（医薬品のライフサイクルマネジメント）：現状と …continuity of product and...

1Pharmaceuticals and Medical Devices Agency

ICH Q12

（医薬品のライフサイクルマネジメント）

：現状と今後の展望

医薬品医療機器総合機構（PMDA）

再生医療製品等審査部

岸岡康博

日本PDA製薬学会開発QA委員会研究成果報告会，平成28年10月31日，学士会館

本発表は演者の個人的見解を示すものであり，PMDA及びICH Q12 EWGの公式な見解ではないことにご留意ください。


Flexibility in post-approval change

Standard program(Traditional approach)

Kn

ow

led

ge

Product LifecycleApprovalApproval

Standard program(QbD approach)

?

Residual Risk

Control Strategy

Post-Approval

CMC Considerations for Accelerated Programs

Where is the acceptable minimum requirement?


背景

現状

今後の展望

本日の内容


平成26年9月

ICH Q12（医薬品のライフサイクルマネジメント）

ICH Quality Vision 2003科学とリスクマネジメントに基づく医薬品のライフサイクル（開発から市販後）全般に適用可能な調和された医薬品品質システムの構築

ICH Q8～Q11，Points to Consider，Q&As

【現状の課題】

これまでライフサイクルの早期（開発から承認まで）に焦点が当たり，承認後の変更に関しての柔軟な運用は実現されていない

承認後の変更に関して要求される資料や薬事手続きが調和されていない

変更によるイノベーションや継続的改善の妨げ

背景


Q12の目的及び適用対象

目的

製品ライフサイクルを通じて，より予測可能かつ効率的な方法でCMCに関する変更を行うことが可能となる枠組みの構築。

規制当局及び企業のリソースの最適化。

イノベーションや継続的改善のサポート，安定供給への寄与。

適用対象

既承認の化成品や生物薬品（バイオテクノロジー応用医薬品/生物起源由来医薬品）を含む医薬品に適用する（ただし，ジェネリック医薬品への適用については，各規制当局により判断される）。


背景

現状

今後の展望

本日の内容


解決すべき課題 Regulatory Dossier Explore the development of a harmonised approach to “regulatory commitments” for inclusion in the

guideline. Such approaches could enable post approval changes that facilitate continual improvement and encourage the adoption of innovative technologies.

Delineate the appropriate level of detail and information necessary for regulatory assessment and inspection in the dossier, in order to create a more enabling post approval change management system.

Pharmaceutical Quality System (PQS) aspect Establish criteria for a harmonised risk-based change management system based on product, process

and/or clinical knowledge that effectively evaluates the impact of change on quality, and, as applicable to safety and efficacy.

Clarify expectations and reinforce the need to maintain a knowledge management system that ensures continuity of product and process information over the product lifecycle.

Post-Approval Change Management Plans and Protocols Introduce the concept of a post-approval management plan that can be used to proactively identify

post-approval changes and the mechanism to submit and assess these changes by regulatory authorities (Assessors and Inspectors)

Establish criteria for post-approval change management protocols that can be adopted by the ICH regions (enabling a harmonised proactive approach for lifecycle management)

Encourage enhanced product development and control strategy approaches (Quality by Design (QbD)) providing opportunities for scientific and risk based foundations for post-approval change management plans.

ICH Q12コンセプトペーパーからの抜粋


現在のEWGでの主な議論内容

Established Conditions

Product specific Lifecycle Management Strategy

Post Approval Change Management Protocols

Pharmaceutical Quality System (Change Management)

Application of Q12 for currently marketed products


Established Conditions (Regulatory Commitments)

ICHでは，承認申請時の添付資料はCommon Technical Document（CTD）として調和されているが，資料中のどの情報を変更したときに，承認後の薬事手続きが必要となるかについては調和されていない。

ICH Q12では，変更に際し承認後の薬事手続きが必要となる情報と，それ以外の情報を明確に区別する。

Established Conditions (ECs)の現在の定義

legally binding information defined in an approved Marketing Authorization Application

any change to an established condition, as defined in an approved application, would initiate a post-approval regulatory submission

any change to a non-established condition does not require regulatory interaction


“Must have ECs”


The identification of EC’s for manufacturing process parameters is linked to productand process understanding, and should be focused on the critical process parameters(see decision tree—Yasuhiro’s figure). As described in Q8/11, an applicant can chooseeither a traditional or an enhanced approach to development, or a combination ofboth.

In a traditional development approach, the elements of the control strategy that isincluded in the EC’s typically include a significant number of input parameters (processparameters and materials) along with outputs, as the relationship between input andresulting quality attributes may not be very well understood typically resulting in ahigher number CPP’s.

