【最近のウォーニングレター】ASTROM通信 260号

三寒四温の季節となりましたが、いかがお過ごしでしょうか？
さて今回も、アメリカ食品医薬品局(FDA)がアメリカ国外の製薬会社向けに出したウォーニングレター2件を見ていきたいと思います。
FDAがどのような点を問題視して指摘しているかをご確認いただければ幸いです。

最近のウォーニングレターの概要　　

注：文中のXXはウォーニングレターでマスキングされている文言及び具体的な社名・品名等です。

■Warning Letter 320-23-06■

2022年6月23日～7月1日のインドの製造所の査察でみつかった原薬製造の重大なCGMP違反について発した2022年12月7日付ウォーニングレターには、下記の指摘事項があげられています。

●指摘１

貴社の品質部門は、貴社の製造所で製造された原薬がCGMPを遵守していることを保証する責任を果たしていない。

＜指摘１詳細＞
貴社の品質部門(QU)は、紙及び電子記録の適切な文書管理を保証することを怠った。例えば、我々査察官は、貴社の微生物試験室近くの管理されていない一時保管室にて、多数のログブック、記入フォーム、部分的に記入された“分析のためのサンプル依頼（SAP以外）”を見た。また我々査察官は、シュレッダーにかけられた文書を含む“緊急使用”のラベルが貼られた文書シュレッダーを、貴社の文書センタで見た。貴社の文書管理担当者は、文書に記録された相対湿度、温度、データに関する情報が含まれていると見受けられるシュレッダー内の文書が何か特定できなかった。
また貴社は、貴社のコンピュータ化システムを適切に管理することを怠った。例えば、複数ユーザのソフトウエアにログインするためのユーザ名とパスワードが、上級管理職の微生物学者の管理されていないノートに手書きされていた。そのログイン情報は、製品やXX水のサンプルを保管するためのインキュベータのような試験装置を管理するために使用されるソフトウエア用のものだった。
データ・インテグリティを保証するためには、実施されたアクションは、特定の個人に帰属可能である必要がある。貴社は複数の標準操作手順を改訂する予定で、新しい文書管理センタと文書管理チームを作ることにより、文書管理を一元化するつもりであると回答した。
また貴社は、貴社の上級管理職の微生物学者は“ICDAS”ソフトウエアの管理者の役割を持っていたが、その後オペレータの役割が再割り当てされたと回答した。しかし貴社の回答は、今後の紙、電子記録、文書化手順がCGMPを遵守することを保証するための詳細な計画を提出していない。
また貴社の回答は、貴社の製造所の不適切な文書管理の影響と範囲の包括的で回顧的なリスクアセスメントを含んでおらず、アクセスが各ユーザの役割と管理者の役割を管理するのに適切であると保証するために、階層化されたユーザのアクセスと管理に完全に対処していないので、不十分である。
貴社の文書化手順はCGMPに遵守している製造所の手順ではない。文書管理は、適切な品質システムを維持するうえで不可欠である。
この文書への回答の中で、以下の情報を提供せよ：貴社の文書化手順は、CGMPに遵守している製造所の手順ではない。文書管理は、適切は品質システムを維持するために不可欠である。

・貴社のQUが効果的に機能するために権限とリソースを与えられていることを保証するための包括的　なアセスメントと改善のための計画アセスメントはこれに限定さないが、以下のことも含むべきである：
　〇貴社で使用されている手順が堅固で適切かどうかの判断
　〇適切な手順に準拠していることを評価するための、貴社の作業全体のQUの監督の規定
　〇QUがロットの処遇を決定する前の、各ロット及び関連情報の完全で最終的なレビュ
　〇全ての製品の同一性、濃度、品質、純度を保証するための、調査の監督及び承認とその他全て
　　のQU職務の遂行

・文書化手順の不十分な場所を特定するための、貴社の製造及び試験の作業を通して使用される
　文書化システムの完全なアセスメント
　貴社の作業を通じて、貴社が帰属可能で判読可能、完全で原本性があり正確で同時性がある記録を
　保持していることを保証するために、貴社の文書化手順を包括的に改善する詳細な是正処置・予防
　処置(CAPA)の計画を含めよ。

