1.Ajaz S. Hussain, Ph.D.Fellow, Swiss Society for PharmaceuticalSciencesNew Affiliation:Chief Scientific Officer & PresidentBiotechnologyWockhardt Ltd.Chemometrics, Pharmacometrics andEconometrics Dimensions of Quality byDesign5/25/20121

2. A philosophical explorationScientific understanding and risk-basedregulatory decisions on Quality by Design5/25/20122 3. Motivation FDA Initiatives launched a decade ago have had a profoundimpact on the global pharmaceutical sector Process Analytical Technology Quality by Design Efforts to conducts risk-based regulatory review and inspections Good guidelines and significant regulatory efforts around the world Significant industrial programs and efforts Academic programs and scholarly contributions Yet, the number of compliance issues, recalls, drugshortages, warning letters, etc., today rival thesituation a decade ago Why? What is missing? How can we improve thesituation?5/25/20123 4. Looking back, brieflyHow good are the scientific explanations inregulatory submissions?5/25/20124 5. Dr. Woodcocks Challenge in 2000Will this $ X00 million consent decree improve quality of the real[physical] product?How effective is process validation? Is it not just a well-rehearseddemonstration. 3 times?Is our system truly a modern quality system?Are our specifications based on sound science and riskprinciples?How is c in cGMP established?Do current regulations support continuous improvement?How efficient is pharmaceutical manufacturing?5/25/20125 6. Compliance and noncomplianceare complex behaviorsThe product of habits and routines.AutomaticThe intentional pursuit of various goals,such as to maximize ones utility, fulfill amoral obligation such as duty or trust, ordispose of ones fear of sanctions.PlannedCan be the result of regulateesincapacity, incompetence, ignorance ormisunderstanding of regulatoryprescriptions.OtherBrehm and Hamilton (1996)5/25/20126 7. Framing & conceptualizingI can see clearly nowVision 2020Scientific explanationyields understanding Perspectives onRegulation: Law,Discretion, andBureaucratic Behavior(Kagan and Scholz, May1980) Good citizens Vs.{political citizens,incompetent, and/oramoral} For FDA to be science andrisk-based it needsscientific data &http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-Presentation.ppt5/25/20127 8. Making the case (in the US) for CMCreview of development reportsCreating a common ICH vision (desired state)to develop ICH Q8, Q9 and Q105/25/20128 9. How good are the scientificexplanations in regulatorysubmissions?First principlesMechanisticunderstandingCausal links predictperformanceUnivariatemethodsEmpirical data viatrial-n-error Variability in cGMPcompliance?, Variability in critical toquality attributes (e.g.,within and between lots;also now individualunits), Variability in PK/PD &outcome (e.g., intra- andinter- individualvariability), Other .Humans aredriven toacquire andprovideexplanations(but notnecessarily toregulators).5/25/20129 10. Three perspectives on improving scientificunderstanding through development reports(2003)Developmentreports still astumblingblock in GMPInitiativeDevelopment reports remain a point ofcontention . manufacturers are skepticalabout how FDA will use the data,. howmuch information to share with the agencyAjaz Hussain(FDA, CDER) "What is needed is the knowledge that iscaptured within that report, .." He saidthat if companies can share thatknowledge, the agency can . set moremeaningful specifications to manage thosechanges in less burdensome ways.http://www.thefreelibrary.com/Development+reports+still+a+stumbling+block+in+GMP+Initiative.+(CMC).-a01040312695/25/201210 11. Three perspectives on improving scientificunderstanding through development reports(2003)DougEllsworth(FDA NewJerseyDistrictOffice)Currently the agency spends a lot of time looking atdeviations, failure investigations, things that are aresult of a less- than- ideal product or processknowledge. "Well know were getting close wheninvestigators can spend more time on adequacy ofthe quality system and not necessarily how theproduct has been adequately validated," he said.GerryMigliaccio(Global QAChief,Pfizer)"We will have a victory if I can sit back and set Pfizerquality standards based on regulations and guidancedocuments not based on warning letters and 483swill improve our process, ..requirements arepredictable and the process for getting that changeis streamlined, straightforward and very timely. .. achange that can be done without prior approval,where weve demonstrated the knowledge of ourprocess."5/25/201211http://www.thefreelibrary.com/Development+reports+still+a+stumbling+block+in+GMP+Initiative.+(CMC).-a0104031269 12. FDA & ICH InitiativesPAT Initiative Guidance +Review,Compliance &Inspection TeamICHGuidelines Q8, Q9 andQ10 (Q11)Additionally Office ofGeneric Drugsefforts5/25/201212 13. Scientific explanations yieldunderstanding; quality of explanationsdifferMaking a Case for Regulatory Utility ofChemometrics, Pharmacometrics andEconometrics5/25/201213 14. Although understanding arises fromexplanation, a question remainsExplanation could besubjective -- a feeling ofgrasping the connectionbetween explanandum andexplanans; if so Such understanding would bedenied any epistemological statusTherefore, scientificunderstanding, in a regulatorycontext, best communicated Explanation, Prediction, and ConfirmationTHE EPISTEMOLOGICAL STATUS OF SCIENTIFIC THEORIES: AN INVESTIGATION OF THESTRUCTURAL REALIST ACCOUNT Ioannis Votsis, LONDON SCHOOL OF ECONOMICS ANDPOLITICAL SCIENCE (2004) 5/25/201214how do you know what you know? 15. What is scientific and what is not?The U.S. Supreme Court: An Evolved Theory of Science(2000)The theoretical underpinnings of the methodsmust yield testable predictions by means ofwhich the theory could be falsifiedThere should be a known rate of error thatcan be used in