Pharmaceutical 6-Sigma Pharmaceutical 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 Workshop Annual Midwest Biopharmaceutical Statistical WorkshopMay 23-25, 2005 * Ball State University, Muncie, INMay 23-25, 2005 * Ball State University, Muncie, IN

OutlineOutline

• Background & TerminologyBackground & Terminology

• Pharmaceutical product and process Pharmaceutical 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 the What are the steps necessary for the pharmaceutical continuous improvement pharmaceutical continuous improvement journey in the 21journey in the 21stst Century? Century?

Remembering a few Guru’s of Remembering a few Guru’s of QualityQuality

““Failure of management to plan for the future and Failure 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 cost all of which raise the manufacturer's cost and price that the purchaser must pay.” - Deming and price that the purchaser must pay.” - Deming

Manufacturing Process Manufacturing Process PerformancePerformance

• A set of causes and conditions that A set of causes and conditions that repeatedly come together to transform repeatedly 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 are Quality characteristics of the outcomes are indicators of performanceindicators of performance– Will vary over time and location, and analysis Will 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

Decisions: Interpretation of Decisions: Interpretation of variationvariation

• Decisions are often based on interpretation of Decisions are often based on interpretation of patterns of variationspatterns of variations– Indicative of a trend or of random variation (that is Indicative 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 taking Spending 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 and Crying wolf” too often may desensitize a quality system and

reduce its alert level to address a “real wolf” when one will reduce its alert level to address a “real wolf” when one will appear appear

Methods to Manage Variation: A Methods to Manage Variation: A Historical PerspectiveHistorical Perspective

5000 BC 1800 AD 1924

Fitness for Use

Specifications &

Tolerances

ControlChart

Interchangeability of parts

Provost and Norman. Quality Progress December 1990

Shewhart’s Common & Special Shewhart’s Common & Special Causes of VariationCauses of Variation

• Common causes of variation are inherently part Common causes of variation are inherently part of the process (or system) all the time and affect of 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 of Special causes are those that arise because of specific circumstances, i.e., not present all of the specific circumstances, i.e., not present all of the time and do not affect every one working in the time and do not affect every one working in the systemsystem

• A “Control Chart” is a tool to distinguish between A “Control Chart” is a tool to distinguish between the two types the two types

Nolan and Provost. Quality Progress, May 1990

Stable and Unstable ProcessStable and Unstable Process

• A process (or a system) that has only common A process (or a system) that has only common cause affecting the outcomes is called a stable cause 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 its When such a process is demonstrated to meet its

intended function, variation in such a system are intended function, variation in such a system are acceptableacceptable

• When both common and special cause affect the When both common and special cause affect the outcomes – Unstable process (magnitude of outcomes – Unstable process (magnitude of variation from one time period to the next is variation from one time period to the next is unpredictable)unpredictable)

Nolan and Provost. Quality Progress, May 1990

Stable and Unstable ProcessStable and Unstable Process

Stable & CapableStable & Capable UnstableUnstable

Benefits of a Stable Process (Deming) Benefits of a Stable Process (Deming)

• The process has an identity; its performance is The process has an identity; its performance is predictablepredictable– Rational basis for planning leading to the concept of “just Rational basis for planning leading to the concept of “just

in time manufacturing”in time manufacturing”

• Cost of quality is predictable - Productivity is at a Cost of quality is predictable - Productivity is at a maximum and costs at a minimum for a give maximum and costs at a minimum for a give systemsystem

• The effect of changes in the process can be The 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 changes to In an unstable system it is difficult to separate changes to

the process from special causes. Therefore, it is difficult the process from special causes. Therefore, it is difficult to know when a change results in improvementto know when a change results in improvement

Nolan and Provost. Quality Progress, May 1990

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

““Six Sigma”Six Sigma”A 3 process - because 3 standard deviations fit between target and

acceptance goalposts

TargetTarget CustomerCustomerSpecificationSpecification

1

2

3

33

Before

TargetTargetCustomerCustomer

SpecificationSpecification

After

13

6

6

Continuous improvement:Continuous improvement:By reducing variabilityBy reducing variability

we improve the processwe improve the process

““Design for Design for Six Sigma”Six Sigma”

““Defects ~ 66807 ppm”Defects ~ 66807 ppm”

““Defects ~ 3.4 ppm”Defects ~ 3.4 ppm”

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 the centering 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 = process S = acceptance criteria width; P = process width (+/- 3width (+/- 3σσ limits); D = design center; X = limits); D = design center; X = process averageprocess average

Process Capability & “Sigma”Process Capability & “Sigma”

CpCp Sigma*Sigma* Defect Defect (OOS)(OOS)

0.670.67 ± ± 22σσ 5%5%

1.01.0 ± ± 33σσ 0.13%0.13%

1.331.33 ± 4± 4σσ 60 ppm60 ppm

1.661.66 ± 5± 5σσ 1 ppm1 ppm

2.02.0 ± ± 66σσ 2 ppb2 ppb

* Statistical * Statistical σσ; not the “Six Sigma” calculation (Bhote and Bohte, 2000); not the “Six Sigma” calculation (Bhote and Bohte, 2000)

