1

Design Space and Control Strategy

Fritz ErniGlobal Quality Operations

Novartis Basel

SAQOlten 2006

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OutlineICH Q8, Q9 and Q10 – The Vision of the desired stateQ8 is a Door Opener for

Describing Quality by DesignIncluding more Science and Risk ManagementIncluding PATInclude Design Space

Introduces the concept of Design SpaceDescribes how to define what is criticalRedefines what is a ChangeQuality Risk Management supports the Control StrategySummary

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Global Challenges

• Rising Global Regulatory Bar• Consent decrees and enormous fines from

manufacturing compliance deficiencies• Higher safety hurdles for marketing

approval• Challenge of Sustaining Product Pipeline &

Flow• Biotech contribution less than expected• Government price control• Challenge of Earning Stakeholders Trust

Ref: Fred Hassan – CEO Schering-Plough

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FDA’s 21st Century Quality Initiative

• Goals

1. Encourage the early adoption of new technological advances by the industry

2. Facilitate industry application of modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance

3. Encourage implementation of risk-based approachesthat focus both industry and FDA attention on critical areas

•Woodcock, FDA

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FromFrom‘‘blind complianceblind compliance’’

to to ‘‘science and risk science and risk

based compliancebased compliance’’Ajaz Hussain, FDAAjaz Hussain, FDA

The Paradigm ChangeThe Paradigm Change

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ICH agreed Desired State

• Product quality and performance achieved and assured by design of effective and efficient manufacturing processes

• Product specifications based on mechanisticunderstanding of how formulation and process factors impact product performance

• An ability to effect Continuous Improvement and Continuous "real time" assurance of quality

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2004 20052006

FDA PAT guideline

FDA DraftQuality Systems

FDA : Innovation and ContinuousImprovement in

Pharmaceutical Manufacturing

FDA Pharmaceutical cGMP for the 21st Century –a Risk based Approach

GMP and Regulatory Actions

Expert Working Groups (EWG)ICH

Q8Pharmaceutical Development

Q9Risk Management

Q10 Pharmaceutical Quality System

Update Q6A/B ?

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Process Analytical Technology : PAT

•FDA‘s Vision :

Paradigm Change: Quality by design replaces Testing to Document Quality

Product and Process specifications based on mechanistic understanding of how factors affect product performanceProcess understanding leading to

Real Time Quality assuranceContinous Improvement

Regulatory policies tailored to scienceRisk based approaches

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The role of Process Understanding

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Process Understanding

•Pharma •Air Plane

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Challenges to ‘Understanding’Understanding involves Measurements

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Challenges to Analytical Science

The need for increased Process understanding is a massive Boost for Analytical Science

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Challenges to Analytical Science

adequate Tools?

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Challenges to Analytical Science

adequate Tools !

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Challenges to Analytical Science

We need the adequate Tools

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Global Harmonisation (ICH+GCG)

Expert Working Groups (EWG)

WHO

Global Cooperation Group

APEC : Asia Pacific Economic Cooperation

ASEAN : Assoc. South East Asian Nations

GCC : Gulf Cooperation Council

PANDRH : Pan American Network for Drug Reg. Harm.

SADC : South African Dev. Community

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What is Q8 be!

• Guideline for the description what is in P2

• Describes the minimal Standard for P2

• Opens door to get closer to the ‘Desired State’

• Science based• Includes Risk Management• Continuous improvement• Real Time Release

ICH Q8Door opener for

Quality by Design

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What is Quality by Design

Elements of a QbD

• Systematic Development Approach• Formulation Understanding• Process Understanding• Packaging Understanding• Application of Quality Risk Management• Advanced Control Strategy

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Quality by Design

Extended PAT tools replacing the need for end product testing

Limited and simple IPC

Focus on formulation and process robustness – understanding and controlling variability

Focus on process reproducibility – often avoiding or ignoring variability

Flexible process within design space, allowing continuous improvement

Process is fixed, disallowing changes

Quality assured by well understood product and process, moving controls upstream without relying on end-product testing as much as possible

Quality assured by end-product testing and inspection

A systematic approachMainly empirical approachQuality by Design(ideal)Conventional PD

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1. Drug substance– Key physicochemical characteristics– Compatibility

2. Excipients3. Drug product

– Rationale for type of product– Formulation development– Overages– Physicochemical and biological properties– Performance testing

4. Manufacturing Development5. Container closure system (and delivery devices)6. Microbiological attributes7. Compatibility

P2 Content per CTD-Q

Where to put information in on Quality by designScienceRisk ManagementContinous improvementReal Time Release

When to update the document

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Where do we stand?

