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AAPS WORKSHOP

SEPTEMBER 11 12, 2006

Quality By Design

Implementation

Dominic Ventura, Ph.D.

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Quality by DesignThe Desired State

Product quality and performance achieved andassured by design of effective and efficientmanufacturing processes

Product specifications based on mechanisticunderstanding of how formulation and processfactors impact product performance

An ability to affect continuous improvement andcontinuous real time assurance of quality

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Quality by Design

Mitigating Risk in Pharmaceutical Development

A process is well understood when:

All critical sources of variability are identified and explained

Variability is managed by the process, and,

Product quality attributes can be accurately and reliablyPREDICTED over the DESIGN SPACE established formaterials used, process parameters, manufacturing,environmental and other conditions.

Guidance for Industry: PAT A Framework for Innovative PharmaceuticalDevelopment, Manufacturing and Quality Assurance,page 6

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Quality by Design?Product Development Knowledge (Public Databases or in Submissions)

Level of Sophistication

HIGH

MEDIUM

LOW

Details Resolve

HIG

MEDIU

LO(HISTORICAL) DATA DERIVED FROM

TRIAL-N-ERROR EXPERIMENTATION

HEURISTIC RULES

EMPIRICALMODELS

MECHANISTICMODELS

1stPrinciples

Dr. Ajaz Hussein

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Material

CharacteristicsHamaker constant

Dielectric constant

Youngs modulus

Particle

AttributesPSD

Shape

Composition

Equipment

DesignGeometry

Constituent parts

Material properties

Operating

ConditionsSpeed of moving parts

Temperature

Humidity

Bulk MechanicalPropertiesAngle of repose

Unconfined yield stress

Forces Actingon Particles

Adhesion forces

Impact forces

Performance

of a Unit

Dr. Ajaz HusseinAIChE Journal 47: 107-125 (2001)

Quality by Design

Performance of a Solids Processing Units

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Quality by DesignThe Way Forward

Identify and control all sources of

variability

Raw materials

Process

Environmental

Manage variability through the

process

Uncertainty the inability to determine or

the ambiguity in the true state of a system

caused by a combination of variability and

incomplete knowledge (ICH Q9)

Reduce UNCERTAINTY Control VARIABILITY

Mitigate risk

Knowledge transfer to manufacturing and regulatorybodies

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MANUFACTURING

EXCELLENCE

LEVELS

OF

MANUFACTURING

EXCELLENCE

TIME

L

AU

N

C

H

Learning Before Doing

Learning By Doing

QbD

Continuous Improvement

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Where To Start

Dosage Form Considerations

Extended Release vs. Immediate?

Clinical Considerations

Established IVIVcDrug Product Attributes

Low Dose?

Drug Substance Attributes

Stable Polymorph, hydroscopic?

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Basic Concept of BCS

Drug

Product

Absorbed

drug

Dissolved

Drugkd

kp

kd = dissolution rate

function of drug solubility and drug

product quality attributes

kp = permeability rate

major function of API structure

minor dependence on salt form and

excipients.

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DEFINITIONS

Critical Quality AttributesPurity

Potency

BioavailabilityCritical Process Parameters

- Critical To Quality Attributes

(API, DP properties that can affect

CQAs)

- Key Process Variables

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DrugDrug

ReleaseRelease

RateRate

Disintegration,Disintegration,

Erosion and GranuleErosion and Granule

DissolutionDissolution

APIAPISolubilizationSolubilization

(rate/extent)(rate/extent)

PorosityPorosity

APIAPI Form SelectionForm Selection

(Salt, Polymorph, Particle(Salt, Polymorph, Particle

Size)Size)

HardnessHardness WettingWetting

Swelling/Swelling/

WaterWater

PenetrationPenetration

DP Excipient Selection, DP Process SelectionDP Excipient Selection, DP Process Selection

API Form Selection, API Process SelectionAPI Form Selection, API Process Selection

Quality AttributesQuality Attributes

Of Drug ProductOf Drug Product

Features of Quality by Design: doing things consciously*Features of Quality by Design: doing things consciously*

*A Quality by Design Approach to Dissolution Based on the Biopharmaceutical Classification*A Quality by Design Approach to Dissolution Based on the Biopharmaceutical Classification

System, R. ReedSystem, R. Reed

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RISK MANAGEMENT

Risk Benefit

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Quality Risk Assessment (QRA)

FMEA: Risk scores based on

probability, severity, and detectability

Risk Prioritization Matrix

Quality Function Deployment

Fish bone or Ishikawa diagram Pareto Chart

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ELEMENTS OF A SUCCESSFUL QbD

PROGRAM

Robust Product

Process

Formulation

& Materials

Equipment

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Risk Prioritization Matrix

QUALITYATTRIBUT

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Tablet Hardness

Basic risk facilitation methods

Cause EffectDiagram

for Tablet

Hardness

Compression

Roller Compaction

Raw MaterialBlending

EnvironmentalMaterial

Transfer

Hardness of Tablet

(Friability)

Pre & Post CompressionPress speed

Feeder speedMaterial addition

Feed frame settingFill Weight

Cam selectionTooling

Roll GapRoll force

Porosity (den)PSD

Ribbon strength

APIHPMC

TALCMg. Stea

Temp.Humidity

Blend time

Blend rpm

Order ofddn.Fill Vol.

