一気に気温が上がり、最高気温が20度台になる日も出てきましたが、いかがお過ごしですか。
さて今回は、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1件と、国内の製薬会社向けに出したウォーニングレター1件を、FDAがどのような点を指摘したかを確認していきたいと思います。
是非、お読み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 320-22-11■
FDAが2021年8月2日～8月7日にインドの原薬製造施設を査察してみつかつた原薬製造に関する重大なCGMP違反について発した2022年2月2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
原薬に触れる装置表面が、公式またはそれ以外の制定された規格を超えて原薬の品質を変えないことを保証することの不履行
＜指摘１詳細＞
貴社は、原薬の製造に使用されている装置がその使用目的に合っていて、適切にメンテナンスされていることを保証するのを怠った。例えば：
- さびのような残留物が、XXの管とホースを含む、清浄とラベル表示された製品と接触する装置表面で発見された。
- スクリューから出る黒い物質が原薬を汚染するのを防ぐためにテープがXXのへらに使用されていた。
- 装置の部品にXXを付けるためにXXが使用されていた。
- いくつかの穴がXXで発見された。
さらに、貴社には、製造及び品質管理のラボの装置の適格性を評価するための手順が欠けていた。
貴社は現在、適格性評価がされていない装置内で原薬XXを製造し試験している。
貴社は回答の中でさびのような残留物はさびの訳がないと述べた。貴社の回答は不適切である。
貴社はXXの管とホースの茶色がかった残留物の発生源を特定することを怠った。貴社の回答は、貴社の原薬を汚染する異物のリスクを増加させる装置の不十分な状態や破損した状態に適切に対処していない。特に貴社の原薬XXは、無菌注射剤XXの製造に使用されるものである。
この文書への回答の中で以下の情報を提供せよ：
- 設備・装置の所定の慎重な作業の管理・監督を実施するための是正処置・予防処置(CAPA)の計画
この計画は、特に、装置/設備の性能の問題の迅速な検知、効果的な修理の実施、適切な予防保全の計画の順守、装置/設備のインフラのタイムリーな技術的更新、継続的なマネジメントレビュのために改善されたシステムを保証すべきである。 - 貴社の装置が適切な設計、適切なサイズ、その使用目的のために適切に設置されていることを保証するための計画を提出せよ。
計画は、製品の接触面が中間体や原薬の品質を変えないことを保証するCAPAを含むべきである。
●指摘２
貴社の製造工程があらかじめ定められた品質特性を満たす原薬を再現可能な方法で製造できることを示すことの不履行
＜指摘２詳細＞
貴社は、原薬XXのための製造工程をバリデートすることを怠った。貴社は、原薬XXのロットは顧客の注文により製造されているので、原薬XXの製造工程はバリデートしていなかったと述べた。
貴社は、正当な理由や変更管理もなく、製造工程へのいくつかの変更を行った。例えば、貴社は、追加する水とXXの量を変更した。
FDAのタイダンス文書Process Validation : General Principles and Practices for general principles and approaches that FDA considers to be appropriate elements of process validation
を見よ。
プロセスバリデーションは、そのライフサイクルを通して工程の設計の正常さと管理状態を評価するものである。製造工程の各重要な段階は、原材料、中間材料、最終製品が意図された品質であることを保証するために設計され管理されていなければならない。
性能適格性評価は、初期の管理状態が確立されていることを判断する。上首尾の性能適格性評価は商品流通の前に必要である。その後、工程性能と製品品質に影響を与えるばらつきの継続的で慎重な管理は、貴社が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必要である。
適切なプロセスバリデーション業務の不履行は、工程のばらつきの理解が不十分であったり、性能の傾向の検知に失敗したりして、医薬品の品質の不備のリスクを増す可能性がある。この文書への回答の中で以下の情報を提供せよ：
- 全ての製品の製造のライフサイクルを通じて、継続的な管理を保証する改善計画
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基準を満たしていることを保証する、より、データ駆動型で科学的に理にかなったプログラムを提出せよ。プログラムは、これに限定されないが、装置の使用目的の適合性の評価、投入原材料の品質の保証、各製造工程のステップの能力と信頼性の判断とその管理、工程の性能と製品の品質の慎重で継続的なモニタリングを含むべきである。 - 関連する手順も併せて、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貴社のバリデーションプログラムの詳細なサマリ