• Q8 Step 4 signed by 6 ICH partners and observers

• Confirmed main Strategic issues

• Clarifying ‘baseline’ and ‘optional’expectations

• Outlined areas of potential regulatory flexibility that could be expected when presenting ‘optional’ information

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Q8 – General ConceptsQbD and Risk Management

• The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the application of scientific approachesand quality risk management to the development of a product and its manufacturing process.

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Q8 – General ConceptsQbD and Risk Management

• The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

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Q8 – General ConceptsWhat is minimal requirement

At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified.

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Q8 – General ConceptsWhat is critical?

Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product.

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Q8 – General ConceptsOptional process understanding

In addition, the applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters.

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Q8 – General ConceptsWhat we get in return

This scientific understanding facilitates establishment of an expanded design space. In these situations, opportunities exist to develop more flexible regulatory approaches, for example, to facilitate:

• risk-based regulatory decisions (reviews and inspections);• manufacturing process improvements, within the approved

design space described in the dossier, without further regulatory review;

• reduction of post-approval submissions;• real-time quality control, leading to a reduction of end-

product release testing.

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Possible Regulatory Flexibility– Continuous Improvement

– Real time release– Reduced or elimination of routine end product testing

– Expanded design space– Independence on scale– Independent of equipment– Independent of site– Independent from drug substance manufacturing if within spec

– Process Validation– Process validation replaced by Concurrent Process Verification using validated methods

(qualified controls)

– Stability Testing– Reduced confirmation stability studies for any changes within the design space– Reduced annual stability batches

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Q8 – General ConceptsReview - Inspection

The Pharmaceutical Development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors.

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Q8 – Strategic Questions :Submissions and Post Approvals

It is first produced for the original marketing application and can be updated to support new knowledge gained over the lifecycle of a product

31

Process understanding

Key for making a good story!

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Q8 – Strategic Questions :

What is the Design Space?

Will be the Base for Continuous Improvement!

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Design Space• Is Key for claiming Process Understanding

• Process understanding is Key forQuality Risk Management

• QRM is the base for any Control Strategy

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Design Space

The multidimensional combination and interactionof input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

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Q8 – Design Space :

Redefines what is a Change?

Base for all Post Approval Changes

36EFPIA PAT Team

EFPIA PAT Topic Group

Chris Potter AstraZeneca: ChairmanRafael Beerbohm Boehringer-IngelheimAlastair Coupe PfizerFritz Erni NovartisGerd Fischer Sanofi-AventisStaffan Folestad AstraZenecaGordon Muirhead GSKStephan Roenninger F Hoffmann-La RocheAlistair Swanson Pfizer

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An Industry View of QbD in Dossier: Key Scientific Elements and ‘Flow’

TargetTargetProductProduct

ProfileProfile

ControlControlStrategyStrategy

PriorPriorKnowledgeKnowledge

Product/Product/ProcessProcessDev.Dev.

Product/Product/ProcessProcessDesignDesignSpace Space

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

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

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

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

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)

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Design Space (ICH Q8)

The multidimensional combination and interactionof input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.

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Design Space• Is Key for claiming Process Understanding

• Process understanding is Key forQuality Risk Management

• QRM is the base for any Control Strategy

40EFPIA PAT Team

Dissolution profiles of examplain hydrochloride tablets - effect of lubrication level pH 6.8

0

20

40

60

80

100

120

0 5 10 15 20 25 30 45

Time (minutes)

Mea

n %

dis

solu

tion

1% Mg St2% Mg St3% Mg St

41EFPIA PAT Team

Design of Experiments (DoE)

Air flow

Inle

t tem

pera

ture

Degradation and fines

Air flow

Inle

t tem

pera

ture

Degradation and fines

Air flow

Inle

t tem

pera

ture

Degradation and fines

Air flow

Inle

t tem

pera

ture

Fines

Air flow

Inle

t tem

pera

ture

Degradation

Air flow

Inle

t tem

pera

ture

Fines

Air flow

Inle

t tem

pera

ture

Fines

Air flow

Inle

t tem

pera

ture

Degradation

Air flow

Inle

t tem

pera

ture

Degradation

Effect of inlet temperature and air flow on degradation and generation of fines

42EFPIA PAT Team

Examplain Design Space –Graphical Description

Known edge of failure due to fines

% H2O

2.0%1.5%

18.5%

Drying time

Known edge of failure due to degradation

Regions of uncertainty17.5%

Trajectories describing the boundaries of the design space where product quality is assured