・コンピュータシステムのセキュリティとインテグリティに関する包括的なアセスメントとCAPAの
　計画
　報告には、貴社の試験用の各コンピュータシステムに関する設計と管理の脆弱性の特定と貴社の
　試験用の各コンピュータシステムの適切な改善を含めよ。

●指摘２

貴社の原薬が、品質及び純度に関し制定された基準に従うことを保証するのに、全ての試験手順が
科学的に理にかなって適切であると保証することを怠っている。

＜指摘２詳細＞
貴社は、貴社の試験手順が適切にバリデートされ、制定された手順が遵守されていると保証する
ことを怠った。例えば、貴社の回収の検証は、ベータラクタムの環境モニタリングの方法が綿棒の
サンプリングによりベータラクタムの残留物を回収できると示すのに不十分だった。さらに貴社の
制定した綿棒での収集手順は、守られていなかった。科学的に理にかなった試験手順は、ベータ
ラクタムで汚染された原薬が適切に検出できる保証を含んだ、交叉汚染を防ぐために効果的な
ベータラクタムの封じ込めプログラムに必要不可欠な部分である。
ベータラクタム医薬品による非ベータラクタム医薬品の汚染は、アナフィラキシーや死亡の可能性
もある、患者の安全性に対する大きなリスクをもたらす。ペニシリンの汚染に、許容可能なリスク
と判断された安全なレベルはない。非常に低いレベルのペニシリンやその他のベータラクタムに
さらされた敏感な患者には、重度のアレルギー反応が発生する可能性がある。
貴社の回答は、製品の品質に影響がないと述べている。しかし、貴社の正当化の理由は、非ベータ
ラクタム医薬品が製造されている建物内でベータラクタムを検知するために使用されている、
バリデートされておらず遵守もされてない方法によって実施された試験に基づいているので、貴社
の回答は不適切である。さらに、貴社の製造所の非ベータラクタム製造建物内でのベータラクタム
の環境モニタリングでペニシリンを検知するための貴社の方法は、非常に低いレベルの汚染を検知
するのに十分な感度がない。詳細は、FDAが公開している、0.2ppbのLOD(limit of detection)の
分析方法を見よ。
アレルギー反応が起こる可能性のある投与量の閾値が非常に低いため、ベータラクタムの施設は、
非ベータラクタムの施設と完全かつ包括的に分離されている必要がある。
詳細は、FDAのガイダンス文書
Non-Penicillin Beta-Lactam Drug : A CGMP Framework for Preventing Cross-Contamination
を見よ。
この文書への回答の中で、以下の情報を提供せよ：
・貴社の試験業務、手順、方法、文書、分析者の能力に関する包括的なアセスメント
　レビュに基づき、貴社の試験システムを改善し、その効果を評価するための詳細な計画を提出せよ。
・これに限定されないが、ベータラクタム製造建物と共用エリア(例：カフェテリア)の排気装置の
　サンプリング及び試験を実施するかどうかの検討と、過去2年間の関連する試験結果を含めたベータ
　ラクタムの交叉汚染を防ぐための封じ込めの管理の包括的な評価
・0.2ppbのLODを達成するために貴社の環境内及び非ベータラクタム医薬品内のベータラクタムの
　汚染を分析するためのFDAの分析方法をバリデートし実装するか、0.2ppbと同等もしくはそれより
　よい分析方法をバリデートし実装するという約束

●指摘３

貴社は、規格を満たすために、原薬の各ロットの重大な逸脱や不具合を調査するための文書化された
手順を制定し遵守することを怠った。

＜指摘３詳細＞
貴社は、原薬XXの2ロットにあった黒い粒子を適切に調査し、根本原因を特定することを怠った。
例えば、XXのロットXXに関する貴社の調査報告は、非金属の炭化した製品の残留物であったと述べた。
さらに貴社の報告は、分析者がサンプルを”溶液内に溶解する“際にみつかったと述べている。
しかし査察中、貴社はその結論を裏付けるデータを我々査察官に提出することができなかった。適切
なCAPAを実装するために、根本原因を特定するのに必要な十分に文書化され徹底的で科学的に正当な
調査が必要である。
貴社の回答は、原薬内の金属の粒子の存在を制限値内にとどめるためにXXをインストールしたことを
示している。しかし貴社は、貴社の提示した根本原因を裏付け、適切なCAPAを割り出すためのデータ
を提出しなかったので、貴社の調査は不十分なままである。具体的には、炭化した製品の残留物、
不十分な洗浄等の非金属汚染源、反応性が高く、相加作用があり、吸収力のある製品表面などの金属
汚染源に完全に対処しなかった。

