Quality by Design ISPE Pacific Rim08JUL2013.ppt

1 Applying Quality by Design to Generic Drug ManufacturingBikash Chatterjee President & CTO Pharmatech Associates12 Agenda What is QbD? Why it has become important What companies need to know, overview How to set up a team to develop QbD Process understanding Knowledge space Design space Required statistical processes Practical application of the ideas-Case Study Review of past records to determine CPP-Case Study Development of acceptable operation range Benefits Cost savings3 QbD s Proposition QbD concerns the making of drug substances and drug products QbD is the new pharmaceutical Quality system that: Replaces current GMP concepts Does not depend on the trial and error approach of drug substance and drug product development & production Is a systemic, knowledge and risk-based Quality methodology Complies with the general purpose of product Quality : the product is suitable for use Patient driven philosophy A Quality system customizedfor pharmaceuticals QbD is GMP for the 21stcentury4 What is Quality by Design (QbD)?

2 First introduced in 1985 by Dr. Juran Juran said most Quality problems are designed into the process. A clear plan is needed to identify and eliminate these issues No single a systematic approach to development that begins with predefined objectives and emphasizes product and process understandingandprocess control , based onsound science andquality risk ICH Q8 Definition of QbD6 Another Way of Thinking about QbD Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined Design space. 7 Understandingwhat factors have an impact on variation in your process and also on your product s performance ; thenestablishing a control plan tomonitor and maintain product Quality My definition of QbD8 Elements of Quality by Design (QbD) GMPsGMPsEUUSFDAPIC/SICHQ8,Q9Q10Q11 GMPsEUUSFDAPIC/SRiskQualityTa r g e tProductProfileCTPPC riticalQualityAttributesCQAsQbDCriticalP rocessParametersCPPsControlStrategyDesig nSpace9 Quality by Design StagesQbDQuality PlanningQuality Target Product Profile (QTPP) Quality Critical Attributes (QCAs) Quality ControlCritical Process Parameters (CPPs) control StrategyQuality ImprovementProcess ControlProcess MonitoringQuality PlanningQuality ImprovementQuality Control10 What is Quality by Design (QbD)?

3 Pharma s version of Juran s ModelProcessControl FeaturesProduct DevelopmentQTPPCQAsInputsProcessOutputsQ bD Implementation11 Sources of Variation Management ManMethod Cause CauseCause Cause CauseCause CauseCause Cause Effect(Y) Cause CauseCause Cause CauseCause CauseCause Cause MeasurementMachineMaterial12 Agenda What is QbD? Why QbD has become important What companies need to know, overview How to set up a team to develop QbD Process understanding Knowledge space Design space Required statistical processes Practical application of the ideas-Case Study Review of past records to determine CPP- Case Study Development of acceptable operation range Benefits Cost savings13 Business Dynamics 14 Why Has QbD Become Important?

4 Business DriversoNew market opportunitiesoImproved market competitivenessoImproved profitability oReduced product risk exposure15 QbDThree Areas of Better Faster Cheaper Quality Time/Flow Waste/Costs16 Drive Financial PerformanceIncrease Revenue: Grow the Business Improve customer satisfaction, sales, throughput, and competitive positionDecrease the Cost of Goods Sold Reduce process variation and defects, improve yield Identify and eliminate root causes of problems Develop systems robust to problems Reduce unnecessary costs and excessive cycle time17 QbD is a Better Business Model R&D drives new innovative products Do we really need QbD? The conservative criticism All the billions of dollars poured into research and development in the won t mean a thing.

5 We must streamline and strengthen the regulatory science Areas cited where this is being accomplished include FDA s partnership with ICH around Quality by Design (QbD)New FDA commissioner Margaret Hamburg s keynote address at Regulatory Affairs Professionals Society annual conference in Philadelphia, September 2009 Conclusion: QbD is a way to innovate within the pharmaceutical industry18 Regulatory Drivers for QbDEscalating and non-uniform compliance expectations: - ASEAN Harmonization Activities- ICH, PIC/S, EU, CFDA (China), MHLW (Japan), CDSCO (India), MOH (Malaysia), FDA Thailand, NA-DFC (Indonesia)19US/EU/PIC/S QbD Regulatory TimelineASEAN Harmonization Milestones A-CTD Implemented A-CTR & technical guidelines established (maintenance and enhancement of common interpretation ongoing) Post-Market Alert System established GMP Inspection MRA finalized Training identified Pan-ASEAN registration19992002200520062009 PPWGIWGGMPMRATFBA/BETFA-CTDI mplementation2021 Regulatory Drivers-ICH Q8, 9, 10, 11 ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle ( )

