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嘉峪檢測(cè)網(wǎng) 2024-11-21 08:22
11月19日，F(xiàn)DA發(fā)布了對(duì)津藥達(dá)仁堂京萬(wàn)紅(天津)藥業(yè)有限公司的警告信，警告信中列舉了該公司限制、延遲或拒絕FDA檢查，以及GMP違規(guī)的情況：
限制訪問(wèn)記錄：
FDA 要求提供工藝驗(yàn)證報(bào)告和批生產(chǎn)記錄。盡管該公司將文件逐行翻譯給 FDA 檢查人員，但所提供的翻譯副本分別針對(duì)批生產(chǎn)記錄中組分的總凈重和工藝驗(yàn)證報(bào)告中的工藝參數(shù)進(jìn)行了不合理的編輯。此外，還編輯了設(shè)備確認(rèn)記錄，包括所有關(guān)鍵工藝參數(shù)，以及相應(yīng)的可接受范圍和記錄范圍。
該公司之所以提供編輯的副本，是因?yàn)楣咀罡吖芾韺右蟊Ｗo(hù)批記錄、工藝驗(yàn)證研究和設(shè)備參數(shù)中包含的信息。當(dāng)檢查組解釋說(shuō)未能提供所要求的記錄將被記錄為拒絕時(shí)，該公司確認(rèn)了拒絕。
檢查組要求提供2016 年至 2024 年啟動(dòng)的CAPA清單；該公司僅提供了 2024 年的 CAPA 清單。
限制拍照：在檢查過(guò)程中，檢查人員試圖對(duì)灌裝機(jī)進(jìn)行拍照，但是管理層表示，檢查人員不允許對(duì)設(shè)備進(jìn)行拍照。
限制訪問(wèn)區(qū)域：管理層不允許檢查人員進(jìn)入執(zhí)行某生產(chǎn)操作的房間。
GMP違規(guī)：
檢查人員在灌裝機(jī)上觀察到殘留物，但是這兩臺(tái)設(shè)備都被標(biāo)識(shí)為干凈。
灌裝機(jī)有幾顆螺絲缺失，電機(jī)外殼面板破損，灌裝機(jī)料斗沒(méi)有蓋子，并使用老化破損的繩子與設(shè)備綁在一起。FDA認(rèn)為其設(shè)備不適合其預(yù)期用途。
盡管聲明了生產(chǎn)工藝已經(jīng)過(guò)驗(yàn)證且設(shè)備已經(jīng)過(guò)確認(rèn)，但是沒(méi)有提交支持信息。
用于藥品的放行和穩(wěn)定性測(cè)試的分析方法沒(méi)有穩(wěn)定性指示能力。
該公司尚未進(jìn)行強(qiáng)降解試驗(yàn)，以識(shí)別可能存在足夠數(shù)量以需要在穩(wěn)定性試驗(yàn)期間進(jìn)行測(cè)試的降解物。
警告信翻譯如下：
Warning Letter 320-25-08
October 30, 2024
Dear Mr. Zhang:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Tianjin Darentang Jingwanhong Pharmaceutical Co., Ltd., (also known as Tianjin Pharmaceutical Da Ren Tang Group Jing Wan Hong Co., Ltd.), FEI 3006283468, at No. 20 Daming Street, Xiqing, Tianjin, Tianjin, China, from March 18 to 22, 2024.
FDA 于 2024 年 3 月 18 日至 22 日檢查了位于中國(guó)天津市西青市大明街 20 號(hào)的貴方藥品生產(chǎn)工廠津藥達(dá)仁堂京萬(wàn)紅(天津)藥業(yè)有限公司，位于中國(guó)天津市天津市西青市大明街 20 號(hào)，3006283468。
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
本警告信總結(jié)了對(duì)于藥品現(xiàn)行藥品生產(chǎn)質(zhì)量管理規(guī)范 （CGMP） 法規(guī)的重大違規(guī)。請(qǐng)參閱21 CFR 第 210 和 211 部分。
Our investigators documented your firm limited and/or refused an FDA inspection. Under section 501(j) of the FD&C Act, 21 U.S.C. 351(j), your drugs are adulterated in that they have been manufactured, processed, packed, or held in an establishment where the owner or operator has limited inspection and/or refused inspection.
