Understanding the Philosophy of QbD

Understanding the Understanding the Philosophy ofPhilosophy of

QualityQuality by Design by Design (QbD)(QbD)

Tom SamGlobal Regulatory CMC

Organon, part of Schering-Plough Corporation

What is Quality?What is Quality?

Quality

Patient(or surrogate)

Target ProductQuality Profile

Requirements= need or

expectations

“Good pharmaceutical quality represents an acceptably low risk of failing to achieve

the desired clinical attributes.”

Which quality Which quality do we accept for ourdo we accept for our

medicines ?medicines ?E.g. in terms of E.g. in terms of

number of defects?number of defects?

0,01

0,1

1

10

100

1000

10000

100000

1000000DPMO(defectspermillionopportunities)

2σ 3σ 4σ 5σ 6σ 7σ

Best-in-class

Airlines baggagecheck in

Restaurant bills

Lufthansa (6,6σ)

Quantas, SAS

Air India(5,8)Egypt Air (5,8σ)

Source: Motorola, Air Safety Online

Which quality do we acceptWhich quality do we acceptfor the manufacture for the manufacture of our medicines ? of our medicines ?

0,01

0,1

1

10

100

1000

10000

100000

1000000DPMO(defectspermillionopportunities)

2σ 3σ 4σ 5σ 6σ 7σ

Best-in-class

Airlines baggagecheck in

Restaurant bills

Lufthansa (6,6σ)

Quantas, SAS

Air India(5,8)Egypt Air (5,8σ)

Source: Motorola, Air Safety Online

With which quality do we With which quality do we manufacture our medicines: 6manufacture our medicines: 6σσ, ,

55σσ, , 44σσ, , 33σσ, , 22σσ ? ?

Current Mfg

Quality provided

to patients

?

How do we fill this quality gapHow do we fill this quality gapin the pharmaceutical industry?in the pharmaceutical industry?

SigmaSigma ppm Defectsppm Defects YieldYield

22σσ33σσ44σσ55σσ66σσ

308,537308,53766,80766,8076,2106,210

2332333.43.4

69.2%69.2%93.3%93.3%99.4%99.4%99.98%99.98%99.99966%99.99966%

Cost of QualityCost of Quality25-35%25-35%20-25%20-25%12-18%12-18%4-8%4-8%1-3%1-3%

Current Mfg

Quality providedto patients

Data from: Dr. Doug Dean & Frances Data from: Dr. Doug Dean & Frances BruttinBruttinPriceWaterhouseCoopersPriceWaterhouseCoopers

…………by testing !!!!by testing !!!!

The quality mantraThe quality mantra

““Quality can not be tested into Quality can not be tested into

products; it has to be built in by products; it has to be built in by

designdesign””

Our Quality gurusOur Quality gurus

““It is not necessary It is not necessary to change. Survival is to change. Survival is not mandatory.not mandatory.””We should We should work on our work on our processes, processes, not the not the outcome of outcome of our processes. our processes.

Conclusion Conclusion

The pharmaceutical The pharmaceutical industry has to change its industry has to change its

manufacturingmanufacturing

Paradigm shift in pharmaceutical Paradigm shift in pharmaceutical manufacturingmanufacturing

Quality by Testing and Inspection

Enhanced• product knowledge• process understanding

Quality by Designquality assured by a well designed product & process

Quality by Testing and Quality by Testing and InspectionInspection

end testingtesting

Static “black box process” in a stringent regulatory environment

Manufacturing:

Control:

““Quality can not be tested into Quality can not be tested into products; it has to be built in by products; it has to be built in by

designdesign””

Quality by DesignQuality by Design

end testingcontrol

Dynamic “scientific” process in a flexible regulatory environment

Manufacturing:

Control Strategy:

Current Current SubmissionsSubmissionsFocus more on data and format and less on Focus more on data and format and less on critical analysis and scientific critical analysis and scientific justification/rationalejustification/rationaleContain voluminous data that is not always Contain voluminous data that is not always presented in a comprehensive or scientific presented in a comprehensive or scientific mannermannerOften contain insufficient pharmaceutical Often contain insufficient pharmaceutical development informationdevelopment informationConcentrate mostly on chemistry and product Concentrate mostly on chemistry and product specifications but less on manufacturing processspecifications but less on manufacturing processReflect apprehension on what to share with FDAReflect apprehension on what to share with FDA

Moheb Nasr, March 29, 2006

Focuses primarily on reproducibility rather Focuses primarily on reproducibility rather than robustnessthan robustnessTypically 3 consecutive batchesTypically 3 consecutive batches

Using the Using the ““bestbest”” operations, e.g., day shift operations, e.g., day shift Usually same lots of raw materialsUsually same lots of raw materialsDoes this ensure a Does this ensure a ““state of controlstate of control”” ? ?