工程パラメータのECsの考え方(1)

Under discussion


In an enhanced development approach, the greater product and process knowledge(including interaction between inputs and outputs) can better inform the CQA’s andresulting CPP’s, leading to control strategy that can be more focused on the impactinginput parameters, generally resulting in a lower number of CPP’s. In certain cases,(performance based), the EC’s can be solely focused on the control of intendedoutputs rather than process inputs. This can include less complex steps with readilydefined outputs as well as steps with in-line continuous monitoring (e.g., NIR for ablending step).

In all cases, the rationale of the development approach should be provided. Acombination of traditional approach and enhanced approach (performance and/orparameter focused) can be followed for a given unit operation or for the completemanufacturing process. The level of details to be provided is considered as acontinuum based on the knowledge demonstrated. Furthermore, where risk topatients cannot be excluded or outputs not directly measured (e.g. viral safety),additional measures to mitigate the residual risk should be considered (e.g. includeCPP related to viral clearance in case of performance focused approach). (Lastparagraph can be omitted—for further discussion)

工程パラメータのECsの考え方(2)

Under discussion


Quality Risk Management

How to determine AMs of PPs in Mfg. process? (before MAA)

Criticality Assessment-Impact on defined CQAs?-

Non-AM

Process Parameters

CPP (incl. pCPP) Non-CPP

AM (PCA) AM (MCN)

-Prior knowledge-Process characterization studies

Yes or Unknown No

Control Strategy

No Yes

-Risk is well controlled?--Severe harm if the control is failed?-

Yes No

-Remained as high risk?-

Develo

pm

ent

Sub

missio

nA

pp

roval

Under discussion


Quality Risk Management

AM (PCA)

Criticality Assessment-Impact on defined CQAs?-

Non-AM

CPP (incl. pCPP) Non-CPP

AM (PCA) AM (MCN)

-Continuous Monitoring-Product Quality Review /Annual Product Review-New knowledge on CQAs

Yes (or Unknown) No

Control Strategy

Yes

-Risk is well controlled?--Severe harm if the control is failed?-

Yes No

-Remained as high risk?-

Non-AMAM (MCN)

Co

mm

ercial Man

ufactu

ring

Sub

missio

nA

pp

roval

How to determine AMs of PPs in Mfg. process? (after MAA)

Ap

pro

val

Under discussion


期待

Development Post-Approval

現在 Development Post-Approval

将来


The identification of EC’s for analytical methods is linked to the extent of methodunderstanding and typically include:

• Method Description:

The level of detail included in the method description is linked to the complexity ofthe method (e.g., HPLC vs cell-based Bioassay). The method elements selected, asEC’s should generally focus on the critical aspects of the method required to ensureits intended performance rather than detailed operating conditions.

• System suitability

• Product specification Acceptance Criteria

規格及び試験方法のECsの考え方

Under discussion


ECsに関する議論

ECs特定の考え方

ECsの改訂方法

製造方法並びに規格及び試験方法に関するECsの事例

各国・地域での運用


目的

The PSLCM strategy document facilitates communication between the Marketing Authorization Holder (MAH) and Health Authorities (assessors and inspectors) on approved ECs and the mechanism for making future change of the ECs. In the context of Q12, PSLCM strategy is a description of the planned changes and the regulatory approaches (Q12 tools) the MAH proposes to use for managing those changes. The PSLCM document summaries the information relating to the lifecycle management strategy for the product in one location, and could include some or all of the following information (or references to the information located elsewhere in the CTD).

Product specific Lifecycle Management Strategy（1）


内容 ECs: EC makes legal binding commitment made between regulatory and MAH. Whenever these ECs are subject for change,

the PSLCM document need to be updated. Refer to Section for EC.

Report category for making changes of approved ECs: The change reporting category need to follow regional requirement, which may be dependent on the product and process understanding. This category is included in Table XX .

Reference to relevant product development: Product development is useful information to show understanding of the product quality, EC, control strategy and essentials of the product information. Any further approval or changes will be a part of product development.

PACMPs: PACMP is a regulatory tool that enables planning and implementation of future change(s). Refer to Section for PACMP.

Post-approval CMC commitments: In case MAH has a post-approval CMC commitment, i.e., continuation of stability study.

Planned post approval changes: If the MAH anticipates a change to an EC, whether or not that change is associated with a PACMP, the MAH should briefly describe the planned change to provide transparency on anticipated change of ECs. These include those planned post approval changes that do not constitute a commitment to implement the change as described above.

EC change revision history: as changes to ECs are made over the lifecycle the product, this section in the PSLCM strategy document will capture a brief description of changes to facilitate transparency. This may be an important information to be used as a platform between regulators and MAH for mutual understanding of current ECs, how product development and mutual understandings, and whether there is any PACMP / post-approval CMC commitment exists at the time of submitting new changes.

The PSLCM may also include a description of the company’s strategy for future manufacturing changes that are being considered, however the strategic plan is for information only and is not a commitment to implement the strategy. The strategy may refer to proposed future submissions, including those associated with approved post-approval change management protocols (PACMPs).