我們的檢查人員記錄了貴公司對(duì) FDA 檢查的限制和/或拒絕。根據(jù)FD&C 法案 第 501（j） 節(jié)（21 U.S.C. 351（j）），你們的藥品因限制檢查和/或拒絕檢查被認(rèn)定為摻假。
Additionally, because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
此外，由于你們的制造、加工、包裝或保存方法、設(shè)施或控制不符合 CGMP，你們的藥品被認(rèn)定為FD&C 法案 第 501（a）（2）（B） 節(jié)、21 U.S.C. 351(a)(2)(B)所指的摻假商品。
We reviewed your April 15, 2024, response to our Form FDA 483 in detail.
我們?cè)敿?xì)審查了你們于 2024 年 4月 15 日對(duì)我們的 FDA 483 的回復(fù)。
During our inspection, FDA investigators observed specific violations including, but not limited to, the following.
在我們的檢查期間，F(xiàn)DA 檢查人員觀察到了具體的違規(guī)行為，包括但不限于以下：
Limiting the Inspection
限制檢查
Your firm limited and refused to permit the FDA inspection as follows:
貴公司限制并拒絕允許 FDA 檢查，具體如下：
Limiting Access to Records
限制訪問(wèn)記錄
Your firm limited access to manufacturing records that our inspection team was entitled to inspect. For example, during the inspection, FDA investigators requested the process validation report for your over-the-counter (OTC) drug product “(b)(4)” and the manufacturing production batch record for Batch(b)(4). Although you translated the documents line by line to the FDA investigators, translated copies provided were unreasonably redacted for the total net weights of components in the production batch record and processing parameters in the process validation report, respectively. In addition, records of equipment qualification for the following units were also redacted: (b)(4) tank ID 447, (b)(4) tank ID 344, and (b)(4) tank ID 264. Redactions included all critical process parameters, such as (b)(4), and corresponding acceptable and recorded ranges.
貴公司限制了我們檢查組對(duì)有權(quán)檢查的生產(chǎn)記錄的訪問(wèn)。例如，在檢查期間，F(xiàn)DA 檢查人員要求提供您的XX藥品的工藝驗(yàn)證報(bào)告和XX批次的批生產(chǎn)記錄。盡管你們將文件逐行翻譯給 FDA 檢查人員，但所提供的翻譯副本分別針對(duì)批生產(chǎn)記錄中組分的總凈重和工藝驗(yàn)證報(bào)告中的工藝參數(shù)進(jìn)行了不合理的編輯。此外，還編輯了XX罐 ID 447、XX罐ID 344 和 XX罐 ID 264的設(shè)備確認(rèn)記錄。編輯包括所有關(guān)鍵工藝參數(shù)，例如（b）（4）以及相應(yīng)的可接受范圍和記錄范圍。
Your firm provided redacted copies because you stated that you are required by the firm’s top management to protect the information included in batch records, process validation studies, and equipment parameters. Your firm’s actions during this inspection significantly hindered FDA from fully assessing your compliance with CGMP. When our inspection team explained that your failure to provide the requested records would be documented as a refusal, you acknowledged the refusal.
貴公司之所以提供編輯的副本，是因?yàn)槟銈兟暶鞴镜淖罡吖芾韺右竽銈儽Ｗo(hù)批記錄、工藝驗(yàn)證研究和設(shè)備參數(shù)中包含的信息。貴公司在此次檢查期間的行為嚴(yán)重阻礙了FDA 全面評(píng)估你們對(duì) CGMP 的符合性。當(dāng)我們的檢查組解釋說(shuō)，你們未能提供所要求的記錄將被記錄為拒絕時(shí)，你們確認(rèn)了拒絕。
Our inspection team documented other instances in which your firm limited the inspection by providing some, but not all, of the records requested that FDA had authority to inspect. For example, the inspection team requested the list of corrective actions and preventive actions (CAPAs) initiated from 2016 to 2024; however, you limited the inspection by providing the list of CAPAs issued in 2024 only.