Validation Validation ““freezesfreezes”” the process the process Most continuous improvement requires Most continuous improvement requires regulatory approval or notificationregulatory approval or notificationLow efficiency is locked in!Low efficiency is locked in!

Current Current Process ValidationProcess Validation


Pharmaceutical Manufacturing Pharmaceutical Manufacturing -- Cost of QualityCost of Quality

Direct costs: Direct costs: Rejects / failuresRejects / failures

Indirect costs:Indirect costs:Rework / reRework / re--teststestsCAPACAPA--systemsystemChange Control systemChange Control system…………

SigmaSigma ppm Defectsppm Defects YieldYield22σσ33σσ44σσ55σσ66σσ

308,537308,53766,80766,807

6,2106,2102332333.43.4

69.2%69.2%93.3%93.3%99.4%99.4%99.98%99.98%99.99966%99.99966%

Cost of QualityCost of Quality25-35%25-35%20-25%20-25%12-18%12-18%4-8%4-8%1-3%1-3%

Pharma-now

Pharma-future

Data from: Dr. Doug Dean & Frances Data from: Dr. Doug Dean & Frances BruttinBruttinPriceWaterhouseCoopersPriceWaterhouseCoopers

How to escape from 2 How to escape from 2 –– 3 3 σσ ??

Source: A. Hussain, ISPE Brussels, 2004

Sci

entif

ic u

nder

stan

ding

CORRELATIVE KNOWLEDGEWhat Is Correlated to What?

“CAUSAL" KNOWLEDGEWhat “Causes” What?

MECHANISTICKNOWLEDGE

How?

DESCRIPTIVE KNOWLEDGE: What?N

eed

for

regu

lato

ry o

vers

ight

Nee

d fo

r re

gula

tory

ove

rsig

ht Knowledge based decisions

Knowledge based decisions

Desired StateDesired State

Current StateCurrent State

We need more knowledge about our We need more knowledge about our products and processesproducts and processes

FirstPrinciples Why?

What is Quality by Design (QbD)?What is Quality by Design (QbD)?A systematic scientific A systematic scientific approach to product and approach to product and process design and development.process design and development.

TheThe product is designed to meet patient requirementsproduct is designed to meet patient requirements

TheThe process is designed to consistently meet product process is designed to consistently meet product critical quality attributescritical quality attributes

TheThe impact of starting materials and process impact of starting materials and process parameters on product quality is understoodparameters on product quality is understood

CriticalCritical sources of process variation are identified and sources of process variation are identified and controlledcontrolled

TheThe process is continually monitored and updated to process is continually monitored and updated to allow for consistent quality over timeallow for consistent quality over time


Guidances for Quality by DesignGuidances for Quality by DesignICH Q8 (step 4ICH Q8 (step 4) )

Note for Guidance on Pharmaceutical DevelopmentNote for Guidance on Pharmaceutical Development(EMEA/CHMP/167068/2004). 14 November 2005(EMEA/CHMP/167068/2004). 14 November 2005

ICH Q8(R1) ICH Q8(R1) Annex Annex November 2007: (November 2007: (EMEA/CHMP/ICH/518819/2007)

ICH Q9 (step 4) ICH Q9 (step 4) Quality Risk Management. 9 November 2005. Quality Risk Management. 9 November 2005. FDA Guidance for Industry PATFDA Guidance for Industry PAT —— A Framework for Innovative A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality AssurancePharmaceutical Development, Manufacturing, and Quality Assurance. . Sept 2004 Sept 2004

PAT information in Quality dossiersPAT information in Quality dossiers.. Reflection Paper Reflection Paper

Doc. Ref. EMEA/INS/277260/2005. 20 March 2006.Doc. Ref. EMEA/INS/277260/2005. 20 March 2006.

