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Pharmaceutical 6 Sigma and QbD May 2005 Ball State University

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Pharmaceutical product and process quality – what is the current “sigma”?
Challenges in moving towards “6-sigma” levels?
What are the steps necessary for the pharmaceutical continuous improvement journey in the 21st Century?

Published in: Design

Pharmaceutical 6 Sigma and QbD May 2005 Ball State University

  1. 1. Pharmaceutical 6-SigmaPharmaceutical 6-Sigma Quality by DesignQuality by Design Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D. Office of Pharmaceutical ScienceOffice of Pharmaceutical Science CDER FDACDER FDA The 28The 28thth Annual Midwest Biopharmaceutical Statistical WorkshopAnnual Midwest Biopharmaceutical Statistical Workshop May 23-25, 2005 * Ball State University, Muncie, INMay 23-25, 2005 * Ball State University, Muncie, IN
  2. 2. OutlineOutline • Background & TerminologyBackground & Terminology • Pharmaceutical product and processPharmaceutical product and process quality – what is the current “sigma”?quality – what is the current “sigma”? • Challenges in moving towards “6-sigma”Challenges in moving towards “6-sigma” levels?levels? • What are the steps necessary for theWhat are the steps necessary for the pharmaceutical continuous improvementpharmaceutical continuous improvement journey in the 21journey in the 21stst Century?Century?
  3. 3. Remembering a few Guru’s ofRemembering a few Guru’s of QualityQuality ““Failure of management to plan for the future andFailure of management to plan for the future and to foresee problems has brought about wasteto foresee problems has brought about waste of manpower, of materials, and of machine-time,of manpower, of materials, and of machine-time, all of which raise the manufacturer's costall of which raise the manufacturer's cost and price that the purchaser must pay.” - Demingand price that the purchaser must pay.” - Deming
  4. 4. Manufacturing ProcessManufacturing Process PerformancePerformance • A set of causes and conditions thatA set of causes and conditions that repeatedly come together to transformrepeatedly come together to transform inputs into outcomesinputs into outcomes – Inputs: Information, Materials, ....Inputs: Information, Materials, .... – Outcomes: Products, Information,…Outcomes: Products, Information,… • Quality characteristics of the outcomes areQuality characteristics of the outcomes are indicators of performanceindicators of performance – Will vary over time and location, and analysisWill vary over time and location, and analysis of this variation is generally a basis for actionof this variation is generally a basis for action Nolan and Provost. Quality Progress, May 1990
  5. 5. Decisions: Interpretation ofDecisions: Interpretation of variationvariation • Decisions are often based on interpretation ofDecisions are often based on interpretation of patterns of variationspatterns of variations – Indicative of a trend or of random variation (that isIndicative of a trend or of random variation (that is similar to what has been observed in the past)similar to what has been observed in the past) – Misinterpretation leads to lossesMisinterpretation leads to losses • Blaming people for problems beyond their controlBlaming people for problems beyond their control • Spending unnecessary resources investigating and/or takingSpending unnecessary resources investigating and/or taking actions to address perceived trends nothing has changedactions to address perceived trends nothing has changed • ““Crying wolf” too often may desensitize a quality system andCrying wolf” too often may desensitize a quality system and reduce its alert level to address a “real wolf” when one willreduce its alert level to address a “real wolf” when one will appearappear
  6. 6. Methods to Manage Variation: AMethods to Manage Variation: A Historical PerspectiveHistorical Perspective 5000 BC 1800 AD 1924 Fitness for Use Specifications & Tolerances Control Chart Interchangeability of parts Provost and Norman. Quality Progress December 1990