この文書への回答の中で、以下の情報を提供せよ：
・逸脱、不一致、苦情、規格外の結果(OOS)、不具合の調査をする貴社のシステム全体の包括的な
　アセスメント
　このシステムを改善するための詳細なアクションプランを提出せよ。貴社のアクションプランは、
　これに限定されないが、調査能力、調査の範囲の決定、根本原因の評価、CAPAの効果、品質部門の
　監督、文書化手順の大幅な改善を含むべきである。貴社が、調査の全ての段階が適切に実施される
　ことをいかに保証するつもりか述べよ。

●データ・インテグリティの改善

貴社の品質システムは、貴社が製造した医薬品の安全性、有効性、品質を裏付けるデータの正確性
と完全性を適切に保証していない。CGMPを遵守したデータ・インテグリティ業務を確立し、それに
従うためのガイダンスとして、FDAのガイダンス文書Data integrity and Compliance with Drug CGMP
を見よ。

我々は、貴社が貴社の作業を監査しFDAの要件を満たす助けをするためのコンサルタントを使用して
いることを知っている。この文書への回答の中で、以下の情報を提供せよ：
Ａ．アメリカに出荷された医薬品のデータのレビュ結果を含む、データ記録と報告の不正確な範囲の　　包括的な調査
　　貴社のデータ・インテグリティの欠如の範囲と根本原因の詳細な記述を含めよ。
Ｂ．みつかった不具合の貴社の医薬品の品質への潜在的な影響についての現在のリスクアセスメント
　　貴社のアセスメントには、データ・インテグリティの欠如の影響を受けた医薬品のリリースに
　　よる患者のリスクの分析と、継続的な作業により引き起こされるリスクの分析を含めるべきで
　　ある。
Ｃ．全社的なCAPAの詳細を含む、貴社の経営戦略
　　是正処置の詳細な計画には、貴社が、微生物及び分析のデータ、製造記録、FDAに提出される
　　全てのデータを含む、貴社で生成された全てのデータの信頼性と網羅性をいかに保証するつもり
　　かも記述せよ。

●CGMPコンサルタントの推奨

我々が貴社で発見した逸脱の性質に基づき、もし貴社がアメリカ市場向け医薬品の製造を再開する
つもりであれば、CGMPの要件を満たすように貴社を支援するために適格性のあるコンサルタントを
雇うことを強く勧める。貴社がFDAと共に貴社のコンプライアンス状態の解決を達成しようとする前に、適格なコンサルタントが貴社のCGMP遵守に関し貴社の全ての作業の包括的な監査を実施し、貴社の是正処置・予防処置の完了と効果も評価すべきである。貴社のコンサルタントの使用は、CGMPを
順守するための貴社の義務を軽減するものではない。貴社の経営陣には、継続的なCGMP順守を保証
するために、全ての不備とシステムの欠陥を解決する責任が残る。

●結論

この文書で挙げた逸脱は、貴社の製造所に存在する違反の包括的なリストでもない。貴社には、
全ての逸脱を調査し、原因を判断し、再発やその他の逸脱の発生を防止する責任がある。
FDAは2022年11月21日に輸入警告措置66-40をとった。
全ての逸脱を速やかに是正せよ。完全に対応され、我々が貴社のCGMPの遵守を確認するまで、FDAは
貴社の製造業者としての新薬の申請やリストの補完の承認を保留するだろう。また、我々は、貴社
が全ての逸脱に対する是正処置を完了したことを確認するために再査察を行うかもしれない。

