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◆要　旨製薬企業における品質保証は、ここ40～50年の間、

GMP（医薬品の製造管理及び品質管理に関する基準）やISO9000（品質マネジメントシステム）の適用を中心に進歩してきた。一方、1991年に第１回の日・米・EU三極による医薬品規制調和国際会議（ICH）が開催され、以来、承認審査に関する手続きや基準の国際的統一化が進められ、品質に関しても各種ガイドラインの整備が進められてきた。

そして2003年、ICH品質部門は「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）全般に適用可能な国際調和医薬品品質システム」を目指すことをビジョンに据え、品質に係わる国際調和ガイドラインは大きな転換期を迎えた。同時期、米国FDAは「21世紀に向けた医薬品cGMP：リスクに基づいたアプローチ」を提唱、欧州では拡大欧州共同体が設立され、日本でも改正薬事法の完全施行やグローバル化を目指した合併が相次ぐなど、国際的に変動の兆しが認められた。奇しくも、製薬業界の製造・品質管理体制が「将来有望な新薬を発明することがある割には、その製造技術は、ポテトチップメーカーや石鹸メーカーに比べ

て遥かに遅れている。」とWall Street Journalで酷評された時期でもある。

その中で生まれたのが、ICH Q8「製剤開発」、Q9「品質リスクマネジメント」、Q10「医薬品品質システム」の所謂“ICH Qトリオ”である。これらのガイドラインは、「医薬品を承認された製造方法に従って製造し、品質試験で保証する」から、「最適の製造方法を確立することで品質を作り込む」という品質保証のパラダイムシフトを推進し、製薬企業におけるリスクの低減と医薬品の品質向上を図るものである。

本講演では、こうした内容を踏まえ、ICH Qトリオにおける新しい製剤開発と品質保証のアプローチについて簡潔に説明する。

◆キーワードデザインスペース（Design Space: DS）：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。

クオリティバイデザイン（Quality by Design : QbD）：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。

重要工程パラメータ（Critical Process Parameter: CPP）：工程パラメータのうち、その変動が重要品質特性に影響を及ぼすことから、当該工程が望ましい品質を生み出すことを保証するために監視や管理をする必要があるもの。

重要品質特性（Critical Quality Attribute: CQA）：望ましい製品の品質を保証するために適切な境界、範囲、分布内にあるべき物理的、化学的、生物的、微生物学的特性又は性質。

セッションⅠ健康長寿科学研究におけるレギュラトリーサイエンスの意義講演４

製剤開発及び品質保証におけるレギュラトリーサイエンス

アステラス製薬株式会社製剤研究所製剤分析第一研究室長

略　歴 1989　　大阪大学大学院薬学研究科博士前期課程修了 藤沢薬品工業株式会社入社　物性研究所に配属2004　　Fujisawa Healthcare Inc.（アメリカ）薬事部門へ

出向2005　　山之内製薬株式会社との合併によりアステラス製薬株

式会社に社名変更2006　　アステラス製薬株式会社製剤研究所製剤分析研究室に

帰任2007　　博士学位（東邦大学薬学博士）授与2009　　アステラス製薬株式会社製剤研究所製剤分析第一研究

室長

三村 尚志

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Regulatory science would be indispensable to develop such NCEs/NBEs smoothly, less costly and globally, and to deliver real need new drugs to patients rapidly.

Paradigm Shift of Quality Management in Pharmaceutical Industry　　For the past 4-5 decades, quality management in pharmaceutical Industry has progressed by applying GMP (Good Manufacturing Practice) and ISO9000 (Quality Management System). The original GMP concept established in the US in 1962 and the original ISO9000 was issued in 1987. It is noteworthy that the concept of statistical quality control (SQC) was introduced from the US to Japan in 1950 and it has already touched on quality management with the phrase: Quality should be established during the manufacturing. After that, the first meeting of ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) was held among the regulatory authorities and experts from the pharmaceutical industry of Japan, EU and the United States in 1991. Since then, the review process and regulatory requirements in new drug application have been discussed to harmonize among the three regions. As a result, the following quality (ICH-Q) guidelines have been established.

