PMDA perspective on Quality by

Design for pharmaceutical

products

Junichi Fukuchi, Ph.D.

Office of Cellular and Tissue-based Products

Pharmaceuticals and Medical Devices Agency (PMDA)

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 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.

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Introduction of PMDA
• NAME: Pharmaceuticals and
Medical 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

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 Outline
 PMDA experience with QbD
 Example
 small molecule: Edoxaban Tosilate Hydrate
 biologics: Pertuzumab
 QbD assessment project
 PMDA comments on the Q&As

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 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.

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 Example QbD Approach
Product Profile • Define Quality Target Product Profile (QTPP)

CQAs • Determine “potential” critical quality attributes

(CQAs)

Risk • Link raw material attributes and process parameters

Assessment
to CQAs and perform risk assessment

Design Space • Develop a design space (optional and not required)

Control • Design and implement a control strategy

Strategy

Continual • Manage product lifecycle, incl. continual

Improvement
improvement
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Modified from http://www.ich.org/products/guidelines/quality/training-programme-for-q8q9q10/presentations.html
 PMDA Experience with QbD
 Applications with QbD in Japan
Number of approved products (up to Jan 2014)

2008 2009 2010 2011 2012 2013

3 3 2 11 11 12

 Consultations with PMDA on QbD

Number of Consultations (up to Jan 2014)

2007 2008 2009 2010 2011 2012 2013

1 0 2 2 4 4 3

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 Example :
Edoxaban Tosilate Hydrate (1)

Some review reports are translated into English.

http://www.pmda.go.jp/english/service/drugs.html
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 Example :
Edoxaban Tosilate Hydrate (2)

 Approved in April 2011

 RTRT : Uniformity of dosage units,
Dissolution and Assay
 DS : Uniformity of dosage units,
Dissolution and Assay
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 Example :
Edoxaban Tosilate Hydrate (3)

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 Example :
Edoxaban Tosilate Hydrate (4)
 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*?

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

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 Example :
Edoxaban Tosilate Hydrate (5)
 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?

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 Example :
Edoxaban Tosilate Hydrate (6)

 PMDA required the applicant to perform the dissolution test

included in the specifications at release from the early post-
marketing phase, and to confirm the performance of the
equation for calculating the dissolution rate, by
simultaneously carrying out the dissolution test on the
commercial lots after approval, based on the production
plan for the drug product as well.
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 Example :
Pertuzumab (1)
Report on the Deliberation Results

May 21, 2013

Evaluation 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

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 Example :
Pertuzumab (2)

 Approved in June 2013

 DS: manufacturing process of the drug substance

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 Example :
Pertuzumab (3)

• What reviewers focused on

• Identification of CQAs
• Classification of Process Parameters
• Establishment of Design Space (DS)
• Design of Control Strategy

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 Example :
Pertuzumab (4)
 Identification of CQAs

Criticality should be primarily based upon severity of harm.

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 Example :
Pertuzumab (5)
 Establishment of Design Space (DS)

DS should be defined not only by CPPs* but also by some

non-CPPs*. (*:classified by the applicant )
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 Example :
Pertuzumab (6)
 Design of Control Strategy

Although potential residual risks remain,

they will be managed by the modified control strategy.

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 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.

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 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.

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 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.
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 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.

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 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.
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 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.

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 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.

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

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 PMDA comments on the Q&As
(DS verification at commercial scale 1)
Looking back on the case of edoxaban tosilate hydrate

PMDA required the applicant to perform the dissolution test included

in the specifications at release from the early post-marketing phase,
and to confirm the performance of the equation for calculating the
dissolution rate, by simultaneously carrying out the dissolution test
on the commercial lots after approval, based on the production plan
for the drug product as well.

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 PMDA comments on the Q&As
(DS verification at commercial scale 2)
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.
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 PMDA comments on the Q&As
(DS verification at commercial scale 2)
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.

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 PMDA comments on the Q&As
(DS verification at commercial scale 4)
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.

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 PMDA comments on the Q&As
(DS verification at commercial scale 4)
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.
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 PMDA comments on the Q&As
(DS verification at commercial scale 4)

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.

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 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.

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 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

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 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/WC50014821
5.pdf)

 Questions and Answers on Design Space Verification

(http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/11/WC50015378
4.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)

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Thank you for your attention

QbD Assessment Project at PMDA

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