【最近のウォーニングレター】ASTROM通信 261号

日ごとに暖かさを感じられるようになりましたが、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 320-23-08■

2022年4月26日~5月9日のインドの製造所の査察でみつかった医薬品製造の重大なCGMP違反について発した2022年12月15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、無菌とうたわれている医薬品の微生物汚染を防ぐために作られた、無菌及び滅菌工程の

バリデーションを含む文書化された手順に従うことを怠った。(21 CFR 211.113(b))

<指摘1詳細>

〇不適切な培地充填

貴社の培地充填は、商用の作業を正確にシミュレートできていなかった。我々査察官は、貴社の培地充填中、シミュレートされた無菌作業は、酢酸メドロキシプロゲステロン注射用懸濁(USP)150mg/mL、1mlプレフィルドシリンジおよびバイアルの商用の無菌作業に十分に対応していないことに気付いた。例えば、査察のデータは以下のことを示している:
A.職員は、約XXグラムの滅菌済XXを配合タンクにXXまで手動で追加するシミュレーションを実施した。しかし商用製造の場合、約XXグラムの滅菌済有効成分が配合タンクに追加されていた。この手動の作業XXはXXまでかかり、日常の商用製造中XXの変更が含まれていた。
B.約XXグラムの滅菌済XXが、XXの密封されたXX容器からXXまたはXX以上の小型缶に手作業でうつされていた。この作業は、約XXグラムの滅菌済原薬が、異なるXXのXXパウチからXXの小型缶に手動でうつすという商用製造と一致していなかった。商用製造で使用されるパウチは、以前に開封され、再度密封されていた可能性がある。
分注や調合はリスクの高いステップで、これらの作業の後に追加の滅菌ステップはなかった。
貴社のオペレータは、長時間にわたる手作業の非常に集中が必要な無菌作業を実施していた。
それ故、工程のシミュレーションの期間は、実際の製造作業と非常によく似ている必要がある。
培地充填プログラムが汚染のリスク要因を組み込まず、実際の製品曝露を厳密にシミュレートしていない場合は、工程の管理状態と無菌保証は、正確に評価できない。

〇不十分な無菌行動

無菌原薬の分注や、無菌原薬の配合タンクへの追加等の、貴社のマニュアルでの集中した無菌作業の培地充填や煙の検証は、貴社のオペレータによる不十分な無菌行動を明らかにした。例えば、これに限定されないが、以下のことを含む:
・オペレータは、XXを器具のように使って無菌XXをXXするために、手袋をはめた手を小型缶に入れた
・オペレータは小型缶にXXストッパーを戻す前に、製品の接触面に触れた
・重要なエリア内でのオペレータの動きは、必ずしもゆっくりと熟考したものではなかった
・これに限定されないが、オペレータは、無菌XXを出す間、複数回開いたXX容器に手をのばし、中を見るために、自分のほうに小型缶を傾けるなど、さまざまな作業中にXXエアを遮断した
貴社の回答は不十分である。貴社は2021年11月に、貴社の作業において深刻な欠陥とリスクが明らかになった重大な培地充填の不具合を経験した。貴社は、貴社の出荷された医薬品の品質や無菌性がこれらの不備により影響を受けたかどうかを評価するためのタイムリーなリスクアセスメントを実施することを怠った。貴社は影響を受けたロットの回収を開始するまでに5ヶ月以上放っておいた。不備を積極的に特定しタイムリーで持続可能な是正処置・予防処置(CAPA)を実施することの不履行は、患者を危険にさらすため受け入れられない。
我々は、貴社が2021年11月30日をもってXXブロックでの、酢酸メドロキシプロゲステロン注射用懸濁液のプレフィルドシリンジおよびバイアルの製造業務を中止したことを知っている。この判断は、貴社の培地充填の不具合の調査を通して特定されたリスクに基づく。我々は、XXを備えた新しいブロックへ製造作業を移す予定であることを知っている。
無菌工程を使って無菌医薬品を製造する際CGMP要件を満たす助けとして、FDAのガイダンス文書Sterile Drug Products by Aseptic Processing – Current Good Manufacturing Practiceを見よ。
この文書への回答の中で、以下の情報を提供せよ:
・製造中の適切な無菌業務とクリーンルームでの行動を保証するための貴社の計画
 全ての製造ロットの効果的な監督監視を保証するための手順を含めよ。また、無菌作業とそのサポート作業中の品質部門(QU)の監督(例:監査)の頻度について述べよ。
・不十分な無菌技術とクリーンルームでの行動が、貴社の医薬品の品質と無菌性にどのように影響したかを評価する、徹底的な回顧的レビュとリスクアセスメント
・商用製造の最悪の条件を適切に組み込むことを含んだ正確なシミュレーションを保証するための、貴社の培地充填プログラムとCAPAの包括的なレビュ
・貴社のコンサルティングを行っているサードパーティのリスト
 サードパーティの責任と、彼らの活動の完了までの大体の時間枠

