Diane M. PaskietDirector of Scientific Affairs

West Pharmaceutical Services, Inc.IFPAC - 2014 28th International Forum

January 23, 2014 - Washington, DC

Assuring Drug Product Quality and Patient Safety through the Application of QbD to Packaging and Delivery Systems

2013 Check-Up: Drug Development and Manufacturing Challenges

Inadequate manufacturing capability is a frequent cause of critical drug supply shortfalls (cited lyophilization and sterile manufacturing)

QbD in development is becoming the standard way for small molecule innovator drugs; Biotech and generic companies are shifting toward QbD but at a slower pace.

http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm.

Inability to understand reasons for manufacturing failures

Circa 2002Janet Woodcock M.D. Director, Center for Drug Evaluation and Research

Justification of QbD for Packaging Components

Proactive Approaches to Pharmaceutical ManufacturingQbD for Component Manufacturing Process

QbD for Plunger Design

Meeting Needs of Patients

Application of QbD to Packaging and Delivery Systems

Science BasedCompatibility

Final product and manufacturing processPerformance

System fit and functionality-fill/finishSafety for Intended Use

Understanding materialProtection

Stability

Appropriate ControlsRisk Management

Critical Control Points

Meeting Needs of Patient/CaregiverCollaborations

Informed Decisions for Suitable Packaging Components

Goals:Pharmaceutical Manufacturing

Improve development capabilitySeamless tech transferEfficient manufacturingReduce atypical productComponent consistencyFacilitates review process

Suitability Evidence Based

Significance:Packaging Component

Support regulatory reviewsRisk managementScience based

Collaborative communicationLifecycle management

Continuous improvement Facilitates investigations/change control/OOS/atypicals

Knowledge managementDesign history

Justification of QbD for Components

Patient CentricPatient Centric

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Example of Product Requirement Matrix

QTPP Design Inputs Design Outputs Control Strategy Summary Risk

Risk Summary-Rationale for ControlsSupports Investigations and Continuous Improvement

Risk Summary-Rationale for ControlsSupports Investigations and Continuous Improvement

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QTPP – fit for use with injectable pharmaceuticalsCQAs (Particle Example)

Start by Identification and Quantification of User Needs

CQA Test Method Units Requirement

Particles per size range ≥5 but <10um

Automated Filter Counting Test Method

Particles/ 10cm2

≤100

Particles per size range ≥10 but <25um ≤60

Particles per size range ≥25 but <50um ≤10

Particles per size range ≥50 but <100um ≤1

Particles per size range ≥100um ≤0.2

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Every step of the process is examinedReview all documented work instructionsObserve operations on shop floor Includes steps of control strategy

Create a detailed process map Fully defines all aspects of the manufacturing process

Existing Process Baselined as the Basis for Development Work

CQAs

Cause & Effect Analysis

200+ Process parameters in 43 Process steps Ranked

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Calculate RPN (risk priority number) to rank the risksSeverity X Probability X Detection

Determine actions to mitigate unacceptable risks

Failure Mode and Effects Analysis(FMEA)

Process Description

Potential Failure Mode

Potential Effects of Failure

SEV

Potential Causes

PROB

Current Process Controls

DET

RPN

Recommended action

Trim Line Clearance and Set Up

Dirty trim solution

Bioburden, endotoxin, extractables, particles at unacceptable levels

5 Solution tub not cleaned

2 Product release testing for bioburden, endotoxin, extractables, particles,Training program, SOP

3 30

Review and improve current procedures

Process Improvement

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Studied particle load throughout the processIdentified process steps that increase and decrease particle loadStopper rinsing showed significant reduction

Targeted for optimization

DOEs Revealed Mitigation Strategy Feeding into of Design Space

Examples for Particles

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Statistically designed experiment of stopper rinsing process