工程の性能適格性評価と、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を継続的にモニタリングするための貴社のプログラムについて述べよ。 - 販売されている貴社の各医薬品の工程の性能適格性評価を実施するためのタイムライン
- 貴社の工程の性能適格性評価のプロトコルと、装置と設備の適格性評価に関する文書化された手順を含めよ。
- 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、バリデーション、維持、管理、モニタリングに関する詳細なプログラムを提出せよ。
- 貴社の工程内の、ばらつきをもたらす可能性のある開始時の手順に重点を置いた、モニタリング、サンプリング作業の包括的で独立したアセスメント
(1)工程内のばらつきの検知、(2)開始時の管理、(3)サンプリング計画 を改善するための貴社の改善計画を提出せよ。 - 原薬XXの改訂された製造指図書原本を提出せよ。
- 適切な評価をせずに貴社の製造工程になされた変更の影響を受けた可能性のある、販売されている貴社の原薬XXの独立したリスクアセスメントを提出せよ。
●指摘３
装置の洗浄及びメンテナンスに関する文書化された手順の適切なバリデートの不履行と、装置の洗浄と、原薬の製造に使用するための装置のリリースに関する適切に文書化された手順の制定の不履行
＜指摘３詳細＞
貴社は、貴社のバリデーションマスタプランで要求されている通りに、非専用製造装置の洗浄手順を適切にバリデートすることを怠った。査察中、貴社は、管XX、XX、XXを含む非専用装置に関する文書化された洗浄手順を提出しなかった。装置の作業者は、手順に従わずに装置を洗浄したと述べた。貴社は、装置が他の製品からの交叉汚染を防ぐために適切に洗浄されていることを保証することが欠けていた。
この文書への回答の中で、以下の情報を提出せよ：
- 貴社の医薬品製造作業におけるワーストケースとして特定された条件を取り入れることに特に重点を置いた貴社の洗浄バリデーションプログラムへの適切な改善
改善には、これに限定されないが、以下の全てのワーストケースの特定と評価を含むべきである：- より高い毒性を持つ医薬品
- より高い有効性を持つ医薬品
- 洗浄溶液の中でより低い溶解度の医薬品
- 洗浄を難しくする特性を持った医薬品
- 洗浄を最も難しくする拭き取り場所
- 洗浄前の最大保持時間
それから、洗浄バリデーションと検証に関する手順、貴社の製造工程で使用される全ての製造装置の今までに実施された全ての検証のステータスレポートを提出せよ。それぞれの装置について、多目的か専用かを述べよ。
さらに、新しい製造装置や新しい製品を導入する前に、貴社の変更管理システムでとられるべき手順を述べよ。
- 製品、工程、装置の洗浄手順の検証とバリデーションのための適切なプログラムが実施されていることを保証する最新の標準操作手順のサマリ
- 交叉汚染の範囲の評価をするための洗浄効果の包括的で独立したアセスメント残留物の確認、不完全に洗浄されていた可能性のあるその他の製造装置、交叉汚染された製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十分さを確認すべきであり、2つ以上の製品に製造に使用される製造装置の部品も含むべきである。
- 貴社の洗浄手順と業務の適切な改善と完了のため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を含むCAPAの計画
装置の洗浄のライフサイクル管理に関する貴社の手順の脆弱性のサマリを提供せよ。洗浄効果の向上、全ての製品と装置のための適切な洗浄の実行の継続的な検証の改善、その他の必要な改善を含む、貴社の洗浄プログラムの改善について述べよ。
●指摘４
原薬の安定性をモニタし、適切な保管条件や、リテストまたは使用期限を確認するために結果を使用するよう文書化された継続的な安定性試験プログラムを設計することの不履行
＜指摘４詳細＞
貴社は、原薬XXに関する適切な安定性プログラムを実施することを怠った。例えば、貴社は、適切な安定性プロトコルが欠けていた。貴社は、１つのロット(ロットXX)の保管サンプルの試験から、原薬XXの最新のリテスト日を制定していた。このロットは2016年に製造され、湿度が管理されていないサンプル室で保管されていた。このロットのリテスト日に関わらず、貴社はロットXXに関するバッチレコードを破棄した。
さらに、このバッチレコードは、アメリカで販売されている状態で破棄された。貴社には、原薬XXが保証された有効期間と保管状態を通して品質特性を維持することを保証するための科学的なデータに不足している。これは、貴社の顧客が貴社の原薬から製造した医薬品の品質に悪い影響を及ぼす可能性がある。
この文書への回答の中で、以下の情報を提供せよ：
- 貴社の安定性プログラムの適格性を保証するための包括的で独立したアセスメントとCAPAの計画
改善された貴社のプログラムは、これに限定されないが以下の方法を含むべきである。- 安定性を示す方法