●指摘2

貴社は、適切なサイズで、無菌処理エリア内で汚染や取り違えを防ぐために必要な分離された、または、明確に定義された、または、その他の制御システムを備えた場所で作業を実施することを怠った。(21 CFR 211.42(c)(10))

<指摘2詳細>

〇クリーンルームの設計
無菌の配合と充填に使用される貴社のISO5クリーンルームは、設計が不十分で適切な保護が不足していた。例えば、ルームXXのISO5 エリアは、手動の集中した分注及び配合作業中に、無菌原薬を含む、貴社の無菌成分の潜在的な汚染を防ぐための物理的なバリアが不足していた。
充填ステーションで、分注・配合・シリンジローディング中、オペレータの体や手は、無菌原薬のすぐ近くにあった。さらにオペレータは、広い開口部を持つ大きな漏斗を通じて、無菌成分を配合タンクに手作業で入れる。貴社の煙の検証は、漏斗の周りの非単一方向の再循環気流を示した。
ISO5エリアは、無菌医薬品は曝露され汚染に対して脆弱なので、重要である。貴社の無菌製造工程は、無菌医薬品への汚染の危険を最小化するために設計され、作業が実施されるべきである。
基本的な設計の不備と、手動の集中的な注入は、無菌を維持する能力を損なう。

〇環境モニタリング
貴社は、環境条件をモニタリングするための適切なシステムを確立することを怠った。例えば、貴社は、ルームXX内での無菌分注作業のすぐ近くで菌が生存可能(表面及び空気)な環境のモニタリングを実施しなかった。同様に、無菌原薬が手動で配合タンクに追加される場所で環境モニタリングは実施されなかった。査察中にレビュされたデータは、この無菌作業がXXまで続いたことを示した。貴社のプロトコルは、これらの場所が環境モニタリングにとって”ハイリスク”のサンプリングポイントであると特定することを怠った。さらに、職員のモニタリングデータは適切に記録されていなかった。
慎重で応答性の高い環境及び職員のモニタリングプログラムは、貴社の無菌処理環境の管理状態の有意義な情報を提供するために設計される必要がある。手動の非常に集中した無菌作業を含む作業は、これに限定されないが、ロットの製造条件を適切にモニタする、好機をとらえたサンプリングに重点を置くために、より広範な環境及び職員のモニタリングプログラムを必要とする。
貴社は回答の中で貴社の環境及び職員のモニタリングの不十分さを認めている。貴社は影響を受けた製品は回収され、指摘内容に関係のある特定の充填ラインXXはもはや使用されていないと述べている。貴社は汚染防止の観点から製造工程をマッピングすることを保証するアクションプランの詳細概要を提供している。
貴社は、貴社の品質と作業の管理がいかに適切なクリーンルームの設計、管理、無菌業務、製造中のクリーンルームの行動を保証するかを適切に説明することを怠っている。
この文書への回答の中で、以下の情報を提供せよ:
・これに限定されないが以下のことを含む独立したアセスメントを含む、貴社の無菌工程、装置、施設に関する全ての汚染の危険の包括的で独立したリスクアセスメント
 〇ISO5エリア内のすべての人の相互作用
 〇装置の配置と人間工学
 〇ISO5エリア内と周辺の部屋の空気の品質
 〇施設のレイアウト
 〇職員のフローと原材料のフロー(無菌作業を実施しサポートする全ての部屋全体)
貴社の各無菌作業に関するこの包括的なアセスメントを提出せよ:
・汚染の危険のリスクアセスメントで見つかったことに対応するための、タイムライン付の詳細な改善計画
 無菌工程作業の設計と管理に対してなされる具体的な改善について述べよ。
・これに限定されないが、これらのプログラムを完全に改善するための次のことを含む、貴社の職員及び環境のモニタリングプログラムの包括的で独立したレビュ
 例えば、貴社の分類されたエリア内で、緊急のリスクを迅速に検知し対応するために、意味のある継続的なデータが収集できるように装置、手順、業務の変更について説明せよ。また、無菌的に充填された粉末医薬品の製造を十分にサポートするために、適切な、生存不能微粒子のモニタリングを実施するための計画を含めよ。効果的な改善を保証するために貴社がはじめようとしているCAPAのステップのサマリを含む、プログラム実装のための最新のタイムラインを提出せよ。

