application of risk-based tools & pat strategies in

Jeffrey A. PriemCubist Pharmaceuticals

The Harmonized PAT Solution:Application of Risk-Based Tools & PAT Strategies in Pharmaceutical Product

Manufacture

PDA Boston – December, 2004

Presentation ObjectivesProvide Overview of FDA’s PAT InitiativeProvide Overview of Risk Management & Risk Assessment Tools Provide PAT Strategy for Pharma IndustryPresent Case Example on PAT Strategy

Take Home MessagePAT = Process Understanding + Risk Mitigation


PAT ElementsProcess UnderstandingPrinciples & Tools

PAT Tools• Multivariate Data Acquisition & Analysis tools• Process Analyzers• Process Control SystemsRisk-Based ApproachIntegrated Systems ApproachReal Time Release

PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, & Quality Assurance, Sept 2004


PAT ChallengesTechnologyRegulatory DriverProduct PipelinesAutomationProduct Characterization

Process Understanding, Variation, Specificity, Robustness, Technology, & Regulatory Uncertainty


Risk, Risk Assessments & Risk Management


Risk Assessment:Applications

Risk Assessment ApplicationReactive Situation Proactive Situation

Risk Assessment Project Type

• Crisis Management• Merger & Acquisition• Feasibility

• Mature Process – Risk Mitigation• Re-Engineering (Middle of Development Lifecycle)

• Drug Development “Remediation”• Drug Development

• Crisis Management• Regulatory Issues

• Complaints & Adverse Events• Consent Decree & Warning Letter

• Due Diligence• GCP & GMP Assessment• New Product (Beginning of

Lifecycle)

Financial

Process

Product (Patient Focus)

Regulatory

Risk Assessment Project Type


Quality System Applications & Risk Assessments

Drug Development

Product Traceability

Purchasing Controls

Acceptance Testing

Production & Process Controls

ChangeControl CAPA Root Cause

Analysis

ComplaintsProcess Validation Process Design

Environmental Control


Risk Analysis ApproachesRisk Matrixes

Probability vs. Severity = High, Medium, or Low

“Risk” Definition & CategorizationLevel I = …Level II = …Level III = …

Pre-Defined Question & Decision Tree

“If then, else…”

Occ

urre

nce

Severity

HighRiskMedium Risk

Low Risk

text

Do Control Measure(s) exist for theidentified hazard?

Could the identified hazard(s) occur inexcess of acceptable level(s) or could itincrease to an unacceptable level(s)?

Will a subsequent step eliminate theidentified hazard(s) or reduce its likely

occurrence to an acceptable level?

Not ACCP

Is control at this stepnecessary forIntended Use(SQUIPP)?

Modify Step, Processor Product

NoYes

Yes

Yes

Yes

NoCritical Control Point

No

Does this step eliminate or reduce thelikely occurrence of a hazard to an

acceptable level?

No

Yes


Risk Assessment ToolsFMEA - Failure Modes Effects AnalysisFMECA - Failure Modes Effects & Criticality AnalysisFTA - Fault Tree AnalysisHACCP - Hazard Analysis Critical Control Points

AndCombination Methods – Tools & Approaches


Combination Methods OverviewKey Questions to Ask & Understand

What is the Risk Focus?What are the Risk Requirements?What are the Risk Metrics to be quantified & Measured?What is the Outcome of the Exposure?

As well as…What is it you need?How do you plan to do it?What is the ultimate outcome?What are the challenges?

Balance RA Tools vs. RA Approaches

Format

Content

Context

Intent

Implementation

Integration

Effectiveness


Risk Assessment Application

• Crisis Management• M&A• Feasibility

• Mature Process – Risk Mitigation• Re-Engineering (Middle of Development Lifecycle)

• Design Control (Middle of Design Lifecycle or After Design)

• Product Development• Design Control (Beginning of

Lifecycle)

• Crisis Management• Regulatory Issues

•Consent Decree•Warning Letter•FDA-483

• Due Diligence• GMP Assessment• New Product (Beginning of

Lifecycle)

Reactive Situation Proactive Situation

Risk Management:Applications

Financial

Process

Product

Regulatory

Risk Assessment Categories

(Project Type)