6 ICH Q8 - Pharmaceutical Development ICH Q9 - Quality Risk Management ICH Q10 - Pharmaceutical Quality System ICH Q11 - Development and Manufacture of Drug Substances 22 Agenda What is QbD? Why it has become important What companies need to know, overview How to set up a team to develop QbD Process understanding Knowledge space Design space Practical application of the ideas-Case Study Review of past records to determine CPP-Case Study Required statistical processes Development of acceptable operation range Benefits Cost savings23Is QbD a Shift in Quality Philosophy? You can t test Quality into drug products has been heard for decades so what s new? Quality is based on process and product understanding, not just test results It s a shift in culture: incorporates Quality principles and strong compliance function Incorporates risk assessment and management Refocuses attention and resources on what s important to the customer, the patients, health professionals, payors and distribution chain24 QbD is a Commitment to Improve Continuous improvement is a key element of QbD- G.

7 Taguchi on Robust Design : Design changes during manufacture can result in the last product produced being different from the first product However, in pharmaceutical manufacturing, we want improvement that improves consistency patients and physicians must count on each batch of drug working just like the batches that came before25 QbD for Generic DrugsIn generic pharmaceutical manufacturing, there are additional constraints: Fixed bioequivalence targets Regulatory requirements to duplicate formulation of innovator drug Lack of access to innovator development data26 The Changing Regulatory Compliance EnvironmentQuality by Design Adequate resources for Quality : number, qualifications, etc. Self-assessments play key role Continuous analysis & improvement Change management based on good science Focus on what s important (risk management)Current Regulatory Situation: US/EU Little guidance on adequate resources or qualifications Self-assessments not trusted Annual product reviews instead of continuous analysis Formidable barriers to change, including intimidating enforcement emphasis Seldom admit that anything is not important.

8 Test everything27 Quality by Design (QbD) CharacteristicsBasics: Uses systemic (multivariate statistics) development and manufacturing by use of prior knowledge Risk assessment guided Design and process control Applies to the total life cycle of a product (continuous improvement)Implications: Quality back to the roots: product suited for its purpose Quality is dynamic: continuous improvement Quality must be built in Quality means first time right28 The QbD Development Model is Different Patient Idea Design Space control Strategy Risk Assessment Product Life Cycle Idea Development Preclinical & Licensing Manufacturing Marketing/Clinical TestingSalesTraditionalQdBIn the QbD Development Concept The Chain is Reversed 29 QbD Will Require Enhanced Supplier Management Why?

9 You will need to measure and control the important characteristics of your raw materials and API Clearly defined supplier Quality and supply agreements are necessary30 Agenda What is QbD? Why it has become important What companies need to know, overview How to set up a team to develop QbD Process understanding Knowledge space Design space Required statistical processes Practical application of the ideas Review of past records to determine CPP Development of acceptable operation range Benefits Cost savings31 Building a QbD Organization Starts in product development Multidisciplinary team representing the product development lifecycle Presents opportunities to build in existing commercial experience into the product and process Design phase Presents the opportunity to not repeat mistakes in formulation and product design32 Team StructureQbDCore TeamR&D & MarketingCorporateand Mfg.

10 EngineeringTechnical ServicesRegulatory and QA ComplianceFacilities/GCValidationOversig ht Committee33 QbD Core Team Program Manager Decision makers from all six areas Clear mandate to deliver product. In the US FDA market measured by being the First to File QbDCore Team34 Team Chartering ProcessDefine and Identify: Success metrics for the project Timeline Budgetary and cost tracking assumptions Key stakeholders Project champion and project milestones Extended Chartering to discussion of communication, review and issue resolution mechanism Also established initial team rules: what behaviors would be encouraged and what would not be encouraged35 Managing Team DynamicsTe a m CharterStructureSystemsStaffStrategySkil lsStyleKnowledge ManagementProductSelectionDevelopment And CharacterizationSite Selection/Process Design /Tech UnderstandingProcess PredictabilityMeasurementContinuousMonit oringPhase 1 Phase 2 Phase 3 Phase 4 Phase 5 Key Activity QTPP StrategicAnalysis Site Capability Analysis ProjectTimeline Risk AnalysisKeyActivity Platform Knowledge Identify CPP MSA CMA RiskAnalysis Process Risk Analysis Commercial FactorsGo/No GoGo/NoGoGo/No GoKeyActivity Site Suitability Mapping CPP MSA Process Risk Analysis Confirmation Process DOE ProcessValidationKey Activity