Regulatory Challenges: Lecture @ University of Michigan 21 Feb 2013

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Information about Regulatory Challenges: Lecture @ University of Michigan 21 Feb 2013

Published on June 15, 2013

Author: a2zpharmsci



To frame the current challenges in (the implementation of) Pharmaceutical QbD in a manner that will provide you an opportunity to:
(1) Leverage prior learning about medical device QSR to inform and understand key issues in regulation of pharmaceutical QbD
(2) Provide an example of a ‘real world’ uncertainty that you should not hesitate to take-on based on the fundamentals of engineering science and practices you have learned

Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D., Chief Scientific Officer & President BiotechnologyQuality By Design in Bio/Pharmaceutical Development2/21/20131BME/Chief598QualitySystemsandRegulatoryInnovation

Ajaz S. Hussain, Ph.D.BME/ChE 598: Lecture Topics2/21/20132 Current Status and Future Trends in Biomedical Regulations Overview of Quality System Regulation (QSR) for Medical Devices and In-Vitro Diagnostics Design Controls in Biomedical Innovation Process Human Factors and Reliability Engineering for Patient Safety Corrective and Preventive Action (CAPA) and Root Cause Analysis Role of Registries in Ensuring Quality and Safety of Orthopaedic and Other Devices Quality By Design in Bio/Pharmaceutical Development Establishing Regulatory Roadmaps for Generic Drugs, Follow-On Biologics and 510k Medical Products Companion Diagnostics and Personalized Medicine FDA Regulation of Mobile Health Devices and other Biomedical ICTs Risk and Regulation of Radiation Exposure in Biomedical Imaging Problems of Regulating Sophisticated Materials and Complex Biomedical Products Global Regulatory Harmonization of Biomedical Products and Services“..this course isintended topreparestudents for areal worldenvironment..”

Ajaz S. Hussain, Ph.D.Real World Environment2/21/20133• Risk and uncertainty• Uncertainty = Risk + OpportunityContinual change• How do you reduce risk?• How do you maximize opportunity?Regulatoryuncertainty• Minimize risk and identify opportunity• Precise vocabulary and clear communicationFundamentals

Ajaz S. Hussain, Ph.D.Relevant regulatory guidelines2/21/20134International Conference on Harmonisation -QualityQ8(R2) Pharmaceutical Development (PDF - 402KB) 11/20/09International Conference on Harmonisation -QualityQ9 Quality Risk Management (PDF - 113KB) 06/01/06International Conference on Harmonisation -QualityQ10 Pharmaceutical Quality System (PDF - 274KB) 04/07/09International Conference on Harmonisation -QualityQ8, Q9, and Q10 Questions and Answers (PDF - 185KB) 11/01/11International Conference on Harmonisation -QualityQ8, Q9, & Q10 Questions and Answers -- Appendix: Q&As fromTraining Sessions (Q8, Q9, & Q10 Points to Consider)07/25/12International Conference on Harmonisation -QualityQ11 Development and Manufacture of Drug Substances (PDF -708KB)11/19/12

Ajaz S. Hussain, Ph.D.Objective of this lecture2/21/20135 To frame the current challenges in (the implementation of)Pharmaceutical QbD in a manner that will provide you anopportunity to Leverage prior learning about medical device QSR to inform andunderstand key issues in regulation of pharmaceutical QbD Provide an example of a ‘real world’ uncertainty that you should nothesitate to take-on based on the fundamentals of engineering scienceand practices you have learned

Ajaz S. Hussain, Ph.D.Quality by Design What is ‘quality’? What is ‘design’? How does ‘design’deliver ‘quality’? Biologics Drugs Device Combination products2/21/20136Hint: Medical Device Quality System is designed to “assure that products are safe andeffective for their intended use and consistently meet the specifications as defined by results ofclinical and/or detailed technical design and validation

Ajaz S. Hussain, Ph.D.Biologics, Drugs, Devices & Combinations2/21/20137• Why?• How?• What?Different butoverlappingregulatory schema• 21 CFR 56 (IRB’s)• 21 CFR 58 (GLP)• 21CFR 11 (Electronic records)• 21 CFRR 800-1050 (devices)• 21 CFR 807 (510(k))• 21 CFR 812 (IDE)• 21 CFR 814 (PMA)• 21 CFR 21 CFR 820 QSR (GMP)Devices

Ajaz S. Hussain, Ph.D.Design Control for a Biologic or DrugProduct?• Design Planning• Design Input• Design Output• Design Reviews• Design Verification• Design Validation• Design Transfer• Design Changes• Design History FileElementsof DesignControl(Device) A tablet product ? ? ?2/21/20138

Ajaz S. Hussain, Ph.D.Design: Art or Science2/21/20139 The natural sciences are concerned with how things are...designon the other hand is concerned with how things ought to be Scientific design is based on scientific knowledge but utilizes amix of both intuitive and non-intuitive design methods Through the application of scientific knowledge in practicaltasks, design ‘makes science visible’Cross, Nigel (2001). Designerly ways of knowing: design discipline versus design science. Design Issues, 17(3), pp. 49–55.