出典：https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/centrient-pharmaceuticals-india-private-limited-640196-12072022

～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～～

■Warning Letter 320-23-07■

2022年7月18日～7月22日のブラジルの製造所の査察でみつかった原薬製造の重大なCGMP違反について 発した2022年12月8日付ウォーニングレターには、下記の指摘事項があげられています。

●指摘１

貴社は、データへの不正なアクセスや変更を防ぐためにコンピュータ化システムに十分な管理を
怠った。また、貴社はデータの脱落を防ぐための適切な管理を怠った。

＜指摘１詳細＞
貴社には、電子データ及びソフトウエアシステムのシステムセキュリティとアクセス管理がなかった。貴社の分析者たちはデータを削除し上書きするアクセス権を持っていた。我々査察官は、赤外線分光
光度計のコンピュータや、紫外線可視分光光度計のコンピュータのゴミ箱に100を超える削除された
ファイルをみつけた。具体的には、複数の削除された分析ファイルのファイル名には、ロット番号が
含まれ、貴社がアメリカに輸出している原薬XXに関するファイルが含まれていた。査察官は、紫外線
可視分光光度計及び赤外線分光光度計のスタンドアロンのコンピュータシステムは、特定の個人に
帰属するユーザ名を使用する代りに、共通のユーザ名を使っていることを確認した。ウインドウズの
オペレーティングシステムにサインインするためにパスワードは不要で、分析ソフトウエアは追加の
ユーザログインを必要としなかった。さらに貴社は、紫外線可視分光光度計及び赤外線分光光度計を
操作するために使用するスタンドアロンのコンピュータのバックアップをしていなかった。
データ・インテグリティを保証するために、実行されたアクションは貴社のCGMPコンピュータシステム内の特定の個人に帰属する必要があり、装置は、権限を持つ者以外の削除や変更を防ぐために、適切に管理される必要がある。
貴社は回答の中で、自動化されたデータシステムのアクセス許可を制限し、スタンドアロンの
コンピュータ化システムのバックアップ手順を実装し、ゴミ箱でみつかったファイルの内容をレビュ
するための調査を開始したと述べた。しかし、以前の医薬品の分析のトレーサビリティの全体的な
欠如に対応していないし、医薬品をリリースするために使用された以前の分析データの妥当性を確認
するための包括的な戦略も含んでいないため、貴社の回答は不十分である。さらに貴社は、これらの
管理が、ロットのリリースやその他の品質レビュの判断のために信頼した記録が完全で正確であることをいかに保証するつもりかも示さなかった。

この文書への回答の中で、以下の情報を提供せよ：
・コンピュータシステムのセキュリティと完全性についての、包括的な第三者のアセスメントと、
　是正処置・予防処置(CAPA)の計画

　貴社の試験用の各コンピュータシステムの設計と管理の脆弱性を特定し、適切な改善を確認する
　レポートを提出せよ。レポートには、これに限定されないが、以下のことを含めよ：
　〇貴社の試験室内のスタンドアロンとネットワークの機器を含む全てのハードウエアのリスト
　〇ハードウエア、ソフトウエア、ネットワーク化されていないシステム(例：PLC)の脆弱性の特定
　〇ソフトウエアの構成(機器のソフトウエアとLIMS)のリスト、管理者権限を含む全てのユーザの
　権限の詳細、貴社の各試験システムの監督の役割
　　ユーザ権限については、試験室のコンピュータシステムにアクセスできる全ての職員の役割と
　　関連する権限(管理者権限を持つユーザに許された特定の権限を含む)、職員の組織上の所属と
　　肩書を明記せよ。
　〇これに限定されないが、一意のユーザ名/パスワードが常に使用され、その機密性が保護されて
　　いるかどうかを含む、システムセキュリティの規定
　〇ユーザの役割の割り当てと管理に関する手順の更新と関連する教育に関する詳細な概要
　〇貴社の電子記録内の情報の全ての追加、削除、変更が承認され、全てのデータが保持されて
　　いることを保証するための、電子データの厳格で継続的な管理を保証する貴社の改善された
　　プログラム
　〇貴社の電子記録内の情報の全ての追加、削除、変更が承認され、全てのデータが保持されて
　いることを保証する、紙ベースのデータの厳格で継続的な管理を確実にする貴社の改善された
　プログラム
　〇品質保証(QA)マネージャ、経営幹部、適切なIT専門知識(例：インフラストラクチャ、構成、
　　ネットワーク要件、管理者権限を含む職務の分離)を持つ内部監査員の監督に関する規定
　〇紙ベースのシステムや電子システムに記録されたかどうかに関わらず、全ての品質管理試験
　　が分析者によって適切に実施され、別の責任者(例：マネージャ)から第二層のレビュを受けて
　　いることを保証する、改良された標準操作手順(SOP)
　〇スタンドアロンの機器(例：天秤、pHメータ、含水量試験)から電子システムを介して生成
　　されたデータのLIMSネットワークへの流し込みを増やすための技術的改善
　〇監査証跡データのレビュの詳細な手順
　〇試験データの管理、レビュ、全ての保持のための暫定的な管理手段と手順の変更