- 販売が許可される前の、販売されている容器密閉システムにおける各医薬品の安定性の研究
- 使用期間が妥当であるかどうかを判断するために、毎年各製品の代表的なロットがプログラムに追加されるような継続的なプログラム
- 各段階（タイムポイント）で試験される特性の詳細な定義
- 改善された安定性プログラムの、これら及びその他の要素を説明する全ての手順
●指摘５
製造から独立し、品質保証と品質管理の職務を遂行する品質部門を持つことの不履行
＜指摘５詳細＞
貴社の品質部門は、信頼できる作業を保証するための適切な責任と権限が不足していた。貴社の品質部門は、以下に示す通り、貴社の設備の適切な文書化手順を保証することを怠った：
- ロットの製造記録のログブックは、数ページが破られているのが見つかった。
- ”Controlled Copy“というスタンプのない、複数のサイン済で、部分的に完了したバッチレコードが、非公式の研究開発研究所でみつかった。
- アメリカで販売中にも関わらす、原薬XXロットXXの製造及び分析の記録を含むバッチレコードの破棄
貴社はそのロットの保管サンプルも破棄した。
貴社は、リテスト期間内の原薬について、適切な記録保管手順を制定し、それに従う責任がある。
この文書への回答の中で以下の情報を提供せよ：
- 貴社の品質部門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計画
アセスメントは、これに限定されないが以下のことを含むべきである：- 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
- 適切な手順の順守を評価するための、品質管理部門の作業全体の監督の規定
- 品質部門のロットの出荷判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
- 調査の監督と承認及び全ての製品の同一性、濃度、品質、純度を保証するための品質部門のその他の職務からの解放
- これに限定されないが、新たに発生した製造/品質の問題に積極的に対応し、継続的な管理状態を保証するためのリソースのタイムリーな提供を含む、品質保証と信頼できる作業を、経営陣がサポートする方法
- 文書化手順の不十分な場所を判断するための、貴社の製造及び試験の作業を通じて使用される文書化システムの完全なアセスメント
貴社が作業を通して、帰属可能で、判読可能で、完全で、原本性があり、正確で、同時性の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CAPAの計画を含めよ。
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。
FDAのガイダンス文書Data Integrity and Compliance with Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices
を見よ。
我々は、貴社の改善を支援す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。
この文書への回答の中で以下の情報を提供せよ：
- アメリカに出荷された医薬品に関するデータレビュの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落の範囲と根本原因の詳細な記述を含めよ。 - 貴社の医薬品の品質で発見された不具合の潜在的な影響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落の影響を受けた医薬品のリリースにより患者に引き起こされるリスクの分析と、継続的なオペレーションによって引き起こされるリスクの分析を含めるべきである。 - 貴社のグローバルなCAPAの計画の詳細を含む経営戦略
詳細な是正処置の計画は、微生物及び分析データ、製造記録、FDAに提出された全てのデータを含む貴社により生成された全てのデータの信頼性と完全性を貴社がいかに保証しようとしているかについて述べるべきである。
●医薬品登録違反
省略
●追加の原薬のCGMPガイダンス
FDAは原薬がCGMPに則って製造されているかどうかを判断する際に、ICH Q7で概説されている期待を考慮する。
FDAのガイダンス文書Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API
を見よ。
●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、我々はCGMPの要件を満たすように貴社を支援するために貴社の作業を評価す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
