QbD Application in Japan: PMDA Perspective

QbD Application in Japan: PMDA Perspective

Yasuhiro Kishioka, PhD.ReviewerOffice of Cellular and Tissue‐based ProductsPharmaceuticals and Medical Devices Agency

CMC Strategy Forum Japan 2013Hotel Okura, Tokyo, Japan, December 9 – 10, 2013

DisclaimerThe views and opinions expressed in this presentation are those of the presenter and should not necessarily represent the views and opinions of the PMDA.

Take‐home messages

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• The application of Quality by Design (QbD)* is for better quality assurance. *: defined in ICH Q8 (R2)

• The use of QbD will provide a better communication between regulators and industries. (…hopefully)

• Description in application form (AF) is one of the most important topics. However, AF (with modification(s) (if necessary))would be a good regulatory system to adopt a QbD concept.

Outline

1. Introduction2. QbD Application of Biologics in Japan 3. Future Perspectives

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• Q8(R2): Pharmaceutical Development • Q9: Quality Risk Management• Q10: Pharmaceutical Quality System• Q11: Development and Manufacture of Drug Substances (Chemical/Biotechnological entities)

• ICH Q‐IWG Points to Consider (R2)• Q‐IWG on Q8, 9, 10 Q&A’s (R4)

Guideline

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Quality by Design (Q8(R2))

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• A systematic approach to development• begins with predefined objectives and emphasizes product and process understanding and process control

• based on sound science and quality risk management.

• Quality cannot be tested into products; i.e., quality should be built in by design.

Modified from http://www.ich.org/products/guidelines/quality/training‐programme‐for‐q8q9q10/presentations.html

Example QbD Approach

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• Define Quality Target Product Profile (QTPP)Product Profile

CQAs

Risk Assessment

Design Space

Control Strategy

• Link raw material attributes and process parameters to CQAs and perform risk assessment

• Determine “potential” critical quality attributes (CQAs)

• Develop a design space (optional and not required)

Continual Improvement

• Design and implement a control strategy

• Manage product lifecycle, incl. continual improvement

Control Strategy (Q10)

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• A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.

• The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in‐process controls, finished product specifications, and the associated methods and frequency of monitoring and control.

Critical Quality Attribute (CQA)

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• A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (Q8(R2))

• Quality Attribute criticality is primarily based upon severity of harm and does not change as a result of risk management. (Q‐IWG PtCs (R2))

Critical Process Parameter (CPP)

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• A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (Q8(R2))

• Process Parameter criticality is linked to the parameter’s effect on any critical quality attribute. It is based on the probability of occurrence and detectability and therefore can change as a result of risk management. (Q‐IWG PtCs (R2))

Critical Process Parameter (CPP) (Cont.)

Critical

• The criticality of a parameter is linked to the risk of the parameter’s effect on a CQA.

• Although the risk associated with a parameter can be reduced by implementing a control strategy that changes the probability of occurrence and detectability as a result of risk management, the parameter remains a CPP. Criticality can evolve long term (during life cycle) when more knowledge is gained.

Modified from Dr. Mats Welin’s slide 2013 APEC Harmonization Center Biotherapeutics Workshop , September 25 – 27, 2013

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Design Space (Q8(R2))

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• The multidimensional combination and interaction of 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

QbD Assessment Project

http://www.pmda.go.jp/english/service/qbd_e.html (in English)

QbD Assessment Project Team

Chemical‐WG Biotech‐WG

Reviewer

ReviewerInspector Inspector

InspectorReviewer

ReviewerReviewer

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Reviewer

ReviewerInspector

Outline


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http://www.info.pmda.go.jp/shinyaku/P201300075/450045000_22500AMX01001000_A100_1.pdf

Pertuzumab application

• The applicant has applied QbD approach to develop the product, and design space was proposed in the manufacturing process.

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• Classification of Process Parameters‐Ranges tested/investigated were discussed.‐Some non‐CPPs (classified by the applicant ) should be described in AF.

Review points

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• Identification of CQAs‐Criticality should be primarily based upon severity of harm.

• Establishment of Design Space (DS)‐DS should be defined not only by CPPs* but also by some non‐CPPs*. (*:classified by the applicant )

• Design of Control Strategy‐Although potential residual risks remain, they will be managed by the modified control strategy.

Outline


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• Classification of Process Parameters

Issues We Need to Discuss

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• Identification of CQAs

• Establishment of Design Space (DS)

• Description in Application Form

• Application of QbD concept to Analytical Methods

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3.2.S.1 General Information3.2.S.2 Manufacture3.2.S.3 Characterisation3.2.S.4 Control of Drug Substance3.2.S.5 Reference Standards or Materials3.2.S.6 Container Closure System3.2.S.7 Stability

Module 1Application form (in Japanese)

Module 2 (QOS) (in Japanese)

Module 3 (in Japanese or English)

•Specification•Shelf life•Mfg. process•Mfg. site•Etc.

Raw data

Quality Review/Regulation in JapanMajor review documentApproval Matters

2.3.S.1 General Information2.3.S.2 Manufacture2.3.S.3 Characterisation2.3.S.4 Control of Drug Substance2.3.S.5 Reference Standards or

Materials2.3.S.6 Container Closure System2.3.S.7 Stability

Regulatory Flexibility

<Quality information>Im

pact on Quality

Low

High

Matters for Partial Change Application (PCA)

Matters for Minor Change Notification (MCN)

Application Form

Module 2(QOS)

Module 3

•Specification•Mfg. process•etc.

Quality Review/Regulation in Japan (Cont.)

Figure Inspired by Dr. Shikano’s slide 19

•Mfg. process•Process characterization•etc.



<Quality information>Im

pact on Quality

Low

High



Application Form

Module 2(QOS)

Module 3








PCA

MCN


<Quality information>

Application Form

Module 2(QOS)

Module 3




Impact on Q

uality

Low

High

• To ensure the quality of the product• To clarify/understand mfg. process



• The application of Quality by Design (QbD)* is for better quality assurance.

• The use of QbD will provide a better communication between regulators and industries. (…hopefully)

• Description in application form (AF) is one of the most important topics. However, AF (with modification(s) (if necessary))would be a good regulatory system to adopt a QbD concept.

Take‐home messages

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*: defined in ICH Q8 (R2)

Thank you for your attention!

Pharmaceuticals and Medical Devices AgencyOffice of Cellular and Tissue‐based Products

Yasuhiro Kishioka, PhD.

http://www.pmda.go.jp/ (in Japanese)http://www.pmda.go.jp/english/index.html (in English)

Acknowledgements Colleagues in the Office of Cellular and Tissue‐based Products QbD Assessment Project Members

Documents

QbD Application in Japan: PMDA Perspective