QbD Approach and Regulatory Challenges in Japan Approach and Regulatory Challenges in Japan YOSHIHIRO MATSUDA Ph.D. Deputy Division Director Pharmaceuticals and Medical Devices Agency

QbD Approach and Regulatory Challenges in Japan

YOSHIHIRO MATSUDA Ph.D.Deputy Division DirectorPharmaceuticals and Medical Devices Agency (PMDA)

26th AnnualEuroMeeting

25-27 March 2014ACV, Vienna

Austria

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Introduction of PMDA

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・ NAME: Pharmaceuticals andMedical Devices Agency

・ Date of Establishment : April 2004Established as an IncorporatedAdministrative Agency (IAA) inApril, 2004.

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

PMDA Experience with QbD• Applications with QbD in Japan

Number of approved products (up to January in 2014)

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• Consultations with PMDA on QbDNumber of Consultations (up to January in 2014)

2008 2009 2010 2011 2012 20133 3 2 11 11 12

2007 2008 2009 2010 2011 2012 20131 0 2 2 4 4 3

Example : Edoxaban Tosilate Hydrate (1)

http://www.pmda.go.jp/english/service/drugs.html5

Some review reports are translated into English.


• Approved in April 2011• RTRT : Uniformity of dosage units, Dissolution

and Assay• The first case when RTRT for Dissolution was

approved in Japan

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


• What reviewers focused on – Is the dissolution method adequately set?– Is it enough to determine the factors affecting

the dissolution?• In this case, the concept of the control strategy

was changed by applicant after NDA.→What is the reason why applicant needed to

change the concept?→What influence will the changes have on the

construction of the model?

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• Continued– Is the validation/verification of the model

adequate?• The verification of the model throughout the

lifecycle is essential.– How reliable is the model?

• To know the limits of the prediction model• To consider the uncertainty of models

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• PMDA considered that this case is the highestimpact model among the High-Impact Models inICH Q-IWG Point to consider because thejudgment for release is based on the indirectindicator.

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• To facilitate innovation, regulators and industry need to work in cooperation.

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• PMDA assessed– The relationship between each of the

extracted variables and dissolution had been investigated appropriately.

– The maintenance program was established to ensure the model’s continuity.


• However this case was the first one in Japan and PMDAhas little experience to ensure the dissolution by indirectindicators

• Finally PMDA required the applicant to perform thedissolution test included in the specifications at releasefrom the early post-marketing phase, and to confirm theperformance of the equation for calculating thedissolution rate, by simultaneously carrying out thedissolution test on the commercial lots after approval,based on the production plan for the drug product aswell.

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One of our challenges and the best way to move forward!

QbD Assessment Project• In November 2011, PMDA launched a new project team

to handle the participation in the EMA-FDA pilot programas an observer.

• The project team consists of reviewers, inspectors, etc..– Office of New drug I~V, GMP&QMS Inspection, International

Programs, Standards and Guidelines Development

• 1 parallel assessment application• 1 biotech product that followed the consultative advice

pathway• Comments on 2 sets of Q&As that have been published

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PMDA involved in･･･

What PMDA learnt from our experiencein the pilot program• Our concerns about QbD are basically the same as FDA and

EMA.• There are no great differences in the evaluation approaches

of QbD, FDA, EMA or PMDA.

• Reviewers need a lot of time to assess the QbD approacheven now and we tend to ask more questions than with thetraditional approach.

• Regulatory actions, especially post approval change actions,might be a little different because the regulatory framework ofeach regulatory agency is different.

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But we have realized that ・・・

Post-authorisation procedure

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Risk of Changes Japan US EU

High

Moderate

Low

Partial change(Application for approval of variation)

Major change(Prior approval supplement)

Type II variation(Application for approval of variation)

Minor change(Notification within 30 days after implementation or shipping)

Moderate change1)Supplement-

changes being effected (CBE) in 30 days

Type IB variation(Notification before implementation and MAHs must wait a period of 30 days)

2)Supplement-changes being effected (CBE)

Type IAIN variation(Immediate notification)

Minor change(Annual report)

Type IA variation(Notification within 12 months after implementation)

Relationship between Application Form and CTD Documents in Japan

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Module 2 (QOS)CTD Module3

Application Form

Raw data

……….

………

……….

Matters to be described in manufacturing field of Application Form

All processes from raw material(s) to packaging process– A flow diagram of manufacturing process including:

• Raw materials• Charge-in amount• Yield• Solvent• Intermediate materials• Process parameter (e.g. Target Value/Set Value)

– A narrative description of manufacturing process• Acceptance criteria of starting material(s) and intermediate materials• In process control, Design Space and RTRT etc.

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How to describe partial change matters and minor change matters• Enter target/set values of process

parameters and standard charge-in amounts in– 《》 : partial change matter– 『』 : minor change matter

• Enter items other than target/set values in– “ ” : minor change matter– No parentheses : partial change matter

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Example of manufacturing description on AFStep 1 (Critical Step)

CP-6『(230kg)』, tetrahydrofuran『(1300L)』, sodiumcarbonate『(42.4kg)』 are combined. Ethyl chloroformate“158～592kg” is added and the mixture is heated attemperature up to reflux. ・・・・Water (“25 to 35%” *weight per weight of ethanol) isadded and the mixture is stirred at 『20℃』

* Water quantity is relative to the ethanol quantity, ethanol volume andcrystallization temperature are parameters establishing Design Spacewhich controls the quantity of total impurities.

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Acknowledgement : Sakuramil (Sakuramil S2 mock)http://www.nihs.go.jp/drug/section3/H23SakuramillMock(Eng).pdf

Challenges• How to decrease our burden?

– To share our experience and knowledge• QbD Pilot Program, Workshop, Training･･･

– To take advantage of Module 2 (over all summary)• How to encourage continuous improvement?

– To increase flexibility in post approval changes• Application form, annual reporting system, post approval

change management protocol･･･

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Thank you for your attention

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