What is Continuous What is Continuous ImprovementImprovement• Two concepts that describe Two concepts that describe

Continuous Improvement are Continuous Improvement are – KAIZEN (KAIZEN (Ky’ zen)Ky’ zen) a Japanese word is a Japanese word is

often translated in the west as ongoing, often translated in the west as ongoing, continuous improvementcontinuous improvement

– Evolutionary Operation (EVOP)Evolutionary Operation (EVOP)

• It is distinguished from “innovation” It is distinguished from “innovation” and “corrective actions”and “corrective actions”

Tablet core potency - blend segregation in the bin

NIR in Production

Elements necessary for Elements necessary for Continuous ImprovementContinuous Improvement• Human resources are the most Human resources are the most

important company asset important company asset • Processes must evolve by Processes must evolve by

gradual improvement rather gradual improvement rather than radical changes than radical changes

• Improvement must be based on Improvement must be based on statistical/quantitative statistical/quantitative evaluation of process evaluation of process performanceperformance

Slides from Norman Winskill and Steve HammondFDA Science Board Nov. 2001

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Total RSD, %0 1 2 3 4 5 6 7 8 9 10 11 12

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Need to recognize the underlyingoperating characteristics of our specifications

Quality System Requirements QS-9000Quality System Requirements QS-9000Third Edition element 4.2.5—Continuous Third Edition element 4.2.5—Continuous Improvement (1998).Improvement (1998).

• For those product characteristics and process parameters that For those product characteristics and process parameters that can be evaluated using variable data, continuous improvement can be evaluated using variable data, continuous improvement means optimizing the characteristics and parameters at a means optimizing the characteristics and parameters at a target target value and reducing variation around the valuevalue and reducing variation around the value. .

• For those product characteristics and process parameters that For those product characteristics and process parameters that can only be evaluated using attribute data, continuous can only be evaluated using attribute data, continuous improvement is not possible until characteristics are conforming. improvement is not possible until characteristics are conforming. – If attribute data results do not equal zero defects, it is by definition If attribute data results do not equal zero defects, it is by definition

nonconforming product. Improvements made in these situations are nonconforming 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 processes Continuous improvement [shall be undertaken] in processes that have demonstrated stability, acceptable capability and that have demonstrated stability, acceptable capability and performanceperformance..

What is the current What 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 3 or 3rdrd time” time”

• What is the minimum regulatory “sigma” value?What is the minimum regulatory “sigma” value?– One interpretation: “A process is no longer considered One interpretation: “A process is no longer considered

validated when the recall rate exceeds 10%”?validated when the recall rate exceeds 10%”?

What is the current What is the current pharmaceutical “sigma” value?pharmaceutical “sigma” value?

Process Quality at about “2Process Quality at about “2σσ”?”?

Product Quality > “5Product Quality > “5σσ”?”?

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:

Pharmaceutical “Customer” Pharmaceutical “Customer” SpecificationsSpecifications

• Often combine attribute (no unit outside..) Often combine attribute (no unit outside..) and continuous variable (RSD) in quality and 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%”

Process Capability and VariabilityProcess Capability and Variability

• Without the “attribute” criterionWithout the “attribute” criterion– Assuming a Assuming a stable processstable process; normal ; normal

distributiondistribution– Mean = 100%, %RSD = 7.8%, n=30Mean = 100%, %RSD = 7.8%, n=30

• Cp=Cpk = 1.07 and Cp=Cpk = 1.07 and • ~ “3~ “3σσ” process” process

– Standard Deviation = 2.0%Standard Deviation = 2.0%• Cp=Cpk = 4.17Cp=Cpk = 4.17• >”6>”6σσ” process” process

Combined CriteriaCombined Criteria

PQRI Blend Uniformity Working Group Report

> 40% can be rejected

~ 10% can be rejected“σ < 2”

Other ChallengesOther Challenges

Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• IfIf we chose to use a calibrator tablet for a we 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 what What is the measurement for the Calibrator and what is its variability?is its variability? σσ22

(C*Measurement)(C*Measurement)

•• Since Since σσ22(Calib.)(Calib.) is not known; we have to use is not known; we have to use σσ22

(Total for (Total for Calib.)Calib.)

•• σσ22Total for ProductTotal for Product = = σσ22

ProductProduct + + σσ22Total for Calib.Total for Calib.

Hussain, A.S. Biopharmaceutics and Drug Product Quality:Hussain, A.S. Biopharmaceutics and Drug Product Quality: Performance Tests Performance 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

Difficult questions faced by Difficult questions faced by Manufacturing Groups and RegulatorsManufacturing Groups and Regulators……•• Assumption of independent variable?Assumption of independent variable?

•• Another aspect Another aspect –– is the measurement capability for a is 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 disintegration What if there are differences such as disintegration mechanism and buoyancy between the Calibrator and mechanism 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 Tests Performance 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

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 is Zero 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 a Confounded 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 is Our 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

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

Pharmaceutical Challenges in Pharmaceutical 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 the Are 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 regulatory Reducing 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 system value – 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?