  7. 7. Shewhart’s Common & SpecialShewhart’s Common & Special Causes of VariationCauses of Variation • Common causes of variation are inherently partCommon causes of variation are inherently part of the process (or system) all the time and affectof the process (or system) all the time and affect every one working in the systemevery one working in the system • Special causes are those that arise because ofSpecial causes are those that arise because of specific circumstances, i.e., not present all of thespecific circumstances, i.e., not present all of the time and do not affect every one working in thetime and do not affect every one working in the systemsystem • A “Control Chart” is a tool to distinguish betweenA “Control Chart” is a tool to distinguish between the two typesthe two types Nolan and Provost. Quality Progress, May 1990
  8. 8. Stable and Unstable ProcessStable and Unstable Process • A process (or a system) that has only commonA process (or a system) that has only common cause affecting the outcomes is called a stablecause affecting the outcomes is called a stable process (in a state of statistical control)process (in a state of statistical control) – When such a process is demonstrated to meet itsWhen such a process is demonstrated to meet its intended function, variation in such a system areintended function, variation in such a system are acceptableacceptable • When both common and special cause affectWhen both common and special cause affect the outcomes – Unstable process (magnitude ofthe outcomes – Unstable process (magnitude of variation from one time period to the next isvariation from one time period to the next is unpredictable)unpredictable) Nolan and Provost. Quality Progress, May 1990
  9. 9. Stable and Unstable ProcessStable and Unstable Process Stable & CapableStable & Capable UnstableUnstable
  10. 10. Benefits of a Stable ProcessBenefits of a Stable Process (Deming)(Deming) • The process has an identity; its performance isThe process has an identity; its performance is predictablepredictable – Rational basis for planning leading to the concept ofRational basis for planning leading to the concept of “just in time manufacturing”“just in time manufacturing” • Cost of quality is predictable - Productivity is at aCost of quality is predictable - Productivity is at a maximum and costs at a minimum for a givemaximum and costs at a minimum for a give systemsystem • The effect of changes in the process can beThe effect of changes in the process can be measured with greater speed and reliabilitymeasured with greater speed and reliability – In an unstable system it is difficult to separate changesIn an unstable system it is difficult to separate changes to the process from special causes. Therefore, it isto the process from special causes. Therefore, it is difficult to know when a change results in improvementdifficult to know when a change results in improvement Nolan and Provost. Quality Progress, May 1990
  11. 11. Cost of Quality (Taguchi)Cost of Quality (Taguchi)
  12. 12. ““Six Sigma”Six Sigma” A 3σ process - because 3 standard deviations fit between target and acceptance goalposts TargetTarget CustomerCustomer SpecificationSpecification 1σ 2σ 3σ 33σσ Before TargetTarget CustomerCustomer SpecificationSpecification After 1σ 3σ 6σ 6σ Continuous improvement:Continuous improvement: By reducing variabilityBy reducing variability we improve the processwe improve the process ““Design forDesign for Six Sigma”Six Sigma” ““Defects ~ 66807 ppm”Defects ~ 66807 ppm” ““Defects ~ 3.4 ppm”Defects ~ 3.4 ppm”
  13. 13. Process Capability: Cp and CpkProcess Capability: Cp and Cpk • Cp does not take into account any non-Cp does not take into account any non- centering of the process relative to thecentering of the process relative to the specification limitsspecification limits • Cp = S/PCp = S/P • Cpk = (1-K)CpCpk = (1-K)Cp • K = [(D-X)/(X/2)] or [(X-D)/(S/2)]K = [(D-X)/(X/2)] or [(X-D)/(S/2)] – S = acceptance criteria width; P = processS = acceptance criteria width; P = process width (+/- 3width (+/- 3σ limits); D = design center; X =σ limits); D = design center; X = process averageprocess average