この文書で挙げた逸脱は、貴社の製造所に存在する逸脱の包括的なリストでもない。貴社には、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2021年12月13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。全ての逸脱に完全に対応され、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、貴社が全ての逸脱の是正処置を完了したことを確認するために再査察をするかもしれない。
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■CMS#614058■
2021年1月12日～2月18日のイリノイ州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2021年12月21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。
●医薬品CGMP違反
●指摘１
貴社は、貴社が製造した医薬品が持つとされる、または、持つと表示されている同一性、濃度、品質、純度を貴社の医薬品が持っていることを保証するために設計された適切に文書化された製造の手順と工程管理を制定することを怠り、その文書化された製造及び工程管理の全ての手順に従うことを怠った。
＜指摘１詳細＞
我々査察官は、XXシステムのバリデーションプロトコルの不備と実行中の逸脱を文書化した。貴社の製薬用水システムの検証中に、システムの性能パラメータの逸脱が発生した。例えば：
- 微生物の管理を継続するためのシステムの能力に影響を与えるXXの濃度が、システムの貯蔵タンク内のXXで記録された。2018年1月のXX日中XXでXXの測定値がXXの限界値を下回った。
これらの発生は、逸脱としてバリデーションレポート内に文書化されておらず、貴社が製薬用水システムはバリデートされているとみなす前にレビュされなかった。 - 製薬用水システムのバリデーションでは、定期的なXXの消毒に加えて実施される化学的な消毒のタイプと頻度を裏付ける科学的なデータを提供できなかった。貴社のプロトコルも、貴社の製薬用水システムの消毒プログラムのこれらのパラメータを評価するための規定に 欠けていた。貴社の現在の業務は化学的消毒XXを実施することである。
- そのプロトコルが許容可能と判断された場合、サンプリングと試験の削減を可能とするが、 貴社は、何が許容可能の基準かを定義していなかった。貴社はXXで、XXと同じくらい高い結果を得たのだが、貴社はそれでもXXの頻度までサンプリングと試験を削減した。
貴社は貴社の製薬用水システムが、医薬品の製造に適し、少なくとも、アメリカ薬局方の精製水のモノグラフと適切な微生物の限界値を満たす水を一貫して製造できることを示さなかった。
使用目的に適した高純度の精製水を一貫して保証するために貴社の製薬用水システムを設計することはが不可欠である。貴社の医薬品の成分として使用される水の中の高度のバイオバーデンまたは好ましくない微生物は、消費者に重大なリスクをもたらす可能性がある。
貴社は回答の中で、再バリデーションに続いて貴社の製薬用水システムの再評価を実施すると約束した。
また貴社は、貴社のバリデーションプログラムのギャップのアセスメントを実施することと、全ての職員のためにCGMPと品質システムの包括的な教育を実施することを約束した。
この文書への回答の中で、以下の情報を提供せよ：
- 貴社の製薬用水システムの設計、管理、維持の包括的で独立したアセスメント及び付随する是正処置・予防処置(CAPA)
- 適切な製薬用水システムを据え付け運用するための徹底的な改善計画
改善されたシステムの設計または新しいシステムが一貫して、アメリカ薬局方のモノグラフと、適切な微生物の限界値(総菌数、好ましくない微生物)を順守したXX水を一貫して製造することを保証するための、安定した継続的な管理、維持、モニタリングプログラムを含めよ。 - 後者に関しては、貴社により製造される製品に使用することを考慮して、水の総菌数の限界値が適切であることを保証せよ。
●指摘２
貴社は、ロットが既に出荷されたどうかに関わらず、ロットやその成分がその規格を満たすために、説明のつかない不一致や不具合を徹底的に調査することを怠った。
＜指摘２詳細＞
貴社の製薬用水システムはバリデーション以降、微生物汚染と動作パラメータからの多数の逸脱 にさらされた。これらの逸脱の多くは、調査もされず、CAPAの実施にもつながっていなかった。
- 2020年1月1日から2020年6月30日の間に、貴社の製薬用水システムのポートXXとポートXXから採取された7つのサンプルの中のセパシア菌の汚染物質の確認に対応した調査が実施されなかった。セパシア菌の汚染物質は、貴社の手順または、貴社のXX水の規格において、好ましくない微生物としては識別されなかった。貴社のXX製薬用水システム内の好ましくない微生物の存在は、貴社の医薬品の品質に悪影響を与える可能性がある。
- ポートXXとポートXXで採取された3つのサンプル内でのセパシア菌の発見により、貴社の製薬用水システムのバリデーション中に貴社はCAPAを開始した。これらのポートは製造用の水を供給する。CAPAの調査は、供給ポートXXからサンプルポートXXへのXXの根本原因の可能性を特定し、貴社はXXを提案した。しかしCAPAは、フィルタの追加や、是正処置がなぜ行われなかったかの説明もなく約1年半後に終了された。その後、貴社は2020年に複数回ポートXXでセパシア菌を確認した。
