The Application of QbD in Pharmaceutical Development

James KraunsoePharmaceutical and Analytical R&D

AstraZeneca CharnwoodPQG 12 November 2008

Outline of presentation• Quality by Design (QbD) in Pharmaceutical

Development• Objectives and benefits in AZ

– “Science based processing”• Where did it come from?

– How is it different to how things were (are) done?• What does it include?

• Examples of how it might be done• Focus on a tablet manufacturing process

• Summary

AZ QbD Primary Objective• Achieve Robust First Time:

– Apply throughout product and process development– During product development, scale-up and manufacturing– To product and API manufacture

– Use standard approach and standard tools eg.– Risk Assessment– Process Analytical Technologies– Design of experiments (DOE)

– Enhance product and process understanding

Science Based Processing

The benefits of QbD at AZ• Understanding the processes has lead to greater

robustness and certainty of supply

• Development using QbD has enabled AZ to identify variability and hence control processes better

• The use of QbD has increased the understanding of the functionality of input materials and the impact on formulation

Pharma Quality System• “A Framework for Innovative Pharmaceutical Manufacturing and

Quality Assurance” (FDA Guidance on PAT, 2004)• ‘Pharmaceutical cGMPs for the 21st Century – a Risk Based

Approach’ (FDA, 2004)• ICH Q8 (Pharmaceutical Development)

– November 2005– Annex to Q8; November 2007 (Step 3)

• ICH Q9 (Quality Risk Management)• November 2005

• ICH Q10 (Pharmaceutical Quality System)• June 2008

• Major change in the Regulations?• From “testing quality in…” to “building quality in…”

ICH Q8• The guideline indicates areas where the demonstration of greater

understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches. The degreeof regulatory flexibility is predicated on the level of relevant scientific knowledge provided.

• For example• “…demonstrate enhanced knowledge of product performance over a

range of material attributes, manufacturing process options and process parameters.”

• “…product of the intended quality…under different operating conditions, at different scales, or with different equipment should be provided.”

Annex to ICH Q8• Provides further clarification of key concepts

• ”…describes the principles of quality by design (QbD);”• ”…shows how concepts and tools … could be put into practice .”

• For example• Target Product Profile• Critical Quality Attibutes• Appropriate manufacturing process and control strategy• Design space• Product lifecyle managemenat and continuous improvement

• Links to ICH Q9 and Q10

ICH Q9• Purpose is to offer a systematic approach to

quality risk management• Provide

• Quality risk management principles• Examples of tools• Definitions and link to ISO

• Starting point to define (standardised) internal risk assessment procedure

ICH Q9 – Risk Management Tools

Risk Review

Risk Assessment

Risk Evaluation

unac

cept

able

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateRisk Management Process

Output / Results of theRisk Management Process

Equivalent Element of AZIRM Framework

UNDERSTAND

IDENTIFY

ASSESS

MANAGE

REVIEW

Quality Risk Management Process (ICH Q9)

Risk M

anagement Tools

Ris

k C

omm

unic

atio

n

Risk Review

Risk Assessment

Risk Evaluation

unac

cept

able

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateRisk Management Process

Output / Results of theRisk Management Process

Equivalent Element of AZIRM Framework

UNDERSTAND

IDENTIFY

ASSESS

MANAGE

REVIEW

Quality Risk Management Process (ICH Q9)

Risk M

anagement Tools

Ris

k C

omm

unic

atio

n

Failure Mode Effect

(& Criticality) Analysis

Fault TreeAnalysis

Ishikawa(Fish Bone)

Process Mapping

Hazard Analysis & Critical

Control Point

Hazard Operability

Analysis

ICH Q10• Comprehensive model for an effective pharmaceutical

quality system• Based on International Standards Organisation (ISO) quality

concepts• Includes Good Manufacturing Practice (GMP)• Complements ICH Q8 “Pharmaceutical Development” and ICH Q9

“Quality Risk Management”• ”Implementation of ICH Q10 throughout the product lifecycle

should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities.”

Flow of QbD EFPIA Working Group

TargetTargetProductProduct

ProfileProfile

Definition of Product Intended Use and pre-definition of Qualitytargets (wrt clinical relevance, efficacy and safety)

Product/Product/ProcessProcessDesignDesignSpace Space

Summary of Scientific Understanding of Product andProcess.Justification and description of Multi-dimensional Space that Assures Quality(interrelation-ships and boundaries of Clinical Relevance).

ControlControlStrategyStrategy

Definition ofControl Strategybased on Design Space leading to Control of Quality and Quality Risk Mgmt.(Process Robustness)

Product/Product/ProcessProcessDev.Dev.