●指摘3

貴社は、医薬品の製造、加工、梱包、保管において、適切な設計、適切なサイズ、意図した使用と、その使用及び洗浄のために作業を容易にする適切な配置の機器を使用することを怠った。(21 CFR 211.63)

<指摘3詳細>

貴社は、粘性の非経口医薬品の充填に適した装置を確認して使用することを怠った。不適切に設計されたバイアル充填装置は、テストステロンシピオネート注射液200mg/mL, 1mLバイアルにかなりの異物混入をもたらした。さらに貴社の製造部門は、故障した装置の使用を防ぐための適切な職員の実務と監視監督を制定することを怠った。
貴社は、摩擦によって生成される医薬品の粘性の性質を考慮して、充填装置XXの設計を決定した。
この摩擦は、XX作動中に研磨効果を引き起こし、充填中のバイアル内に黒っぽい細かい金属の微粒子が入った。貴社は、これらのXXは一度損傷すると直せないと説明した。報告によると、設備から取り除かれたそうだが、交叉汚染の根本原因が特定された約2年後の2022年4月5日に承認された製造指図記録内で承認された装置として記載されていた。
特に、損傷したXX(H102)の一つは、テストステロンシピオネートの複数のロットを充填するために使用されていた。
適切に設計されメンテナンスされている装置のみが医薬品の製造に使用されていることを保証するのは貴社の責任である。
我々は、我々の査察後、貴社はテストステロンシピオネート注射のXXの調査に関係する5つの市場のロットを自発的に回収したことを認識している。
貴社の回答は不十分である。貴社の回答は、損傷し不適切に設計されたXXの継続的な使用を許した貴社の変更管理システムの不備に対処することを怠っている。貴社は、損傷したXXは分離され、テストステロンシピオネートの充填に使用されなかったが、うっかりして製造記録から削除されていなかったと述べた。また貴社は、関連するXX(H102)は再調整され、使用が許可されたと述べた。
しかし、貴社は、査察中、これらの損傷されたXXは再調整できないと述べ、それらは適切に設計されていなかったことを認めた。また貴社の回答には、XXとXXを含む製造装置の設計とライフサイクルの管理を徹底的に評価するリスクアセスメントを含んでいなかった。
この文書への回答の中で、以下の情報を提供せよ:
・施設と装置の定期的で慎重な運用の管理監督を実装するためのCAPAの計画
この計画は、とりわけ、装置/施設の性能の問題の迅速な検知、修理の効果的な実施、適切な予防保全スケジュールの遵守、装置/施設インフラのタイムリーな技術的更新、適格な生産管理職員、継続的なマネジメントレビュのためシステムの改善を含むべきである。貴社の計画は、会社全体で適切なアクションがとられていることも保証すべきである。
・貴社の装置の使用目的への適合性に対処する徹底的な評価とリスクアセスメント
 貴社は、装置が適切に設計され、継続的な管理と保守に関する安定したプログラムがあるかどうかの判断を含める必要がある。また、品質保証が、これらの重要な目的を達成するために運用で使用されるシステムの有効性をいかに監督するかについても述べよ。
・XXやXXによって製造された欠陥のあるXXが充填作業中に使用されていないことを保証するための、製造記録の独立した回顧的レビュ
・この文書の日付時点で使用期限内にある無菌医薬品の、変色及び微粒子の調査に関連する調査を含む、全ての苦情の独立した回顧的レビュ医薬品の名前、ロット番号、製造日、ライン番号、苦情の概要、考えられる根本原因の記述、CAPAの 計画、CAPAの状況を含めよ。
・システムの不備と必要とされるCAPAを特定する苦情システムの包括的で独立したレビュ
・貴社の変更管理システムの包括的で独立したアセスメント
 このアセスメントには、これに限定されないが、変更が適切に正当化され評価されレビュされ、貴社のQUにより適合の最終判断までがレビュされていることを保証するための手順を含むべきである。貴社の変更管理プログラムは、変更の有効性を判断するための規定を含めるべきである。

