Established Conditions for manufacturing process PMDA ......Established Conditions for manufacturing process –PMDA perspective Pharmaceuticals and Medical Devices Agency Office of

1Pharmaceuticals and Medical Devices Agency 1Pharmaceuticals and Medical Devices Agency

Established Conditions for manufacturing process – PMDA perspective

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

Kyoko Sakurai, Ph.D.

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

CMC Strategy Forum JAPAN 2016

2Pharmaceuticals and Medical Devices Agency

Outline

1.Established Conditions: Background2.Application Form in Japan3.ECs for manufacturing process


Established Conditions：Background 1

Before ICH Q12 Focus on early stage aspects of product lifecycle

ICH Q8(R2): Pharmaceutical Development

ICH Q9: Quality Risk Management

ICH Q10: Pharmaceutical Quality System

ICH Q11: Development and Manufacture of Drug Substances(Chemical Entities and Biotechnological /Biological Entities)

ICH Q12 is intended to provide a framework to facilitate the management of post-approval manufacturing changes in a more predictable and efficient manner across the product lifecycle.


Common Technical Document (CTD) format has been defined for a marketing application, there are no previously harmonized approaches to define which elements in a dossier are considered relevant to assuring process performance and desired product quality.

Needs for clarity on what dossier changes would require a regulatory submission.

In ICH Q12 guideline, changes which require a regulatory submission or not are clearly distinguished.

Established Conditions：Background 2


Established Conditions (ECs) legally binding information considered necessary to assure product

quality contained in a regulatory submission, submitted by the applicant,

and approved, as necessary, by the regulatory authority may be specifically proposed in a submission or may be implicit

based on existing regulation or guidance

any change to ECs necessitates a submission to the regulatory authority that is consistent with regional regulations or guidance; or as agreed upon during review and approval of the marketing application

Draft

Established Conditions：Definition


Draft

Implicit Established Conditions

・・・・


Approved Matters = Established Conditions ?

Module 2 (QOS)

Module 3

Module 1(AF)

Summarized

Japan

Extracted

Established Conditions

ICH

Module 3

?Approved Matters


Outline

1.Established Conditions2.Application Form in Japan3.ECs for manufacturing process


Application Form in Japan

Contents of Application Form are the approved matters in Japan.CTD M2 and M3 are review documents.

CTD M2.3 (QOS)

CTD M3

Application Form (included in Module 1.2)

extracted

summarized……….

………

……….


Inquiry/ Response

F2F meeting

PMDAApplicantExternal

Expert discussion

Approval

Review report

Application

experts

Manufacturingsite

GMP audit

Pharmaceutical

Affairs and Food

Sanitation CouncilLabour and Welfare

Ministry of HealthConsultation

Opinion(Positive/Negative）

Review Process of MAA with document flow -Focus on CMC-

（Approval Letter）

AF,M2,M3

Review reportAF Review report

AF,M2

AF,M2,M3

AF,M2,M3

AF(M2,M3, if needed)


Module 2 (QOS)

Module 3

Legally binding

Not-Changeable without regulatory procedures (PCA/MCN)

Changeable without regulatory procedures (PCA/MCN)

Japan’s Effective/Efficient/Flexible Quality Regulation

Module 1 (Application Form)

MAH’s Compliance and Responsibility


Approval contents (CTD1.2 Application form)

Japanese accepted name(non-proprietary name) Name of the product Composition Manufacturing Process and Process Controls Dosage and Administration Indications Storage condition and Shelf life Specifications and Analytical Procedures Drug Product Manufacturer(s) Drug Substance Manufacturer(s)


Outline

1.Established Conditions2.Application Form in Japan3.ECs for manufacturing process


Established Conditions (ECs) for Manufacturing Process inputs, process parameters, and outputs that are necessary to

ensure product quality details and classification of ECs will depend on the extent to which

the company can apply knowledge from product and process understanding to manage the risk to product quality

ECs for Manufacturing ProcessDraft


EC

EC identification

NoYes

Prior-approval

(Tell and Do)

Notification

(Do and Tell)

No reporting

(Do and Record)

EC

RE

PO

RT

ING

Yes No

Does the variability

have an impact on

CQA?

1) High severity of harm?

2) Risk remains high?

