pmda perspective on quality by design for pharmaceutical products · 2019-03-28 · quality by...

PMDA perspective on Quality by Design for pharmaceutical

products

Junichi Fukuchi, Ph.D.

Office of Cellular and Tissue-based ProductsPharmaceuticals and Medical Devices Agency (PMDA)

Annual conference of PSK on Apr 17, 2014 1

Disclaimer The information within this presentation・・・

Is not intended to create any new expectations beyond current regulatory requirements.

Is not official views of PMDA. Contains my personal point of view.


Introduction of PMDA

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• NAME: Pharmaceuticals andMedical Devices Agency

• Date of Establishment: April 2004 Established as an Incorporated Administrative Agency (IAA) in April, 2004

http://www.pmda.go.jp/english/index.html

Annual conference of PSK on Apr 17, 2014

OutlinePMDA experience with QbD

Example small molecule: Edoxaban Tosilate Hydrate biologics: Pertuzumab

QbD assessment project

PMDA comments on the Q&As


Quality by Design (Q8(R2)) Quality cannot be tested into products; i.e.,

quality should be built in by design. 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.


Annual conference of PSK on Apr 17, 2014Modified 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

PMDA Experience with QbD

Applications with QbD in JapanNumber of approved products (up to Jan 2014)

Consultations with PMDA on QbDNumber of Consultations (up to Jan 2014)


2007 2008 2009 2010 2011 2012 2013

1 0 2 2 4 4 3

2008 2009 2010 2011 2012 2013

3 3 2 11 11 12

Example : Edoxaban Tosilate Hydrate (1)

http://www.pmda.go.jp/english/service/drugs.html

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Some review reports are translated into English.



Approved in April 2011

RTRT : Uniformity of dosage units, Dissolution and Assay

DS : Uniformity of dosage units, Dissolution and Assay

9Annual conference of PSK on Apr 17, 2014


Identification of factors affecting the dissolution

The subsequent systematic analysis of the factors based on the design of experiments (DoE) provided an equation for calculating the dissolution rate

Is it possible to ensure the dissolution by the mathematical model in fact the same as in the example of the Sakura Tablet*?

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* Sakura Tablet was used in ICH Q-IWG Workshop.



What reviewers focused on Is the dissolution method adequately

set? Is it enough to determine the factors

affecting the dissolution? Is the validation/verification of the

model adequate? How reliable is the model?



PMDA required the applicant to perform the dissolution testincluded in the specifications at release from the early post-marketing phase, and to confirm the performance of theequation for calculating the dissolution rate, bysimultaneously carrying out the dissolution test on thecommercial lots after approval, based on the productionplan for the drug product as well.


Example : Pertuzumab (1)

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Report on the Deliberation Results

May 21, 2013Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau

Ministry of Health, Labour and Welfare

[Brand name] Perjeta Intravenous Infusion 420 mg/14 mL[Non-proprietary name] Pertuzumab (Genetical Recombination)[Applicant] Chugai Pharmaceutical Co., Ltd.[Date of application] May 25, 2012



Approved in June 2013

DS: manufacturing process of the drug substance



• What reviewers focused on• Identification of CQAs• Classification of Process Parameters• Establishment of Design Space (DS)• Design of Control Strategy



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.

QbD assessment project In Nov., 2011, PMDA launched a new project team to

handle the participation in the EMA-FDA pilot program as an observer.

The team consists of reviewers, inspectors, etc..

The team participates in teleconferences, supports core reviewers of each QbD application, and shares the experiences learnt from the project with reviewers of CMC in PMDA.

PMDA involved in 2 parallel assessment applications and Comments on 2 sets of Q&As (total 15) published by EMA&FDA on Aug 20 and Oct 24, 2013.


PMDA comments on the Q&As(QTPP & CQA)

Q1: What are the Agencies’ expectations in a regulatory submission for QTPP?

A1 (essence): The Agencies’ expectation is that applicants will provide the QTPP, which describes prospectively the quality characteristics of a drug product that should be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.