Q1: StabilityQ2: Analytical ValidationQ3: ImpuritiesQ4: PharmacopoeiaQ5: Quality of Biotechnological ProductsQ6: SpecificationsQ7: Good Manufacturing Practice　　 (for Active Pharmaceutical Ingredients)

　　In 2003, ICH Quality announced a new vision for ensuring drug product quality, “A harmonized pharmaceutical quality system applicable across

Introduction　　When we look at the prospect of Japanese medical needs in 2015 reported by Japan Health Science Foundation , a rough proport ional correlation can be observed between satisfaction with medical treatment and contribution of medicine to medical treatment. And there are three disease groups to be paid attention from the view point of unmet medical needs. The first one is a group for high-satisfaction and high-contribution. Lifestyle-related diseases such as peptic ulcer, high blood pressure and hyperliipemia belong to this group, and relatively fulfilling medicines have been already in present. The second one is a group for mid-satisfaction and low-contribution. Cancers for uterus, stomach, prostate, colon, breast, uterine and liver are belong to this group. Medical technology for cancer have made a remarkable progress, but more contribution of medicines are highly expected. The third one is a group for low-satisfaction and low-contribution. Remarkable diseases in this group are diabetic and mental diseases, and these diseases can be targets for new drug researches.　　To meet such unmet med ica l needs , pharmaceutical industry has started to pay attention to new biological entities (NBEs) such as antibody drugs, nucleic acid drugs, regenerative medical drugs and vaccines in addition to new chemical entities (NCEs) of small molecular drugs.

SessionⅠThe Significance of Regulatory Science in Scientific Research on Health and LongevityLecture 4

Regulatory science in pharmaceutical developmentand quality management

Senior Director, Pharmaceutical Analysis I, Pharmaceutical Research & Technology Laboratories, Astellas Pharma Inc.

Past RecordsCompleted the first course of the Ph.D. program, Pharmaceutical Department, Osaka University Analytical Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.Regulatory Affairs, Fujisawa Healthcare Inc, USMerger with Yamanouch Pharmaceutical Co., Ltd. and establishment of Astellas Pharma, Inc.Pharmaceutical Analysis, Pharmaceutical Research & Technology Laboratories, Astellas Pharma Inc.Received Ph.D. (Pharmaceutics), Toho UniversitySenior Director, Pharmaceutical Analysis I, Pharmaceutical Research & Technology Laboratories, Astellas Pharma Inc.

1989

20042005

2006

20072009

Hisashi Mimura

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product and process understanding and process control, based on sound science and quality risk management. This paradigm shift would lead us to risk reduction of pharmaceutical industry and achievement of advanced drug product quality.

Quality by Design (QbD) in Manufacturing of Cefamezin-alfa Non-Vial Kit (For Imaginary Example)　　Cefamezin-alfa is a pentahydrate crystalline form of cefazolin sodium, and marketed in Japan as an non-vial kit. The non-vial kit is a product that crystalline powder of cefamezin-alfa is filled in a plastic capsule connected to a transfusion plastic bottle (Figure 1). The target product profile (TPP) is good chemical stability against high temperature storage condition and light exposure condition, and fast dissolution speed at the time of preparation for administration.　　Critical quality attribute (CQA) in QbD is defined as a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. Then the CQA of cefamezin-alfa non-vial kit is considered to be water content, which should be controlled between 4.3-5.0 mol/mol of water throughout the manufacturing and storage before use, included in the crystalline powder of cefamezin-alfa. Although the most stable hydration state of cefamezin-alfa is pentahydrate (5 mol/mol), it was proved that the change in the hydration state between 4.3-5.0 mol/mol was isomorphic, i.e. the change does not cause any reduction of crystallinity and transition to other crystal form with different hydration state. In addition, the change in the hydration state between 4.3-5.0 mol/mol does not affect the chemical stability, whereas deviation from the hydration range results in reduction of chemical stability. Dehydration under 4.3 mol/mol causes reduction of crystallinity and hydration over 5.0 mol/mol creates water absorption layer where chemical degradation take place. Therefore, considering that the capsule of