Under discussion

Decision Tree for Identification of and

Reporting Changes to ECs for Mfg. processes

Impact to CQA cannot be

reasonably ruled out


Established Conditions (ECs) for Manufacturing Process include relevant parameters and attributes that impact product quality or for which an impact on product quality cannot be ruled out Prior to approval (Tell and Do): ECs for which a change :

could result in a high severity of harm if the control fails is associated with significant risk that is not robustly controlled

Notification (Do and Tell): ECs for which a change : is associated with moderate of low risks that are robustly controlled

Non-Reportable (Changes made under PQS; notification is not required) : parameters that do not have an impact on product quality information provided only as “complementary” or “supportive”

ECs for Manufacturing Process


What to be described in Mfg. process section of AF

Guideline for Descriptions on Application Forms for Marketing Approval of Drugs, etc. under the Revised Pharmaceutical Affairs Law (in English)PFSB/ELD Notification No. 0210001/ February 10, 2005

Manufacturing Facility• Manufacturing process • Manufacturing process section has subsection entitled with the name of

manufacturer<Example>【No】:001【 Name 】: XXX.Inc.【 Manufacturing process 】: Responsibility: Cell culture step, Purification step, Testing of DS 1.Cell Culture・・・・・【 Next step 】: 002

http://www.pmda.go.jp/files/000153677.pdf


n-2 Seed Bioreactor Step

The ○L seed expansion bioreactor culture fluid is transferred to “○ L” culture vessel containing 『▽ L』 of ▲Medium to a viable cell density of 『 1 x 105 cells/mL 』 , cultured at 『 37℃』 , 『 pH○』 and DO maintained 『 ○% 』. The n-2 seed bioreactor is cultured ♦ -♦ days or until final viable cell density is 『 x 106 cells/mL』 .

In-process test: • Bioburden: < ○○ CFU/mL• Endotoxin: < ○○ EU/mL

Description of Mfg Process in AF:How it should be described – Seed bioreactor expansion –

○L Seed Expansion Bioreactor Step

The inoculum expansion culture fluid is transferred to “○ L” culture vessel containing 『○ L』 of ▲Medium to a viable cell density of 『 1 x 105 cells/mL 』 , cultured at 『 37℃』 , 『 pH○』 and DO maintained 『 ○% 』. The ○L seed expansion bioreactor is cultured ♦ -♦ days or until final viable cell density is 『 x 106 cells/mL』 .

In-process test: • Bioburden: < ○○ CFU/mL• Endotoxin: < ○○ EU/mL

The purpose of these steps is to expand the cell culture and provide sufficient cells to next step

<Current>


○L, n-2 Seed Bioreactor Step

The cells are expanded using ▲Medium.

In-process test:

• final viable cell density : x 106 cells/mL

<Future>

Description of Mfg Process in AF:How it should be described – Seed bioreactor expansion –


Viral Inactivation (Critical Step)

Protein A pool is adjusted to pH 3.0 - 4.0 with 『 1.0 M』 phosphoric acid. The Solution is incubated for 30 – 60 minutes at 20 – 24 ℃. Subsequently the pH is adjusted to『 6.0』 with『 1.0 M 』 Tris base.

pH 3.0 - 4.0 incubation time 30 – 60 minutes hold temperature 20 – 24 ℃

Prior to approval (Tell and Do):

Description of Mfg Process in AF:How it should be described – Viral Inactivation –

<Current>




Notification (Do and Tell) or No-reportable ??

EC identification and reporting category will depend on company’s development approach and process understanding


<Current>



Protein A pool is adjusted to pH 3.0 - 4.0 and incubated for 30 – 60 minutes at 20 – 24 ℃ and then neutralized.



or

<Future>



Thank you for your attention!

Acknowledgements AMED* research group (*: Japan Agency for Medical Research and Development) special thanks to Haruhiro Okuda and Akiko Ishii-Watabe JPMA Biopharmaceutical Committee Technical Working Committee JPMA General Regulation Subcommitte Regulatory Affairs Committee

PMDA Q12 Working Group Colleagues in the Office of Cellular and Tissue-based Products

Documents

Established Conditions for manufacturing process PMDA ......Established Conditions for manufacturing process –PMDA perspective Pharmaceuticals and Medical Devices Agency Office of