Q2: What are the Agencies’ expectations in a regulatory submission for CQAs?

A2 (essence): The Agencies’ expectation is that applicants will provide a list of CQAs for drug substance, finished product, and excipients when relevant. This list should also include the acceptance limits for each CQA, and a rationale for designating these properties as a CQA. The basis of the control strategy should be to ensure that the drug substance and finished product CQAs are consistently within the specified limits.


PMDA comments on the Q&As(QTPP & CQA)

Q1: What are the Agencies’ expectations in a regulatory submission for QTPP?

Ans.-keywords: provide the QTPP, linked to safety and

efficacy of the drug product

Q2: What are the Agencies’ expectations in a regulatory submission for CQAs?

Ans.-keywords: provide a list of CQAs, acceptance limits,

rationale, consistent with control strategy

PMDA comments:

Agree. In addition, the explanation of the CQA identification process is also very important. We expect to provide the explanation with risk assessment methods/tools.


PMDA comments on the Q&As(Three-tier classification)

Q3: Would the Agencies accept a three-tier classification of

criticality for process parameters?

A3 (essence):

The Applicant proposed an approach to risk assessment and determination of criticality that includes a three-tier classification for quality attributes and process parameters: critical, key and non-critical.

The Agencies do not support the use of the term Key Process Parameters (KPP) since it is not an ICH terminology.

The Agencies are amenable to the applicant using this terminology in the pharmaceutical development. However, in the 3.2.P.3.3 and 3.2.P.3.4, the description of all parameters that have an impact on a CQA should be classified as critical.


PMDA comments on the Q&As(Three-tier classification)

Q3: Would the Agencies accept a three-tier classification of

criticality for process parameters?

Ans.-keywords: not supporting the use of KPP

(amenable) in the pharmaceutical development

(classified as critical) in the 3.2.P.3.3 & 3.2.P.3.4

PMDA comments:

•PMDA does not recommend to use non-ICH terminology.

•If applicants use the term for the purpose of facilitated communication, PMDA would not refuse the terminology such as “key”. PMDA does not support any ICH terminology which is used differently from ICH definition.


PMDA comments on the Q&As(process description)

Q4: What are the Agencies’ expectations in a regulatory submission for manufacturing process descriptions?

A4 (essence):

The same requirements apply to the level of detail in the manufacturing process description irrespective of the development approach.

It is important that the process descriptions be comprehensive and describe process steps in a sequential manner including batch size(s) and equipment type. The process parameters that are included in the manufacturing process description should not be restricted to the critical ones.


PMDA comments on the Q&As(process description)

Q4: What are the Agencies’ expectations in a regulatory submission for manufacturing process descriptions?

Ans.-keywords: same requirements irrespective of the development approach, not restricted to the critical PPs

PMDA comments:

In Japan, there is a requirement for a full description of the manufacturing process except generic drugs.


PMDA comments on the Q&As(DS verification at commercial scale 1)

Q7: Why would a DS be verified during the product lifecycle?

A7 (essence): Movements from one area to another area within the design space within the approved design space in an unverified areamay pose higher or unknown risks due to potential scale –up effects and/or model assumptions.

Q8: What is the purpose of DS verification at commercial scale?

A8 (essence): Within design space boundaries scale-up effects are under control and do not adversely affect the expected product quality at commercial scale.

Q10: How can a DS be verified at commercial scale?

A10 (essence): It is neither necessary to verify entire areas of design space nor to identify the edge of failure. In principle, more than one area of a design space may be verified at the time of submission but the design space can, as appropriate, also be further verified over the product lifecycle.



Q7: Why would a DS be verified during the product lifecycle?

Ans.-keywords: unknown risk moving from NOR to unverified area

Q8: What is the purpose of DS verification at commercial scale?

Ans.-keywords: DS boundaries scale-up effects

Q10: How can a DS be verified at commercial scale?

Ans.-keywords: not necessary, entire area of DS, edge of failure

PMDA comments:

Agree. PMDA recommends industries verify the DS over the product lifecycle within their Pharmaceutical Quality System (PQS).