Known edge of failure due to fines

% H2O

2.0%1.5%

18.5%

Drying time

Known edge of failure due to degradation

Regions of uncertainty17.5%

Trajectories describing the boundaries of the design space where product quality is assured

43EFPIA PAT Team

PAT Development ApproachTarget Product Profile

Drug substance and Excipient properties; prior knowledge

Proposed formulation and manufacturing processInitial Risk Identification

Determination of Cause – Effect relationships

Risk-based classification (Risk Evaluation)

Proposed Parameters to investigate (e.g. by DOE)(Risk Reduction)

FORMULATION FORMULATION DESIGN SPACEDESIGN SPACE

PROCESS DESIGN PROCESS DESIGN SPACE BY UNIT SPACE BY UNIT

OPERATIONOPERATIONCONTROL STRATEGYCONTROL STRATEGY

Form

ulat

ion

unde

rsta

ndin

gFo

rmul

atio

n un

ders

tand

ing

Proc

ess

unde

rsta

ndin

gPr

oces

s un

ders

tand

ing

QUALITY RISK QUALITY RISK MANAGEMENTMANAGEMENT

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Real-Time MonitoringReal-Time Monitoring

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

-1 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3

t[1]

T i m e / M a tu r i ty ($ T i m e )

B a t c h F in g e r p r in t /G o ld e n B a t c h - P r e d ic t e d s c o r e s f o r t [1 ]

3 s td . d e v . A v e r a g e B a tc h - 3 s td . d e v . 1 0 0 3 4 1 2

M1

S I M C A -B a t c h O n -L in e V ie w 2 . 1 - 7 / 2 9 / 2 0 0 5 1 2 : 4 8 : 5 6 P M

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Plot For One VariablePlot For One Variable

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

MVD1

-MS:L

N_DY

A520

0963

6_AIR

VOL

Time/Maturity ($Time)

520096_DR_A - MVD1-MS:LN_DYA52009636_AIRVOL 3 std. dev.Average Batch-3 std. dev.666022_D

M1

SIMCA-Batch On-Line View 2.1 - 5/24/2005 7:57:47 AM

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Assay – Training Set & Test SetAssay – Training Set & Test Set

90.091.092.093.094.095.096.097.098.099.0

100.0101.0102.0103.0104.0105.0106.0107.0108.0109.0110.0

90.0 91.0 92.0 93.0 94.0 95.0 96.0 97.0 98.0 99.0 100.0 101.0 102.0 103.0 104.0 105.0 106.0 107.0 108.0 109.0 110.0

Y O

bser

eved

- A

ssay

Y Predicted - Assay

Observed vs. Predicted - Assay - Training Set & Test Set

RMSEP = 0.502927

WorksetTest Set

y=0.983*x+1.7R2=0.9268

SIMCA-P+ 10.5 - 8/8/2005 10:57:20 AM

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MVBA ResultsMVBA Results

9 09 19 29 39 49 59 69 79 89 9

1 0 01 0 11 0 21 0 31 0 41 0 51 0 61 0 71 0 81 0 91 1 0

9 0 9 1 9 2 9 3 9 4 9 5 9 6 9 7 9 8 9 9 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7 1 0 8 1 0 9 1 1 0

Y O

bser

ved

Y P r e d i c te d

O b s e r v e d v s P r e d ic t e d - C o n t e n t U n if o r m it y

R M S E E = 0 . 1 0 5 0 2 5

y = 1 .0 0 1 * x -0 .0 9 6 5 8R 2 = 0 .9 7 7 3

S I M C A - P + 1 1 - 7 / 2 6 / 2 0 0 5 3 : 4 6 : 4 0 P M

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MVBA ResultsMVBA Results

9 09 19 29 39 49 59 69 79 89 9

1 0 01 0 11 0 21 0 31 0 41 0 51 0 61 0 71 0 81 0 91 1 0

9 0 9 1 9 2 9 3 9 4 9 5 9 6 9 7 9 8 9 9 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 1 0 6 1 0 7 1 0 8 1 0 9 1 1 0

Y O

bser

ved

Y P r e d i c te d

O b s e r v e d v s P r e d ic t e d - D is s o lu t io n

R M S E E = 0 .3 1 6 8 0 3

y = 1 .0 0 4 * x -0 .3 9 9R 2 = 0 .9 8 0 6

S I M C A - P + 1 1 - 7 / 2 6 / 2 0 0 5 3 : 4 7 : 3 9 P M

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ICH Q8 : Important points for Industry

Open the door for submitting Quality by Design dataNo escalation of requirement

Defines BaselineDefines optional opportunities

Optional Update of P2 for adding knowledge for PACDefines : What is a critical parameterDesign Space: What is/is not a changeRegulatory Flexibility

Continuous improvementReal time release

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Q8 Next steps

• June 2006 ICH EWG Japan– Q8 addendum for specific dosage forms– Q8 for API’s ?