Risk Management ConceptICH Q9: Quality Risk Management

Risk Analysis

Risk Evaluation

Risk Control

Monitoring & Performance Measurement

Risk Assessment

Risk Management

Risk Management Planning

ISO 14971


The Harmonized PAT Solution


RegulatorsOrganizationCustomer

The “Simplified” Process Model

PerformanceRequirements DRIVE

MetricsMeasurementMonitoring

ProcessRequirements Performance


Materials

MethodsPeople

EnvironmentEquipment

Measurement

Input Process Output

Process Understanding Concept:Process Variation


Harmonized PAT

Real Time Release

Integrated Systems Approach

Risk-Based Approach

Process Understanding

PAT Tools• Multivariate Data

Acquisition & Analysis Tools

• Modern Process Analyzers / process analytical chemistry tools

• Process & Endpoint monitoring & control tools

• Continuous Improvement & KM

PAT Elements

• Implement test strategies

• Optimize Process

• Implement Optimization points

• Apply Technology

• Identify critical attributes• Identify automation

attributes• Identify monitoring &

control elements• Obtain Knowledge of

product & process specifications & requirements

• Provide understanding of QS interfaces

• Analyze risk at product, process, & quality systems perspective

• Define Mitigation Strategy

• Provide Risk Based Decision Processes

• Provide Rationale on where to apply Technology

• Provide Framework to facilitate Process Understanding & Decision Making Process

• Provide Framework to execute Risk-based strategies

Process Optimization

Process Analysis


Risk Management

PAT Strategy

Real Time Release

Integrated Systems Approach

Risk-Based Approach


PAT Tools• Multivariate Data

Acquisition & Analysis Tools

• Modern Process Analyzers / process analytical chemistry tools

• Process & Endpoint monitoring & control tools

• Continuous Improvement & KM

PAT Elements

• Implement test strategies

• Optimize Process

• Implement Optimization points

• Apply Technology

• Identify critical attributes• Identify automation

attributes• Identify monitoring &

control elements• Obtain Knowledge of

product & process specifications & requirements

• Provide understanding of QS interfaces

• Analyze risk at product, process, & quality systems perspective

• Define Mitigation Strategy

• Provide Risk Based Decision Processes

• Provide Rationale on where to apply Technology

• Provide Framework to facilitate Process Understanding & Decision Making Process

• Provide Framework to execute Risk-based strategies


Process Analysis


Risk Management

PAT Strategy


PAT Application Example

Technology Transfer & Process Validation



Identify product requirementsDefine how they were derivedQuantify robustness & adequacy Correlate Attributes to Interfaces

ProcessSystemComponent

ProcessSpecificationIdentification

Process Map

Identify Each Process StepIdentify Elements for Variation:Equipment, Measurement,Personnel, Methods, Materials,Environment, Controls &Monitoring

Process Flow ProcessIdentify Process Step OutcomeMap Key Inputs: Data /Information and Procedures /guidanceMap Process Outputs &DeliverablesIdentify Quality SystemInterfaces, PerformanceMeasures, & Milestones

Process Flow Diagram

Harmonized PAT SolutionActivity Key Elements


Process UnderstandingProcess Identification Deliverable

Matrix of those Elements of Variation


ProcessOutcomes

Process Flow Diagram

"Knowledge Document"Development & Responsibilities

Key Inputs

Data / Information Procedures /Guidance

Key Outputs(Outputs fromProcess Step)

Quality System Interfaces orPerformance Measures

Planning

Document Development

Document Review

Deployment

DetermineDocuments to be

developed

Determine Priority

DetermineSchedule /Milestones

DetermineResource

ObtainResponsible CSGroup Approval

Obtain KMI ExecManagement

Approval

EstablishedDocuments /CS Group

Rationale toDrive

Consensus

CS Group SpecificService & Documents

MatrixMDCASCQSVCIT

Exec MgmtApproval

ResourcesTimelinesDeliverables

CS GroupApproval

ServicesDocumentsResources

QS Interfaces:Personnel:

KMI Executive ManagementCS Group Directors

KMI Strategic PlanResource Utilization / Planning

Obtain consensuson services thateach CS Groupprovides,documents neededto support services,and resourcesrequired to supportthe development ofthose documentsObtain Approval toproceed for:

PersonnelCommitmentsTimelinesDeliverablesDeliverablesformat

Obtain TemplateFormat

DetermineTechnical Content

for Document

Draft & DevelopDocument

Solicit feedback

TemplateDocument

CS Group Input /Feedback on

Technical Content

PreliminaryDraft

Document

QS Interfaces:Personnel:

CS Group SME'sKM for Templates & Technical ContentsearchesBO - Administration for KMI Documents________- Reference Resources

Performance Measures:Conformance to approved scheduledConformance to template standard

Performance Measures:Conformance to approved scheduledConformance to template standardConformance to Technical Contentreference materials & interpretation