Overview ofQuality by Design key actions and decisions taken to develop New Scientific Knowledge, e.g. DoE, PAT, Risk Assessmentand Risk Control

PriorPriorKnowledgeKnowledge

Summary ofPrior Scientific Knowledge(drug substance, excipients; similar formulations and processes). Initial Risk Assessment

RegulatoryRegulatoryFlexibilityFlexibility

Proposal of Regulatory Flexibility based on Product and Process Scientific Knowledgeand Quality Risk Mgmt.(Materials, Site, Scale etc)

Examples:EFPIA Mock P2 – ExamplainFDA/Conformia – ACE tablet case study

QbD in practice:A tablet manufacturing process…

Raw Materials

WetGranulation

Fluid Bed Drying

Milling

Blending

Compression

Film Coating

Final Product Testing

ICH Q9: Quality Risk Assessments• QRA process (FMEA based)

• Structured assessment of potential failure modes and their effects

• Severity (S) – consequences of a failure occuring • Probability (P) or occurrence – likelihood of a failure occuring• Detectability (D) – how readily will the failure be detected if it

did occur

• Define scoring criteria for each• Overall risk expressed as a Risk Priority Number

(RPN) = S x P x D• Criticality can also be expressed as S x P• Multi-disciplinary team of technical/project experts

with trained facilitator(s)

Example QRA Risk Summary Matrix(Immediate Release Tablet)

Raw Material Variability Process Unit Operations

Quality Attribute

Man

nito

l

Avi

cel

Povi

done

Cro

scar

mel

lose

So

dium

Mag

nesi

um

Stea

rate

API

Dry

mix

ing

Wet

gran

ulat

ion

Wet

mill

ing

Dry

ing

Dry

mill

ing

Ble

ndin

g

Com

pres

sion

Film

coa

ting

Stor

age

of

inte

rmed

iate

s

Hardness 24 18 75 50 24 24 27 18 27 27 27 18 8

Appearance/ Description 36 36 36 27 27 27 27 27 18 18

Disintegration 36 36 75 75 36 36 6 6 6 27 6

Thickness

Friability

Weight 24 24 16 18 18 18

Granule moisture 8 8 8 8 8 50

Light degradation 24 24 24 24 24 24 24 36 24)

Degradation (other)

Identification

Assay/content uniformity 24 36 36 36 36 32

Dissolution 32 48 32 32 32 48 24 24 24 24 24 12

No appreciable risk (not scored)

Low Risk

Internediate Risk

High Risk

Eg. Relates to known phenomenon of tablet hardening on stability;S = 5, P = 3, D = 5

• ‘Criticality’ (S x P) score used to define critical parameters for both canister filling and packing

• RPN low risk due to controls in place (IPCs)

• Supported in-process control regime

QRA output – Example Pressurised Metered Dose Inhaler

Recirculatesuspension to filling machine

Fit meteringvalve to can

Check-weigh canisters

In-process control

Dispense into addition vessels

Purge air from can

Crimp metering valve onto can

Homogenisesuspension

Add API and excipientsto sealed vessel with agitation

Pressure fill suspension into canister

Store canistersvalve down to equilibrate

100% function test and checkweigh

Foil wrapin bulk

Label canister, assemble into actuator, individualfoil wrap

Propellant addition to vessel during filling

stage

Stress test to 55°CPropellant

recovery/ CIP

Recirculatesuspension to filling machine

Fit meteringvalve to can

Check-weigh canisters

In-process control

Dispense into addition vessels

Purge air from can

Crimp metering valve onto can

Homogenisesuspension

Add API and excipientsto sealed vessel with agitation

Pressure fill suspension into canister

Store canistersvalve down to equilibrate

100% function test and checkweigh

Foil wrapin bulk

Label canister, assemble into actuator, individualfoil wrap

Propellant addition to vessel during filling

stage

Stress test to 55°CPropellant

recovery/ CIP

High criticality parameters/steps

Flow of QbD EFPIA Working Group

TargetTargetProductProduct

ProfileProfile

Definition of Product Intended Use and pre-definition of Qualitytargets (wrt clinical relevance, efficacy and safety)

Product/Product/ProcessProcessDesignDesignSpace Space

Summary of Scientific Understanding of Product andProcess.Justification and description of Multi-dimensional Space that Assures Quality(interrelation-ships and boundaries of Clinical Relevance).

ControlControlStrategyStrategy

Definition ofControl Strategybased on Design Space leading to Control of Quality and Quality Risk Mgmt.(Process Robustness)

Product/Product/ProcessProcessDev.Dev.