●指摘4

貴社は、そのロットが既に出荷されたかどうかに関わらず、ロットやその成分の、説明のつかない規格との不一致や不具合を徹底的に調査することを怠った。(21 CFR 211.192)

<指摘4詳細>

貴社のクリーンルームの水漏れの調査は、適切なCAPAが不足し、影響を受けた可能性のある他のロットに調査を広げなかったため、不十分であった。
例えば、暖房、換気、空調(HVAC)ダクトフロアを経由した業務フロアからISO5の充填エリアの真上の天井まで水が漏れた。貴社の調査報告は、古い破裂したXXからの漏れにより、業務フロアに水がたまったことを指摘していた。その時点で水は、USPメドロキシプロゲステロン酢酸エステル注射用懸濁液が製造されている無菌充填室に入る前のXX仕切天井の上で集められた。貴社の職員は、業務フロア上にかなりの水が溜まっていることを確認していた。
貴社は天井の隙間をふさいだが、修理がされた後、業務フロア、XXのLAF天井、HVACダクトフロアのカビの成長と水の被害を十分に調査していなかった。また貴社は、水漏れが発見される約2ヶ月前の、XXの最後の予防保全以降この部屋で製造されたUSPメドロキシプロゲステロン酢酸エステル注射用懸濁液の影響を受けた可能性のあるロットに調査の範囲を拡大することも怠った。
貴社は回答の中で、水漏れは発見された日に分離されていたと述べた。貴社は、調査は他のロットへの水漏れの影響を評価していなかったと認めている。貴社はこのラインで製造されたUSPメドロキシプロゲステロン酢酸エステル注射用懸濁液150mg/mL, 1mLバイアルの販売された全てのロットについて、この調査と関係のない事象で2022年5月17日に回収を開始した。
貴社の回答は不十分である。貴社はこの漏れに対応するためのアクションを開始したことを認識しているが、貴社の調査は、水漏れや湿気により施設に残った可能性のある施設の損害や微生物汚染に十分に対処することを怠った。
この文書への回答の中で、貴社の逸脱、不一致、苦情、OOS結果、不具合を調査するシステム全体の包括的で独立したアセスメントの情報を提供せよ。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供せよ。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、調査の範囲の判断、根本原因の評価、CAPAの効果、品質保証部門の監督、文書化手順の大幅な改善を含めるべきである。全ての調査の段階が適切に実施されていることをいかに保証するかについて対処せよ。

●指摘5

貴社は、公式、または、その他の制定された要求を超えて医薬品の安全性、同一性、濃度、品質、純度を変える可能性のある誤動作や汚染を防ぐために、適切な間隔で装置や器具を洗浄、メンテナンス、必要に応じて消毒/殺菌することを怠った。 (21 CFR 211.67(a))