  14. 14. Process Capability & “Sigma”Process Capability & “Sigma” CpCp Sigma*Sigma* DefectDefect (OOS)(OOS) 0.670.67 ±± 22σσ 5%5% 1.01.0 ±± 33σσ 0.13%0.13% 1.331.33 ± 4σ± 4σ 60 ppm60 ppm 1.661.66 ± 5σ± 5σ 1 ppm1 ppm 2.02.0 ±± 66σσ 2 ppb2 ppb * Statistical σ; not the “Six Sigma” calculation (Bhote and Bohte, 2000)* Statistical σ; not the “Six Sigma” calculation (Bhote and Bohte, 2000)
  15. 15. What is ContinuousWhat is Continuous ImprovementImprovement • Two concepts that describe ContinuousTwo concepts that describe Continuous Improvement areImprovement are – KAIZEN (KAIZEN (Ky’ zen)Ky’ zen) a Japanese word is oftena Japanese word is often translated in the west as ongoing, continuoustranslated in the west as ongoing, continuous improvementimprovement – Evolutionary Operation (EVOP)Evolutionary Operation (EVOP) • It is distinguished from “innovation” andIt is distinguished from “innovation” and “corrective actions”“corrective actions”
  16. 16. Tablet core potency - blend segregation in the bin NIR in Production Elements necessary forElements necessary for Continuous ImprovementContinuous Improvement • Human resources are the mostHuman resources are the most important company assetimportant company asset • Processes must evolve by gradualProcesses must evolve by gradual improvement rather than radicalimprovement rather than radical changeschanges • Improvement must be based onImprovement must be based on statistical/quantitative evaluation ofstatistical/quantitative evaluation of process performanceprocess performance Slides from Norman Winskill and Steve Hammond FDA Science Board Nov. 2001 ProbabilityofMeetingCriteria, Total RSD, % 0 1 2 3 4 5 6 7 8 9 10 11 12 0 20 40 60 80 100 120 Need to recognize the underlying operating characteristics of our specifications
  17. 17. Quality System Requirements QS-9000Quality System Requirements QS-9000 Third Edition element 4.2.5—Third Edition element 4.2.5— Continuous Improvement (1998).Continuous Improvement (1998). • For those product characteristics and process parameters thatFor those product characteristics and process parameters that can be evaluated using variable data, continuouscan be evaluated using variable data, continuous improvement means optimizing the characteristics andimprovement means optimizing the characteristics and parameters at aparameters at a target value and reducing variation aroundtarget value and reducing variation around the valuethe value.. • For those product characteristics and process parameters thatFor those product characteristics and process parameters that can only be evaluated using attribute data, continuouscan only be evaluated using attribute data, continuous improvement is not possible until characteristics areimprovement is not possible until characteristics are conforming.conforming. – If attribute data results do not equal zero defects, it is by definitionIf attribute data results do not equal zero defects, it is by definition nonconforming product. Improvements made in these situations arenonconforming product. Improvements made in these situations are definition corrective actions, not continuous improvement.definition corrective actions, not continuous improvement. • Continuous improvement [shall be undertaken] in processesContinuous improvement [shall be undertaken] in processes that have demonstrated stability, acceptable capability andthat have demonstrated stability, acceptable capability and performanceperformance..
  18. 18. What is the currentWhat is the current pharmaceutical “sigma” value?pharmaceutical “sigma” value? • How should we define pharmaceutical “sigma”?How should we define pharmaceutical “sigma”? – Product qualityProduct quality • % of units in a batch outside the regulatory or compendial% of units in a batch outside the regulatory or compendial acceptance criteriaacceptance criteria • % of batches recalled% of batches recalled – Process qualityProcess quality • % of batches rejected% of batches rejected • % of batches “right 2% of batches “right 2ndnd or 3or 3rdrd time”time” • What is the minimum regulatory “sigma” value?What is the minimum regulatory “sigma” value? – One interpretation: “A process is no longer consideredOne interpretation: “A process is no longer considered validated when the recall rate exceeds 10%”?validated when the recall rate exceeds 10%”?