Discharge rateSurface

DischargeStorage

MoistureTransport

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Pareto Chart: Relative Importance of

Inputs

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

HPM

C

K100CR

POROSITY

PRESSSPEED

CO

MPRESSION

FORCE

FE

EDER

SPEED

LUBETIME

PSD

OFINTRA-

GRANU

LAR

BLEND

APIPARTICLESIZE

BLEND

TIME

PRE-C

OMPFORCE

EXCIPIENT

PA

RTICLESIZE

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DEFINITIONS

Design Space Clinical Relevance

Control Space Process Capability

Control Strategy Change Control

Continuous Improvement

Regulatory Considerations

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Robust Manufacturing Processes

Process and Control Parameters

Clinical relevance

Ribbon Attributes

Porosity

Process Parameter Attributes

Blending time/end point

Roll force

Roll gap

Roll speedFeed screw rate

Milling conditions

Blend time/end point

Compression forcePress speed

Feeder speed

Granule Attributes

psd

Tablet Attributes hardness

Bin Blend

Roller Compaction

Bin Blend

Compression

Film Coating

Raw MaterialAttributes

Hypromellose Viscosity, Methoxyl,hydroxypropyl content,

Particle size

Blend Uniformity

Blend Uniformity

Pan Speed

EEF

Appearance,

Tablet weight gain

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Critical & Non Critical Parameters

Control Space/Design Space (Example)

Table 3.1-6: Roller Compaction

Unit Operation

Critical / Non-

Critical

Parameter

Control Space Design Space Key Attributes

Roller Compaction

-Roll Gap

-Roll Force

CriticalCritical

Table 3.1-7 for

100 mg andTable 3.1-8 for

200 mg

Table 3.1-7 for 100

mg andTable 3.1-8 for 200

mg

Particle Size

Distribution

(in line)

Tablet Hardness

Dissolution

-Feed Screw Speed Non-Critical

Not Applicable Not Applicablea

Roll Speed Non-Critical7-9 6-10

Milling

-Pre-granulator

-Fine Screen

granulator

Non-Critical

Non-Critical

Adjust rpm to

maintain

throughput

Adjust rpm to

maintain throughput

a. Controlled by Roll Gap

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52.11%

Polymer conc. 40-52.1%

Roll Gap 1.8 2.2 mm

Roll force 45-65 bar

Polymer conc. 40-52.1%

Roll Gap 3.0-3.8 mm

Roll force 55-65 bar

Poly

mer

Roll

force

R

oll

g

ap

40%

55 bar 65 bar

3.0 mm

3.8 mm

40%

52.11%

Scale

up

Poly

mer

Roll

force

R

oll

gap

45 bar 65 bar

1.8 mm

2.2 mm

Pilot-scale (design space) Manufacturing scale (predicted

design space)

Quality by Design -Tablet DevelopmentScale-up Parameters for Roller Compaction

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Quality by Design - Tablet DevelopmentConfirmation of Design Space at Mfrg Scale

Poly

mer

Roll

force

Roll

gap

52.1%

40.0%

55 bar 65 bar

3.0

mm

3.8

mm

4.0 mm

2.8 mm

3.2 mm

3.4 mm

3.6 mm

3.8 mm

70 bar

Failed batch

Good batch

Batches ManufacturedOutside the of the RollCompaction DesignSpace Fail TabletCompression

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Control/Design Space Critical Process

Parameters Critical Process Parameters (CPP) identified using a risk analysis

investigated extensively using a DOE.

Design Space

Established on the basis of the DOE and experience during

manufacture of clinical/registration batchesIn certain cases where response of critical quality attribute

studied/investigated was insignificant, extrapolation was used toexpand/establish design space

Control SpaceSubset of design space established on the basis of processcapability, prior knowledge

Intent is to stay within the control space during commercialmanufacturing

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Control/Design Space Non-

Critical Process Parameters

Non-Critical Process Parameters those identified as low

risk which lead to low probability of product failure

Design Space

Established on the basis of range studies (in some cases

DOEs) and manufacturing experience at various scales

Control Space

Subset of design space established on the basis of process

capability, prior knowledge

Intent is to stay within the control space during commercial

manufacturing

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Design Space and Control Space

Design SpaceMulti-dimensional space that encompasses combinations of productdesign, manufacturing process design, critical manufacturing processparameters and component attributes that provide assurance of suitableproduct quality and performance

Control SpaceMulti-dimensional space that encompasses process operatingparameters and component quality measurements that assure process orproduct quality. It is a subset of the design space

Control Strategy

Strategy/Methodology to mitigate risks associated with the batch whenthe critical and non-critical process parameters fall outside the controlspace butwithin the design space

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Control strategy - Critical Process Parameters

HPMC

Single point dissolution within control space

Dissolution profile when HPMC outside control space butwithin design space is used

Roll Gap and Roll Force

Single point dissolution within control spaceDissolution profile when roll gap and roll force are outside

control space but within design space is used

Impact of product being manufactured outside control space and

within design space will be assessed through the Event ReportForms

If control space is revised based on experience duringmanufacturing, will manage the change through the plant changecontrol system and notify the agency via the annual report

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i i f i i i

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Decision Tree for Batch Disposition Based

on Control/Design Space Non-CPPs

Are all non-CPPs withintheir control

spaces?

Generate anEventReportForm

NO

YES

Batch

disposition

No action,proceed as

usual

Impact of Eventand action

assessed by QA

Track and TrendEvents to monitor

type and number ofoccurrences

React and studywhen number of

occurrences indicateout of trends

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Closing Statement

Lead or Bleed!

Just Do It!

The future aint what it use to be!