INTRODUCTION TO

ICH Q8 & Q9 GUIDELINES

K. S. BABU
Head - Corporate Regulatory Affairs
Watson Pharma., India
November 29, 2007
FOREWORD

EMPHASIS

 Interpretation of guidance documents

 Regulatory relevance & applications

 Bonus: Q10 guideline, due to its relevance

2
 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”)

3
 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
4
 REGULATORY STATUS OF ICH Q 8 - Annexure

Reached Step 3 in Nov. 2007:

- Regulatory Consultation & Discussion

- Draft Guideline

EU / MHLW / FDA: TO BE NOTIFIED

5
 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
6
 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.

7
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

8
 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

9
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)

10
 Q8: Related EU Directives and Guidelines

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

CPMP/QWP/155/96 Guideline on Development Pharmaceutics

NTA Volume 2B - Common Technical Document

Note for guidance on development pharmaceutics

(EMEA/CHMP/167068/2004)

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

11
 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.

12
 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

13
 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

14
 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.,)
15
 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.

16
 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.

17
 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.
18
 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.

19
 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
20
 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.
21
 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.

22
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)

23
 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)
24
 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
25
 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

26
 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
27
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 28
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)

29
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”

30
MANAGING RISKS IN A COMPANY …

Company

Strategic risks Operational risks Financial risks Compliance risks

Environmental

Regulatory filing
Competitor Company Shareholder Patient
advantage viability harm harm Quality / GMP

Safety & Efficacy

ICH Q9

31
EMEA NOTE ON Q9

32
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

33
 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
34
 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

35
 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” 36

Quality Risk Management Process

37
 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
38
 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?
39
 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.

40
Importance of Communication in QRM

Communication
facilitates trust
and understanding

Regulators Industry
operation operation
- Reviews - Submissions
- Inspections - Manufacturing

41
 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

42
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
43
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
44
 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 informe d
dec isi on s.
 Effective QRM can provide regulators with greater
assu ranc e of a com pa ny’s ab ility to de al
with poten ti al risks.
 QRM can facilitate be tt er use of re so urc es 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. 45
The new paradigm

“risk-based”
concepts and
principles

Q8
Q9 Q10

46
Incremental steps

Pharmaceutical Development (Q8)

Changed Past: Data transfer / Variable output
Paradigm Present: Knowledge transfer / Science
based / Consistent output

Quality Risk Management (Q9)

Past: Used, however poorly defined
Present: Opportunity to use structured
process thinking

Pharmaceutical Quality Systems (Q10)

Q10

Past: GMP checklist

Q8

Future: Quality Systems across product

Q9

life cycle

47
How Q9 interacts with Q8 and Q10
Risk from Manufacturing site

High
Q10 Pharm. Quality Systems

t
en
em
ov
pr
im
l
ua
Using Q9
in
nt

Quality Risk
co

Management
Low Q8 Pharmaceutical Development
principles
Low High
Product / Process Risk
48
 ICH Q9 Link back to patient risk

Opportunities to impact
risk using quality risk
Design management Q9

Process

Materials Manufacturing

Facilities
Distribution

Patient

Q8 Q10
49
A Vision of the Future
Old Approach New Approach
Quality decisions divorced Quality decisions and filing
from science and risk committments based
evaluation. on Process
Broad Concept Adherence to filing Understanding and
commitments. Risk Management.
Quality by Design.
Post-factum sampling and Management of variability
quality testing. Process control
Process Validation. focused on critical
Quality attributes.
Continuous Quality
Verification.
Systems designed to inhibit Changes managed within
changes & minimize company's quality
business risks. system.
Systems Discourages Real time batch
improvement & release feasible.
innovation.
Compliance focus. Regulatory scrutiny adjusted
Changes require prior to level of Process
approval. Understanding.
Regulatory Continuous
improvement allowed
within Design Space.
Remarks
Design Space concept
introduced to integrate
process knowledge with
regulatory evaluation.
Quality by design definition
applied. Measure critical
process parameters to
control output product
quality.
Regulators and industry
place higher reliance /
trust / understanding
on systems.
Multidisciplinary
evaluation and decision
making.
Requires mechanisms to
communicate Process
Understanding data
("inspectable rather
than reviewable").
50
 Regulatory Guidelines
Read… Repeat… Ruminate…

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

THANK YOU !

51