The Harmonized PAT Solution Application of Risk Based Tools Process Analytical Technology Strateg

7/31/2019 The Harmonized PAT Solution Application of Risk Based Tools Process Analytical Technology Strateg

1/35

Jeffrey A. Priem

Cubist Pharmaceuticals

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

Manufacture


2/35

Page 2PDA Boston December, 2004

Presentation Objectives

Provide Overview of FDAs PAT Initiative

Provide Overview of Risk Management & RiskAssessment Tools

Provide PAT Strategy for Pharma Industry

Present Case Example on PAT Strategy

Take Home Message

PAT = Process Understanding + Risk Mitigation


3/35


PAT Elements Process Understanding

Principles & Tools PAT Tools

Multivariate Data Acquisition & Analysis tools

Process Analyzers

Process Control Systems Risk-Based Approach

Integrated Systems Approach

Real Time Release

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


4/35


PAT Challenges

Technology

Regulatory Driver

Product Pipelines

Automation

Product Characterization

Process Understanding, Variation, Specificity,

Robustness, Technology, & RegulatoryUncertainty


5/35


Risk, Risk Assessments & RiskManagement


6/35


Risk Assessment:

ApplicationsRisk Assessment Application

Reactive SituationProactive Situation

Risk AssessmentProject Type

Crisis Management Merger & Acquisition

Feasibility

Mature Process Risk Mitigation Re-Engineering (Middle ofDevelopment 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 ofLifecycle)

Financial

Process

Product

(Patient Focus)

Regulatory

Risk AssessmentProject Type


7/35


Quality System Applications & Risk

Assessments

DrugDevelopment

Product

Traceability

Purchasing

Controls

AcceptanceTesting

Production &Process

ControlsChange

ControlCAPA Root Cause

Analysis

ComplaintsProcessValidation Process Design

EnvironmentalControl


8/35


Risk Analysis Approaches Risk Matrixes

Probability vs. Severity = High, Medium,

or Low

Risk Definition & Categorization

Level I =

Level II =

Level III =

Pre-Defined Question & Decision

Tree If then, else

Occurrence

Severity

HighRiskM

edium

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

No

Critical Control Point

No

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

acceptable level?

No

Yes


9/35


Risk Assessment Tools FMEA - Failure Modes Effects Analysis

FMECA - Failure Modes Effects & CriticalityAnalysis

FTA - Fault Tree Analysis

HACCP - Hazard Analysis Critical Control Points

And

Combination Methods Tools & Approaches


10/35


Combination Methods Overview Key Questions to Ask &

Understand

What is the Risk Focus? What are the Risk Requirements?

What are the Risk Metrics to bequantified & 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


11/35


Risk Assessment Application

Crisis Management M&A

Feasibility

Mature Process Risk Mitigation Re-Engineering (Middle ofDevelopment Lifecycle)

Design Control (Middle of DesignLifecycle or After Design)

Product Development

Design Control (Beginning ofLifecycle)

Crisis Management

Regulatory Issues

Consent Decree

Warning Letter

FDA-483

Due Diligence

GMP Assessment

New Product (Beginning ofLifecycle)

Reactive SituationProactive Situation

Risk Management:

Applications

Financial

Process

Product

Regulatory

Risk Assessment

Categories

(Project Type)


12/35


13/35


The Harmonized PAT Solution


14/35


RegulatorsOrganizationCustomer

The Simplified Process Model

PerformanceRequirements DRIVE

MetricsMeasurementMonitoring

ProcessRequirements Performance


15/35


16/35


Harmonized PAT

Real Time Release

Integrated SystemsApproach

Risk-Based Approach

Process Understanding

PAT Tools

Multivariate DataAcquisition & AnalysisTools

Modern ProcessAnalyzers / processanalytical chemistrytools

Process & Endpointmonitoring & controltools

Continuous

Improvement & KM

PAT Elements

Implement

teststrategies

OptimizeProcess

ImplementOptimizationpoints

ApplyTechnology

Identify critical attributes

Identify automationattributes

Identify monitoring &control elements

Obtain Knowledge of

product & processspecifications &requirements

Provide understanding ofQS interfaces

Analyze risk at product,

process, & quality systemsperspective

Define Mitigation Strategy

Provide Risk

Based DecisionProcesses

ProvideRationale onwhere to applyTechnology

ProvideFramework tofacilitate ProcessUnderstanding &Decision MakingProcess

ProvideFramework toexecute Risk-based strategies

ProcessOptimization

ProcessAnalysis

ProcessUnderstanding

Risk Management

PAT Strategy

Real Time Release

Integrated SystemsApproach

Risk-Based Approach


PAT Tools

Multivariate DataAcquisition & AnalysisTools

Modern ProcessAnalyzers / processanalytical chemistrytools

Process & Endpointmonitoring & controltools

Continuous

Improvement & KM

PAT Elements

Implement

teststrategies

OptimizeProcess

ImplementOptimizationpoints

ApplyTechnology

Identify critical attributes

Identify automationattributes

Identify monitoring &control elements

Obtain Knowledge of

product & processspecifications &requirements

Provide understanding ofQS interfaces

Analyze risk at product,

process, & quality systemsperspective

Define Mitigation Strategy

Provide Risk

Based DecisionProcesses

ProvideRationale onwhere to applyTechnology

ProvideFramework tofacilitate ProcessUnderstanding &Decision MakingProcess

ProvideFramework toexecute Risk-based strategies

ProcessOptimization

ProcessAnalysis

ProcessUnderstanding

Risk Management

PAT Strategy


17/35


PAT Application Example

Technology Transfer & Process

Validation


18/35


Process

Understanding Identify product

requirements

Define how they werederived

Quantify robustness& adequacy

Correlate Attributesto Interfaces

Process

System Component

ProcessSpecification

Identification

Process Map

Identify Each Process StepIdentify Elements for Variation:

