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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
3Pharmaceuticals and Medical Devices Agency
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.
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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
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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
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Draft
Implicit Established Conditions
・・・・
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Approved Matters = Established Conditions ?
Module 2 (QOS)
Module 3
Module 1(AF)
Summarized
Japan
Extracted
Established Conditions
ICH
Module 3
?Approved Matters
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Outline
1.Established Conditions2.Application Form in Japan3.ECs for manufacturing process
9Pharmaceuticals and Medical Devices Agency
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……….
………
……….
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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)
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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
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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)
13Pharmaceuticals and Medical Devices Agency
Outline
1.Established Conditions2.Application Form in Japan3.ECs for manufacturing process
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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
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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
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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
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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
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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>
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○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 –
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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>
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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.
Notification (Do and Tell) or No-reportable ??
EC identification and reporting category will depend on company’s development approach and process understanding
Description of Mfg Process in AF:How it should be described – Viral Inactivation –
<Current>
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Viral Inactivation (Critical Step)
Protein A pool is adjusted to pH 3.0 - 4.0 and incubated for 30 – 60 minutes at 20 – 24 ℃ and then neutralized.
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.
or
<Future>
Description of Mfg Process in AF:How it should be described – Viral Inactivation –
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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
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