PMDA required the applicant to perform the dissolution test includedin the specifications at release from the early post-marketing phase,and to confirm the performance of the equation for calculating thedissolution rate, by simultaneously carrying out the dissolution teston the commercial lots after approval, based on the production planfor the drug product as well.


Looking back on the case of edoxaban tosilate hydrate


Q11: How should DS verification protocol be addressed in the submission?

A11 (essence):

EU authorities’ expectation is that a protocol for design space verification be submitted in section 3.2.R of the application. At the time of submission, a proposed design space not verified at commercial scale should be accompanied by an appropriate verification protocol. The protocol would be assessed at the time of review.

FDA’s expectation is that any plans for design space verification be available at the manufacturing site as an element of the change control, validation, and/or knowledge management strategy. Providing data for initial design space verification and a high-level overview of the plan for design space verification over the product lifecycle can be beneficial to the review of the application.



Q11: How should DS verification protocol be addressed in the submission?

Ans.-keywords:

verification protocol (EMA), high-level overview (FDA)

PMDA comments:

PMDA would not always request applicants to submit a protocol for DS verification. However, like FDA’s expectation, a high level overview of the plan will enhance reviewer’s understanding of the applicant’s control strategy. The detailed protocol should be available at the manufacturing site as a part of PQS.



Q13: How can a DS be verified at commercial scale for

biological products? (EMA)

A13 :

Principles laid down for chemical products are applicable to biological products. In addition, verification studies should provide evidence that the quality attributes of the product are comparable prior to and after the change. This could include a proposal for modular sets of tests and acceptance criteria to be deployed, taking into account the nature of the change and its associated risk.



Q13: How can a DS be verified at commercial scale for

biological products? (EMA)

Ans.-keywords: comparable prior to and after the change

PMDA comments:

Agree. In general, the manufacturing process of biological products is more scale-dependent than that of chemicals (e.g. cell culture process). Therefore the applicants are encouraged to explain how the residual risks are controlled by the proposed control strategy throughout the lifecycle management of the product.



Looking back on the case of Pertuzumab

Design of Control Strategy


Although potential residual risks remain, they will be managed by the modified control strategy.

Summary of PMDA comments

Our concerns about QbD applications are basically same as the EMA and FDA.

There is no great differences in the evaluation of QbD approaches among EMA, FDA and PMDA, so far.

Depending on the framework of each regulatory agency, the regulatory actions for the evaluation of QbD may have a little difference.


References(1)Review reports translated into English

(http://www.pmda.go.jp/english/service/drugs.html)

---Please visit the review report of Edoxaban Tosilate Hydrate & Pertuzumab

QbD Approach and Regulatory Challenges in Japan (Y. Matsuda, 26th Annual EuroMeeting , DIA)

(http://www.pmda.go.jp/english/service/pdf/qbd/201404_Session1205_v4e.pdf)

QbD Application in Japan: PMDA Perspective (Y. Kishioka, CMC Strategy Forum Japan 2013)

(http://www.pmda.go.jp/english/service/pdf/qbd/201312-qbd_app-e.pdf)

Pharmaceutical Development P2 with Enhanced Approach (Sakura Tablet)

(http://www.nihs.go.jp/drug/section3/English%20Mock%20QOS%20P2%20R.pdf)

---used for training material of Q-IWG


References(2) EMA-FDA pilot program for parallel assessment of Quality-by-Design applications: lessons

learnt and Q&A resulting from the first parallel assessment

(http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/08/WC500148215.pdf)

Questions and Answers on Design Space Verification

(http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/11/WC500153784.pdf)

Sakuramill S2 mock

(http://www.nihs.go.jp/drug/section3/H23SakuramillMock(Eng).pdf)

---applying risk assessment and DS to control mutagenic impurities (for ICH-M7)


Thank you for your attention


http://www.pmda.go.jp/english/service/qbd_e.htmlQbD Assessment Project at PMDA

pmda perspective on quality by design for pharmaceutical products · 2019-03-28 · quality by...

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