ichq8, 9 & 10 the history and overview
TRANSCRIPT
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ICH Q8, 9 & 10 the History and
Overview
ICH Q8, 9 & 10 the History and
Overview
Peter H. GoughDavid Begg Associates
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History of Pharmaceutical Quality ManagementHistory of Pharmaceutical Quality Management
1960’s and before: Reliant solely on Quality Control
Focused on the Product SpecificationDefect Detection by End Product Testing
AdvantageSometimes detects defects
DisadvantagesFaults found too lateOften failsHigh Cost
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History of Pharmaceutical Quality ManagementHistory of Pharmaceutical Quality Management
Early-1970’s: added Quality Assurance & GMPWritten ProceduresFocus on the Production ProcessDefect Prevention using Process Controls
AdvantagesDocumented SystemsImproved Quality
DisadvantageQuality still owned by "Quality Department"
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Quality Management in Other IndustriesQuality Management in Other Industries
Since 1980’s; Total Quality conceptQuality Culture, everybody is responsible for Quality Continual ImprovementHolistic approach
AdvantagesQuality is by design and is habitual6-sigma process capability, or better
DisadvantageDifficult to achieve, taking sustained commitmentNot adopted by Pharmaceutical industry
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Why had pharmaceutical quality management failed to evolve?Why had pharmaceutical quality management failed to evolve?
The Regulatory processes
Industry practiceSeparation of Development and Manufacturing worlds
The Regulatory processes
Industry practiceSeparation of Development and Manufacturing worlds
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Product life-cycle circa. 2003Product life-cycle circa. 2003
Discovery Withdrawal
Development Manufacture
GMP
Time
GLP & GCP
MarketingApproval
No Integrated Quality System
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Marketing AuthorisationMarketing Authorisation
Huge financial pressures on companies to obtain a Marketing Authorisation
Forced to accept specifications, etc. that are not optimal
Different Regulatory Authorities pose different demands, based on common data
Huge financial pressures on companies to obtain a Marketing Authorisation
Forced to accept specifications, etc. that are not optimal
Different Regulatory Authorities pose different demands, based on common data
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Post-approval changes and improvementPost-approval changes and improvement
Regulatory Authority requirements for post-approval changes present a barrier to the improvement of manufacturing processes and controls.
Regulations are National or Regional.
Pharmaceutical manufacturing today is increasingly global
Regulatory Authority requirements for post-approval changes present a barrier to the improvement of manufacturing processes and controls.
Regulations are National or Regional.
Pharmaceutical manufacturing today is increasingly global
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Post-approval change – the barrier to improvementPost-approval change – the barrier to improvement
Example:Tablet product - manufactured at 1 site; supplied to 100+ marketsChange to manufacturing process or controls:
Have to submit ca. 20 variations worldwideApproval times vary from 2 to 36 monthsHow 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?
Example:Tablet product - manufactured at 1 site; supplied to 100+ marketsChange to manufacturing process or controls:
Have to submit ca. 20 variations worldwideApproval times vary from 2 to 36 monthsHow 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 ImprovementOther Barriers to Continual Improvement
Reviewers not familiar with new technology
Extended review times
GMP inspectors not familiar with new technology
Risk of inspection findings
OutcomeA large disincentive to continuous improvementPharmaceutical quality management stuck in the 1970s
Reviewers not familiar with new technology
Extended review times
GMP inspectors not familiar with new technology
Risk of inspection findings
OutcomeA large disincentive to continuous improvementPharmaceutical quality management stuck in the 1970s
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A New Approach to RegulationA New Approach to Regulation
2001 - 2002
American Food and Drug Administration (FDA) suggested a new approach
Process Analytical Technology (PAT)21st Century GMP initiatives.