evaluating the results.The methods should preferably be publishedin a peer-reviewed journal.The methods should be generally acceptedwithin the relevant scientific communityFrancis BaconsScientific MethodKarl PoppersFalsification TheoryThomas KuhnsParadigm Shiftshttp://www.fjc.gov/public/pdf.nsf/lookup/sciman00.pdf/$file/sciman00.pdf 5/25/201215 16. Analysis of KnowledgeTruthandFalsitybefore beliefsThe Correct Analysis ofKnowledgeS is [internally/externally]justified in believing thatp.S believes p.S is justified inbelieving p.p is true.S knows p.Unconscious Knowledge and Epistemic Status. LUS M. AUGUSTO. UNIVERSITY OF SUSSEX, June5/25/201216 17. Prescription for troubleHow flaw in FDA safety net may poserisk to public with generic drugs Tom Abate, Todd Wallack, Chronicle Staff Writers San Francisco Chronicle. Sunday, December 22,2002The issues [Company X] had tested its generic with chocolatemilk. [Ref.product] was chased with apple juice. Did that matter?http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2002/12/22/MN35888.DTL&ao=all5/25/201217 18. What role can Chemometrics, Pharmacometicsand Econometrics play?The Correct Analysis ofKnowledgeS believes p.S is justified inbelieving p.p is true.S knows p.Unconscious Knowledge and Epistemic Status. LUS M. AUGUSTO. UNIVERSITY OF SUSSEX, June5/25/201218Build a case example viadiscussion with the audience 19. Epistemological Status of RiskUnderstanding multidisciplinary (cGMP, CMC,Clin. Pharm., Tox., Clinical, Public Health)perspectives on risk is important5/25/201219 20. Is risk a metaphysical or anepistemological category?the mental state of an individual who experiencesuncertainty or doubt or worry as to the outcome ofa given event.Subjectiverisk:the variation that occurs when actual losses differfrom expected losses.Objectiverisk:the combination of probability and negativeconsequence that exists in the real world.Real risk:the measurement of that combination obtained byconstructing a model of the real world.Observedrisk:the rough estimate of real risk made by anuntrained member of the general public.Perceivedrisk:A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)5/25/201220 21. Distinguishing risk fromuncertaintyRisk can be considered as an orderedapplication of knowledge to the unknownDifferent disciplines have a particularknowledge approach with which they confrontthe unknown so as to order its randomnessand convert it into a risk propositionA disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)5/25/201221 22. This concept of risk can act as amirrorReflecting thepreoccupations,strengths, andweaknesses ofeach disciplineas they grapplewith uncertainty Acceptable variance in cGMP compliance,critical to quality attributes (in the context ofsafety and efficacy)?5/25/201222A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005) 23. Preoccupations, strengths, andweaknesses of each disciplineRegulatory utility of pharmacometrics has advanced rapidly inFDA and EMA; it is having a significant impact on clinical trialdesigns and science and risk-based decisions in the clinicalpharmacology disciplinesRegulatory utility of chemometrics is sporadic and withdifficulties; there are lessons to be learned from regulatoryapplications of pharmacometricscGMP risk classifications remain subjective to a large degree;utility, within regulatory agencies, of econometric approaches isworth considering5/25/201223 24. Opportunities; only when thedisciplinary divides are bridged Estimate of variance in PK/PD &outcomes (e.g., intra- and inter-individual variability)Pharmacometrics Estimate of variance in critical to qualityattributes (in the context of PK/PDvariability)Chemometrics Estimate of variance in cGMPcompliance (in the context of acceptablevariance in critical to quality attributes)Econometrics?5/25/201224 25. Why? What is missing? How canwe improve the situation?The FDA & ICH initiatives haveprovided incentives for a fewcompanies to progress aheadsignificantly, with new technologiesand systems, while others have notWithin the regulatory realm how weset specifications and assess riskhave progressed incrementally; atthis rate the Vision 2020 may beexpected to be visible broadly overtime, by 2020?5/25/201225 26. Backup slides5/25/201226 27. Econometric analysis?Does offshore productionpose an added quality riskrelative to domesticproduction?Our findings indicate thatPuerto Rico plants operatewith a significantly higherquality risk than matchingplants operated by thesame firm located in themainland U.S., onaverage. If so, what factorsinfluence the quality risk? Quality risk in offshoremanufacturing: Evidencefrom the pharmaceuticalindustry. Volume 29,Issues 78, November2011, Pages 737752,Journal of OperationsManagement5/25/201227 28. Chemometrics The chemical discipline that uses mathematicaland statistical methods, (a) to design or selectoptimal measurement procedures andexperiments, and (b) to provide maximumchemical information by analyzing chemical data.5/25/201228 29. Other examplesScale-up factor 10X3 batches in process validationSignificant body of data for stability requirments80 125%How do you know what you know?5/25/201229 30. Process understanding (PATGuidance)A process is generally considered well understoodwhen (1) all critical sources of variability are identified and explained; (2) variability is managed by the process; and, (3) product quality attributes can be accurately and reliablypredicted over the design space established for materials used,process parameters, manufacturing, environmental, and otherconditions.The ability to predict reflects a high degree ofprocess understanding. Although retrospective process capability data are indicative ofa state of control, these alone may be insufficient to gauge orcommunicate process understanding.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf 5/25/201230