<指摘5詳細>

貴社は医薬品の製造に使用されている装置を適切に洗浄し、メンテナンスすることを怠った。

例えば:
A.我々査察官は、XXがクリーンであると判断された後、XXの上に目に見える残留物を発見した。
  また、XXにXXが付着した隙間の内側に、色のついた微粒子と沈殿物がみつかつた。査察中、貴社の分析試験は、沈殿物が原薬XXを含んでいることを確認した。
    装置の洗浄記録は、XXの上の、XXの分解を含む前の医薬品の完全な除去として定義されたType-Bの洗浄が実施されたことを示していた。
B.我々査察官は、XXボウル-IIの製品の接触面に多数の傷とへこみを発見した。さらに、XX内のXXにつながったXXガスケットの上部に光沢のある金属片がみつかった。
  不十分に洗浄・メンテナンスのされた装置は、交叉汚染と医薬品の品質低下につながる可能性がある。
貴社は、エンジニアリング職員がいなかったので、洗浄作業中にXXは分解されなかったと述べた。
残留物と粉末は、以前に製造された医薬品(同じ医薬品)だった。また貴社は、XXガスケットの上の光沢のある破片を確認し、金属片の脱落は組立及び分解作業中に発生した可能性が高いと述べた。
貴社は、この査察に応じて実施されたXXのプロトコルベースの目視検査は、同じものは見つからなかったと述べた。
貴社の回答は不十分である。貴社は、貴社の影響アセスメントは継続中で、前回のキャンペーン以後に製造されたロットは保留中であると述べた。しかし、貴社は損傷し不十分に洗浄された装置がどれくらい長い間使用されていたかの情報を提供していない。また貴社はその装置を使って製造され販売された医薬品のリスクアセスメントを提出していない。
貴社は、貴社のXX状態XX㎎、XX錠剤XX㎎の汚点、しみ、傷に関連して2020年1月以降に受けて確認された苦情に十分に対処することを怠った。
この文書への回答の中で、以下の情報を提供せよ:
・交叉汚染の危険の範囲を評価するための、洗浄の効果の包括的で独立した回顧的レビュ
 残留物、不十分に洗浄された可能性のある他の製造装置の特定と、交叉汚染された医薬品が販売のためにリリースされたかどうかのアセスメントを含めよ。アセスメントは、洗浄手順や業務の不備を確認し、2製品以上を製造するために使用されている製造装置の各部品を網羅せよ。
・貴社の洗浄手順と実務の改善、完了までのタイムラインを含む、貴社の洗浄プログラムの回顧的なアセスメントに基づくCAPAの計画
 装置の洗浄のライフサイクル管理の手順の脆弱性の詳細なサマリを提供せよ。洗浄効果、全ての製品及び装置の適切な洗浄の実施の継続的な検証の改善、その他全ての必要とされる改善を含む、洗浄プログラムの改善について述べよ。
・貴社の製品の異物混入の調査と苦情の独立したレビュ
 レビュは、これに限定されないが、汚染源、製品に関連したリスク、適切な調査とCAPAを含む貴社のプログラムの包括的な評価をすべきである。
・使用期限内にあり、非専用装置XXで製造された医薬品の汚染に関するテストをするための貴社のプロトコル
・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計画
 アセスメントには、これに限定されないが、以下の評価を含めるべきである:
  〇貴社で使用されている手順が安定していて適切かどうかの判断
 〇適切は手順の遵守を評価するための、貴社の作業全体のQUの監督に関する規定
 〇QUによるロットの処遇の決定前に、各ロットとそれに関連する情報の完全で最終的なレビュが実施されているかどうかの判断
 〇調査の監督と承認と、全ての製品の同一性、濃度、品質、純度を保証するための、QUのその他全ての業務の遂行

●公定書の違反

FDAは、アメリカの輸入用にXXで製造されたUSPXXカプセルXX㎎ロットXX(使用期限:2024年1月)のサンプルを収集した。貴社の医薬品XXは、溶解の規格を満たしていなかった。これらの結果は、医薬品が、濃度、品質、純度が、医薬品が説明された公定書に定められた規格を満たしていないという点で、501(b)(21 U.S.C.351(b))の意味で混ぜ物をされていることになる。


●役に立たない品質システム

この文書で示した重要な調査結果は、貴社がCGMPに従って効果的な品質システムを運用していないことを示している。信頼できる施設や装置を保証するための製造作業の効果的な監督の欠如に加えて、QUに十分にリソースが与えられていない、または、QUの責任を果たすための権限が与えられていないことがわかった。さらに、会社の全てのレベルが、主要な品質リスクを効果的に特定し、必要に応じて上級管理職に迅速にエスカレーションされる事を保証するための内部のコミュニケーションとシステムが経営陣によって実装されていなかった。貴社は、システム、手順、製品がFDAの要件に従っていることを保証するために、貴社の全体的な製造作業を迅速かつ包括的に評価すべきである。
安定した効果的な品質システムがうまく機能することを保証するためには上級管理職のリーダシップの役割が重要である。CGMPの規制要件である21 CFR 210, 211を満たすために品質システムとリスクマネジメントのアプローチを実装する助けとして、FDAのガイダンス文書Quality Systems Approach to Pharmaceutical CGMP Regulationsを見よ。

