適格性評価とは

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GMPにおいて、「適格性評価」(Qualification)と呼ばれる、他の業界では使用されない特殊な用語が存在する。一般に構造設備のようなGMPハードのバリデーションについては、適格性評価を行う。わかりやすく説明をすると、「プロセスバリデーション」は、「GMPハード」と「GMPソフト」の両方に対して実施し、「適格性評価」は「GMPハード」に対して実施する。
では、「適格性評価」とは、いったいどのようなものであるのだろうか。
原薬GMPのガイドライン」の用語集に、以下のような定義が記載されている。

バリデーション
特定の工程、方法又はシステムが、一貫して、予め設定した判定基準に適合する結果を与えるという高度の保証を提供する文書によるプログラム。
適格性評価
装置又は付帯システムが適切に据え付けられ、正しく作動し、実際に期待される結果が得られることを証明し、記録する活動。適格性評価はバリデーションの一部であるが、個々の適格性評価のステップのみではプロセスバリデーションとはならない。

つまり、バリデーションの活動の中に、適格性評価が含まれていることがわかる。
原薬GMPのガイドライン」12.30には、「適格性評価」について以下のような記載がある。

12.30 プロセスバリデーションの作業を始める前に、重要な装置および付帯設備の適格性評価を完了すること。適格性評価は、通常、以下の作業を個々に、又は組み合わせて実施する:
設計時適格性評価(DQ):設備、装置又はシステムが目的とする用途に適切であることを確認し文書化すること。
設備据付時適格性評価(IQ):据付け又は改良した装置又はシステムが承認を受けた設計および製造業者の要求と整合することを確認し文書化すること。
運転時適格性評価(OQ):据付け又は改良した装置又はシステムが予期した運転範囲で意図したように作動することを確認し文書化すること。
性能適格性評価(PQ):設備およびそれに付随する補助装置およびシステムが、承認された製造方法および規格に基づき、効果的かつ再現性よく機能できることを確認し文書化すること。

つまり、適格性評価は、
DQ(Design Qualification:設計時適格性評価)
IQ(Installation Qualification:設備据付時適格性評価)
OQ(Operation Qualification:運転時適格性評価)
PQ(Performance Qualification:性能適格性評価)
から構成される。ただし、「バリデーション基準」では、DQについて明確ではない。
「プロセスバリデーションの作業を始める前に、重要な装置および付帯設備の適格性評価を完了すること」という記載のとおり、適格性評価はプロセスバリデーションの前提条件であることがわかる。ただし、「重要な装置および付帯設備」とあるので、構造設備等のGMPハードに対する適格性評価について対象となる。ここでいう構造設備(装置および付帯設備)は、一般的なもので、コンピュータ制御されたもの(つまりコンピュータ化システム)とは限らない。例えば、遠心分離器のようにコンピュータ制御されていない、すなわちソフトウェアが搭載されていないものも含まれているのである。
また「原薬GMPのガイドライン」の5.41には、以下の記載がある。

5.41 コンピュータのハードウェアおよびソフトウェアについては、適切な据付時適格性評価および運転時適格性評価により、課せられた業務の実行に適合していることを実証すること。

つまり、コンピュータ化された構造設備に対して、プロセスバリデーションの前提条件である適格性評価を実施する場合は、据付時適格性評価(IQ)および運転時適格性評価(OQ)を実施しなければならないのである。性能適格性評価(PQ)については、プロセスバリデーションと併せて実施する。
さらに「原薬GMPのガイドライン」の5.42には、以下の記載がある。

5.42 既に適格性が確認されている市販のソフトウェアについては、同じレベルの検査は必要でない。なお、既存のシステムについて、据付時にバリデーションが実施されていない場合には、適切な文書化された記録が入手できるならば、回顧的バリデーションにより検証する場合がある。
つまり、市販のソフトウェア等は、当該供給者がすでに品質を保証しているので、製薬企業側で同等の作業を繰り返す必要はない。
そもそも適格性評価は、製薬企業に特異なレギュレーションであり、例えば化学会社や食品会社が同様な構造設備を導入したとしても、適格性評価は実施しない。つまり、適格性評価はいわば上乗せの品質保証であるといえる。そこで、適格性評価は、製品品質に直接影響し、かつ重要な要因についてのみ実施することになる。つまり、リスクの高い要因について念のため確認を行うということである。(図?参照)

設計段階でDQを、製作・施工段階でIQを、試験・検査・試運転段階でOQとPQを行うことである。

適格性評価の対象

据付時適格性評価(IQ)

IQは、初期の適格性評価で、機器が必要とされ期待されたサービス内容を持つことを確認する作業である。日本語では、据付時適格性評価と呼ばれる。
IQの目的は、構造設備等のGMPハードが、正しく据え付けられたかを確認することである。
IQでは、主に以下の事項を評価するが、幾つかのアクションは、サプライヤの社内で行われることもある。製造業者(製薬会社)は、使用に適した設備であるかどうかという評価、チャレンジ、テスト等に責任を負う。
機器の設計概要(IQの配慮事項の列挙)
据付条件
キャリブレーション、予防保全、洗浄スケジュール
安全性概要
サプライヤの文書、印刷物、図面およびマニュアル
ソフトウェアの文書
スペアパーツのリスト
環境条件