  19. 19. What is the currentWhat is the current pharmaceutical “sigma” value?pharmaceutical “sigma” value? Process Quality at about “2Process Quality at about “2σ”?σ”? Product Quality > “5Product Quality > “5σ”?σ”? If so, are we not trapped in a “corrective action crisis”If so, are we not trapped in a “corrective action crisis” and also wasting lot of resources?and also wasting lot of resources? For many products and processes:For many products and processes:
  20. 20. Pharmaceutical “Customer”Pharmaceutical “Customer” SpecificationsSpecifications • Often combine attribute (no unit outside..)Often combine attribute (no unit outside..) and continuous variable (RSD) in qualityand continuous variable (RSD) in quality decision processdecision process • For example: Dose Content UniformityFor example: Dose Content Uniformity – Upper Specification Limit = 125%Upper Specification Limit = 125% – Lower Specification Limit = 75%Lower Specification Limit = 75% – Standard Deviation not to exceed 7.8%Standard Deviation not to exceed 7.8% – Test sample size 30Test sample size 30 – ““No unit in 30 is outside 75-125%”No unit in 30 is outside 75-125%”
  21. 21. Process Capability andProcess Capability and VariabilityVariability • Without the “attribute” criterionWithout the “attribute” criterion – Assuming aAssuming a stable processstable process; normal; normal distributiondistribution – Mean = 100%, %RSD = 7.8%, n=30Mean = 100%, %RSD = 7.8%, n=30 • Cp=Cpk = 1.07 andCp=Cpk = 1.07 and • ~ “3~ “3σ” processσ” process – Standard Deviation = 2.0%Standard Deviation = 2.0% • Cp=Cpk = 4.17Cp=Cpk = 4.17 • >”6>”6σ” processσ” process
  22. 22. Combined CriteriaCombined Criteria PQRI Blend Uniformity Working Group Report > 40% can be rejected ~ 10% can be rejected “σ < 2”
  23. 23. Other ChallengesOther Challenges Difficult questions faced byDifficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators…… •• IfIf we chose to use a calibrator tablet for awe chose to use a calibrator tablet for a Gauge R&R study....Gauge R&R study.... •• σσ22 (Total for Calib.)(Total for Calib.) •• == σσ22 (Calib.)(Calib.) ++ σσ22 C* MeasurementC*Measurement •• What is the measurement for the Calibrator and whatWhat is the measurement for the Calibrator and what is its variability?is its variability? σσ22 (C* Measurement)(C* Measurement) •• SinceSince σσ22 (Calib.)(Calib.) is not known; we have to useis not known; we have to use σσ22 (Total for(Total for Calib.)Calib.) •• σσ22 Total for ProductTotal for Product == σσ22 ProductProduct ++ σσ22 Total for Calib.Total for Calib. Hussain, A.S. Biopharmaceutics and Drug Product Quality:Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance TestsPerformance Tests for Drug Products, A Look Into the Future.for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004
  24. 24. Difficult questions faced byDifficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators…… •• Assumption of independent variable?Assumption of independent variable? •• Another aspectAnother aspect –– is the measurement capability for ais the measurement capability for a Calibrator tablet representative of the drug product?Calibrator tablet representative of the drug product? What if there are differences such as disintegrationWhat if there are differences such as disintegration mechanism and buoyancy between the Calibrator andmechanism and buoyancy between the Calibrator and the drug product?the drug product? Other ChallengesOther Challenges Hussain, A.S. Biopharmaceutics and Drug Product Quality:Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance TestsPerformance Tests for Drug Products, A Look Into the Future.for Drug Products, A Look Into the Future. USP Annual Scientific Meeting "The Science of Quality“. September 26–30, 2004
  25. 25. Other ChallengesOther Challenges • ““Root cause unknown”Root cause unknown” – Common cause Vs. Special Cause?Common cause Vs. Special Cause? – The Common cause trapThe Common cause trap • ““Zero tolerance” (e.g., OOS during stability testing – when isZero tolerance” (e.g., OOS during stability testing – when is this simply a sample size issue?)this simply a sample size issue?) • Confounded metrics (e.g., dissolution Q values instead of aConfounded metrics (e.g., dissolution Q values instead of a “rate” metric - % label amount confounded with content“rate” metric - % label amount confounded with content uniformity)uniformity) • Our decision system for mass production isOur decision system for mass production is based on a “compounding pharmacy” modelbased on a “compounding pharmacy” model – Mind set – we are not learning from other sectorsMind set – we are not learning from other sectors
  26. 26. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf
  27. 27. Pharmaceutical Challenges inPharmaceutical Challenges in moving towards 6 Sigma?moving towards 6 Sigma? • Are we measuring the “right” characteristics?Are we measuring the “right” characteristics? • Are our measurement systems capable?Are our measurement systems capable? • Are we establishing the “right” acceptance criteria for theAre we establishing the “right” acceptance criteria for the clinical trial product?clinical trial product? • The process is “approved” and “validated” – why bother?The process is “approved” and “validated” – why bother? • Zero defect mindset – better not to know the “sigma”?Zero defect mindset – better not to know the “sigma”? • Reducing variability can result in a change in regulatoryReducing variability can result in a change in regulatory acceptance criteria to keep the system at a low “sigma”acceptance criteria to keep the system at a low “sigma” value – how else would you know if your quality systemvalue – how else would you know if your quality system is working?is working? For some products we may already be at Six Sigma,For some products we may already be at Six Sigma, but we may not be able to prove it?but we may not be able to prove it?