Established Draftdocument whichsatisfies CS GroupService needsDocumentdeveloped conformsto select industrystandards & KMIhas establishedposition on how KMIconforms to suchrequirements

Critical Success Factors:Understanding of concept & context ofproject by Exec Mgmt & CS GroupDirectorsObtain Buy-in from Exec MgmtObtain Buy-in from CS Group Directors

Critical Success Factors:Templates established to focus onTechnical Content IssuesAuthor Time to develop documentStaying on track with development(Focused)

Perform "QA"review & technical

content review

Perform InternalCS Group Review

of DocumentPreliminaryDraft

Document

Technical ContentDocuments

(References)


(References)

Critical Success Factors:Reviewer time commitmentStaying on track with scheduleAccessibility of SME's in event techcontent is not available / accessible

Obtain CS GroupConsensus onapproach anddeliverableCapture draftdocument(something is betterthan nothing)

Review & Approval

Forwarddocument to KM

Quality System Interfaces:CS Group "QA" Review & SMEsBO - Administration (DocumentManagement Log-in)KM - Facilitate process

Log Document &Establish Tracking

Forwarddocument to KMICross functionalReview Board

Perform review

Performance Measures:Conformance to approved scheduledConformance to Technical Contentreference materials & interpretation

Critical Success Factors:Reviewer time commitmentAccessibility of ReviewersStaying on track with scheduleAccessibility of SME's in event techcontent is not available / accessibleFocused Reviewers Reviews (Mitigatingthe propensity to word smith & redesigndocument)

Quality System Interfaces:KMI Review Team - Cross-FunctionalManagement Review Team (Principal /Senior Consultant) to review, providefeedback & approvalKM - Facilitate processCS Group Author & Mgmt - processfeedback

Edits Required?

No

Yes ConsiderComments

DocumentApproved?

Yes

Yes No

Provide rationalewhy changes not

made

Incorporaterecommended

changesNo

Transition for Implementation:Change ControlInternal TrainingDeployment on Knowledgebase

DraftDocument

DocumentTracking & Log

Entry

Review Edit's &Red-lines

Revise

Obtain collectiveKMI TechnicalReview ondocument &componentspresented(Consensus &Agreement)

DraftDocument


Quality System Interfaces:BO - Administration (DocumentManagement)EO - Internal Training_____ - Website

DocumentDeliverableTraining MaterialsKnowledgebaseAccess

Approved,controlled, deployed& trained document

ApprovedDocument

ReviewComments

Justification /Rationale

Services Provided/ CS Group

Index ofDocuments

needed to supportservices

KMI Document /Tracking #

ApprovedDocument

PAREXEL / KMI Policies:Change ControlPosting / Handling ofknowledge asset

CS GroupConsensus on

Deliverable

KMKM

KM

KM

CS G

rp D

ir &

KMKM

I Exe

c M

gmt,

CS G

rp D

ir &

KMCS

Grp

Dir

& SM

E's

CS G

rp D

ir, A

utho

r, &

SME'

sKM

IRe

vTm

CS Grp Dir &Author

CS Grp Dir& Author

KMI(?)

CS Grp

Dir & KM

© 2002 KMI, a division of PAREXEL International, LLCKMI, a division of PAREXEL International LLC, (KMI) considers this document to be confidential & for the sole use of KMI. All rights reserved. No part of this document may be reproduced or

transmitted in any form, by any means (electronic, photocopying, recording, or otherwise) with written permission of KMI

Continuous Improvement

Review &Revisions

Quality System Interfaces:BO - Administration (Document ChangeControl)CS Group's - Review & RevisionKM - Facilitate Process

KMI DocumentManagement &Change Control

Procedure

KMI DocumentReview &

Revision Plan

Performance Measures & CSF's:To be determined

Implement KMIDocument Review &Revision Processesto KMI KnowledgeDocuments

Filename: KM Doc Development PFD rDr0.vsd

ProcessMap

Process Workflow

Specifications

Productand

Process

Equipment /Systems Personnel

Measurement

EnvironmentProcedures

Materials

Process Map

Process WorkflowFlow diagram of processes &activities

Process OutcomePer each level

Key InputsDate & Information into theProcessProcedures & Guidance thatDrive Process

Key OutputsDeliverables Result forProcessActivities Result fromProcess

Quality System InterfacesQuality Program LinkagePoints

Performance MeasurementMetrics to measureperformance


Process AnalysisDefine Product RisksIdentify Process RisksIdentify Quality System Risk AreasCorrelate Risks to Mitigation Strategies


Process AnalysisProcess Risk Assessment

Process Fault Tree AnalysisFailure ofSterility

QC Test Eq1149 out ofCalibration

FermentationProcess

SamplingProcess

QC Test Equip1149 Failure

Tree Example


Process AnalysisProcess HACCP Deliverables

TimeLevel

ofDetail

& Effort

Hazard Identification

Hazard Analysis

Critical ControlPoints

HACCPPlan

Focus is on those Critical Elements of the Process!


