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デザイン･スペース（design space, DS）とプロセス解析工学(Process Analytical Technologies, PAT)

有限会社 レギュラトリーサイエンス研究所

秦 武久

平成2１年４月

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ICH Qトリオの目的：

安全性と有効性が保障され、一定の高い品質を有した医薬品製剤を安定的に提供することが医

薬品企業の責務である。

しかしながら、残念なことに、医薬品の開発過程から市販に至る製品のライフサイクルの中で医

薬品の製造や品質に関わる問題が多く発生している。 日欧米の医薬品規制当局は大きな懸念

を抱き、GMPと調和させながら、より高い品質を有した医薬品製剤を安定的に製造、提供する新

しい枠組み、品質システムの構築を図りつつある。

近代的品質システムの構築

ICH Q8： 製剤開発

ICH Q9： 品質リスクマネジメント

ICH Q10 ： 品質システム

このICH Qトリオ（Q8, Q9及びQ10）における重要なコンセプトとしてクオリティ・バイ・デザイン

（Quality by Design)やデザインスペース（Design Space)がある。

GMP（CGMP)承認された品質規格の製品を恒常的に製造、管理することにより、安全性と有効性を保証する。

That part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use GQP：Good Quality Practice 医薬品の品質保証における基準

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ICHQ8, Q9及びQ10による品質システムの構築

品質リスクマネジメント

Q9製剤開発

Q8

品質システムQ10

現行GMP

Ref. Dr. Evdokia Korakianity, Quality Sector, EMEA

RSI Regulatory Science Institute. Inc.

Eric P. Duffy, PhDDirector, Division of Post-Market Evaluation,

ONDQA, CDER, FDA

クオリティ・バイ・デザイン（Quality by Design)

事前の目標設定に始まり、製品及

び工程の理解並びに工程管理に重

点をおいた、確立された科学及び

品質リスクマネジメントに基づく体系

的な開発アプローチ。

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デザインスペース：

品質を確保することが立証されている入力変数（原料の性質など）と工程パラメータの

多元的な組み合わせと相互作用。

デザインスペース内で運用することは変更とはみなされない

デザインスペース外への移動は変更とみなされる

通常は承認事項一部変更のための規制手続きが開始されることになる。

デザインスペースは申請者が提案し、規制当局が評価し、承認する

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欧州医薬品庁（EMEA）のプロセス解析工学 （PAT）への取り組み

PATチームを2004年に設立する:

http://www.emea.europa.eu/Inspections/PAThome.html

PATの定義：

Process Analytical Technologies (PAT)：a system for designing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes for raw and in-process materials and also processes with the goal of ensuring final product quality". The PAT initiative focuses on building quality into the product and manufacturing processes, as well as continuous process improvement.

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PAT:http://www.emea.europa.eu/Inspections/PATQaA.html

Question 1： PATを適用すると、規制当局の承認なしで変更は可能か？

When PAT is implemented will the manufacturer be allowed to make changes to the process without need for regulatory "approval"?

Answer 1

It is anticipated that the introduction of PAT-based systems will change the way knowledge is presented in the dossier demonstrating greater understanding of the variables that affect product quality attributes, as well as the methods to monitor and control them. One of the expected outcomes is that a "Design Space" within the boundaries of the knowledge described in the development part of the dossier will be established and the process control strategy will fall within this space. We envisage that manufacturers will be able to introduce adjustments without the need for a variation submission provided the manufacturer operates within the "Design Space" defined in the original submission or subsequent variation.

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Apply for Design Space or Process Analytical Technology (PAT) in my application

Questions & Answers

43. Can I apply for Design Space or Process Analytical Technology (PAT) in my application? 申請時にデザインスペースあるいはPATを申請できるか？

The ICH Q8 (Pharmaceutical Development) introduces the notion of Design Space, defined as the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. The Design Space is proposed by the applicant as part of the MAA and thus is subject to assessment.

Additionally the establishment of a robust Design Space is in line with new approaches on quality which focus on building quality into the medicinal product by design (the so-called QbD concept)

PAT is defined as a system for analysing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.

PAT is a tool that allows enhanced control of the manufacturing process, can improve process understanding and so facilitates building quality into products and the development of a Design Space. ICH Q9 (Quality Risk Management) provides an approach and a selection of tools which can be used to manage risks associated with these processes.

（Ref. http://www.emea.europa.eu/htms/human/presub/q43.htm）

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Apply for Design Space or Process Analytical Technology (PAT) in my application

The main PAT tools are: PATの手段は

Multivariate data acquisition and analysis;

Modern process analysers or process analytical chemistry tools;

The introduction of the PAT system can bring a number of advantages:

Possibilities to introduce “real time release”;

Reduction of cycle times;

Improved product quality;

Possibilities for more efficient and effective control of some changes;

The introduction of PAT system can be applied to new or existing authorised medicinal products.

When to inform the EMEA of the introduction of PAT or Design Space approaches in my application

- Where Design Space concepts or PAT approaches are used, Marketing Authorisation applicants should indicate this in their letter of intent. It is of interest for the Agency and CHMP to be aware of their use so it can be taken into account in the appointment of (Co)-Rapporteurship, as particular expertise from (Co)-Rapporteurs may be needed.

- In addition, when requesting a pre-submission meeting, the applicant should identify it in the relevant question of the pre-submission request form.

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デザインスペース及びPATのベネフィット-リスク

ベネフィット

科学とリスクに基づいて製剤設計、製

造を評価できる

規制当局の審査を受けずに変更で

き、設計、製造に柔軟性が高まる

承認後の提出書類を低減できる

製品出荷試験を少なく、あるいはなく

すことが出来る可能性がある。

工程の十分な理解が重要であること

がわかる

リスク

個々の企業が独立にデザインスペー

スを構築、評価する

多大な資源が必要である

時間がかかる

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製剤分野での遠赤外スペクトルの応用DRAFT GUIDELINE ON THE USE OF NEAR INFRARED

SPECTROSCOPY BY THE PHARMACEUTICAL INDUSTRY AND THE DATA REQUIREMENTS FOR NEW SUBMISSIONS AND VARIATIONS、

London, 16 February 2009、EMEA

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RSI Regulatory Science Institute. Inc.