●指摘２

貴社の品質部門は、原薬のロットを出荷する前に、製造指図記録と試験管理の記録をレビュする
ことを怠った。

＜指摘２詳細＞
貴社の品質部門(QU)は、出荷のために原薬をリリースする前に、ロットに関連する文書の適切な
評価を保証するために、明確に定義されたプロセスまたは他の十分な管理システムを持つことを
怠った。
〇品質部門の責任
貴社のQUは、貴社のクロマトグラフィシステムのソフトウエア内で試験中に生成されたローデータ
の完全な記録のレビュをしなかった。例えば、QUは、適切な方法が使用され、シーケンスが適切に
設定され、マニュアルの積分が適切に実施されたことを保証するためにシステム内のスペクトル
データと該当する監査証跡をレビュしなかった。
貴社は回答で、クロマトグラフィのソフトウエアで生成されたデータの電子的レビュを実施し、
過去2年以内にアメリカに商業的に出荷された原薬のリリースと安定性のために生成された分析データ
のリスクアセスメントを実施するプロセスを実装する予定であると述べた。しかし、レビュ担当者が、クロマトグラフィの方法、注入シーケンス、システムの適合性の観点から、クロマトグラフィの
システムから各試験中に生成されたローデータの完全な記録を評価するかどうかなど、既存のデータ
の電子的レビュをいかに実施するかのプロセスの詳細な記述に欠けていたため、貴社の回答は不十分
である。さらに貴社の回答は、ピークの面積の適切な判断を保証するために、いかにピークの定量中
に使用される手動の積分手順の検証を実施するつもりかを述べていない。
〇試験管理の記録
貴社のQUは、貴社のCGMP文書への変更を防ぐための基本的な管理が整っていることを保証するのを
怠った。例えば、品質管理(QC)の試験室内で試験結果を記録するのに使用される“分析ワークシート
フォーム”は、いつ、誰によって発行されたかを特定するために、フォーム自体に一意の番号、
サイン、またはその他のトレース可能な要素がないので、管理されていない。
貴社は回答で“分析ワークシートフォーム”のトレーサビリティを保証するための手順を実装する
予定であると述べた。しかし、貴社はこれらの文書が発行された後どのように管理されるかの手順
を述べた詳細を提出しなかったし、以前の医薬品の分析に関するトレーサビリティの全体的な欠如を
調査したり、不完全な原薬の品質評価の分析データの記録の影響をレビュするためにリスクアセス
メントを実行するという提案をしなかったため、貴社の回答は不十分である。
貴社のQUは、ロットのリリースを判断する際、テスト中に生成された全てのローデータと、完了した
試験管理記録をレビュしなければならない。
この文書への回答の中で、以下の情報を提供せよ：
・手動の積分手順が、貴社のQUによって承認され監督された手順に従い、定義され限定された
　状況下でのみ実施されることを保証するために貴社が実装しようとしている管理の概要
・使用期限内にあるアメリカに販売された製品の紫外線可視分光光度計及び赤外線分光光度計の
　クロマトグラフィの手動積分の全ての事例の包括的なレビュ
　貴社が分析のために使用した手動積分パラメータの科学的な正当性を提出せよ。科学的な正当性
　が欠けた積分に関し、適切な再積分パラメータを使用して再積分をするための計画を提供せよ。
　再積分結果が制定された原薬の合格基準に従っているかどうかを評価せよ。もしOOSの結果が確認
　された場合、貴社の医薬品の品質を保証するためにとられるアクションを提出せよ。
・使用期限内にあるアメリカに販売された製品の、リテスト期限内のすべてのロットの再分析の
計画
・文書化手順が不十分な場所を特定するための、貴社の製造及び試験の運用中に使用される文書化
　システムの完全なアセスメント
　貴社の作業を通じて、貴社が帰属可能で判読可能、完全で原本性があり正確で同時性がある記録を
　保持していることを保証するために、貴社の文書化手順を包括的に改善する詳細な是正処置・
　予防処置(CAPA)の計画を含めよ。

