Design Regulatory Science Symposium, 21 June 2017 · PDF fileQuality by Design Regulatory Science Symposium, 21 June 2017 ... e.g. limits for non related impurities ... • Quality

Dr. Jobst Limberg |Quality by Design – First Annual Meeting of PEARRL, Cork, 21 .June 2017 | Page 1

Quality by Design

Regulatory Science Symposium, 21 June 2017First Annual Meeting of PEARRL, Cork

Dr. Jobst Limberg, BfArM, Germany

presented at the PEARRL Regulatory symposium 2017 – for personal use only


TopicsofthisPresentation

Regulatory Requirements

Classical approach

Quality by Design• Pharmaceutical Development• Process Analytical technology (PAT)• Design Space (DS)• Continuous Process Validation (CPV)• Risk Assessment and Critical Process Parameters (CCP)

Summary and Conclusions

Classical approachSum

mary and Conclusion


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TheMarketingAuthorisationProcedureforDrugProducts

Positive risk/benefit ratio

Therapeutic efficacy

Clinical safety

Preclinical data

Pharmaceutical quality

Results of the development programmes

Exploratory and confirmatory studies

No significant differences between the proposed drug product and the drug formulation tested in the pivotal clinical studies


mary and Conclusion

RegulatoryRequirem

entsQuality by D

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Qualityasabridgingtool

future productionbatches innovator

marketing authorization application

efficacy inno

vator

tested batchesinnovator quality as

bridging tool

clinical trials trade

future productionbatches generic


mary and Conclusion

RegulatoryRequirem

entsQuality by D

esign



CTD– ContentofMarketingAuthorisationDossier


mary and Conclusion

RegulatoryRequirem

entsQuality by D

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CTD– ContentofMarketingAuthorisationDossier

Module 3Quality

3.1Table of content

3.2Body of data

3.3Literature references

3.2.SSubstance

3.2.PDrug Product

3.2.AAppendices

3.2.RRegional Information

3.2.P.1 Composition drug product3.2.P.2 Pharmaceutical development3.2.P.3 Manufacture3.2.P.4 Control of excipients3.2.P.5 Control of drug product3.2.P.6 Reference standards or materials3.2.P.7 Container closure system3.2.P.8 Stability


mary and Conclusion

RegulatoryRequirem

entsQuality by D

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ClassicalApproach

Focus is on the reproducibility of the process

Validation of the manufacturing process is the key issue

Compendial requirements for known ingredients

Confirmatory test on a small random sample at time of batch release

A specification valid for the shelf life of the drug product “confirms, if tested”

Agreement with the approved model of the drug product


mary and Conclusion


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ClassicalApproach‐ schematicillustration

Manufacturing process

In processcontrols

Process parametersQuality of Ingredients

Confirmatorytesting at time of batch release

Specification

Suitable limits

Variability due to ingredients and process parameters Specification


mary and Conclusion


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SettingSpecifications‐ ClassicalApproach

(1) Based on conventional requirements,e.g. according to pharmacopoeial rules

(2) Based on general toxicological evaluations,e.g. limits for non related impurities (solvents, catalysts)

(3) Based on individual requirements, e.g. limit for an identified impurity qualified by toxicological data

(4) Based on results of representative batches to ensure a consistent quality of the drug product


mary and Conclusion


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ProcessValidationinaClassicalApproach

Pharmaceutical development

Formal validation Life cycleFormal

validation

3 pilot scale batches

3 commercial scale batches

a) Standard manufacturing

Pharmaceutical development

Formal validation Life cycle

3 commercial scale batches

Batches on the market

b) Non standard manufacturing

Marketing Applicationincluding process validation plan

Batches on the marketLaboratory and pilot scale batches

Laboratory and pilot scale batches

Marketing Application


mary and Conclusion


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PharmaceuticalIndustryfacingQualitybyDesignandPAT

Who willcreate allthe dataneeded ?

No moreVariations,hooray !

Betterquality !

What shouldbe includedin the dossier ?



QualitybyDesignApproach

Focus is on the robustness of the process

Development based on systematic experimentation

Design Space

Risk Management

Functionality related tests for ingredients

Real time release control strategy

A specification valid for the shelf life of the drug product “confirms, if tested”

Continuous improvement during the lifecycle of the drug product


mary and Conclusion


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LifecycleofControlStrategyinanenhancedapproach

Development• Risk assessment• Identification of critical parameters• Quality target product profile

Implementation• In process controls• Release specifications• Stability considerations

Continual Improvement• Change control


mary and Conclusion


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QualitybyDesign duringdevelopment:exemplaryoverview


mary and Conclusion


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QualitybyDesignApproach– schematicillustration

Manufacturing Process

Design Space

Controls ProcessAnalytical Technology

Process parameters

Ingredients

Variability of the drug product

ProductVariability

Monitoring

classical approach


mary and Conclusion


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ProcessAnalyticalTechnology(PAT)

PAT concept may include online testing of multiple units and process parameters in an exploratory way