the life cycle of the product emphasizing an integrated approach to quality risk management and science.” Then the vision caused a paradigm shift in ICH-Q guidelines. The pharmaceutical industry also suffered other environmental changes such as: a new proposal of “Pharmaceutical cGMPs for the 21st Century-A Risk-Based Approach” by FDA; European Unit expansion; implementation of the Revised Pharmaceutical Affairs Law in Japan; M&A of Japanese Pharmaceutical Companies ; and so on. On the other hand, there were still many spaces to be improved for the pharmaceuticals in those days as the Wall Street Journal article severely criticized in this way : “Pharmaceutical manufacturing techniques lag far behind those of potato-chip and laundry-soap makers.” This does not mean that the pharmaceutical manufacturing techniques are relatively low, but means that there are a lot of rooms to be improved when we inquire into high quality required for drugs.　　As a result of the paradigm shift, the following ICH guidelines have become available.

Q8: Pharmaceutical DevelopmentQ9: Quality Risk ManagementQ10: Pharmaceutical Quality System (Step 4)

　　These three guidelines are collectively called “ICH Q-trio” and applied across the lifecycle of the product. Product lifecycle includes the following technical activities : pharmaceutical development (in laboratory), scale-up study (from laboratory scale to commercial manufacturing scale) , technology transfer (from laboratory to commercial manufacturing site), commercial manufacturing, out sourcing ( in some cases) , and product discontinuation. The ICH Q-trio drive forward the paradigm shift in pharmaceutical quality management from “Manufacture just following approved method and ensure the quality by release testing only (Quality by testing)” to “Quality should be acquired by optimizing a manufacturing method (Quality by design).” Quality by Design (QbD) is a term defined in ICH-Q8, meaning a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes

SessionⅠThe Significance of Regulatory Science in Scientific Research on Health and Longevity

Lecture 4

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the filling process. The monitored water content can be feedback data to change CPPs within the defined design space.

Conclusion　　Currently, the new QbD concept described in ICH Q-trio guidelines is not a mandatory approach for pharmaceutical industry, being different from the guidelines of ICH Q1-Q7. And the guidelines are still evolving year by year. Therefore pharmaceutical industry should evaluate how QbD can be applied to their manufacturing process considering how effective QbD can work in terms of process understanding, risk assessment, quality assurance and manufacturing cost.　　As just described, appropriate understanding and implementation of pharmaceutical guidelines can enhance a more timely introduction of new medicinal products into medical market, and ensure their availability to patients with adequate high quality.

non-vial kit is made with plastic and has water permeability, water content of cefamezin-alfa should be controlled closely between 4.3-4.5 mol/mol during the capsule filling process so that it will not be over the critical water content of 5.0 mol/mol at the time of medical use across the shelf-life of the product. These well understandings of product properties during pharmaceutical development are very important in QbD.　　Critical process parameter (CPP) in QbD is defined as a process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. In the case of cefamezin-alfa non-vial kit, the CPPs are considered to be temperature, humidity and exposure time during the capsule filling process. These CPPs are to be determined by conducting process optimization and the correlation among the CPPs composes design space . Design space in QbD is 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. Design space is proposed by the applicant and can be subject to regulatory assessment and approval. Then working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory postapproval change process.　　Process analytical technology (PAT) is defined as a system for designing, analyzing, 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. In the manufacturing of cefamezin-alfa non-vial kit, it would be effective to apply PAT to the capsule filling process to monitor water content included in the filled crystalline powder of cefamezin-alfa. Near Infrared (NIR) could be a specific PAT technology that can monitor water content during

SessionⅠThe Significance of Regulatory Science in Scientific Research on Health and LongevityLecture 4