• Q8 Implementation– Learn to use concepts

• Design space• Critical Parameters• Regulatory flexibility

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Quality Risk Management Q9and the Control Strategy

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The Quality Risk Management Process

Risk Review

Ris

k C

omm

unic

atio

n

Risk Assessment

Risk Evaluationunacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

Risk M

anagement tools

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WaterContent

Drying

Granulation

RawMaterials

Compressing

PlantFactors

Operator

Temp/RH

Precompressing

Main Compressing

Feeder Speed

Press Speed

Punch PenetrationDepth

Temp

RH

Air Flow

Shock Cycle

DrugSubstance

P.S.Process Conditions

LOD

Diluents

P.S.LOD

Other

Lubricant

Disintegrant

Binder

Water

Binder

Temp

Spray Rate

Spray Pattern

P.S.

Scrape Down

Chopper Speed

Mixer Speed

Endpoint

PowerTime

Age

Tooling

Operator

Training

Analytical

Method

Sampling

FeedFrame

Cause and Effect Process

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QRM Tools:Failure Mode Effects Analysis (FMEA)

Risk Assessment

Sub-Step Event(Failure mode) Effect

Seve

rity

(S)

[1<2

<3]

Prob

abili

ty (P

)[1

<2<3

<4]

Det

ecta

bilit

y (D

)[1

<2<3

]

Ris

k fa

ctor

(S

*P*D

)

Granulation Drying water content not meet specification of degradation 2 3 1 6

Risk Reduction

Actions:Risk reduction strategy

Sev

erity

(S)

[1<2

<3]

Pro

babi

lity

(P)

[1<2

<3<4

]

Det

ecta

bilit

y (D

)[1

<2<3

]

Ris

k fa

ctor

(S

*P*D

)

Ris

k re

duct

ion

Comments

introduce online NIR 2 1 1 2 4 indirect measurment

introduce IPC analytic 2 2 1 4 2 direct measurement; time consuming

humidity measurement in the exausting air 2 1 2 4 2 indirect measurment;

unspecifoc

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Risk Management processQ

ualit

y A

ttrib

utes

Unit operation

Granulation Drying Blending TabletingDispensation

Dissolution

Disintegration

Hardness

Assay

ContentUniformity

Degradation

Stability

Appearance

Identification

Water

Microbiology

ControlStrategy

Formulation and Process

understanding

Prior knowledge

Significant influence

Initialassessment

First & Second review cycle

Thirdreview cycle

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QRM QRM –– Design Space Design Space –– Control StrategyControl Strategy

Initial QRM Final QRM

Control Strategy

QRM

DoE DoE

Design Space

Design Space

QRM

P2 Document

Continuous Improvement

Real Time Release

Quality Risk Management

DoE

DesignSpace

DoE

Design Space

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Control Strategy

Unit OperationsAttributesControls

Content Uniformity NIR

Water Content – NIRParticle size – FBRM

Dispensation

Blending

Fluidized Bed Dryer

Packaging

Tableting

Identity-NIR

Blend Homogeneity -NIR

Granulation

Extent of Wet Massing - Power

Consumption

Air

Scale

Multivariate Model (predictsDisintegration)

Raw Materials

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Control Strategy• Justification of necessary controls

– Raw Materials Control– In-Process Controls– End Product Controls (if necessary)

• Based on Process and Formulation Understanding

• Drives the Process in the Design Space• Based on Quality Risk Management• To ensure conforming Quality according

Specifications

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SummaryQ8 describes content of Section P2 of the Q-CTDQ8 is a Door Opener for

Describing Quality by DesignIncluding more Science and Risk ManagementIncluding PATInclude Design Space

Introduces the concept of Design SpaceDescribes how to define what is criticalRedefines what is a ChangeQuality Risk Management supports the Control Strategy

60EFPIA PAT Team

EFPIA PAT Topic Group

Chris Potter AstraZeneca: ChairmanRafael Beerbohm Boehringer-IngelheimAlastair Coupe PfizerFritz Erni NovartisGerd Fischer Sanofi-AventisStaffan Folestad AstraZenecaGordon Muirhead GSKStephan Roenninger F Hoffmann-La RocheAlistair Swanson Pfizer