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ICH Q8, 9 & 10

the History and
Overview
Peter H. Gough
David Begg Associates

phg@david-begg-associates.com
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History of Pharmaceutical
Quality Management
z 1960’s and before: Reliant solely on Quality
Control
 Focused on the Product Specification
 Defect Detection by End Product Testing
z Advantage
 Sometimes detects defects
z Disadvantages
 Faults found too late
 Often fails
 High Cost
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History of Pharmaceutical
Quality Management
z Early-1970’s: added Quality Assurance & GMP
 Written Procedures
 Focus on the Production Process
 Defect Prevention using Process Controls
z Advantages
 Documented Systems
 Improved Quality
z Disadvantage
 Quality still owned by "Quality Department"
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Quality Management in Other

Industries
z Since 1980’s; Total Quality concept
 Quality Culture, everybody is responsible for Quality
 Continual Improvement
 Holistic approach
z Advantages
 Quality is by design and is habitual
 6-sigma process capability, or better
z Disadvantage
 Difficult to achieve, taking sustained commitment
 Not adopted by Pharmaceutical industry
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Why had pharmaceutical quality

management failed to evolve?

z The Regulatory
processes
z Industry practice
Separation of
Development and
Manufacturing
worlds
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Product life-cycle circa. 2003

Development Manufacture

GLP & GCP GMP

No Integrated Quality System

Time

Discovery Marketing Withdrawal

Approval
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Marketing Authorisation

z Huge financial pressures on companies

to obtain a Marketing Authorisation
 Forced to accept specifications, etc. that are
not optimal
z Different Regulatory Authorities pose
different demands, based on common
data
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Post-approval changes and

improvement

z Regulatory Authority requirements

for post-approval changes present a
barrier to the improvement of
manufacturing processes and
controls.
z Regulations are National or Regional.
z Pharmaceutical manufacturing today
is increasingly global
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Post-approval change – the

barrier to improvement
Example:
z Tablet product - manufactured at 1 site;
supplied to 100+ markets
z Change to manufacturing process or controls:
 Have to submit ca. 20 variations worldwide
 Approval times vary from 2 to 36 months
 How does industry cope?
„ Run old and new process/controls concurrently?
„ Build 3 years stock?
„ Wait 3 years to implement?
„ Be out of compliance in markets taking longer to
approve?
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Other Barriers to Continual

Improvement
z Reviewers not familiar with new
technology
 Extended review times
z GMP inspectors not familiar with new
technology
 Risk of inspection findings

Outcome
 A large disincentive to continuous improvement
 Pharmaceutical quality management stuck in the
1970s
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A New Approach to Regulation

2001 - 2002
z American Food and Drug
Administration (FDA) suggested a
new approach
 Process Analytical Technology (PAT)
 21st Century GMP initiatives.
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Process Analytical Technology (PAT)

z Not just testing but a philosophy of

z Control in-process rather than end-

product testing
z Minimises risks of poor quality
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PAT Approach – Quality by Design

z Identify the parameters that are critical

to product quality
 Statistically designed experiments
z Measure these parameters
z Control these parameters
 Feed back
 Feed forward
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Paradigm Shift

z Current paradigm:

Starting Processing
Materials parameters Product

Variable Fixed Variable

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Paradigm Shift

z PAT paradigm:

Starting Processing
Materials parameters Product

Variable Variable Fixed

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ICH

International Conference
on Harmonisation
of Technical Requirements for
Registration of Pharmaceuticals
for Human Use (ICH)
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ICH Participants

Expert Working
Groups (EWGs)

Q uality
S afety
E fficacy
M ultidisciplinary
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ICH GMP Workshop

z EU, Japan and ‘observers’ joined

USA to define a new paradigm at
an ICH GMP Workshop in Brussels,
July 2003
z This Workshop agreed a 5 year Vision:
 Create a single, harmonised global quality
standard and interpretation based on good
science and risk management principles
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Incremental Steps to Achieve the

