risk evaluation: comparison of identified and analyzed

risk against a given risk criteria

3 fundamental questions: What might go wrong? What is the likelihood it will go wrong?: Probability What are the consequences? : Severity

39

Risk Control

Decision making: Risk reduction? Or Risk acceptance?

Basis for Judgment: Is the risk above an acceptable level? What can done to reduce or eliminate risks? What is the appropriate balance among benefits, risks

and resources? Are new risks introduced as a result of the identified risks

being controlled?

40

Risk Management methodology

Recognized risk management tools: Basic risk management facilitation methods (Flow charts, check

sheets etc.). Failure Mode Effects Analysis (FMEA). Failure Mode, Effects and Criticality Analysis (FMECA). Fault Tree Analysis (FTA). Hazard Analysis and Critical Control Points (HACCP). Hazard Operability Analysis (HAZOP). Preliminary Hazard Analysis (PHA). Risk Ranking and Filtering. Supporting Statistical Tools.

41

Importance of Communication in QRM

Industryoperation - Submissions- Manufacturing

Regulatorsoperation

- Reviews- Inspections

Communicationfacilitates trust

and understanding

42

Using ICH Q9 will…

• Facilitate - Communication and transparency- More informed, scientifically based decision making- Patient focused actions on quality risks- Realistic and appropriate solutions- Use of existing solutions (Share best practice/prior knowledge)

• Manage critical to quality aspects- Through systems, organisations, processes & products- Maintain responsibility & accountability for QRM

• Focus activity towards patient protection

It should never be used as a “hobby horse” / preconceived idea

43

Opportunity for the Industry & Competent Authorities

• Using the same guideline apply QRM to industry (Development & Manufacture) and regulators (Reviewer & Inspectorate)

• Provides for establishing a defined program for what we already do every day in our jobs

• Supports science-based decision making

• Optimisation of resources

• Prevention from overly restrictive and unnecessary requirements

• Facilitates communication and transparency

44

Challenges for Industry & Competent Authorities

• Interpreting and adopting the concepts of quality risk management into specific areas

- Embed this behavior into quality aspects of business, technology and regulation

- Adopt in existing structures, organizations and Quality System

- Balance the documented use of “informal” and “formal” quality risk management

45

QRM Integration into Industry & Reg Operations

QRM is a process that supports science-based and practical decisions when integrated into quality systems.

Effective QRM can facilitate better and more informed decisions.

Effective QRM can provide regulators with greater assurance of a company’s ability to deal with potential risks.

QRM can facilitate better use of resources by all parties.

Training of both industry and regulatory personnel in QRM processes provides for greater understanding of decision-making processes & builds confidence in QRM outcomes.

46

“risk-based”

concepts and principles

The new paradigm

Q8Q9 Q10

47

Pharmaceutical Development (Q8)Pharmaceutical Development (Q8)

Past: Data transfer / Variable output

Present: Knowledge transfer / Science based / Consistent output

Pharmaceutical Quality Systems (Q10)Pharmaceutical Quality Systems (Q10)

Past: GMP checklist

Future: Quality Systems across product life cycle

Quality Risk Management (Q9)Quality Risk Management (Q9)

Past: Used, however poorly defined

Present: Opportunity to use structuredprocess thinking

Incremental steps

ChangedParadigm

Q8

Q9 Q

10

48

How Q9 interacts with Q8 and Q10R

isk

from

Man

ufac

turin

g si

te

Product / Process Risk

High

Low

HighLow

Using Q9 Quality Risk Management

principles

c

ontinual

impro

vem

ent

Q10

Ph

arm

. Q

ual

ity

Sys

tem

s

Q8 Pharmaceutical Development

49

Q10Q8

ICH Q9 Link back to patient risk

Process

Materials

Design

Manufacturing

Distribution

Patient

Facilities

Opportunities to impact risk using quality risk

management Q9

50

A Vision of the Future

  Old Approach New Approach Remarks

Broad Concept

Quality decisions divorced from science and risk evaluation.Adherence to filing commitments.

Quality decisions and filing committments based on Process Understanding and Risk Management.Quality by Design.

Design Space concept introduced to integrate process knowledge with regulatory evaluation.

Quality

Post-factum sampling and quality testing.Process Validation.

Management of variabilityProcess control focused on critical attributes.Continuous Quality Verification.

Quality by design definition applied. Measure critical process parameters to control output product quality.

Systems

Systems designed to inhibit changes & minimize business risks. Discourages improvement & innovation.

Changes managed within company's quality system.Real time batch release feasible.

Regulators and industry place higher reliance / trust / understanding on systems.Multidisciplinary evaluation and decision making.

Regulatory

Compliance focus.Changes require prior approval.

Regulatory scrutiny adjusted to level of Process Understanding. Continuous improvement allowed within Design Space.

Requires mechanisms to communicate Process Understanding data ("inspectable rather than reviewable").

51

Regulatory Guidelines

Read… Repeat… Ruminate…

“raison d'être” (French; underlying principle)

THANK YOU !THANK YOU !