Process Analysis Quality System Risk Quantification

Scale High: 8.0 to 10Medium: 4.0 to 7.9Low: 0 to 3.9



Define Analysis AreasImplement Corrective Action PlanExecute Optimization StrategiesImplement Technology & Solutions


Forward approvedchange to

implementation teamleader

Create a ChangeImplementation Plan

If appropriate, establisha method for

determining theeffectiveness of the

change

Is the ChangeImplementationPlan approved?

Proceed with plan andprovide progress

updates according toschedule

Complete ChangeImplementation Plan

Submit documentationof completed

implementation toChange Control

Manager

Is changeeffectiveness

monitoringrequired?

No

Yes

Has implementationbeen completed?

Collect & evaluateeffectiveness data

Was changeeffective?

Submit CRF to CCM forMCF closure

Close MCF

No

Yes

No

Yes

Yes

No

End

Prepare for seniormanagement periodic

summary reports.

MFG ProcessPr

oces

s Fl

ow D

iagr

am

& P

roce

ss M

apDeviation

Management

Change ControlMFG Process

Out of Specifications

Cross-Functional Implications

Systems-Based Model & Top-Down Approach

– Integrated Quality Systems– Pre-Planned Linkages for Risk

Management & Performance MeasurementD

evia

tion

Man

agem

ent

Cha

nge

Con

trol

Out

of

Spec

ifica

tions

MFG

Pro

cess


ImplementationMeasureControl & MonitorAnalyzeReviewRefineRevise

Performance

Requirements

DRIVE

Again…


Risk ManagementDefine

ScopeApproachInterfaces Outcome


Discovery

Product Lifecycle:

Development Distribution

Risk Management & Drug Development Lifecycle

BasicResearch

BasicResearch Pre-ClinicalPre-Clinical Product

LaunchProductLaunch

Marketing and Sales

Marketing and Sales

ClinicalClinical

I II III IIIB

IVProductionProduction

Manufacturing

Bottoms-Up ApproachRisk Management & Drug Development


Risk Management & Drug Development Lifecycle

BasicResearch

BasicResearch Pre-ClinicalPre-Clinical Product

LaunchProductLaunch

Marketing and Sales

Marketing and Sales

ClinicalClinical

I II III IIIB

IVProductionProduction

Product Lifecycle:

Discovery Development Manufacturing Distribution

Top Down ApproachRisk Management & Product Lifecycle


Risk Management “System”

Protocol Failure:Validation,

Stability, ActionImplementation

OOS Results

Deviations FromProcedure

Clinical StudyFailures

Complaints

Adverse Events

AuditObservations

N...

Deviation Mgmt/ NCMR

Data observedof ExceptionPreliminaryevaluation &Investigation

CAPAAdverseTrends in dataDataexceptionsPreliminaryevaluation &Investigation

Action analysisteam review for

level III &optional Level II

Review

FormalInvestigation, action

identification &authorization for

Level II/III Results

RegulatoryReview for Level

III & OptionalLevel II Review

Actionimplementation

PlanningProtocol

Creation &Implementation

Action DatabaseAudits

EffectivenessAssessment

Follow-up

Level I

Level I

Level II/III Level II/III

Level II

InputsObservation Records &

PreliminaryInvestigation

Formal Investigation& Action Identification

ActionImplementation

Action Database &Follow-up

Level II / III

Reference: "Risk Management Basics", DeSain, Vercimak, Sutton

Product Design


Outcomes


PAT ApplicationProject Outcomes

Improved Product QualityOptimization of Processes & InterfacesReduction in Production Cycle TimeVariation MitigationProcess Epiphany: The “Ah Ha!” FactorCost Savings & Optimized Resources

• Technology• Personnel• ROI

Defendable Compliance vs. Minimal Compliance

By:Jeff Priem Tel: 781.860.8661Email: [email protected]

The Harmonized PAT Solution:Application of Risk-Based Tools & PAT Strategies in Pharmaceutical Product

Manufacture