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

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
セッションⅠ
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
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
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
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
◆要　旨
製薬企業における品質保証は、ここ40～50年の間、
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。
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
クオリティバイデザイン（Qu a l i t y b y Design :
適用を中心に進歩してきた。一方、1991年に第１
QbD）：事前の目標設定に始まり、製品及び工程の
回の日・米・EU三極による医薬品規制調和国際会
理解並びに工程管理に重点をおいた、確立された科
議（ICH）が開催され、以来、承認審査に関する手
学及び品質リスクマネジメントに基づく体系的な開
続きや基準の国際的統一化が進められ、品質に関し
発アプローチ。
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
重要工程パラメータ（Critical Process Parameter:
マネジメントに基づく医薬品のライフサイクル（開
CPP）
：工程パラメータのうち、その変動が重要品
発から市販後）全般に適用可能な国際調和医薬品品
質特性に影響を及ぼすことから、当該工程が望まし
質システム」を目指すことをビジョンに据え、品質
い品質を生み出すことを保証するために監視や管理
に係わる国際調和ガイドラインは大きな転換期を迎
をする必要があるもの。
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、
重要品質特性（Critical Quality Attribute: CQA）
：
欧州では拡大欧州共同体が設立され、日本でも改正
望ましい製品の品質を保証するために適切な境界、
薬事法の完全施行やグローバル化を目指した合併が
範囲、分布内にあるべき物理的、化学的、生物的、
相次ぐなど、国際的に変動の兆しが認められた。奇
微生物学的特性又は性質。
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
29
SessionⅠ
The Significance of Regulatory Science in Scientific Research on Health and Longevity
Lecture 4
Regulatory science in pharmaceutical development
and quality management
Hisashi Mimura
Regulatory science would be indispensable to
Senior Director, Pharmaceutical Analysis I, Pharmaceutical Research
& Technology Laboratories, Astellas Pharma Inc.
Past Records
1989 Completed the first course of the Ph.D. program, Pharmaceutical
Department, Osaka University Analytical Research Laboratories,
Fujisawa Pharmaceutical Co., Ltd.
2004 Regulatory Affairs, Fujisawa Healthcare Inc, US
2005 Merger with Yamanouch Pharmaceutical Co., Ltd. and
establishment of Astellas Pharma, Inc.
2006 Pharmaceutical Analysis, Pharmaceutical Research &
Technology Laboratories, Astellas Pharma Inc.
2007 Received Ph.D. (Pharmaceutics), Toho University
2009 Senior Director, Pharmaceutical Analysis I, Pharmaceutical
Research & Technology Laboratories, Astellas Pharma Inc.
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)
Introduction
and ISO9000 (Quality Management System). The
When we look at the prospect of Japanese
original GMP concept established in the US in 1962
medical needs in 2015 reported by Japan Health
and the original ISO9000 was issued in 1987. It is
Science Foundation, a rough proportional
noteworthy that the concept of statistical quality
correlation can be observed between satisfaction
control (SQC) was introduced from the US to
with medical treatment and contribution of
Japan in 1950 and it has already touched on quality
medicine to medical treatment. And there are
management with the phrase: Quality should be
three disease groups to be paid attention from
established during the manufacturing. After that,
the view point of unmet medical needs.
The
the first meeting of ICH (International Conference
first one is a group for high-satisfaction and high-
on Harmonization of Technical Requirements for
contribution. Lifestyle-related diseases such as
Registration of Pharmaceuticals for Human Use)
peptic ulcer, high blood pressure and hyperliipemia
was held among the regulatory authorities and
belong to this group, and relatively fulfilling
experts from the pharmaceutical industry of Japan,
medicines have been already in present.
The
EU and the United States in 1991. Since then,
second one is a group for mid-satisfaction and
the review process and regulatory requirements
low-contribution. Cancers for uterus, stomach,
in new drug application have been discussed to
prostate, colon, breast, uterine and liver are belong
harmonize among the three regions. As a result,
to this group.
the following quality (ICH-Q) guidelines have been
Medical technology for cancer
have made a remarkable progress, but more
established.
contribution of medicines are highly expected.
Q1: Stability
The third one is a group for low-satisfaction and
Q2: Analytical Validation
low-contribution.
Q3: Impurities
Remarkable diseases in this
group are diabetic and mental diseases, and these
Q4: Pharmacopoeia
diseases can be targets for new drug researches.
Q5: Quality of Biotechnological Products
To meet such unmet medical needs,
Q6: Specifications
pharmaceutical industry has started to pay
Q7: Good Manufacturing Practice
attention to new biological entities (NBEs) such as
(for Active Pharmaceutical Ingredients)
antibody drugs, nucleic acid drugs, regenerative
In 2003, ICH Quality announced a new vision
medical drugs and vaccines in addition to new
for ensuring drug product quality,“A harmonized
chemical entities (NCEs) of small molecular drugs.
pharmaceutical quality system applicable across
30
The Significance of Regulatory Science in Scientific Research on Health and Longevity
SessionⅠ
Lecture 4
the life cycle of the product emphasizing an
product and process understanding and process
integrated approach to quality risk management
control, based on sound science and quality risk
and science.” Then the vision caused a paradigm
management. This paradigm shift would lead us
shift in ICH-Q guidelines. The pharmaceutical
to risk reduction of pharmaceutical industry and
industry also suffered other environmental changes
achievement of advanced drug product quality.
