Ichq8, 9 & 10 The History And Overview

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ICH Q8, 9 & 10 the History and Overview Peter H. Gough David Begg Associates [email protected]

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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 Approval

Withdrawal

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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 endproduct 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 Materials

Processing parameters

Product

Variable

Fixed

Variable

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Paradigm Shift z PAT paradigm: Starting Materials

Processing 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 Pharmaceutical Development (Q8)

Changed Paradigm

Old:

Data transfer / variable output

New:

Knowledge transfer / Consistent output

Q10

Q9

Q8

Quality Risk Management (Q9) Old:

Unstructured approach

New:

Opportunity to use a structured process

Quality Systems (Q10) Old:

Large variability on Q-systems

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 (Flavour Space) Sweet

Design Space – n-D (Bulk Blend)

Batch process settings

% Moisture

Toast

Peat

Particle Size

Interaction 2

Chocolate Tobacco

Surface Area

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) Supporting statistical tools

Annex I: •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

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