Ajaz S. Hussain, Ph.D.Rest of this lecture..2/21/201310 Evolution of QbD for pharmaceuticals Current state of progress Anticipated changes at FDA to improve implementation ofQbD Often underestimated challenge; effective multidisciplinarycommunication Homework assignment

Ajaz S. Hussain, Ph.D.Assumption2/21/201311• Science (methodology)• Risk (management)• Practices• Guidelines• StandardsRegulations areintended tofacilitatedevelopment ofsystems that ensure‘science based riskmanagement’

Ajaz S. Hussain, Ph.D.Reflections, a decade ago at FDAHistory and evolution of QbD for pharmaceuticals2/21/201312

Dr. Woodcock’s Challenge in 2000“Will this $ X00 million consent decree improve quality of the real [physical] product?How effective is “process validation”? Is it not just a “well-rehearsed demonstration…. 3times”?Is our system truly a “modern quality system”?Are our “specifications” based on sound science and risk principles?How is “c” in cGMP established?Do current regulations support “continuous improvement”?How efficient is pharmaceutical manufacturing?132/21/2013Ajaz S. Hussain, Ph.D.

Ajaz S. Hussain, Ph.D.Quality issues and recalls142/21/2013

Ajaz S. Hussain, Ph.D.Low efficiency15MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)OVERALL CYCLE TIMES:QC TESTING TIMES ARE SIGNIFICANT0510152025TIME(D ays)A B C D E FPR OC ESS CASE STUD YOverall Cycle Time ComponentsPro cess Time sQC Te stin g Time s•[PPT] Final Report on Process Analytical Technology and ... - FDA••(Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001).2/21/2013

Ajaz S. Hussain, Ph.D.Opportunity for improvement169Pharma Manufacturing - Unmet Performance Expectations Utilisation levels - 15% or less(but low levels masked). Scrap and rework - we plan for 5-10%(accepted as necessary). Time to effectiveness - takes years(not challenged). Costs of quality - in excess of 20%(thats the way it is).•[PPT] Final Report on Process Analytical Technology and ... - FDA••(Source: FDA Science Board Meeting, November 16, 2001).2/21/2013

Ajaz S. Hussain, Ph.D.What was not optimal?2/21/201317CMC review cycles, prior-approval supplements,specifications,…Warning Letters, ConsentDecree, Root-causeunknown, “c” inGMP,……..‘Validation’withsuboptimalunderstanding

Ajaz S. Hussain, Ph.D.Quality has to built-in or be by DesignFrom 1987: FDA Guidance: General principles of processvalidation, May 1987To 2004: “The goal of PAT is to enhance understanding andcontrol the manufacturing process, which is consistent with …quality cannot be tested into products; it should be built-in orshould be by design.” (FDA’s PAT Guidance, 2004)2/21/201318QbD

Ajaz S. Hussain, Ph.D.Effective risk-assessment2/21/201319Can occur when both CMC and cGMP functions have a common understanding, andconfidence in, the scientific understanding communicated (in development reports) andestablished at a manufacturing facility where a new product will be manufactured• Acceptable product variability over the intended shelf-life; prior-knowledge,development data and characterization of clinical trial lots - including processcapability (Cpk) assessment• CMC to cGMP knowledge sharing meeting - specific considerations relevant to anovel product and its implications for technology transfer• Multi-functional FMEA; considering manufacturing facility data (Cpk of similarproducts, reject rate, effectiveness of root-cause investigations); also can serve as astructured approach to guide definition of “c” in GMP

Ajaz S. Hussain, Ph.D.Seamless alignment across functions2/21/201320• Necessary for common understanding & confidence• Would allow for an aligned and logical Pharma QbD process• Facilitate prioritization of critical factors that would beaddressed over the development process• Improve scientific communication within FDA and with sponsors• Build confidence in risk-based decisions and to identifyopportunities for ‘less burdensome approaches for continuousimprovement’CMC review, cGMP complianceand investigations team approach(e.g., the previous FDA’s PAT Team)PicturesfromPATTeam-buildingeventinearly2000