such as: a new proposal of“Pharmaceutical cGMPs
for the 21st Century-A Risk-Based Approach”by
Quality by Design (QbD) in Manufacturing of
FDA ; European Unit expansion ; implementation of
Cefamezin-alfa Non-Vial Kit (For Imaginary
the Revised Pharmaceutical Affairs Law in Japan;
Example)
M&A of Japanese Pharmaceutical Companies; and
Cefamezin-alfa is a pentahydrate crystalline
so on. On the other hand, there were still many
form of cefazolin sodium, and marketed in Japan
spaces to be improved for the pharmaceuticals
as an non-vial kit. The non-vial kit is a product
in those days as the Wall Street Journal article
that crystalline powder of cefamezin-alfa is filled in
severely criticized in this way“Pharmaceutical
:
a plastic capsule connected to a transfusion plastic
manufacturing techniques lag far behind those of
bottle (Figure 1). The target product profile (TPP)
potato-chip and laundry-soap makers.”This does
is good chemical stability against high temperature
not mean that the pharmaceutical manufacturing
storage condition and light exposure condition, and
techniques are relatively low, but means that there
fast dissolution speed at the time of preparation
are a lot of rooms to be improved when we inquire
for administration.
into high quality required for drugs.
Critical quality attribute (CQA) in QbD is
As a result of the paradigm shift, the following
defined as a physical, chemical, biological, or
ICH guidelines have become available.
microbiological property or characteristic that
Q8: Pharmaceutical Development
should be within an appropriate limit, range,
Q9: Quality Risk Management
or distribution to ensure the desired product
Q10: Pharmaceutical Quality System (Step 4)
quality. Then the CQA of cefamezin-alfa non-
These three guidelines are collectively called
vial kit is considered to be water content, which
“ICH Q-trio”and applied across the lifecycle of the
should be controlled between 4.3-5.0 mol/mol of
product. Product lifecycle includes the following
water throughout the manufacturing and storage
technical activities : pharmaceutical development
before use, included in the crystalline powder of
(in laboratory), scale-up study (from laboratory
cefamezin-alfa. Although the most stable hydration
scale to commercial manufacturing scale),
state of cefamezin-alfa is pentahydrate (5 mol/mol),
technology transfer (from laboratory to commercial
it was proved that the change in the hydration
manufacturing site), commercial manufacturing,
state between 4.3-5.0 mol/mol was isomorphic,
out sourcing (in some cases), and product
i.e. the change does not cause any reduction of
discontinuation. The ICH Q-trio drive forward
crystallinity and transition to other crystal form
the paradigm shift in pharmaceutical quality
with different hydration state. In addition, the
management from“Manufacture just following
change in the hydration state between 4.3-5.0 mol/
approved method and ensure the quality by release
mol does not affect the chemical stability, whereas
testing only (Quality by testing)”to“Quality should
deviation from the hydration range results in
be acquired by optimizing a manufacturing method
reduction of chemical stability.
(Quality by design).”Quality by Design (QbD) is
under 4.3 mol/mol causes reduction of crystallinity
a term defined in ICH-Q8, meaning a systematic
and hydration over 5.0 mol/mol creates water
approach to pharmaceutical development that
absorption layer where chemical degradation take
begins with predefined objectives and emphasizes
place. Therefore, considering that the capsule of
Dehydration
31
SessionⅠ
The Significance of Regulatory Science in Scientific Research on Health and Longevity
Lecture 4
non-vial kit is made with plastic and has water
the filling process. The monitored water content
permeability, water content of cefamezin-alfa
can be feedback data to change CPPs within the
should be controlled closely between 4.3-4.5 mol/
defined design space .
mol during the capsule filling process so that it will
not be over the critical water content of 5.0 mol/
Conclusion
mol at the time of medical use across the shelf-
Currently, the new QbD concept described in
life of the product. These well understandings
ICH Q-trio guidelines is not a mandatory approach
of product properties during pharmaceutical
for pharmaceutical industry, being different from
development are very important in QbD.
the guidelines of ICH Q1-Q7. And the guidelines
Critical process parameter (CPP) in QbD is
are still evolving year by year.
defined as a process parameter whose variability
pharmaceutical industry should evaluate how QbD
has an impact on a critical quality attribute and
can be applied to their manufacturing process
therefore should be monitored or controlled to
considering how effective QbD can work in terms
ensure the process produces the desired quality.
of process understanding, risk assessment, quality
In the case of cefamezin-alfa non-vial kit, the CPPs
assurance and manufacturing cost.
are considered to be temperature, humidity and
As just described, appropriate understanding
exposure time during the capsule filling process.
and implementation of pharmaceutical guidelines
These CPPs are to be determined by conducting
can enhance a more timely introduction of new
process optimization and the correlation among
medicinal products into medical market, and
the CPPs composes design space . Design space
ensure their availability to patients with adequate
in QbD is defined as the multidimensional
high quality.
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 cefamezinalfa. Near Infrared (NIR) could be a specific PAT
technology that can monitor water content during
32
Therefore

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