●CGMPコンサルタントの推奨

我々が貴社で発見した違反の性質に基づき、我々は、CGMPの要件を満たすように貴社を支援するために、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ことを強く勧める。
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

この文書で挙げた違反は、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、全ての違反を調査し、原因を判断し、再発やその他の違反の発生を防止する責任がある。
FDAは2022年12月7日に輸入警告措置66-40をとった。
全ての違反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、貴社が全ての違反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/sun-pharmaceutical-industries-ltd-636199-12152022

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

■Warning Letter 320-23-11■

2022年9月12日~9月16日のトルコの製造所の査察でみつかった医薬品製造の重大なCGMP違反について発した2023年2月13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、各成分の同一性についてサンプルを試験することと、純度、濃度、品質に関して文書化された規格への一致を試験することを怠った。また貴社は、一定の間隔で、貴社の成分の供給者の分析試験の信頼性をバリデートし確認することを怠った。(21 CFR 211.84(d)(1), 211.84(d)(2))

<指摘1詳細>

貴社は、貴社のOTC医薬品を製造するために成分を使用する前に、入荷した成分の同一性に関して適切に試験することを怠った。また貴社は、貴社の供給者の分析試験結果をバリデートせず、代わりに供給者への質問への回答を信頼し、供給者の適格性評価を怠った。
さらに、貴社は純度、濃度、品質の規格に関し、適格性評価を行っていない供給者から得た分析証明書(COA)を信頼した。同一性、純度、濃度、品質について、貴社が成分を分析しないことにより、貴社は、入荷した成分が適切な規格を満たしていることを保証することを怠った。
この文書への回答の中で、以下の情報を提供せよ:
・成分、容器、蓋の全ての供給者がそれぞれ適格性を評価され、原材料には適切な使用期限またはリテスト日が付与されるかどうかを判断するための、貴社の原材料システムの包括的で独立したレビュ
 レビュは、入荷した原材料の管理が、不適切な成分、容器、蓋の使用を防ぐために適切かどうかも判断すべきである。
・製造で使用するために入荷した成分の各ロットを試験しリリースするために貴社が使用している化学及び微生物学的な品質管理の規格
・各成分のロットが同一性、濃度、品質、純度の全ての規格に一致することをいかにテストするかの記述

 各成分のロットの濃度、品質、純度を試験する代わりに、供給者から得たCOAの結果を受け入れるつもりなら、初期のバリデーションと定期的な再バリデーションを通じて、供給者の結果の信頼性をいかに厳格に確認するつもりかを明記せよ。さらに、入荷した成分の各ロットについて、少なくとも1つの同一性試験を常に実施するという約束を含めよ。
・各成分の製造業者から得たCOAの信頼性を評価するための、全ての成分の試験から得た結果のサマリ
 このCOAのバリデーションプログラムを述べた貴社の標準操作手順書も提出せよ。
・貴社が製造した医薬品を試験する契約施設の適格性評価と監督に関するプログラムのサマリ

●指摘2

貴社は貴社が製造した医薬品がそれが持つとうたっている、または表示されている同一性、濃度、品質、純度を持つことを保証するために設計された製造及び工程管理の文書化された手順を制定することを怠った。(21 CFR 211.100(a))