Ajaz S. Hussain, Ph.D.Process Analytical Technology2/21/201321• Understanding & controllingvariability• Removing fear of largesamples & new analytics onold processes• Opening the door to real-timerelease & ‘Design for SixSigma’Processunderstanding• Validation of new methodsbased on mechanisticunderstanding• Improvements without “prior-approval supplement”• Opening the door to ‘Lean’;improvements managed withinquality systemContinuousimprovement• Understanding technologies,functions & each other• Finding lean solutions tofacilitate improvement• Ensuring quality in real-timefrom review, compliance andinspections perspectivesReview-Compliance-Investigator Team

Ajaz S. Hussain, Ph.D.Understanding via development reports?2/21/201322• a point of contention…. manufacturersare skeptical abouthow FDA will use thedata,…. how muchinformation to sharewith the agency• "What is needed is theknowledge .. capturedwithin that report, ….. ifcompanies can share thatknowledge, the agencycan …. set moremeaningful specificationsto manage those changesin less burdensomeways”.• “….spends a lot of timelooking at deviations,failure investigations,things that are a result ofa less- than- idealproduct or processknowledge. … theproduct has beenadequately validated,"• … will improve ourprocess, ..requirementsare predictable and theprocess …streamlined,..and very timely. .. achange …done withoutprior approval, whereweve demonstrated theknowledge of ourprocess."ValidationTimes1May2003

Ajaz S. Hussain, Ph.D.Regulatory efforts (2000 – present)2/21/201323

Ajaz S. Hussain, Ph.D.Now, a option to submit …2/21/201324•Is a option•With the anticipation it willnot delay approval process•Not add new requirementsDevelopmentReports forCMC review•Demonstrate science-baseddevelopment so thatregulators can make risk-based decisions•Reviewer to gain confidenceto support continuousimprovement without prior-approval supplementsWhy?•Guidance per ICH Q8-10•Design space?•Review process?•Role of compliance &investigators?•Less burdensome approachto improvements?How?• Risk-basedspecifications?• Less burdensomeapproaches forimprovement?What?

Ajaz S. Hussain, Ph.D.High level of uncertaintyCurrent state of progress2/21/201325

Ajaz S. Hussain, Ph.D.An ongoing struggle2/21/201326 Recent industry comments suggest an ongoing struggle; forexample, “QbD is in its infancy” or “not focused on QbD” State of QbD Implementation: Adoption, Success andChallenges (McKinsey Report, 2011*) Negative perceptions - quality related recalls, warning letters,consent decrees, drug shortages, etc.

Ajaz S. Hussain, Ph.D.Functional alignment, improved collaborationsChanges at FDA to improve implementation of QbD?272/21/2013

Ajaz S. Hussain, Ph.D.Proposed changes in CDER, FDA2/21/201328

Ajaz S. Hussain, Ph.D.Outside Pharma sector (in the 1990’s)?2/21/201329LEAN SIX SIGMA ISO to QS-9000 Baldridge Award,Deming Prize, etc.Measure, analyze,and reduce• wait time• inventory• batch size• process time• rework• Use specificmetrics• Collect data• Analyze data• Collect controldataMonitor andmeasure processperformanceContinuousImprovementMeasure andimprove• processes• business results• overallorganizationalperformanceAn important area of focus: Statistical analysis and Continuous Improvement (not just CAPA)

Ajaz S. Hussain, Ph.D.Non-pharmaceutical Design for Six Sigma*2/21/201330IdentifyCritical to Customer(internal andexternal) Factors.Critical to QualityFactorsPrioritizationDesignCritical to ProductFactors.Validated Selection(Analytical) CriteriaKey Process Input &Output VariablesOptimizeCritical to ProcessTolerancesOptimize inputsSensitivity (Risk)AnalysisDemonstrateCapabilityValidateScale-upEquipmentQualificationMistake-proofing &SOPsCustomer approval,review & reflection*Norm Kuchar at General Electric Corporate Research and Development.Other approaches - Define, Measure, Analyze, Design, Verify (parallel to theDMAIC process and is advocated by American Society for Quality)

Ajaz S. Hussain, Ph.D.Design for Six Sigma & Pharma QbD2/21/201331Identify Design Optimize ValidateQTPP CQA Riskassessment Design space ControlstrategyContinuousimprovementDesign for Six SigmaPharma QbD as currently implemented: Advisory Committee for Pharmaceutical Science and ClinicalPharmacology July 27, 2011