  28. 28. The Pharmaceutical Quality:The Pharmaceutical Quality: Challenges and OpportunitiesChallenges and Opportunities Quality – Clinical Gap! CMC & CGMP Commitments* CMC – CGMP Gap* “Market Failure”! “Corrective Actions” the only * leverage for continuous improvement Specification – Capability Gap* *Opportunity for continuous improvement* Challenges to overcome! http://www.ge.com/sixsigma/SixSigma.pdf
  29. 29. What are the stepsWhat are the steps necessary for thenecessary for the pharmaceutical continuouspharmaceutical continuous improvement journey in theimprovement journey in the 2121stst Century?Century?
  30. 30. DFSS & Six SigmaDFSS & Six Sigma
  31. 31. DFSSDFSS Six SigmaSix Sigma
  32. 32. The Goal and Characteristics ofThe Goal and Characteristics of Pharmaceutical Quality Decision SystemPharmaceutical Quality Decision System • ““TheThe quality of drug substances andquality of drug substances and drug productsdrug products is determined by theiris determined by their design, development, in-processdesign, development, in-process controls, GMP controls, processcontrols, GMP controls, process validation, and by specificationsvalidation, and by specifications applied to themapplied to them throughoutthroughout development and manufacturedevelopment and manufacture.”.” Characteristics Goal Life-cycle ICH Q6AICH Q6A
  33. 33. What is the ICH Q8 Opportunity?What is the ICH Q8 Opportunity? Specifications In process controls Development Design Process validation GMP Controls ICH Q6AICH Q6A Decision CharacteristicsDecision Characteristics “…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.”
  34. 34. Steps NecessarySteps Necessary • Ask the “right questions”Ask the “right questions” – Begin with end in mind – Intended useBegin with end in mind – Intended use • System based (connecting the key disciplinesSystem based (connecting the key disciplines and regulatory submission sections)and regulatory submission sections) • Facilitate structured product developmentFacilitate structured product development process, yet not dictate a specific processprocess, yet not dictate a specific process • Leverage pre-approval changes & “bridgingLeverage pre-approval changes & “bridging studies”studies” • Cumulative – and support use prior knowledgeCumulative – and support use prior knowledge • Scientific hypothesis formatScientific hypothesis format
  35. 35. Constructing and JustifyingConstructing and Justifying “Design Space”“Design Space” • Build on “minimal” expectations such asBuild on “minimal” expectations such as stability, bioavailability, and otherstability, bioavailability, and other performance assessment to “test ofperformance assessment to “test of hypothesis”hypothesis” • Scientific risk assessmentScientific risk assessment • Opportunity to demonstrate the level of processOpportunity to demonstrate the level of process understanding and reliability of proposed “designunderstanding and reliability of proposed “design space”space”
  36. 36. Steps NecessarySteps Necessary • Routine productionRoutine production – Process control – stable process in a state of controlProcess control – stable process in a state of control • Control charts of variables (not attributes)Control charts of variables (not attributes) – Target value +/- Upper and Lower LimitsTarget value +/- Upper and Lower Limits – Process capability analysisProcess capability analysis – Not “hypothesis testing” on every lotNot “hypothesis testing” on every lot • Specification and Process ValidationSpecification and Process Validation – Hypothesis testingHypothesis testing – Parametric or non parametric tolerance intervalParametric or non parametric tolerance interval – No penalty for higher sample sizeNo penalty for higher sample size – Continuous quality verificationContinuous quality verification