Aim of pharmaceutical Aim of pharmaceutical developmentdevelopment

To design a To design a qualityquality productproduct and a and a qualityquality manufacturing processmanufacturing process to to deliver the product in a reproducible deliver the product in a reproducible manner.manner.To provide To provide scientific understandingscientific understanding to to support the establishing of support the establishing of specifications and manufacturing specifications and manufacturing controls. controls.

Definition: Quality by DesignDefinition: Quality by Design

A systematic approach to developmentA systematic approach to developmentthat begins with predefined objectivesthat begins with predefined objectivesand emphasizes and emphasizes -- product and process understanding product and process understanding -- and process control,and process control,based on sound science and quality risk based on sound science and quality risk management.management.

EMEA

/CH

MP/

ICH

/518

819/

2007

Pharmaceutical DevelopmentPharmaceutical DevelopmentAssess critical attributesAssess critical attributes of raw materials, of raw materials, solvents, APIs excipientssolvents, APIs excipientsEnhance knowledge over a wide range of Enhance knowledge over a wide range of material material attributesattributes (e.g. particle size distribution, moisture (e.g. particle size distribution, moisture content), processing options and process content), processing options and process parametersparametersDecrease Decrease variabilityvariability of quality attributes (product of quality attributes (product and material defects, manufacturing defects, and material defects, manufacturing defects, human errors)human errors)Select optimal process designSelect optimal process design: e.g. terminal : e.g. terminal sterilization vs. aseptic processsterilization vs. aseptic processAssess the Assess the need for additional studiesneed for additional studies (e.g. (e.g. bioequivalence, stability) relating to scale up and bioequivalence, stability) relating to scale up and technology transfertechnology transfer

EnhancedEnhanced Understanding leads to Understanding leads to Design SpaceDesign Space

Applicant can choose to conduct pharmaceutical development studies that canlead to an enhanced knowledge of productperformance over a wider range of materialattributes, processing options and processparameters.

Scientific understanding facilitatesestablishment of expanded Design Space,potentially leading to opportunities to develop moreflexible regulatory approaches

Design SpaceDesign Space

The material attributes and process parameters The material attributes and process parameters that assure quality.that assure quality.

The The multidimensionalmultidimensional combination combination and interactionand interaction of input variables of input variables (e.g. material attributes) and (e.g. material attributes) and process parameters that have been demonstrated toprocess parameters that have been demonstrated toprovide assurance of quality. provide assurance of quality.


Knowledgespace

Design Space

Operating space

Working Working withinwithin the design spacethe design space is is notnot generally considered as a changegenerally considered as a change of the of the approved ranges for process parameters and approved ranges for process parameters and formulation attributes.formulation attributes.

Movement Movement outout of the design space isof the design space isconsidered to be a changeconsidered to be a change and would and would normally initiate a regulatory post normally initiate a regulatory post approval approval changechange processprocess..”” ICH Q 8 - Definitions

Design Space

Design Space Design Space (multidimensional !)(multidimensional !)

Knowledgespace

Design Space

Operating space 1

Design Space for Biotech Design Space for Biotech manufacturingmanufacturing

Steven Kozlowskia and Patrick Swann

Key process parameters for the Key process parameters for the drying operationdrying operation

Process Analytical Process Analytical TechnologiesTechnologies

A system for designing, analyzing, and A system for designing, analyzing, and controlling manufacturingcontrolling manufacturingthrough timely measurements (i.e. through timely measurements (i.e. during during processingprocessing) of critical quality and ) of critical quality and performance attributes of performance attributes of -- raw materials and raw materials and -- inin--process materials andprocess materials and-- processes with processes with the the goal of assuring final product qualitygoal of assuring final product quality

Definition Definition ‘‘RiskRisk’’(ISO/IEC Guide 51)(ISO/IEC Guide 51)

The combination of The combination of -- the probability of the probability of

occurrence of harm andoccurrence of harm and-- the severity if that harmthe severity if that harm

R = P x S[ Risk Priority Number = R x S x detectability ]

4. Risk Review

1. Risk Assessment

2. Risk Control

Initiate Quality Risk Management Process

Output / Result of the QualityRisk Management Process

FormalRisk Management Process

Risk Management Risk Management is about:is about:knowing the processes (manufacturing and business)knowing the processes (manufacturing and business),understanding what is truly important,understanding what is truly important,not spending time on a low risk activity, process, not spending time on a low risk activity, process, event, event, or system or system BECAUSE IT JUST DOESNBECAUSE IT JUST DOESN’’T MATTER!T MATTER!focusing money, time, energy, and people on the focusing money, time, energy, and people on the things that are really important; i.e.,things that are really important; i.e.,focusing efforts and resources on the things focusing efforts and resources on the things that provide quality assurance to our customers.that provide quality assurance to our customers.