我們的檢查組記錄了貴公司通過(guò)提供部分（而不是全部）FDA 有權(quán)檢查的記錄來(lái)限制檢查的其他情況。例如，檢查組要求提供2016 年至 2024 年啟動(dòng)的CAPA清單；但是，你們僅提供 2024 年的 CAPA 清單。
Limiting Photography
限制拍照
During the inspection, our inspection team attempted to take photos of the filling machines ID-192, and ID-197, which were observed to be dirty and in an apparent state of disrepair, despite the equipment status being identified as clean. This equipment is currently used to manufacture a drug intended for U.S. distribution. Your management stated that the investigators were not allowed to take photographs of the equipment as part of the inspection. When our inspection team explained that failure to allow photography would be documented as a refusal, you acknowledged the refusal.
在檢查過(guò)程中，我們的檢查組試圖對(duì)灌裝機(jī) ID-192 和 ID-197 進(jìn)行拍照，盡管設(shè)備狀態(tài)被確定為干凈，但觀察到它們很臟并且明顯處于年久失修的狀態(tài)。該設(shè)備目前用于生產(chǎn)在美國(guó)分銷的藥物。你們的管理層表示，檢查人員不允許對(duì)設(shè)備進(jìn)行拍照來(lái)作為檢查的一部分。當(dāng)我們的檢查人員解釋說(shuō)，不允許拍照將被記錄為拒絕時(shí)，你們確認(rèn)了拒絕。
Limiting Access to Areas
限制訪問(wèn)區(qū)域
Your management did not permit our inspection team to access the manufacturing room where(b)(4) and (b)(4) are performed. When our inspection team explained that failure to allow FDA to access and evaluate manufacturing equipment and operations would be documented as a refusal, you acknowledged the refusal.
你們的管理層不允許我們的檢查團(tuán)隊(duì)進(jìn)入執(zhí)行XX和XX操作的房間。當(dāng)我們的檢查團(tuán)隊(duì)解釋說(shuō)，不允許FDA 訪問(wèn)和評(píng)估生產(chǎn)設(shè)備和操作將被記錄為拒絕時(shí)，你們確認(rèn)了拒絕。
Delaying, Denying, Limiting, or Refusing a Drug Inspection
延遲、限制或拒絕藥品檢查
When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document:Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection (June 2024) at https://www.fda.gov/media/86328/download.
當(dāng)持有人、經(jīng)營(yíng)者或代理人延遲、限制或拒絕檢查時(shí)，根據(jù)FD&C法案第501（j）條，這些藥物可能被視為摻假。請(qǐng)參閱 FDA 指南：構(gòu)成延遲、限制或拒絕藥品或器械檢查的情況（2024 年 6 月）。
GMP Violations
GMP違規(guī)
1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
貴公司未能根據(jù)藥品的性質(zhì)對(duì)設(shè)備和器具進(jìn)行適當(dāng)?shù)那鍧?、維護(hù)和/或消毒，以防止出現(xiàn)改變藥品安全性、特性、劑量、質(zhì)量或純度超出官方或其他既定標(biāo)準(zhǔn)的故障或污染 （21 CFR 211.67（a））。
You failed to demonstrate that your cleaning practices are adequate to remove contaminants from equipment used to manufacture your topical drug product, "(b)(4)." On March 19, 2024, our investigators observed residues on filling machines ID-192 and ID-197, despite both being identified as clean.
你們未能證明清潔方法足以去除用于制造外用藥品 （b）（4） 設(shè)備中的污染物。2024 年 3 月19 日，我們的檢查人員在灌裝機(jī) ID-192 和 ID-197 上觀察到殘留物，但是這兩臺(tái)設(shè)備都被標(biāo)識(shí)為干凈。
In addition, your filling machines were not adequately maintained and were observed to be in a state of disrepair. For example, the filling machine ID-192 had several missing screws and a broken motor housing panel, and filling machine ID-197 lacked a cover for the(b)(4) bowl and was observed with degraded and cracked (b)(4) bands apparently holding the equipment together. As such, your equipment was not suitable for their intended use.
此外，你們的灌裝機(jī)沒(méi)有得到充分維護(hù)，并且被發(fā)現(xiàn)處于年久失修的狀態(tài)。例如，灌裝機(jī) ID-192有幾顆螺絲缺失，電機(jī)外殼面板破損，灌裝機(jī) ID-197 沒(méi)有XX斗的蓋子，并且觀察到使用老化破損的XX繩與設(shè)備綁在一起。因此，你們的設(shè)備不適合其預(yù)期用途。
In your response, you acknowledge the incomplete cleaning of filling machine ID-192 and state that the equipment’s cleaning procedure is revised. You also state that the conditions identified above filling machine ID-197 are repaired.
