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?

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. 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. 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. 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. 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. 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. 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. 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. Stable and Unstable ProcessStable and Unstable Process
Stable & CapableStable & Capable UnstableUnstable

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. Cost of Quality (Taguchi)Cost of Quality (Taguchi)

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Combined CriteriaCombined Criteria
PQRI Blend Uniformity Working Group Report
> 40% can be rejected
~ 10% can be rejected
“σ < 2”

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. 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. 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. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

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. 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. 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. DFSS & Six SigmaDFSS & Six Sigma

31. DFSSDFSS
Six SigmaSix Sigma

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. 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. 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. 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. 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. 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. 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. 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. 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. 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?