Vision
z The GMP Workshop agreed that the
Vision would be achieved by
“incremental steps”
 Q8 EWG, on Pharmaceutical Development,
established in September 2003
 Q9 EWG, on Quality Risk Management,
established in November 2003
 Q10 EWG, on Pharmaceutical Quality
Systems, established in November 2005
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Achieve by Incremental Steps

Changed Pharmaceutical Development (Q8)

Old: Data transfer / variable output
Paradigm
New: Knowledge transfer /
Consistent output

Quality Risk Management (Q9)

Old: Unstructured approach
New: Opportunity to use a structured
process

Quality Systems (Q10)

Q10
Q8

Old: Large variability on Q-systems

Q9

New: Consistency on Q-systems

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Flexible Regulatory Approach

z Regulators evaluate risk, based on:
 Product and process design (Q8)
(Q8)
 Measures to evaluate and manage risks (Q9)
 Quality system implementation (Q10)
z Regulators determine risk and modify level of
oversight accordingly for:
 Submissions
 Post-approval change review
 GMP inspections
z Result:
 Removal of barriers to continuous improvement
 Efficient use of resources by industry and regulators
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ICH Q8
“Pharmaceutical
Development”
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Q8 seeks to Deliver
z Product quality and performance
achieved and assured by design of
effective manufacturing processes
z Product specifications based on
mechanistic understanding of how
formulation and process factors impact
product performance
z An ability to affect continuous
improvement and continuous "real time"
assurance of quality
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Q8 Key Concepts

z Q8 is the way that PAT concepts can be

integrated with the Regulatory process
z Information from pharmaceutical
development studies is a basis for risk
management (using Q9)
 Identify critical parameters, which carry the
risk
z This assessment helps define the
‘design space’
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Design Space

z 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 .
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Design Space

Knowledge Space

Design Space

Batch process settings

z The batch process settings are NOT

registered and, hence, moving them within
the Design Space is NOT a change
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Design Space

z 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 .
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n-Dimensional Design Space

Describing Flavour – Coffee Design Space – n-D
(Flavour Space) (Bulk Blend)
Sweet Batch process
settings % Moisture
Toast
Peat Particle
Interaction 2 Size

Chocolate
Surface
Area
Tobacco
Interaction 1

Cinnamon
% lubricant
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ICH Q8 (R1)
z Received Step 2 approval 1 Nov. 2007
z Hoped to reach Step 4 in June 2008
z ICH Q8 (R1) provides an annex to Q8 guideline.
z 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
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ICH Q8 (R1) – Design Space

z 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
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ICH Q8 (R1) – Appendix 1

- Overall Development
‘Minimal’ Approach QbD Approach
Mainly empirical Systematic, relating mechanistic
understanding of input material
Developmental research often attributes and process
conducted one variable at a time parameters to drug product
CQAs

Multivariate experiments to
understand product and process

Establishment of design space

PAT tools utilised

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ICH Q9
“Quality Risk Management”
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ICH Q9 - Principles of Quality Risk

Management
Two primary principles:
1. The evaluation of the risk to quality
should be based on scientific knowledge
and 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.
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ICH Q9 –
Quality Risk Management Process
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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)
Annex I:
Supporting statistical tools •Short description
•Potential areas
of use
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ICH Q10
“Pharmaceutical Quality
Systems”
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ICH Q10 – Objective

z 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
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Q10 – Introduction

Q10 will:
z Augment existing GMPs
z Provide a bridge between different
regional regulations
z Complement and facilitate
implementation of Q8
“Pharmaceutical Development” and
Q9 “Quality Risk Management”
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Q10 - Enablers

z The enablers provide the means for

science- and risk-based decisions
related to product quality
z Knowledge Management
 Manage knowledge from development
through commercialisation to
discontinuation
z Quality Risk Management (Q9)
 Proactive approach to managing risks to
quality
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The ‘Desired State’

z Product quality and performance
achieved by design
z Specifications based on mechanistic
understanding of how formulation and
process factors impact product
performance
z Continuous “real time” assurance of
quality
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ICH 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 and in
EU in March 2008
Q10 – Pharmaceutical Quality Systems
 At Step 3 of ICH process
 Expect final ICH approval in June 2008
e-mail: phg@david-begg-associates.com

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