- 貴社の製薬用水システムのバリデーション中、サードパーティのサービス技術者は、水のタンクの内側にシミをみつけ、原因の調査をしていることを指摘した。貴社は原因の文書化またはサービス技術者の発見への対応に欠けていいた。
- 消毒手順XXの逸脱は、貴社の逸脱手順に従って記録されていなかった。我々は、オゾン消毒中、保管タンクXXとループ供給でXXの最小レベルが満たされていない時に、動作パラメータに調査やCAPAの実施の不備のパタンを発見した。
貴社は回答の中で、第三者の専門家を雇うことと、調査の教育を実施することを約束した。また、貴社は、全てのCAPA、規格外(OOS)、傾向外(OOT)のレビュを行うことを約束し、2019年1月1日から現在までの品質管理データを無効にした。また、貴社は、セパシア菌群(BCC)を好ましくない微生物として含めるために、2021年1月11日時点で貴社の精製水の規格も改訂した。
貴社は、いくつかのOOSとOOTの結果、逸脱、予期しない不一致を正確に分類することを怠ったので、貴社の回答は不十分である。
この文書への回答の中で以下の情報を提供せよ：
- 最終的にアメリカに販売されたロットかどうかに関わらず、アメリカ向け製品に関し、全ての無効化したOOSの結果(工程内、リリース、安定性の試験を含む)の回顧的で独立したレビュと、各OOSに関し、以下のことを含む分析でみつかったことをまとめたレポート：
- 無効化されたOOSの結果に関し、科学的に正当な理由やエビデンスが、最終的、または、非決定的に、試験のエラーを原因として示しているかどうかを判断せよ。
- 最終的に試験が根本原因であると確認した調査に関し、論理的根拠を提供し、同じまたは同様の根本原因に対して脆弱な全てのその他の試験方法が改善のために特定されていることを保証せよ。
- 回顧的レビュで、試験室が非決定的な根本原因と特定されたか、または、根本原因が特定されなかった全てのOOSの結果について、製造の徹底的なレビュ（例：バッチレコード、製造段階の適切性、装置/設備の適合性、原材料のばらつき、工程の能力、逸脱の履歴、苦情の履歴、ロットの不合格の履歴）を含めよ。各調査に関し、製造が潜在的な根本原因となっているもののサマリと、製造作業の改善を提出せよ。
- 使用期限内にあり、販売された医薬品のロットに関連した全てのGMP文書の包括的で回顧的なレビュと、全てのOOSの結果、OOTの結果、逸脱、予期しない不一致が分類され、適切に調査されていることを保証するための、製造に使用される装置及びシステムの情報
- 貴社の現在の設計において、製薬用水システムが再検討されたかどうか説明せよ。最近は微生物の減少の最良の手段を示しているが、貴社は現在XXシステムを持っている。
- 発見された製薬用水システムの不具合の潜在的影響を受けた、現在アメリカに販売されているか、使用期限内の全ての医薬品のロットの品質についての詳細なリスクアセスメント
リスクアセスメントに応じて、顧客への通知や製品の回収等、貴社がとろうとしているアクションを明確に述べよ。 - この違反に対応するために割り出された全てのCAPAのタイムフレーム付きの詳細な記述
●指摘３
貴社は、成分、医薬品の容器、蓋、中間材料、ラベル、医薬品が、同一性、濃度、品質、純度の適切な基準に従っていることを保証するために設計された、科学的に妥当で適切な規格、基準、サンプリング計画、テスト手順を含む試験の管理を制定することを怠った。
＜指摘３詳細＞
貴社は、販売前に、セパシア菌群を含む特定の好ましくない微生物の増殖を抑制するための防腐剤システムの能力を評価するために、貴社の最終医薬品の中の抗菌有効性の十分な検証をしなかった。
例えば、セパシア菌を用いた0.12％クロルヘキシジングルコン酸塩経口リンス(製品XX)に関する検証は2020年7月まで行われなかった。特に、BBCは、有効期限内のいくつかのロットの製品内で、数えきれない(TNTC)レベルを含む、過度のレベルまで急増していることがわかった。この製品の多くのロットは、過度の微生物汚染により市場から回収された。製品XXは、貴社の委託製造業者により製造されている。
貴社は回答の中で、製品固有の情報の規定と維持の適格性と、規制要件をみたしていることを判断するために、「SAI製品に関する米国の規制情報」というタイトルの貴社の手順を評価することを約束した。
貴社は、貴社で貴社のために製造された製品に関し、微生物試験にBCCを追加することを約束した。
貴社は、潜在的に好ましくない微生物に対応することを含む、管理の適切さを保証するために、製造設備内で新しい微生物が特定された場合に行う措置を制定するための手順を開発し実装することを約束した。
この文書への回答の中で新しい製品を支えるための適切な検証の実施を含んだ、貴社の製造及び工程開発プログラムがいかに貴社製品の品質を形成するかを述べよ。
●指摘４
貴社は、全ての成分、医薬品の容器、蓋、中間材料、包装材料、ラベル、医薬品を承認または拒否する責任と権限を持った適切な品質管理部門を制定することを怠った。