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

What are the steps necessary What are the steps necessary for the pharmaceutical for the pharmaceutical continuous improvement continuous improvement journey in the 21journey in the 21stst Century? Century?

DFSS & Six SigmaDFSS & Six Sigma

DFSSDFSSSix SigmaSix Sigma

The Goal and Characteristics of The Goal and Characteristics of Pharmaceutical Quality Decision SystemPharmaceutical Quality Decision System

• ““The The quality of drug substances and quality of drug substances and drug productsdrug products is determined by their is determined by their design, development, in-process design, development, in-process controls, GMP controls, process controls, GMP controls, process validation, and by specificationsvalidation, and by specifications applied to them applied to them throughout throughout development and manufacturedevelopment and manufacture.”.”

Characteristics

Goal

Life-cycle

ICH Q6AICH Q6A

What is the ICH Q8 Opportunity?What is the ICH Q8 Opportunity?

Specifications

In process controls

Development

Design

Process validation

GMP Controls

ICH Q6A ICH Q6A Decision CharacteristicsDecision Characteristics

“…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.”

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 disciplines System based (connecting the key disciplines and regulatory submission sections)and regulatory submission sections)

• Facilitate structured product development Facilitate structured product development process, yet not dictate a specific processprocess, yet not dictate a specific process

• Leverage pre-approval changes & “bridging Leverage pre-approval changes & “bridging studies”studies”

• Cumulative – and support use prior knowledge Cumulative – and support use prior knowledge • Scientific hypothesis format Scientific hypothesis format

Constructing and Justifying Constructing and Justifying “Design Space”“Design Space”

• Build on “minimal” expectations such as Build on “minimal” expectations such as stability, bioavailability, and other stability, bioavailability, and other performance assessment to “test of performance assessment to “test of hypothesis”hypothesis”

• Scientific risk assessmentScientific risk assessment• Opportunity to demonstrate the level of process Opportunity to demonstrate the level of process

understanding and reliability of proposed “design understanding and reliability of proposed “design space” space”

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 Validation Specification 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

Specifications, Standards and Specifications, Standards and Control LimitsControl Limits• Specification = Specification =

StandardStandard– Non-conformance Non-conformance

rejection or recallrejection or recall• Control limitControl limit

– Target valueTarget value– Common cause Common cause

variabilityvariability• Alert limitAlert limit

– Potential “Special Potential “Special cause” – investigate, cause” – investigate, take necessary action take necessary action to prevent OOS to prevent OOS

If, Specification = StandardsIf, Specification = Standards(no room for risk based decision)(no room for risk based decision)

Control LimitControl LimitAlert LimitAlert Limit

Scope of the Proposed Guideline Scope of the Proposed Guideline (ICH Q10) (ICH Q10)

• Comprehensive quality system for product Comprehensive quality system for product life cycle that life cycle that – Complements existing GMP’s Complements existing GMP’s – Focuses on those elements that facilitate Focuses on those elements that facilitate

application of ICH Quality Guidelines (e.g., application of ICH Quality Guidelines (e.g., ICH Q8), and ICH Q8), and

– Facilitates continuous improvement in Facilitates continuous improvement in pharmaceutical manufacturing pharmaceutical manufacturing

Proposed GuidelineProposed Guideline

• The starting point for a harmonized The starting point for a harmonized pharmaceutical quality system (QS) will be ISO pharmaceutical quality system (QS) will be ISO 9000 standards9000 standards

• Key ConsiderationsKey Considerations– The pharmaceutical context of elements that define The 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 be Elements of the QS that link to science will be

identified and enhanced identified and enhanced • for achieving the integrated systems approach to quality for achieving the integrated systems approach to quality

emphasized in the ICH vision emphasized in the ICH vision • to facilitate continuous improvement over a product life cycle to facilitate continuous improvement over a product life cycle

Goals & CharacteristicsGoals & Characteristics• Product quality and Product quality and

performance achieved and performance achieved and assured by design of effective assured by design of effective and efficient manufacturing and efficient manufacturing processesprocesses

• Product specifications based Product specifications based on mechanistic understanding on mechanistic understanding of how formulation and of how formulation and process factors impact process factors impact product performanceproduct performance

• An ability to effect continuous An ability to effect continuous improvement and continuous improvement and continuous "real time" assurance of "real time" assurance of qualityquality

• Develop effective CAPA – eliminate Develop effective CAPA – eliminate “special cause” variability“special cause” variability

• Utilize Process capability analysis – Utilize Process capability analysis – reduce/control “common cause” reduce/control “common cause” variabilityvariability

• Identify, understand and acquire Identify, understand and acquire ability to predict critical to quality ability 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 and Establish CQA target values and acceptable variability around the acceptable variability around the target valuetarget value

• Utilize a monitoring system that Utilize a monitoring system that demonstrates “state of control” demonstrates “state of control” preferably based on critical material preferably based on critical material attributes (not just end product attributes (not just end product testing)testing)

SummarySummary

• Background & TerminologyBackground & Terminology

• Pharmaceutical product and process Pharmaceutical 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 the What are the steps necessary for the pharmaceutical continuous improvement pharmaceutical continuous improvement journey in the 21journey in the 21stst Century? Century?