The confirmatory testing of a very limited number of units at batch release may be omitted [Real Time Release concept]

Problems arise concerning pharmacopoeial requirements for which specific acceptance criteria for a given number of samples exist, e.g. uniformity of content, disintegration and/or dissolution test

Representativeness of the samples should always be discussed


mary and Conclusion


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PATExample:ManufacturingofTablets

Tablet Compression

Pan CoatingSifting Roller

compactionBlending

Excipients & API dispensingSpecificationsbased on product

NIR MonitoringBlend Uniformity

Laser DiffractionParticle Size

Dispensing

NIR Spectroscopy(At-Line) • Identity• Assay • API to Excipient

ratio

* Slide by C.Moore, FDA


mary and Conclusion


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Chapter5.25.derPh.Eur.„ProcessAnalyticalTechnology(PAT)“‐ Classification

1. Process Analytical Technology (PAT) Introduction

2. Process Analysis interfacing modes• Off‐line, At‐line, On‐line, In‐line• Schematic Illustration• Examples

3. Comparing Classical Analytics to PAT

4. Texts modified in Ph.Eur. in the light of PAT usage

5. Glossary


mary and Conclusion


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SchematicIllustrationofInterfacingModesClassical approach

Summary and Conclusion


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DesignSpace

A virtual, multidimensional space of critical parameters

In this space a product of suitable consistency will be produced

Target formulations which have been used in the pivotal clinical studies should be located inside the proposed design space

Experimental results to establish the proposed borders

Justification of the suitability of the limits • Large number of results for different production batches • In critical products even results of clinical studies


mary and Conclusion


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GraphicalOverview‐ DesignSpace

██ Knowledge Space based on Design of Experiments

██ Design Space based on Knowledge Space

██ Normal Operating Range Inevitable Variability

Normal Operating Ranges

Design Space

Knowledge Space


mary and Conclusion


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HowtosetasuitableDesignSpace?

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9 10

Para

met

er 2

Parameter 1

All inclusive (???)

Statistically justified (?)

Conservative (!)

Early Development

Out of model

DevelopmentClinicalProduction


mary and Conclusion


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ContinuousProcessValidation

Design space verification is to confirm the suitability of the design space and verify that all product attributes are still being met in the new area of operation within the design space.

Pharm. development

Design space validation Life cycleContinuous

Process Verification

pilot scale batches

N commercial scale batches

„Enhanced“ Approach Marketing Applicationincluding verification protocol

Batches on the market

Laboratory and pilot scale batches


mary and Conclusion


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3 commercialscale batches



AssessorsfacingQualitybyDesign

Flexibility may reducevariations

A sciencebaseddossier !

I cannot assesswhat I do notunderstand !I do not

acceptflexibilityin thedossier !



PrerequisitesforadequateassessmentofQualitybyDesignapproaches

Experience in manufacturing of drug products

Mathematical understanding

Good statistical skills

Regulatory experience beside “guideline knowledge”

An open mind towards new concepts


mary and Conclusion


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HarmonisationoftheEvaluation:

Working groups of assessors, inspectors and pharmacopoeias have been established:• BfArM PAT group • EMA PAT team• EDQM PAT expert group• EMA PAT team plus FDA dialogue meetings (see next page)

Conclusions of the working groups:• The use of identical terminology is crucial to avoid misunderstandings.• The patient's needs should be the focus of efforts.• The amount of data to be sent to the regulatory authorities should be

clearly defined on an international level.


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ConsultativeProcedures:EMAandFDA

Consultative procedures started in 2013

Selected applications in USA and/or in Europe that are submitted in one economic region solely

Peer review of assessment reports by experts from both agencies

Consultation during review with the goal to achieve a common point of view and harmonised evaluations in future

Applicable to new marketing authorisation applications and scientific advice procedures

In case of discussion with the applicants the non‐competent authority is “in listening mode” only


mary and Conclusion


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ApplicationsusingQbDapproach

Few applications introduce a quality by design approach without asking for regulatory flexibility, i.e. real time release strategies, design space.

Accepted with no major problems because the conventional documentation has been augmented.

Some applications introduce a quality by design approach with a real time release (RTR) strategy for quality attributes. Most common attributes for RTR are identity, uniformity of single dosage unit and/or assay.

A complete RTR concept is not known to me, especially the testing for impurities maybe hardly accepted by the regulatory authorities due to lack of sensitivity of NIR methodology.


mary and Conclusion


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Thank you very much foryour attention!

ContactFederal Institute for Drugs and Medical DevicesDivision European and International Affairs Kurt-Georg-Kiesinger-Allee 3D-53175 Bonn

Contact personDr. Jobst [email protected] +49 (0)228 99 307-3353Telefax +49 (0)228 99 307-3534


Design Regulatory Science Symposium, 21 June 2017 · PDF fileQuality by Design Regulatory Science Symposium, 21 June 2017 ... e.g. limits for non related impurities ... • Quality

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