the new quality paradigm in ich q8 q9 q10 q11
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THENEWQUALITYPARADIGMINICH Q8 Q9 Q10 Q11OPPORTUNITIES ANDEXPECTATIONS
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Why do we need itSome background Information
THENEWPARADIGMOR
QUALITYBYDESIGN
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GLOBALHARMONISATION(ICH+GCG)
Expert WorkingGroups (EWG)
WHO Global Cooperation Group
APEC
ASEAN
PANDRH
SADC
www.ich.org
The impact of ICH
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THEROLEOFPROCESSUNDERSTANDING
Pharma Air Plane
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Typical Ingredients of a Tablet
Active 5m
Corn Starch 30m
Lactose 100m
MicrocrystallineCellulose 102100m
Dr. Susanne Keitel
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Pharmaceutical Development Q8Defines what is the minimum (Basel Line)
The role of Process Understanding
Defines what is a Design Space
Defines Regulatory FlexibilityPharmaceutical Development Q8 AnnexDefines what is Quality by Design
The role of a Systematic Approach
Defines Critical Quality Attribute
Examples of Design Space
Defines Control StrategyDevelopment of Drug Substances Q11Defines what is the minimum (Basel Line)
The traditional and enhanced Approaches
Defines Critical Quality Attributes (CQAs)
How to use Quality Risk Management
The newParadigm
QAnnex
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The New Paradigm Quality by DesignHEICH CONCEPTOFTHENEWPARADIGM
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A PROCESSISWELLUNDERSTOODWHEN all critical sources of variability areidentified and explained; variability is managed by the process; and, product quality attributes can beaccurately and reliably predicted over thedesign space
The PAT Guidance
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ICH Q8(R) : DEFINITION
8
Quality by Design:
A systematic approachto development
that begins with predefined objectives and emphasizesproduct and process understandingand process
control, based on sound science and quality risk
management.
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WHATISQUALITYBYDESIGN
Elements of a QbD
Systematic Development Approach
Formulation UnderstandingProcess Understanding
Packaging Understanding
Application of Quality Risk Management
Advanced Control Strategy
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TRADITIONALVERSUSENHANCEDDEVELOPMENT
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Conventional PD Quality by Design(ideal)
Mainly empirical approach A systematic approach
Quality assured by end-
product testing and
inspection
Quality assured by well understood
product and process, moving controls
upstream without relying only on end-
product testing justified in aControl Strategy
Process is fixed, disallowing
changes
Flexible process within design space,
allowing continuous improvement
Focus on process
reproducibilityoften
avoiding or ignoring
variability
Focus on formulation and process
robustnessunderstanding and
controlling variability
Limited and simple IPC
Control Strategy based on end
product testing
Extended PAT tools replacing the need for
end product testing
Extended Control Strategy based on QRM
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Q8 GENERALCONCEPTS: REGULATORYFLEXIBILITYThis scientific understanding facilitates
establishment of an expanded design space. In these
situations, opportunities exist to develop more
flexible regulatory approaches, for example, to
facilitate:
risk-based regulatory decisions (reviews and
inspections);
manufacturing process improvements, within theapproved design space described in the dossier,
without further regulatory review;
reduction of post-approval submissions;
real-time quality control, leading to a reduction of
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POSSIBLEREGULATORYFLEXIBILITY
Continuous Improvement
Real time release Reduced or elimination of routine end product testing
Expanded design space Independence on scale Independent of equipment Independent of site Independent from drug substance manufacturing if within spec
Process Validation Process validation replaced by Concurrent Process Verification using validated
methods (qualified controls)
Stability Testing Reduced confirmation stability studies for any changes within the design space Reduced annual stability batches
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ADDITIONALBENEFITSOFQBD
Faster DevelopmentBetter FormulationsBetter ProcessLess Rejects and OOS OOELess QA investigationsMore consistent and reliable QualityReduced manufacturing costLess Transfer problems
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Q8 GENERALCONCEPTS
WHATISMINIMALREQUIREMENT
At a minimum, those aspects of drug
substances, excipients, container closure
systems, and manufacturing processes thatarecritical to product qualityshould be
determined and control strategies justified.
