gary khoo asia biomfging summit 2009 final presentation

QbDQbD within the regulatory within the regulatory framework: Current and Future framework: Current and Future

PerspectivesPerspectives

Gary Khoo, PhD.A-Bio Pharma

Asia Biomanufacturing SummitSingapore

28 Oct 2009

Gary Khoo Asia Biomnaufacturing Summit 2009

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OutlineOutline

• QbD and regulatory background/ framework• ICH Q8(R1) Update• Current & future perspectives-

implementation and integration• Business considerations• Summary


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QbDQbD Framework:Framework:Quality in Product Life Cycle Quality in Product Life Cycle

Product Design

Process Development

Scale-up & Transfer

Commercial Manufacturing

Clinical PhasesIND BLA

ICH Q8 (R) Pharmaceutical Development

PAT Guidance (2004)/ Process Validation Guidance (2008) draft

ICH Q9 Quality Risk Management

ICH Q10 Pharmaceutical Quality Systems

ICH Q11? Step 2 4Q 2009

Adapted from Mukund Yelvigi, GMP International Workshop 2008, Mumbai


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QbDQbD Framework:Framework:What is Quality by Design?What is Quality by Design?

• Science based, risk based, holistic and proactive approach to pharmaceutical development

• Product, process understanding and process control


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QbDQbD Framework:Framework:Quality by Design: Design SpaceQuality by Design: Design Space

Knowledge Space

Design Space

Acceptable Operating Space

Control Space

Ref: J Pharm Innov (2008) 3:60–68/ Bioprocess Intl. (2008) Mar 16-23


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QbDQbD Framework:Framework:Why Why QdDQdD? An FDA view point? An FDA view point

• Hesitation to implement new, better technologies• Little emphasis on manufacturing and its problems- high

wastage due to mistakes• Development information empirical- inability to predict

scale-up/ roots cause of errors• Differences in how products are regulated from region to

region• Time consuming supplemental application for every

manufacturing change• Dramatic increase in post-approval applications. Real

burden on FDA• Less flexibility on the regulatory side


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QbDQbD Framework:Framework:Changes in approachChanges in approach

Aspect Minimal Approach Enhanced QbDDevelopment

Manufacturing Process

Process controls

Product specifications

Control strategy

Lifecycle management

Empirical, one variable at a time Mechanistic understanding, multivariate understanding

Fixed; validation based on initial full scale batches

Adjust within design space; Lifecycle approach to validation

In-process tests for go/no-go decisions

PAT tools for feed forward/ feed back real time controls

Primary means of control Part of overall quality control strategy within design space

Drug product quality controlled by testing (intermediate/ end product)

Real-time testing/ reduced end product testing

Reactive (corrective action etc.) Preventive, continual improvement

Q8(R1) – Annex to Q8 Pharmaceutical Development,


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ICH Q8 Update:ICH Q8 Update:Annex to Q8 Pharma (R1Annex to Q8 Pharma (R1‐‐FDA/ R2 EMEA)FDA/ R2 EMEA)

• 2 Part guide– Part 1 was finalized (Step 4) in Nov 2005– Part 2 only recently finalized (Nov 2008 –FDA/EMEA

Jun 2009)• Part 1:Core document with baseline

expectations, optional information and regulatory flexibility– General principles of pharmaceutical development– Introduce new concepts

• Part 2: Annexes act as a reference towards the desired state and on the use if risk management

Robert Baum, PhRMA, Public ICH Meeting Brussels Nov 2008


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ICH Q8 Update:ICH Q8 Update:Updates on Updates on QbDQbD submissionssubmissions

• CMC/ Common Technical Document (CTD) sections S2 (Drug Substance) and P2 (Drug Product)

• July 2008, FDA OBP initiated pilot program for biologics.

– 10 supplements and 5 BLAs during initial phase.

• In Sep 2009, this deadline for pilot submissions extended (increasing to 8 BLAs).

– INDs are also now included in the program.

• Mock P2 submission- Several organizations (e.g. EFPIA, PDA) have done this with NCE.