Peter Gough

Two primary principlesTwo primary principles

1. The evaluation of the 1. The evaluation of the quality riskquality risk should should ultimately link back to the ultimately link back to the potential harm potential harm to the patientto the patient..

2. The level of effort, formality and 2. The level of effort, formality and documentation of the quality risk documentation of the quality risk management process should be management process should be commensurate with the level of risk.commensurate with the level of risk.

1. Risk Assessment

Risk Identification

Risk Analysis

Risk Evaluation


The estimation of the risk associated with the identified hazards

Compares the estimated risk against given risk criteria using a quantitative or qualitative scale to determine the significance of the risk.

1. Risk Assessment

2. Risk ControlRisk Reduction

Risk Acceptance

Risk Identification

Risk Analysis

Risk Evaluation


Actions taken to lessen the probability of occurrence of harm and the severity of that harm.

Decision to accept risk(ISO Guide 73).


4. Risk Review

1. Risk Assessment


Risk Acceptance

Risk Identification

Risk Analysis

Risk Evaluation



Review Events

4. Risk Review

1. Risk Assessment


Risk Acceptance

Risk Identification

Risk Analysis

Risk Evaluation


Risk

Com

mun

icat

ion

(3) Risk M

anagement Tools


Review Events

Exchange or sharing of information about risk and risk management between the decision maker and other stakeholders.

4. Risk Review

1. Risk Assessment


Risk Acceptance

Risk Identification

Risk Analysis

Risk Evaluation


Risk

Com

mun

icat

ion

(3) Risk M

anagement Tools


Review Events

Risk Management ToolsRisk Management Tools

Failure Mode Effects Analysis (Failure Mode Effects Analysis (FMEAFMEA))Failure Mode Effects & Criticality Analysis (Failure Mode Effects & Criticality Analysis (FMCEAFMCEA))Fault tree analysis (Fault tree analysis (FTAFTA))Hazard Analysis of Critical Control Points (Hazard Analysis of Critical Control Points (HACCPHACCP))Hazard Operability Analysis (Hazard Operability Analysis (HAZOPHAZOP))Risk Ranking and FilteringRisk Ranking and FilteringPreliminary Hazard Analysis (Preliminary Hazard Analysis (PHAPHA))Supporting statistical toolsSupporting statistical tools

Applying RM principles Applying RM principles in pharmaceutical development (1)in pharmaceutical development (1)Information from pharmaceutical development Information from pharmaceutical development studies is a studies is a basis for risk managementbasis for risk management..

Identify and discuss aspects of API, excipients Identify and discuss aspects of API, excipients and process that present a and process that present a significant risksignificant risk to to drug qualitydrug quality

Risk management principlesRisk management principles can be helpful in can be helpful in prioritising the additional pharmaceutical prioritising the additional pharmaceutical development studies to collect enhanced development studies to collect enhanced knowledge leading to more regulatory flexibility.knowledge leading to more regulatory flexibility.

Applying RM principles Applying RM principles in pharmaceutical development in pharmaceutical development

(2)(2)

An assessment of process robustness can be An assessment of process robustness can be useful in useful in risk assessment and risk reductionrisk assessment and risk reduction, to , to support future manufacturing and process support future manufacturing and process optimisation, especially in conjunction with the optimisation, especially in conjunction with the use of structured use of structured risk management toolsrisk management tools..

Assessment and inspection based on Assessment and inspection based on scientific scientific risk managementrisk management

Quality by Design Quality by Design

1. Product performance1. Product performance2. Product design2. Product design3. Process design3. Process design4. Process performance4. Process performance

ICH-Q8: PDICH-Q9: QRMPAT

Qualityby

Design


Pharmaceutical Quality Pharmaceutical Quality Assessment System (PQAS)Assessment System (PQAS)