Three factors were studies at three levelsWash type Rotation speed Drying time

Measured particle countsOptimized rinse cycle developed and confirmed

Rinsing Process Was Optimized for Maximum Particle Reduction

Key Initial Process Steps CQAProcess Parameter

RM Mix Extrude Mold Rinse&Wash

Silicone Inspect Fiber >10um

Line Clearance

< 60

Sheet Dimension

<60

Control Strategy Derived from Product Requirement Matrix

Summary of risk and adequacy of controls Example: Design Input (1.4) Particles

CQA not impacted by parameter or attribute in Process Step (PS)CQA impacted by parameter or attribute in PS but controlled in different step

CQA primary control implemented in PS through input specifications, work instruction or in process controls

Risk Mapping Across the ProcessCapture prior knowledgeRisk identification and prioritization

Outcome: Screening of variables feeding experimental design

FMEA and HACCPUnderstand factors impacting CQAs

Contribution of detectability and in process controls to overall risk reduction.Justify areas for further study

Use of robust methods and screen variables Outcome: ID critical process parameters and control strategy

Component QTPP-CQA Process Understanding-Control Strategy

Evidence Based

QbD for Component Manufacturing Process

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QbD Plunger Design

2 & 3 RIB

Design Benchmarks

West FluroTec

West uncoated

Competitive

QbD Plan for Concept

Development

Defined design variablesEstablished DOE

Correlation of key attributes

Fabricated cavities

Design Characterization

Define critical specifications

2 Step Molded Styles

Comparison of Average Piston Release and Travel Forces

0.00.51.01.52.02.53.03.54.04.5

0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40

Distance (in)

Forc

e (lb

f)

CZ 1ml (RT 2m) Hypak 1ml Std.(RT 2m)Hypak 1ml Long (RT 2m)Hypak 3ml (RT 2m)Schott TopPac COC (RT 43d)

Engineering Models (FEA)

Break Loose & Extrusion

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QbD Manufacturing ProcessInclude Design Features

GeometryFilm lamination

Overcoming variationsDimensionalSilicone oilBreak loose and extrusion forcesParticulate

Quality Risk ManagementContinuous Improvement

QbD Plunger Overarching Goals

FluroTec® technology is licensed from Daikyo Seiko, Ltd.

Time TempTime X Temp

Delta Force, N 0.935 0.943 0.402

17% Extr. Force, N 0.823 0.200 0.527

50% Extr Force, N 0.878 0.314 0.59

83% Extr Force, N 0.971 0.351 0.565

P-values

DOE and Statistical Analysis Drives System Understanding

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Example: Effect of cure conditions on plunger performance

P- value are > 0.05 indicating there is not a significant relationship between the variablesand the responses over the range evaluated

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Most Consistent Travel Force

1mL long NovaPure compared to standard 1ml long coated plunger – water filled, 25°C/60% RH

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Break Loose and Extrusion in Various Syringe BarrelsForce required to initiate the plunger movement over time

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New ComponentsHolistic View of the Manufacturing process

NovaPure® 4432/50 and 4023/50 stoppers (commercial)

Development of QbD Plunger NovaPure 1mL long plunger 4023/50 (commercial), 4432/50 (in development)

Current ComponentsCustomer specific application

NovaChoice™

QbD Component Understanding from Various Perspectives

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NovaChoiceQTPP and CQAs tailored to customer product and

patient expectationsCollaborative development approach to understand the

complete systemWest Customer Patient

Developed under DA in direct alignment with customerSustainable process for lifecycle management through

knowledge management

Current Products QbD Application

QTPP-CQAsPharmaceutical Manufacturing

EfficiencyProduct compatibility and safety

Quality Risk ManagementDesign Space –Control Strategy Continual Improvement

CollaborationsPatient

Ease of useProtection of product

Patient and Manufacturing Needs

Current and Future

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Trademarks and registered trademarks are the property of West Pharmaceutical Services, Inc. in the United States and other jurisdictions, unless noted otherwise.

Thank you

Packaging and Delivery SystemsEvidence of Quality