2001 - 2002
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)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
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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 parametersFeed backFeed forward
Identify the parameters that are criticalto product quality
Statistically designed experiments
Measure these parameters
Control these parametersFeed backFeed forward
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Paradigm ShiftParadigm Shift
Current paradigm:Current paradigm:
Starting Materials
Variable
Processing parameters
Fixed
Product
Variable
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Paradigm ShiftParadigm Shift
PAT paradigm:PAT paradigm:
Starting Materials
Variable
Processing parameters
Variable
Product
Fixed
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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)
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ICH ParticipantsICH Participants
Q Q ualityS S afetyE E fficacyM M ultidisciplinary
Expert WorkingGroups (EWGs)
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ICH GMP WorkshopICH GMP Workshop
EU, Japan and ‘observers’ joined USA to define a new paradigm at an ICH GMP Workshop in Brussels, July 2003This Workshop agreed a 5 year Vision:
Create a single, harmonised global quality standard and interpretation based on good science and risk management principles
EU, Japan and ‘observers’ joined USA to define a new paradigm at an ICH GMP Workshop in Brussels, July 2003This 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 VisionIncremental Steps to Achieve the Vision
The GMP Workshop agreed that the Vision would be achieved by “incremental steps”
Q8 EWG, on Pharmaceutical Development, established in September 2003Q9 EWG, on Quality Risk Management, established in November 2003Q10 EWG, on Pharmaceutical Quality Systems, established in November 2005
The GMP Workshop agreed that the Vision would be achieved by “incremental steps”
Q8 EWG, on Pharmaceutical Development, established in September 2003Q9 EWG, on Quality Risk Management, established in November 2003Q10 EWG, on Pharmaceutical Quality Systems, established in November 2005
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Pharmaceutical Development (Q8)Pharmaceutical Development (Q8)Old: Data transfer / variable output
New: Knowledge transfer / Consistent output
Quality Systems (Q10)Quality Systems (Q10)Old: Large variability on Q-systems
New: Consistency on Q-systems
Quality Risk Management (Q9)Quality Risk Management (Q9)Old: Unstructured approach
New: Opportunity to use a structured process
ChangedParadigm
Q8
Q9 Q
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Achieve by Incremental StepsAchieve by Incremental Steps
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Flexible Regulatory ApproachFlexible Regulatory ApproachRegulators 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:
SubmissionsPost-approval change reviewGMP inspections
Result:Removal of barriers to continuous improvementEfficient 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:
SubmissionsPost-approval change reviewGMP inspections
Result:Removal of barriers to continuous improvementEfficient use of resources by industry and regulators
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ICH Q8“Pharmaceutical Development”
ICH Q8“Pharmaceutical Development”
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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
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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’
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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 .
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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
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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 .
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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
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ICH Q8 (R1)ICH Q8 (R1)
Received Step 2 approval 1 Nov. 2007Hoped to reach Step 4 in June 2008ICH Q8 (R1) provides an annex to Q8 guideline.This annex elaborates the elements of pharmaceutical development as:
Target Product ProfileCritical Quality Attributes (CQA)Linking material attributes and process parameters to CQAs by risk assessmentDesign SpaceControl StrategyProduct lifecycle management and continual improvement
Received Step 2 approval 1 Nov. 2007Hoped to reach Step 4 in June 2008ICH Q8 (R1) provides an annex to Q8 guideline.This annex elaborates the elements of pharmaceutical development as:
Target Product ProfileCritical Quality Attributes (CQA)Linking material attributes and process parameters to CQAs by risk assessmentDesign SpaceControl StrategyProduct lifecycle management and continual improvement
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ICH Q8 (R1) – Design SpaceICH Q8 (R1) – Design Space
Concept of ‘Design Space’ is elaborated upon with guidance on:
Selection of variablesDefining and describing a design space in a submissionUnit operation design space(s)Relationship of Design Space to scale and equipmentDesign Space versus proven acceptable rangesDesign Space and edge of failure
Concept of ‘Design Space’ is elaborated upon with guidance on:
Selection of variablesDefining and describing a design space in a submissionUnit operation design space(s)Relationship of Design Space to scale and equipmentDesign Space versus proven acceptable rangesDesign Space and edge of failure
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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
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ICH Q9“Quality Risk Management”
ICH Q9“Quality Risk Management”
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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.
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ICH Q9 –Quality Risk Management Process ICH Q9 –Quality Risk Management Process
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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
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ICH Q10“Pharmaceutical Quality
Systems”
ICH Q10“Pharmaceutical Quality
Systems”
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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 controlFacilitates 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 controlFacilitates continual improvement over the product lifecycle
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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”
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Q10 - EnablersQ10 - Enablers
The enablers provide the means for science- and risk-based decisions related to product qualityKnowledge 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 qualityKnowledge Management
Manage knowledge from development through commercialisation to discontinuation
Quality Risk Management (Q9)Proactive approach to managing risks to quality
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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
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ICH Quality GMP Related Activities - Current StatusICH Quality GMP Related Activities - Current Status
Q8 – Pharmaceutical DevelopmentApproved by ICH in November 2005Implemented in EU, Japan and USA during 2006Q8(R1) at Step 3 of ICH process
Q9 – Quality Risk ManagementApproved by ICH in November 2005Implemented in Japan & USA during 2006 and in EU in March 2008
Q10 – Pharmaceutical Quality SystemsAt Step 3 of ICH processExpect final ICH approval in June 2008
Q8 – Pharmaceutical DevelopmentApproved by ICH in November 2005Implemented in EU, Japan and USA during 2006Q8(R1) at Step 3 of ICH process
Q9 – Quality Risk ManagementApproved by ICH in November 2005Implemented in Japan & USA during 2006 and in EU in March 2008
Q10 – Pharmaceutical Quality SystemsAt Step 3 of ICH processExpect final ICH approval in June 2008