• Latest PDA meeting (Frankfurt, 22-23 Sep 2009) presented a Mock P2 based on an antibody process

FDA Federal Register: September 17, 2009 (Volume 74, Number 179) Page 47806-47807


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ICH Q8 Update:ICH Q8 Update:Q&A Release April 2009Q&A Release April 2009

• Establishing design space or using real time release testing is not necessarily expected

• Design space:– multivariate interactions not necessary if justified– can be applicable to scale-up– can be applicable to site-change– can be developed over a single unit operation or a

series of unit operations– Existing products are exempted but may be useful

• Control Strategy:– systematic science and risk-based approach for

controls rather than narrow ranges– control strategies exist even without a design space

June 2009 (EMEA/CHMP/ICH/265145/2009)


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Current/Future Perspectives:Current/Future Perspectives:Key steps for the implementation of Key steps for the implementation of QbDQbD

Identify TPP

Identify CQA

A. Rathore and H Winkle; Nature Biotechnology vol 27, Jan 2009, 26-34


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Current/Future Perspectives:Current/Future Perspectives:Critical Implementation strategyCritical Implementation strategy

• Target Product Profile: dosage, pK, half-life, safety profile, sterility, immunogenicity

• Critical Quality Attributes: What protein attributes give rise to target product profile.

• Defining product design space:– Clinical design space– Non-clinical studies and data

• Defining process design space– Risk analysis, designed experiments, execution and analysis– How are the CQAs created in the process?

• Refining product design space based on what is achievable robustly (Scaled down models)


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Current/Future Perspectives:Current/Future Perspectives:““HolisticHolistic”” vsvs ““unit operationunit operation”” approachapproach

Upstream-fermentation/cell culture

Capture

Polishing

Efficacy/ Potency

Safety/ Purity

• QbD for all unit operations necessary?• Identify critical process steps based on efficacy

and purity (evidence based)• Risk based approach


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Current/Future Perspectives:Current/Future Perspectives:Form An Integrated TeamForm An Integrated Team‐‐ Genentech ModelGenentech Model

Biologics Process Research<10L

Biologics Process Research<10L

Commercialscale production2000lL – 20,000L

Process Devt& Medium Scale

production10L‐500L

Fill & Finish

• Process development, optimisation, scale‐up

• Productivity enhancement• QbD, PAT implementation• Product quality & stability

• New cell line development

• Expression engineering

• Media design• Novel product

• Process scale up • DS Manufacturing facility operations

• COGS improvement• Lean manufacturing

• Vial filling, packing• Lyophilization• Supply chain operations• COGS improvement• Lean manufacturing

FUNCTIONAL EXCELLENCE

CELL CULTURE •Molecular Biologists•Microbiologists•Cell Biologists•Virologists

ANALYTICS•Analytical Biochemists•Biophysical Chemists•Protein Biochemists

PURIFICATION•Chromatographers•Protein Biochemists•Biochemical Engineers

FORMULATION•Formulation chemists•Protein Biochemists•Engineers

ONE CMC TEAM

Taken from Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.


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Current/Future Perspectives:Current/Future Perspectives:Global Global ““RecipeRecipe””, Local control: , Local control: CentocorCentocor ModelModel

Taken from Paul McKenzie Bioproduction Forum Sep 2009


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Business ConsiderationsBusiness Considerations

• Enhanced process and product understanding• Smoother transfers between R&D and

manufacturing• Fewer manufacturing failures• Broad spectrum of industry implementation• CMC Post-Approval Change Management could

be a major factor for implementing QbD• Will Q8, Q9, Q10 (Q11) remain optional or

become a regulatory expectation?

Robert Baum, Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, Maryland, Aug 2009


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Business considerationsBusiness considerations• How will products made with the minimal approach fair

against “QbD” products (regulatory submissions/ “consumer perception”)?

• Different manufacturing expectations, control procedures, etc.– put new requirements on supply chain/quality – Justification for greater resources to incorporate QbD

• Uncertainty over timing of and investment requirements for QbD implementation

• How to manage QbD with Alliance Partners, CROs and Suppliers?

• Design quality into manufacturing processes- how will the management of each site be managed?

Robert Baum, Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, Maryland, Aug 2009


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Business Considerations: Business Considerations: Who can afford Who can afford QbDQbD??

Big Pharma model

SmallBiotechmodel

Taken from Paul McKenzie Bioproduction Forum Sep 2009


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SummarySummary

• QbD has evolved, is still evolving with better understanding of its implementation

• Have a macroscopic view about it’s implementation and key requirements within the regulatory framework

• QbD is still optional but it can benefit business in long term

• QbD starts early; competent partners and CMOs can make a difference

gary khoo asia biomfging summit 2009 final presentation

Business

qbdqbd framework

regulatory framework

future framework

q8 pharmaceutical development

process validation guidance

real time controlsprimary

time mechanistic understanding

validationinprocess