  37. 37. Specifications, Standards andSpecifications, Standards and Control LimitsControl Limits • Specification =Specification = StandardStandard – Non-conformanceNon-conformance rejection or recallrejection or recall • Control limitControl limit – Target valueTarget value – Common causeCommon cause variabilityvariability • Alert limitAlert limit – Potential “SpecialPotential “Special cause” – investigate,cause” – investigate, take necessary actiontake necessary action to prevent OOSto prevent OOS If, Specification = StandardsIf, Specification = Standards (no room for risk based decision)(no room for risk based decision) Control LimitControl Limit Alert LimitAlert Limit
  38. 38. Scope of the ProposedScope of the Proposed Guideline (ICH Q10)Guideline (ICH Q10) • Comprehensive quality system for productComprehensive quality system for product life cycle thatlife cycle that – Complements existing GMP’sComplements existing GMP’s – Focuses on those elements that facilitateFocuses on those elements that facilitate application of ICH Quality Guidelines (e.g.,application of ICH Quality Guidelines (e.g., ICH Q8), andICH Q8), and – Facilitates continuous improvement inFacilitates continuous improvement in pharmaceutical manufacturingpharmaceutical manufacturing
  39. 39. Proposed GuidelineProposed Guideline • The starting point for a harmonizedThe starting point for a harmonized pharmaceutical quality system (QS) will be ISOpharmaceutical quality system (QS) will be ISO 9000 standards9000 standards • Key ConsiderationsKey Considerations – The pharmaceutical context of elements that defineThe pharmaceutical context of elements that define the QS framework will be explainedthe QS framework will be explained – Elements of the QS that link to science will beElements of the QS that link to science will be identified and enhancedidentified and enhanced • for achieving the integrated systems approach to qualityfor achieving the integrated systems approach to quality emphasized in the ICH visionemphasized in the ICH vision • to facilitate continuous improvement over a product life cycleto facilitate continuous improvement over a product life cycle
  40. 40. Goals & CharacteristicsGoals & Characteristics • Product quality andProduct quality and performance achieved andperformance achieved and assured by design of effectiveassured by design of effective and efficient manufacturingand efficient manufacturing processesprocesses • Product specifications basedProduct specifications based on mechanistic understandingon mechanistic understanding of how formulation andof how formulation and process factors impactprocess factors impact product performanceproduct performance • An ability to effect continuousAn ability to effect continuous improvement and continuousimprovement and continuous "real time" assurance of"real time" assurance of qualityquality • Develop effective CAPA –Develop effective CAPA – eliminate “special cause”eliminate “special cause” variabilityvariability • Utilize Process capability analysisUtilize Process capability analysis – reduce/control “common cause”– reduce/control “common cause” variabilityvariability • Identify, understand and acquireIdentify, understand and acquire ability to predict critical to qualityability to predict critical to quality attributes (CQA)attributes (CQA) (product/process/measurement)(product/process/measurement) • Focus on the “critical few”Focus on the “critical few” • Establish CQA target values andEstablish CQA target values and acceptable variability around theacceptable variability around the target valuetarget value • Utilize a monitoring system thatUtilize a monitoring system that demonstrates “state of control”demonstrates “state of control” preferably based on criticalpreferably based on critical material attributes (not just endmaterial attributes (not just end product testing)product testing)
  41. 41. SummarySummary • Background & TerminologyBackground & Terminology • Pharmaceutical product and processPharmaceutical product and process quality – what is the current “sigma”?quality – what is the current “sigma”? • Challenges in moving towards “6-sigma”Challenges in moving towards “6-sigma” levels?levels? • What are the steps necessary for theWhat are the steps necessary for the pharmaceutical continuous improvementpharmaceutical continuous improvement journey in the 21journey in the 21stst Century?Century?

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