KnowledgeKnowledge--rich submissions demonstrating rich submissions demonstrating understanding of product and process understanding of product and process Specifications based on product requirements Specifications based on product requirements for safety, efficacy, and stabilityfor safety, efficacy, and stabilityProcess designed and controlled to robustly Process designed and controlled to robustly and reproducibly deliver quality productand reproducibly deliver quality productRegulatory flexibility based upon enhanced Regulatory flexibility based upon enhanced product and process knowledgeproduct and process knowledgeFacilitated innovation and continuous Facilitated innovation and continuous improvement throughout the product lifecycleimprovement throughout the product lifecycle


CurrentCurrent System System versusversus Desired Desired StateState

Current System:

PQAS

Submission

(Lack of PD Traditional CMC Review

Development

(Empirical)

Submission (Knowledge Rich in PD

Development

(QbD)

Desired State:

& MS)

& MS)


Differing Approaches (1)Differing Approaches (1)AspectAspect Minimal

ApproachEnhanced (QbD) Approach

OverallOverallPharmaceuticalPharmaceuticalDevelopmentDevelopment

• Mainly empirical• Developmental research often conducted one variable at a time

• Systematic, relating mechanistic understanding of input material attributes and process parameters to drug product CQAs• Multivariate experiments to understand product and process• Establishment of design space• PAT tools utilised

EMEA

/CH

MP/

ICH

/518

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2007



ManufacturingManufacturingProcessProcess

• Fixed• Validation primarily based on initial full-scale batches• Focus on optimisation and reproducibility

• Adjustable within design space• Lifecycle approach to validation and, ideally, continuous process verification• Focus on control strategy and robustness• Use of statistical process control methods

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/CH

MP/

ICH

/518

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Process Process Controls Controls

• In-process tests primarily for go/no go decisions• Off-line analysis

• PAT tools utilised with appropriate feed forward and feedback controls• Process operations tracked and trended to support continual improvement efforts post-approval

EMEA

/CH

MP/

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/518

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ProductProductSpecificationsSpecifications

• Primary means of control• Based on batch data available at time of registration

• Part of the overall quality control strategy• Based on desired product performance with relevant supportive data

EMEA

/CH

MP/

ICH

/518

819/

2007



ControlControlStrategyStrategy

• Drug product quality controlled primarily by intermediate and end product testing.

• Drug product quality ensured by risk-based control strategy for well understood product and process• Quality controls shifted upstream, with the possibility of real-time release or reduced end-product testing

EMEA

/CH

MP/

ICH

/518

819/

2007



LifecycleLifecycleManagementManagement

• Reactive (i.e., problem solving and corrective action)

• Preventive action• Continual improvement facilitated

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2007

Changes in Multiple Changes in Multiple Sectors Sectors RequiredRequired

Manufacturers will need to change Manufacturers will need to change approach, invest in new technology, break approach, invest in new technology, break down silos between R&D and production, down silos between R&D and production, be less conservativebe less conservativeInternationally, regulators will need to Internationally, regulators will need to accept and encourage new ways of doing accept and encourage new ways of doing business and harmonize regulatory business and harmonize regulatory approachesapproaches

Janet Woodcock, IFPAC January 28, 2008

Changes Changes RequiredRequiredManufacturers will need to Manufacturers will need to investinvestinin developing this technology for developing this technology for theirtheir processesprocessesEquipment vendors will need to focus on Equipment vendors will need to focus on pharmaceutical marketpharmaceutical marketInternational regulators need to signal International regulators need to signal acceptance (maybe encouragement) and acceptance (maybe encouragement) and modify processes to accommodate PATmodify processes to accommodate PATStandardStandard--setting setting organizations/professional societies organizations/professional societies engage in standards and trainingengage in standards and trainingAcademic research to advance the fieldAcademic research to advance the field


Towards International Towards International Regulatory AcceptanceRegulatory Acceptance

Develop regulatory standards within ICHDevelop regulatory standards within ICHDevelop technical standards within standards Develop technical standards within standards organizationsorganizationsFDA and EU having ongoing discussions about FDA and EU having ongoing discussions about approaches to variations and about modernizing approaches to variations and about modernizing regulation of manufacturingregulation of manufacturingFDA evaluating best strategies to bring in other FDA evaluating best strategies to bring in other nationnation’’s regulators who are outside ICHs regulators who are outside ICH


Integrated approach is Integrated approach is needed on several levels needed on several levels

Industry

Inspectors Patients

Assessors

Integrated approachIntegrated approach

CMC

production quality

regulatory

Understanding the Philosophy of QbD

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