Ajaz S. Hussain, Ph.D.Some observations Seamless alignment across functionsthat are compartmentalized inpharmaceutical regulatory review,compliance & inspection Prioritization of critical factors over thedevelopment process Optimization includes considerationsfor ‘process capability’ Validation includes a notion of ‘design’of SOP’s Outlined to reflect CMC review; possiblycarving out compliance & inspectionfunctions Conceptual compartmentalization of QTPP,CQA’s, etc. Design space substituted for “optimization”?;if so, this was not the original intent Validation not considered; possibly carvingout compliance & inspection functions2/21/201332Design for Six Sigma Current Pharma QbD

Ajaz S. Hussain, Ph.D.Design-space substituted for “optimization”?2/21/201333• Too narrow in scope to be an effectivemeans for realizing ‘less burdensomeapproaches for continuous improvement’• Focuses review staff to seek large amountof empirical data which previously was notsubmittedWould makeoptimization based on‘response surface’methodologies a “newreview requirement”

Ajaz S. Hussain, Ph.D.Get the fundamentals ‘right’Clear communication(Planned compliance)Effective multi-disciplinary communication2/21/201334

Ajaz S. Hussain, Ph.D.Reducing Uncertainty in the Real World2/21/201335Get thefundamentals‘right’EffectivecommunicationPlannedcompliance

Ajaz S. Hussain, Ph.D.Communication challenge2/21/201336Causal linksidentified &quantifiedDifficult toidentify andquantifycausal linksLowconfidence incausal linksVariableinterpretationof identicaldata

Disciplinary perspectives on riskReflecting thepreoccupations,strengths, andweaknesses ofeach disciplineas theygrapple withuncertainty• Acceptable variance in cGMP compliance,critical to quality attributes (in the context ofsafety and efficacy)?37A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)2/21/2013Ajaz S. Hussain, Ph.D.

Ajaz S. Hussain, Ph.D.Simple to ambiguous problemsRoutine operation• Agency staff• Discourse: Internal• SimpleScientific risk-assessment necessary• Conflict: Cognitive• Agency staff &external experts• Discourse: Cognitive• ComplexRisk balancingnecessary• Risk assessmentnecessary• Conflict: Cognitiveand Evaluative• Agency staff,external experts,stakeholders• Discourse: Reflective• UncertainRisk tradeoff analysisand deliberationsnecessary• Risk assessment andbalancing necessary• Conflict: Cognitive,Evaluative,Normative• Agency staff,external experts,stakeholders, publicrepresentatives• Discourse:Participatory• AmbiguousRisk Analysis (2002)382/21/2013

Ajaz S. Hussain, Ph.D.What is scientific and what is not?The U.S. Supreme Court: An Evolved Theory of Science (2000)The theoretical underpinnings of the methods must yieldtestable predictions by means of which the theory could befalsifiedThere should be a known rate of error that can be used inevaluating the results.The methods should preferably be published in a peer-reviewed journal.The methods should be generally accepted within the relevantscientific communityFrancis Bacon’sScientific MethodKarl Popper’sFalsification TheoryThomas Kuhn’sParadigm Shifts$file/sciman00.pdf2/21/201339

Scientific explanations yield understanding;quality of explanations differExplanation could besubjective -- a feeling ofgrasping the connectionbetween explanandum andexplanans; if so• Such understanding would be deniedany epistemological statusTherefore, scientific understanding,in a regulatory context, bestcommunicated …• Explanation,• Prediction, and• ConfirmationTHE EPISTEMOLOGICAL STATUS OF SCIENTIFIC THEORIES: AN INVESTIGATION OF THE STRUCTURAL REALISTACCOUNT Ioannis Votsis, LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE (2004)40how do you know what you know?2/21/2013Ajaz S. Hussain, Ph.D.

Ajaz S. Hussain, Ph.D.Compare and contrast the role of design controlin the development of Medical Devices andDrug ProductsHomework2/21/201341

Ajaz S. Hussain, Ph.D.Summary: Objective of this lecture2/21/201342 To frame the current challenges in (the implementation of)Pharmaceutical QbD in a manner that will provide anopportunity to Leverage your prior learning about medical device QSR to inform andunderstand issues in pharmaceutical QbD Provide an example of a ‘real world’ uncertainty that you should nothesitate to take-on based on the fundamentals of engineering scienceand practices you have learned

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