在你們的回復(fù)中，你們承認(rèn)灌裝機(jī) ID-192 的清潔不完整，并聲明設(shè)備的清潔程序已修改。你們還聲明上述灌裝機(jī)ID-197 的狀況已修復(fù)。
Your response is inadequate because you did not implement sufficient corrective actions related to the status and cleaning of all equipment used in the manufacture of drugs intended for the U.S. market. You also failed to evaluate the potential impact of your filling machines’ condition and inadequate cleaning on the quality of your distributed drug batches.
你們的回復(fù)是不充分的，因?yàn)槟銈儧](méi)有對(duì)所有設(shè)備的狀態(tài)和清潔采取足夠的糾正措施。你們也未能評(píng)估灌裝機(jī)的狀況和清潔不足對(duì)分銷藥品批次質(zhì)量的潛在影響。
2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
貴公司未能建立適當(dāng)?shù)纳a(chǎn)和工藝控制的書(shū)面程序，以確保貴公司生產(chǎn)的藥品具有其聲稱或聲稱擁有的特性、劑量、質(zhì)量和純度 （21 CFR 211.100（a））。
Based on the limitation of the inspection described above, you failed to provide data to demonstrate that you adequately validated your manufacturing processes used to manufacture your OTC drug product and to demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality.
基于上述的檢查限制，你們未能提供數(shù)據(jù)來(lái)證明你們充分驗(yàn)證了用于生產(chǎn)藥品的制造工藝，并證明工藝具有可重復(fù)性和可控性，無(wú)法始終如一地生產(chǎn)出具有一致特性和質(zhì)量的藥品。
Although you state your manufacturing process is validated and equipment is qualified, you do not submit supporting information.
盡管你們聲明生產(chǎn)工藝已經(jīng)過(guò)驗(yàn)證并且設(shè)備已經(jīng)確認(rèn)，但你們沒(méi)有提交支持信息。
3. You firm failed to establish required laboratory control mechanisms (21 CFR 211.160(a)), including those related to stability studies (21 CFR 211.166).
貴公司未能建立所需的實(shí)驗(yàn)室控制機(jī)制 （21 CFR 211.160（a）），包括與穩(wěn)定性研究相關(guān)的機(jī)制 （21 CFR 211.166）。
The analytical method used for the release and stability testing of your drug product “(b)(4)” is not stability indicating.
用于XX藥品的放行和穩(wěn)定性測(cè)試的分析方法沒(méi)有穩(wěn)定性指示能力。
Also, your firm has not performed forced degradation studies to identify degradants that may be present in sufficient quantities to require testing during stability studies.
此外，貴公司尚未進(jìn)行強(qiáng)降解試驗(yàn)，以識(shí)別可能存在足夠數(shù)量以需要在穩(wěn)定性試驗(yàn)期間進(jìn)行測(cè)試的降解物。
In your response, you commit to conduct an “impact factor” and accelerated test to assess the impact of different factors on your drug product stability. You also committed to test three batches per production schedule.
在回復(fù)中，你們承諾進(jìn)行“影響因子”和加速測(cè)試，以評(píng)估不同因素對(duì)藥品穩(wěn)定性的影響。你們還承諾每個(gè)生產(chǎn)計(jì)劃測(cè)試三個(gè)批次。
Your response is inadequate because you did not provide details of your “impact factor” and accelerated test plan and how they relate to the lack of degradation studies. Your plan also fails to include a retrospective evaluation of batches that have been released and are currently within expiry in the U.S. market.
你們的回復(fù)是不充分的，因?yàn)闆](méi)有提供“影響因子”和加速測(cè)試計(jì)劃的詳細(xì)信息，以及它們與缺乏降解試驗(yàn)的關(guān)系。你們的計(jì)劃也未能包括對(duì)已放行且在效期內(nèi)的批次進(jìn)行回顧性評(píng)估。
來(lái)源：GMP辦公室
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