<指摘2詳細>

貴社は、貴社の医薬品を製造するために使用されている工程が適切にバリデートされていることを確証することを怠った。貴社は貴社が製造しアメリカに出荷している多数の医薬品のプロセスバリデーションの検証を実施することを怠った。また、貴社が実施したプロセスバリデーションの検証は、最終製品の適切な試験(例:有効成分の分析試験)が不足していたので不十分である。
さらに貴社は、貴社の医薬品を製造するために使用される装置の適切な適格性評価にも欠けていた。
プロセスバリデーションは、設計とライフサイクルを通じた工程の管理状態の安定性を評価する。
製造工程の重要な段階は適切に設計され、投入する原材料、中間材料、最終製品の品質を保証しなければならない。工程の適格性評価の検証は、初期の管理状態が確立していることを判断するものである。商用流通の前に、工程の適格性評価の検証の達成は不可欠である。その後、製品のライフサイクルを通じて、安定した製造作業を維持していることを保証するために、工程性能と製品品質の継続的で慎重な監督が必要である。FDAがプロセスバリデーションの適切な要素と考える一般的な原則とアプローチに関し、FDAのガイダンス文書Process Validation : General Principlesを見よ。
この文書への回答の中で、以下の情報を提供せよ:
・全ての医薬品の製造のライフサイクルを通じた、継続的な管理監督をより保証する改善計画
工程のばらつきの原因を特定し、製造作業が適切なパラメータと品質の標準を満たすことを保証するデータ駆動型の科学的に理にかなったプログラムを提出せよ。これは、以下に限定されないが、装置の使用目的への適合性の評価、投入した原材料の品質、各製造工程のステップの能力と信頼性とその管理の判断、工程性能と製品品質の慎重で継続的なモニタリングを含む。
・製品のライフサイクルを通じて管理状態を保証するための、関連する手順を添えた、貴社のバリデーションプログラムの詳細なサマリ
 継続的な管理状態を保証するための、工程性能の適格性評価、ロット内及びロット間のばらつきの継続的なモニタリングに関する貴社のプログラムについて述べよ。
・貴社の市販されている医薬品の工程性能の適格性評価(PPQ)を実施するためのタイムライン
・工程性能のプロトコルと装置及び施設の適格性評価の文書化された手順
・継続的な管理状態を保証するための、ロット内及びロット間のばらつきの慎重なモニタリングを含む、貴社の各製造工程の設計、バリデート、維持、管理、モニタリングのための詳細なプログラムを提供せよ。また、貴社の装置と施設の適格性評価のためのプログラムを含めよ。

●指摘3

貴社は、貴社の医薬品の安定性を評価するために設計された適切な文書化された試験プログラムを制定しそれに従うこと、適切は保管条件と使用期限を決めるために安定試験結果を使用することを怠った。(21 CFR 211.166(a))

<指摘3詳細>

貴社は貴社の施設で製造した医薬品の適切な保管条件と使用期限を決めるために安定性プログラムを制定していることを示すのを怠った。例えば、貴社の安定性プログラムは、有効成分、不純物、その他の劣化した製品の試験を含む、貴社の医薬品の適切な試験が不足していた。
適切な安定性の検証がなければ、貴社は、貴社の医薬品が使用期限内に、制定された規格を満たし、品質特性を持ち続けていることを裏付けるための科学的なエビデンスに欠ける。
この文書への回答の中で、以下の情報を提供せよ:
・貴社の安定性プログラムの妥当性を保証するための、包括的で独立したアセスメントと、是正処置・予防処置(CAPA)の計画
 貴社の改善されるプログラムは、これに限定されないが以下のことを含むべきである:
 〇安定性を示す方法
 〇出荷許可前の、販売される容器施栓システムの中の各医薬品の安定性の検証
 〇うたわれている品質保証期限が妥当かどうかを判断するために、各製品の代表的なロットが毎年プログラムに追加されていくような継続的なプログラム
 〇各ステーション(タイムポイント)で試験される特定の属性の詳細な定義
・貴社の改善された安定性プログラムのこれら及びのその他の要素を述べた全ての手順

●CGMPコンサルタントの推奨

我々が貴社で発見した違反の性質に基づき、我々は、CGMPの要件を満たし、このウォーニングレターに対応するように貴社を支援する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CAPA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

この文書で挙げた違反は、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、全ての違反を調査し、原因を判断し、再発やその他の違反の発生を防止する責任がある。
FDAは2023年1月11日に輸入警告措置66-40をとった。さらに貴社の医薬品XXのサンプル結果の違反により、FDAは、2021年5月17日に輸入警告措置66-78をとっている。
全ての違反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、貴社が全ての違反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/delta-kozmetik-sanayi-ve-ticaret-selim-yesil-645478-02132023

まとめ

いかがでしたでしょうか。

1件目のウォーニングレターの指摘内容を読むと、交叉汚染対策の不備に衝撃を受けます。ただ、ここまでの話ではないにしても、洗浄の不備や、使用機器・設備のメンテナンスの不備により、汚染は起こりえますので、是非、FDAの指摘内容を参考にしてみていただければと思います。

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