Equipment, Measurement,Personnel, Methods, Materials,Environment, Controls &Monitoring

Process Flow ProcessIdentify Process Step Outcome

Map Key Inputs: Data /Information and Procedures /guidanceMap Process Outputs &DeliverablesIdentify Quality System

Interfaces, PerformanceMeasures, & Milestones

Process Flow Diagram

Harmonized PAT Solution

Activity Key Elements


19/35



Process Identification Deliverable Matrix of those Elements of Variation


20/35


21/35


Process Analysis Define Product

Risks

Identify ProcessRisks

Identify QualitySystem Risk Areas

Correlate Risks toMitigationStrategies


22/35


Process Analysis

Process Risk AssessmentProcess Fault Tree Analysis

Failure ofSterility

QC Test Eq1149 out ofCalibration

FermentationProcess

SamplingProcess

QC Test Equip1149 Failure

Tree Example


23/35


Process Analysis

Process HACCP Deliverables

Time

Levelof

Detail&

Effort

Hazard

Identification

Hazard

Analysis

CriticalControl

Points

HACCP

Plan

Focus is on thoseCritical Elements

of the Process!


24/35


Process Analysis

Quality System Risk Quantification

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


25/35


Process

Optimization Define Analysis

Areas

ImplementCorrective ActionPlan

ExecuteOptimizationStrategies

ImplementTechnology &Solutions


26/35


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 to

Change ControlManager

Is changeeffectiveness

monitoringrequired?

No

Yes

Hasimplementationbeen completed?

Collect &evaluateeffectiveness data

Was changeeffective?

Submit CRF to CCMforMCF closure

Close MCF

No

Yes

No

Yes

Yes

No

End

Prepare forseniormanagement periodic

summary reports.

MFG Process

Pro

cessFlow

Diagram

&P

rocessM

ap

DeviationManagement

Change ControlMFG Process

Out ofSpecifications

Cross-FunctionalImplications

Systems-Based Model & Top-DownApproach

Integrated Quality Systems

Pre-Planned Linkages for RiskManagement & Performance

MeasurementDeviation

Managemen

t

Change

Control

Outof

Sp

ecifications

MFGPr

ocess


27/35


Implementation Measure

Control & Monitor Analyze

Review

Refine

RevisePerformance

Requirements

DRIVE

Again


28/35


Risk Management Define

Scope

Approach

Interfaces

Outcome


29/35


30/35


Risk Management & Drug Development Lifecycle

BasicResearch

BasicResearch Pre-Clinical

Pre-Clinical ProductLaunch

ProductLaunch

Marketingand Sales

Marketingand Sales

ClinicalClinical

I II III III

B

IVProductionProduction

Product Lifecycle:

Discovery Development Manufacturing Distribution

Top Down ApproachRisk Management &Product Lifecycle


31/35


Risk Management System

Protocol Failure:Validation,

Stability, ActionImplementation

OOS Results

Deviations FromProcedure

Clinical StudyFailures

Complaints

Adverse Events

AuditObservations

N...

Deviation Mgmt/ NCMR

Data observedof Exception

Preliminaryevaluation &Investigation

CAPA

AdverseTrends in data

Dataexceptions


Action analysis

team review forlevel III &optional Level II

Review

Formal

Investigation, actionidentification &

authorization forLevel II/III Results

RegulatoryReview for Level

III & OptionalLevel II Review

Actionimplementation

PlanningProtocol

Creation &Implementation

Action Database

AuditsEffectivenessAssessmentFollow-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


32/35


Risk Management System

Protocol Failure:Validation,

Stability, ActionImplementation

OOS Results

Deviations FromProcedure

Clinical StudyFailures

Complaints

Adverse Events

AuditObservations

N...

Deviation Mgmt/ NCMR

Data observedof Exception


CAPA

AdverseTrends in data

Dataexceptions


Action analysis

team review forlevel III &optional Level II

Review

Formal

Investigation, actionidentification &

authorization forLevel II/III Results

RegulatoryReview for Level

III & OptionalLevel II Review

Actionimplementation

PlanningProtocol

Creation &Implementation

Action Database

AuditsEffectivenessAssessmentFollow-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


33/35


Outcomes


34/35


PAT ApplicationProject Outcomes

Improved Product Quality

Optimization of Processes & Interfaces Reduction in Production Cycle Time

Variation Mitigation

Process Epiphany: The Ah Ha! Factor Cost Savings & Optimized Resources

Technology

Personnel

ROI

Defendable Compliance vs. Minimal Compliance


35/35

By:

Jeff Priem

Tel: 781.860.8661

Email: [email protected]

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

Manufacture

Documents

The Harmonized PAT Solution Application of Risk Based Tools Process Analytical Technology Strateg