Overview ofQuality by Design key actions and decisions taken to develop New Scientific Knowledge, e.g. DoE, PAT, Risk Assessmentand Risk Control

PriorPriorKnowledgeKnowledge

Summary ofPrior Scientific Knowledge(drug substance, excipients; similar formulations and processes). Initial Risk Assessment

RegulatoryRegulatoryFlexibilityFlexibility

Proposal of Regulatory Flexibility based on Product and Process Scientific Knowledgeand Quality Risk Mgmt.(Materials, Site, Scale etc)

ICH Q8: Design of Experiments (DOE)• Formulation Design

• “…enhanced knowledge of product performance over a range of material attributes…”

• Robustness study to understand impact on granulation of varying raw material grades

• Granulation “Endpoint” and tablet quality constant Aims:To establish excipient levels, grades andsuppliers over which ”quality” product canbe made

ICH Q8: Scientific Understanding• Manufacturing process development

• “…product of the intended quality…under different operating conditions, at different scales, or with different equipment should be provided.”

• Confirm both content and uniformity of product• Tablets and process intermediates

70

80

90

100

1400 1180 1000 850 710 500 425 355 250 180 125 90 63 Base

Granule size (µm)

A

110

120

130

140

ctiv

e (%

w/w

)

Content of sieved granules

Aims:To establish equipment type, scales andprocess equipment parameter ranges overwhich ”quality” product can be made

Process Analytical Technology: Granulation process

• Image Eye On-line particle size• On-line particle size during

granulation– Image analysis– On-line display

• Good agreement between on-line Dv50 and off-line Dv50

• Tool to monitor changes in a process to gain understanding 0

100

200

300

400

500

600

700

800

0.00 100.00 200.00 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.00

Granulating time (s)

Parti

cle

size

(µm

) - D

V (0

.5)

0

100

200

300

400

500

600

On-line Impellerpower

Off-line

Aims:1. To use more advanced tools to establish greater process understanding2. To identify potential tools for processcontrol at commercial scale (if required)

Linking this to form a ”Design Space”

”The multidimensional combination and interaction of input variables (eg material attributes) and process parameters that have been demonstrated to provide assurance of quality. ”

Target Product ProfileRefined to understandCritical Quality Attributes (CQAS)

Product and Process DOEsLinked to CQAs: Critical Process Parameters

CQAs

Business: Cost, environmentYield, etc

+

STATE OTHER PERFORMANCE PARAMETERS

STATE CPPS TO BE MONITORED & INTENDED TECHNOLOGY

CONTROLLING CPPs( eg via automation, control of process equipment)

CONTROLLING OTHER PPs( eg via automation, control of process equipment)

Level 1

Level 2

Level 3

PATIENT CRITICAL

OTHER KEYPERFORMANCE REQUIREMENTS Level 3 information

provided, as required,to support Level 2

Specific detail included insubmission

PQLI - Control strategy Model

Level 2 = Outline ofProcess Model (ie. What CPP values or CQAs to be measured & proposed methods)

Level 3 = Details ofProcess Model + Control Model (Controls CPPs)

CPP1 CPPnCPP2

--process understanding --

All product CQAs

Manufacturability

Consider both patient critical and business issues

STAGE 4: DRYING

STAGE 5: DRY

MILLING

STAGE 2: WET GRANULATION

STAGE 3: WET MASS

DE-LUMPING

Granuleparticle size (IPC)

Granule too fine• Feedback to next portion• Adjust water quantity (stage 2)

Granule too coarse• Feed-forward• Recommend screen size (Stage 5)

Improved dry milling controls through modelling

Control strategy – ExampleImmediate Release Tablet

The benefits of QbD at AZ• Understanding the processes has lead to greater

robustness and certainty of supply

• Development using QbD has enabled AZ to identify variability and hence control processes better

• The use of QbD has increased the understanding of the functionality of input materials and the impact on formulation

• Realise greater manufacturing flexibility and opportunities for continuous improvement by demonstrating scientific understanding to Health Authorities

QbD: Final Thoughts• QbD will lead to

• Greater process understanding…– By using DOE and PATs

• More appropriate controls– Fewer for simple products– More for complex products

• Clarification of ”quality”– The patient (defined in Critical Quality Attibutes)– The business (defined by manufacturability)

Acknowledgements• Steve Metcalf• Gavin Reynolds• Jon Sutch

Thanks for listening and any questions

References• http://www.ich.org/

• ICHQ8, ICHQ9 and ICHQ10• http://www.efpia.org/

• Mock P2 - Examplain• http://www.conformia.com/

• FDA/Conformia ”ACE” tablets case study• http://springerlink.com/content/w71655308218/?p

=118bcf51b4d945bd9e212f8298d4bc49&pi=0• PQLI Postition papers on Design Space, Criticality and

Control Strategy