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Q8 GENERALCONCEPTS
WHATISCRITICAL?
Critical formulation attributes and process
parameters are generally identified through anassessment of the extent to which their variation
can have impact on the quality of the drug product.
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ICH Q11
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For Drug Substance from
Chemical Origin
Biotech Origin
Q11 SCOPE
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Manufacturing process development shouldinclude, at a minimum, the followingelements: Identifying potential CQAs associated withthe drug substance so that thosecharacteristics having an impact on productquality can be studied and controlled; Defining an appropriate manufacturingprocess; Defining a control strategy to ensure processperformance and drug substance quality (seeSection 6 on Control Strategy).
MINIMUMREQUIREMENTS
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An enhanced approach to manufacturing processdevelopment would additionally include the followingelements:
A systematic evaluation and scientific understanding ofthe manufacturing process, including use of QRM;
Determination of the functional relationships andrelevant multivariate interactions that link materialattributes and process parameters to drug substanceCQAs; Using the enhanced approach in combination with QRM toestablish a more focused control strategy which caninclude proposals for a design space(s).
Q11 ENHANCEDAPPROACH
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For drug substance development amajor focus is knowledge andcontrol of impurities
IMPORTANCEOFIMPURITIES
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Risk assessment can be used duringdevelopment to identify those parts of theprocess likely to impact potential CQAs anddrive process improvement to mitigate qualityrisk. Further risk assessments can be used tofocus development work in areas where betterunderstanding of the link between process andquality is needed
THEROLEOFRISKMANAGEMENT(QRM)
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Identify potential sources of process variability; Identify the material attributes and process parameterslikely to have the greatest impact on drug substancequality. This can be based on prior knowledge and riskassessment tools; Design and conduct experiments and/or mechanistic studies(e.g., multivariate Design of Experiments, simulations,modelling) to identify and confirm the links andrelationships of material attributes and process parametersto drug substance CQAs; Conduct analysis of the data to establish appropriateranges, including establishment of a design spaceifdesired.
ENHANCEDAPPROACH
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Every drug substance manufacturing process,whether developed through a traditional or anenhanced approach (or some combination thereof),has an associated control strategy.
A control strategy can include, but is notlimited to, the following: Controls on material attributes (including raw materials,starting materials, intermediates, reagents, primary packagingmaterials for the drug substance, etc.); Controls implicit in the design of the manufacturing process(e.g., choice of reagents or media, sequence of operations); In-process controls (including in-process tests and processparameters); Controls on drug substance (e.g., release testing).
6. CONTROLSTRATEGY
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POINTSTOCONSIDER
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POSTAPPROVALCHANGEMANAGEMENTPROTOCOLS
+trategy Results +Strategy Results
CurrentlyEvaluation of a proposedvariation as a whole(Strategy + Results)
Early Step 1:
Submission of aChange ManagementProtocol
Fast Step 2:
Reporting ofimplementation of a changein accordance with anapproved protocol
Type II VariationType IAINor IB
Variation
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CONTENTOFAPOSTAPPROVALCHANGEMANAGEMENTPROTOCOL Support of the proposed change company should submit all relevant information
that can demonstrate that it has acquired adequateknowledge
to prepare and
manage the impact of the change.
The content of the protocol could includedepending on the nature of the change: Justification that there is a definite recognised
future need for the specific change,
within a reasonable timeframe,
and that adequate knowledge has been acquired toappropriately evaluate and manage the change for the specificproduct concerned.
Justification should also be provided for the proposedevaluation strategy.
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SUMMARYQ8, Q9, Q10, Q11 define a new ParadigmSystematic Development ApproachFormulation UnderstandingProcess UnderstandingPackaging UnderstandingApplication of Quality Risk ManagementAdvanced Control Strategy
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QUALITYBYDESIGN:
The Future has started
QbD submissions approved in US and EUincluding Real Time ReleaseNEW : also for BIOTECH Products