●データ・インテグリティの改善

貴社の品質システムは、貴社が製造した医薬品の安全性、有効性、品質を裏付けるデータの正確性
と完全性を適切に保証していない。CGMPを遵守したデータ・インテグリティ業務を確立し、それに
従うためのガイダンスとして、FDAのガイダンス文書Data integrity and Compliance with Drug CGMP
を見よ。

この文書への回答の中で、以下の情報を提供せよ：
Ａ．アメリカに出荷された医薬品のデータのレビュ結果を含む、データ記録と報告の不正確な範囲
　　の包括的な調査
　　貴社のデータ・インテグリティの欠如の範囲と根本原因の詳細な記述を含めよ。
Ｂ．みつかった不具合の貴社の医薬品の品質への潜在的な影響についての現在のリスクアセスメント
　　貴社のアセスメントには、データ・インテグリティの欠如の影響を受けた医薬品のリリースに
　　よる患者のリスクの分析と、継続的な作業により引き起こされるリスクの分析を含めるべきで
　　ある。
Ｃ．全社的なCAPAの詳細を含む、貴社の経営戦略
　　是正処置の詳細な計画には、貴社が、微生物及び分析のデータ、製造記録、FDAに提出される
　　全てのデータを含む、貴社で生成された全てのデータの信頼性と網羅性をいかに保証するつもり
　　かも記述せよ。

●CGMPコンサルタントの推奨

我々が貴社で発見した逸脱の性質に基づき、CGMPの要件を満たすように貴社を支援するために、
貴社は、21 CFR 211.34に記載されている適格性のあるコンサルタントを雇うべきである。貴社が
FDAと共に貴社のコンプライアンス状態の解決を達成しようとする前に、適格なコンサルタントが
貴社のCGMP遵守に関し貴社の全ての作業の包括的な監査を実施し、貴社の是正処置・予防処置の完了と効果も評価すべきである。

●結論

この文書で挙げた逸脱は、貴社の製造所に存在する違反の包括的なリストでもない。貴社には、
全ての逸脱を調査し、原因を判断し、再発やその他の逸脱の発生を防止する責任がある。
全ての逸脱を速やかに是正せよ。完全に対応され、我々が貴社のCGMPの遵守を確認するまで、FDA
は貴社の製造業者としての新薬の申請やリストの補完の承認を保留するだろう。我々は、貴社が
全ての逸脱に対する是正処置を完了したことを確認するために再査察を行うかもしれない。

出典：https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/nortec-quimica-sa-639894-12082022

まとめ

いかがでしたでしょうか。

今回取り上げた2件のウォーニングレターは、どちらもデータ・インテグリティの不備の指摘が
含まれていました。何度も言われているデータ・インテグリティですが、今一度、お使いの
システムのユーザのアクセスの管理、ALCOA(※)の遵守状況をご確認頂ければと思います。

＜ALCOA＞
A：Attributable　帰属性
L：Legible　判読性
C：Contemporaneous　同時性
O：Original　原本性
A：Accurate　正確性

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【発行責任者】

株式会社プロス　『ASTROM通信』担当　橋本奈央子 hashimoto@e-pros.co.jp

※本記事は株式会社プロスの許可を得て転載しております。

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