＜指摘４詳細＞
貴社は、貴社で貴社のために製造された全ての製品が、微生物上の品質と安全性を保証するために、適切な品質特性、抗菌性または防腐剤システムを持っていることを保証するための責任を果たさなかった。例えば、貴社の非無菌の水性の医薬品の規格は、セパシア菌を含んでいなかった。
貴社の医薬品はしばしばセパシア菌やそのほかの好ましくない微生物の感染症に非常に弱い可能性のある患者がいる病院や臨床現場で使用される。貴社の医薬品の中の好ましくない微生物の数やタイプを検知することはロットの処遇を判断するために重要である。
貴社と貴社の委託製造業者XXの間の契約は、貴社の医薬品の製造に関する貴社の責任を特に明らかにしている。貴社の責任は、製品の製造に関し、XXへの技術的及び法的問題に関するサポートの提供を含む。貴社には、貴社の製品の製造に関連する手順や記録のレビュを含む仕組みを通して、貴社の委託製造業者のCGMPの遵守を監督する責任もある。
医薬品は、CGMPに従って製造されなければならない。FDAは、多くの製造業者が、製造施設、試験機関、包装業者、ラベル貼付業者のような独立した委託業者を使用していることを認識している。FDAは、委託業者も製造業者の延長とみなす。
我々は、好ましくない微生物の汚染または相当な汚染のリスクがあるために、2022年6月30日から2022年9月30日までの使用期限を持つ製品XXのロットを最初に回収したことを認識している。我々は、FDAとの更なる議論の後、貴社が製品XXの影響を受けた可能性がある全てのロットを含むよう回収の拡大をしたことも認識している。また、我々は、好ましくない微生物汚染の可能性により、その後、XX、XX、XX、医療機器の回収をしたことも認識している。
貴社は、それらを貴社が製造したか、貴社の代わりに委託製造施設で製造したかに関わらず、貴社の医薬品の品質に責任がある。貴社には、安全性、同一性、濃度、品質、純度を保証するために、医薬品がFD&C Act 501(a)(2)(B)に従って製造されたことを保証することが求められている。
この文書への回答の中で、貴社及び貴社の委託製造業者により実施された全ての活動が、適切で、貴社の品質部門に承認されていることを保証する最新の手順を提供せよ。
●医療機器の品質システム違反
省略
●品質システム
貴社の品質システムは不十分である。GMPに従った品質システムを制定し維持するために、FDAのガイダンスQ8(R2)Pharmaceutical Development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。
●医薬品製造の一時停止
我々は貴社がこの製造施設での医薬品の製造を一時停止したことを認識している。
もし貴社が医薬品の製造を再開するつもりなら、作業を再開する前に通知せよ。
●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、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。
全ての違反を速やかに是正せよ。この問題への即座の適切な対処の不履行は、制限のない差し押さえ、強制命令を含む、さらなる通知のない制限または法的なアクションにつながるかもしれない。未解決の違反は、他の連邦機関の契約授与も妨げるかもしれない。
違反への対処の不履行は、FDAの輸出証明の発行の差し控えにもつながるかもしれない。全ての違反に完全に対応がされ、我々が貴社のCGMPの遵守を確認するまで、FDAは貴社の医薬品製造業者としての新しい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。
まとめ
いかがでしたでしょうか。
2件目のレターで、委託製造業者の管理に関し、“自社で製造したか、自社の代わりに委託製造施設で製造したかに関わらず、医薬品の品質に責任がある。”という指摘がありました。
この指摘は、ウォーニングレターの中では比較的よく見かける指摘ではありますが、昨今、新型コロナの影響で、どの会社も多かれ少なかれ委託製造業者の管理が手薄になっているということがあるのではないでしょうか。
ただでさえ、委託先の管理は難しいところもあると思いますので、コロナ下の今は特に注意が必要かもしれません。
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Oh my goodness! Impressive article dude! Thank you so much, However I am experiencing issues with your RSS. I don’t know why I am unable to join it. Is there anyone else getting identical RSS problems? Anybody who knows the answer can you kindly respond? Thanks!
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