Product specific Lifecycle Management Strategy（2）


（個人的見解）日本でのイメージ（1）

Current(where information may

contain)

Future MAAPartialChange

Application

ECs + reporting categoriesM1.2

(legally binding)M1.2

(legally binding)

*

Reference to relevant product development

M1.13 (chemicals)M2.3.S.2.6

Response to inquiryLCM

*

PACMPs N/A LCM *

Post-approval CMC commitmentsResponse to inquiry

MemorandumLCM

*

Planned post approval changes N/A LCM?? *

EC change revision historyM1.2

(Remarks)M1.2

(Remarks)

*

*: only where changed


（個人的見解）日本でのイメージ（2）

Module 2 (QOS)

Module 3

Module 1(AF)

Summarized

Extracted

Approved Matters+α

Reference to relevant product development PACMPs Post-approval CMC commitments Planed post-approval changes??

Product specific Lifecycle Management Strategy??


+

Strategy

• Planned

studies

• Acceptance

criteria

• Methods

Results +

Strategy

• Planned

studies

• Acceptance

criteria

• Methods

Results

Traditional

Evaluation of a proposed

variation as a ‘whole’

(Strategy + Results)

Early Step 1:

Submission of aChange

Management Protocol

Fast Step 2:

Reporting of implementation of a change in accordance

with an approved protocol

Type II Variation

Type IA or IB Variation

欧州でのPACMPQuestions and answers on post approval change management

protocols (EMA/CHMP/CVMP/QWP/586330/2010)


欧州でのPACMP承認状況

SCOPE TYPE II MAA Line

extension

New site for manufacture and/or QC testing of the

drug substance

Bio: 12 Bio: 1

Che: 4

New site for manufacture and/or QC testing of the

drug product

Bio: 18 Bio: 3

Che: 2

Change to the manufacturing process of the drug

substance

Bio: 12 Bio: 2

Che: 1

Scale-up of the drug substance manufacturing

process

Bio: 3 Bio: 2

Change to the preparation of a cell bank Bio: 1 Bio: 2

Change to the manufacturing process of the drug

product

Bio: 2

Che: 1

Change to the container closure system of the drug

substance or drug product

Bio: 1

Che: 1

Other Bio: 1

TOTAL - 60 for biologics:

10 MAA, 49 Type II, 1 Extension

- 9 for chemicals:

- 7 MAA, 2 Type II

4 PACMPs for biologics not included in the table were withdrawn (2 MAA, 2 Type II)

PACMPs authorised in the centralised procedure (last updated on 22/05/2015) Source: EMA


背景

現状（Established Conditions）

今後の展望

本日の内容


製造販売承認書（承認事項）とECs


Module 2 (QOS)

Module 3

Module 1 (Application Form)

Legally binding

Not-Changeable without regulatory procedures (PCA/MCN)

Changeable without regulatory procedures (PCA/MCN)

Japan’s Effective/Efficient/Flexible Quality Regulation


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)


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）

承認申請審査時の書類の流れ

-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)


製造販売承認書（承認書）

厚生労働省製造販売業者


承認書は,”legally binding document”である。

承認書には，製品品質を担保するために不可欠な（essential）要素を記載する必要がある。

製造販売業者が承認書の内容（承認事項）を変更する場合は，承認後の薬事手続きが必要である。

承認事項（一変事項／軽微事項を含む）は，製品ごとに決められる。

承認書は，承認後変更管理に関して，透明性と柔軟性を与えている。

承認書／承認事項


承認書と審査／調査

Modified from draft Q12 document

承認書

-承認後変更管理の観点から-調査

審査


ICH Q12 EWG

PMDA ICH Q12 EWG（森末政利，原賢太郎，八木聡美）

PMDA Q12対応WG（esp. 大串洋子）

AMED医薬品等規制調和・評価研究事業「医薬品の新規開発と製造変更における品質管理手法に関する研究」

（esp. 奥田晴弘先生，石井明子先生）

日本製薬工業協会バイオ医薬品委員会技術実務委員会

日本製薬工業協会薬事委員会薬事制度部会

PMDA再生医療製品等審査部

謝辞


• ICH Q12• Analytical QbD• Continuous Manufacturing• …Etc.

Discuss New

Concepts/ Guidelines

Review Current

Requirements/ Guidelines

Earlier Access to New Drugs for Patients


Earlier Access to New Drugs for Patients

Discuss New

Concepts/ Guidelines

Review Current

Requirements/ Guidelines

• ICH Q12• Analytical QbD• Continuous Manufacturing• …Etc.


ご静聴ありがとうございました。

医薬品医療機器総合機構（PMDA）

再生医療製品等審査部

岸岡康博

（医薬品のライフサイクルマネジメント） ：現状と …continuity of product and...

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（医薬品のライフサイクルマネジメント）：現状と …continuity of product and...