バリデーション指針とは

バリデーション指針とは

今般の GMP 省令の改正に伴い、バリデーション基準が廃止され、バリデーション指針となった。 
バリデーション指針は『医薬品及び医薬部外品の製造管理及び品質管理の基準に関する省令の一部改正について』（薬生監麻発0428第2号、2021年４月28日）の第４に記載されている 。
本バリデーション指針は、平成25年8月30日付け薬食監麻発0830第１号通知の「第４ バリデーション基準」 を置き換えるものである。

バリデーション指針の目次

バリデーション指針の目次は以下の通りである。

（１）バリデーションの目的等
（２）バリデーションにより検証する事項
（３）バリデーション計画書
（４）バリデーションの責任者の業務
（５）バリデーションの種類等
　　1.　適格性評価（Qualification）
　　2.　プロセスバリデーション（Process Validation：PV）
　　3.　洗浄バリデーション
　　4.　再バリデーション
　　5.　変更時のバリデーション
（６）バリデーション報告書
（７）その他

バリデーション基準にはあった「用語の定義」や「回顧的バリデーション」がなくなった。

バリデーション指針改定の必然性

バリデーション基準を改定した理由は国際基準との整合である。
バリデーション指針の冒頭に下記のような記載がある。

１．GMP省令第13条又は第41条に規定するバリデーションを行うに当たっては、当該医薬品又は医薬部外品の製品品質への影響を考慮し、
下記２．のバリデーション指針又はこれと同等以上の海外のガイドラインを参照することが求められる。
つまり必ずしも本バリデーション指針に従う必要はなく、PIC/S GMP ANNEX 15「Qualification and Validation」（適格性評価とバリデーション）など海外のガイドラインを参照することでも構わないとのことである。

しかし、この要求には些か疑問を感じる。
そもそもPIC/Sは規制当局の集まりであり、加盟国の規制要件や査察基準を統一する目的で組織されている。
けっして製薬企業のための組織やガイダンスではない。
本来は、PIC/Sの要求事項等に従って加盟規制当局が規制要件等を整備し、企業に対して遵守を求めるのが筋ではないだろうか。

「バリデーション」のみならず、「医薬品品質システム」、「品質リスクマネジメント」、「リスクベースドアプローチ」、「データインテグリティ」といった21世紀における新たなGMPの要求事項はほとんどFDAなど海外の規制当局が最初に提唱した概念である。
3極の1つを担う医薬品消費大国の日本が世界に通用する新しい概念の規制要件を提案できていないのは残念である。

また海外の後追いでそれらを省令に盛り込んでいる（改正GMP省令は16年ぶりの改正である）。そのうえで、海外のガイドラインやPIC/Sを参照せよというのは理解に苦しむ。

バリデーションマスタープラン

バリデーション指針ではバリデーションマスタープラン（VMP：バリデーションに関する手順）を作成することを要求している。
バリデーションマスタープランについて、筆者は以前から疑問に思っていることがある。
バリデーションマスタープランはけっして手順書ではなく、あくまでも計画書である。
本来バリデーションマスタープランは、プロジェクト全体としての包括的なバリデーション計画を示したもので、リソースとテクニカルな計画のためにプロジェクトチームへのガイダンスとして使われる上位ドキュメントのことである。
ただし、バリデーション指針や PIC/S GMP ANNEX 15にはその定義が記載されていない。

バリデーション実施項目 

バリデーション指針によると、バリデーションを実施しなければならない事項には下記がある。

　　1.　製造設備、作業所の環境制御設備、無菌操作のための閉鎖式操作設備等の設備
　　2.　製造用水（製造設備及び器具並びに容器の洗浄水を含む。）を供給する装置又はシステム、作業所の空調処理のための装置又はシステム等の製造を支援する装置又はシステム（計測器を含む。）
　　3.　製造工程（保管を含む。）
　　4.　製造設備の洗浄作業
　　5.　原料、資材及び製品（中間製品を含む。）の試験検査の方法（当該試験検査のための装置又はシステムを含む。）

１．構造設備等の適格性評価（Qualification：DQ、IQ、OQ、PQ等）が要求されている。適格性評価はプロセスバリデーションに先立って実施しておかなければならない。
２．「製造を支援する装置」はユーティリティと呼ばれ、製造用水供給システム、空調システムなどが挙げられる。ユーティリティについても適格性評価の実施が要求される。
３．製造工程のバリデーションとは、プロセスバリデーションを指す。
４．製造設備の洗浄作業においては洗浄バリデーションの実施が必要である。
５．試験検査の方法に対しては分析法バリデーションの実施が必要である。

PIC/S GMP ANNEX 15との差異

PIC/S GMP ANNEX 15においては、再バリデーションという用語はなく再適格性評価と呼んでいる。（4章）
また PIC/S GMP ANNEX 15は、ICH Q8との整合を図るためQbDによる製剤開発によって開発された製品については、連続的なプロセスベリフィケーションを可能としている。
しかしながらバリデーション指針においては、従来方式のプロセスバリデーションのアプローチのみが要求されている。 

また GDP（実践輸送規範）に関する輸送のベリフィケーションや包装バリデーションについては割愛されている。
なお、本邦においてはGDPガイドラインは発出済である。

最大の問題点はバリデーション指針によると「プロセスバリデーションは、原則として、商業生産スケールで製品３ロットを繰り返し製造した結果に基づく又はそれと同等以上の手法により行うものである」とある。
しかしである FDAやPIC/S GMPなどでは、具体的に3ロットという指定はない。
むしろ当該バリデーションを実施するにあたって必要なN数を適宜決めることが要求されている。

従来プロセスバリデーションを3ロットで実施するという要求は、2ロットである場合、結果をプロットすれば、必ず直線が引けてしまう。
しかし、少なくとも3ロット以上になると直線上に並んでいるかどうかが判明するためである。
つまりプロセスの直進性能を確かめるために、最低3ロットという要求事項があったのである。

プロセスバリデーションの実施する際には、適切なロット数を適宜決定することが望まれる。

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