運転時適格性評価(OQ)

OQは、プロセスが許容される結果を生み、限界値(ワーストケース)を確立していることを証明する作業である。日本語では、運転時適格性評価と呼ばれる。
OQの目的は、ワーストケーステストなどの製造条件を決めるテストを行って、要件に見合った製品を製造できることを保証するプロセスパラメータのチャレンジ(予備試験)をすることである。
OQを実施することによって、製造プロセスの様々なアクションレベルが、製品特性に応じてわかり、コントロール状態を維持できるようになる。このことは、プロセスの頑健性につながる。
OQでは、主に以下の事項を評価する
プロセスコントロール限界
ソフトウェアパラメータ
原料の仕様
プロセス操作手順
マテリアルハンドリング要件
プロセス変更管理
トレーニング(OQが出来得るスキルを持たせる教育)
短期の安定性と工程能力(プロセスキャパビリティ)
故障モードの影響、アクションレベルとワーストケースの条件(故障モード影響解析:FMEA、故障ツリー解析:FTA)
スクリーニング実験法のような統計的バリデート技術とプロセスを理想化する実験計画法を用いて鍵となるプロセスパラメータをこのフェーズで使用可能に出来る。

性能適格性評価(PQ)

PQは、長期にわたるプロセスの安定性を確立する作業である。日本語では、性能適格性評価と呼ばれる。
PQの目的は、プロセスが恒常的に、規格に合格した製品を、通常の操作条件において生産できることを検証することである。つまり、PQでは、OQで確立した実生産の条件で製品を製造する。同時に様々なアクションレベル、それを含んだ標準操作手順書(SOP)の内容を確認し、チャレンジテストの繰り返しでよりプロセスの保証を高める。
PQでは、主に以下の事項を評価する
OQで確立した実際の製品とプロセスパラメータ並びに手法
製品規格の許容性
OQで確立した工程能力の保証
プロセスの再現(繰り返し)性、長期のプロセス安定性
製品やプロセスのデータは、プロセスのアウトプットが規格内である通常の変動範囲が決まるように解析されるべきである。
通常の変動範囲を知ることで、コントロールされた状態か特定のアウトプットを製造できるのに一定の許容範囲にあるかが明確になる。変動幅を軽減し管理すると高度な品質保証になる。(図4~6参照)

管理する変動要因は、プロセスの特性や繊細さに依存するが、以下の通りである。
温度/湿度/機器の外装・結露
電力供給上の変動/振動/光
環境汚染/プロセス水の純度/人的要因
原料の銘柄違い
原料ロット切り替わりによる原液粘度変動(製品の除去率性能に影響)
CSVとプロセスバリデーション(PV)の違い
筆者がセミナーを実施していて、しばしば受ける質問に「プロセスバリデーション(以下、PV)とCSVはどう違うのか」というものがある。
つまり、PVにおけるDQ、IQ、OQ、PQとCSVにおけるDQ、IQ、OQ、PQはどう違うのかといった疑問である。
厚生労働省が、平成24年4月1日から施行した「医薬品・医薬部外品製造販売業者等におけるコンピュータ化システム適正管理ガイドラインについて」(平成22年10月21日付 薬食監麻発1021第11号 厚生労働省医薬食品局監視指導・麻薬対策課長通知。以下「新ガイドライン」)では、構造設備におけるPVとCSVを混同しているように思われる。
プロセスバリデーション(PV)は、GMPハード+GMPソフトに対して実施する。また、適格性評価(Qualification)は、GMPハードに対して実施する。この場合、GMPハードは、ハードウェアとソフトウェアで構成される。
ソフトウェア(ファームウェア、PLCを含む)により制御されているシステムをコンピュータ化システムと呼ぶ。コンピュータ化システムは、CSVを実施しなければならない。つまりソフトウェアの品質保証を実施しなければならないのである。

そもそも、コンピュータ化システムバリデーション(CSV)は、GMPハード(構造設備および支援システム)に対して適格性評価(Qualification)を行うものである。
一方で、PVは、GMPハードおよびGMPソフト(作業員、原料・資材、製造方法・操作方法、洗浄等の作業等)について、検証を行うものである。
CSVのPQは、実機がユーザ要求仕様書を満たしていることを検証することであり、V-Modelを参照すれば明らかである。
PVのPQは、実機により最低3ロットを実際に生産してみて、プロセスの安定性を検証することである。
ちなみに3ロット以上で実施する理由は、2ロットでは品質等の変動に関して、直進性が分からないためである。
プロセスが、恒常的に規格に合格した製品を、通常の操作条件において生産できることが、PVにおけるPQでの目的である。


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    score οf C+.

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    ‘Joaquin Phoenix Ԁon’t deserve tһis,’ wrote οne
    on X. ‘Whɑt happened to the script?’

    Anotһer usеr added: ‘Stop maҝing sequels ɑs
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    Mɑny social media users have akso slammed tһe movie’s final scene, whіch ѕaw Phoenix’ѕ Arthur Fleck brutally stabbed tо
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