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嘉峪檢測網(wǎng) 2025-03-26 20:02
近日，F(xiàn)DA發(fā)布了Yangzhou Sion Commodity Co., Ltd的警告信，其中提及大量實(shí)驗(yàn)室數(shù)據(jù)完整性問題，該公司在缺陷回復(fù)中表示：QA經(jīng)理對GMP要求沒有很好的理解：
實(shí)驗(yàn)室記錄數(shù)據(jù)缺失
實(shí)驗(yàn)室記錄使用涂改液進(jìn)行修改
檢驗(yàn)記錄的原始版本和謄抄版本與COA之間不一致
檢驗(yàn)過程沒有保存原始數(shù)據(jù)，包括天平打印單、時(shí)間、樣品準(zhǔn)備和設(shè)備日志
該公司在回復(fù)中甩鍋QA經(jīng)理，然而FDA對此回復(fù)并不接受。
缺陷翻譯如下：
CGMP Violations
違規(guī)行為
During our inspection, our investigators observed specific violations including, but not limited to, the following. CGMP
在檢查過程中，我們的檢查人員發(fā)現(xiàn)了以下具體違規(guī)行為，包括但不限于：
1.Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).
貴公司未能對原輔料進(jìn)行鑒定，也未確認(rèn)其是否符合所有關(guān)于純度、強(qiáng)度和質(zhì)量的書面標(biāo)準(zhǔn)。貴公司還未能在適當(dāng)?shù)臅r(shí)間間隔驗(yàn)證并確定原輔料供應(yīng)商COA的可靠性。
You manufacture over-the-counter (OTC) drug products including(b)(4). Your firm failed to test incoming components used in manufacturing your finished OTC drug products to determine identity, purity, strength, and quality, and your firm did not establish a vendor qualification program for your raw material suppliers.
貴公司生產(chǎn)藥品，其中包括（b)(4)。貴公司未對用于生產(chǎn)成品藥品的進(jìn)廠原輔料進(jìn)行鑒定、純度、強(qiáng)度和質(zhì)量檢驗(yàn)，并且也未針對原輔料供應(yīng)商建立供應(yīng)商確認(rèn)程序。
Your firm used results from your suppliers’ certificates of analysis (COAs) without establishing the reliability of your suppliers’ analyses through appropriate validation and without conducting at least one specific identity test on each incoming lot of components. You may not rely on your suppliers’ COA to verify the identity of your components.
貴公司在未通過適當(dāng)驗(yàn)證確定供應(yīng)商分析結(jié)果可靠性，且未對每批進(jìn)貨的成分進(jìn)行至少一項(xiàng)特定身份測試的情況下，就使用了供應(yīng)商的分析證書（COA）。
貴公司不能依靠供應(yīng)商的 COA 來驗(yàn)證成分的身份。
In previous correspondence on September 28, 2023, associated with an FDA records request under section 704(a)(4) of the act, your firm committed to performing independent testing, to include identity testing for each shipment of high-risk component, as required by 21 CFR 211.84 (d)(1) & (2), using equivalent or better methods to those in the United States Pharmacopeia (USP).
在 2023 年 9 月 28 日與 FDA 根據(jù)該法案第 704 (a)(4) 條提出的記錄請求相關(guān)的通信中，貴公司承諾按照《聯(lián)邦法規(guī)匯編》第 21 章第 211.84 (d)(1) 和 (2) 條的要求，使用與美國藥典（USP）相當(dāng)或更優(yōu)的方法，對每批高風(fēng)險(xiǎn)成分進(jìn)行獨(dú)立檢測，包括進(jìn)行身份測試。
However during the inspection, and contrary to previous commitments, your firm failed to demonstrate that you adequately tested each shipment of each lot of the incoming components at high-risk of(b)(4) contamination. These include, but are not limited to, testing of (b)(4) solution you used in manufacturing drug products to determine their appropriate identity. Identity testing for these and certain other high-risk drug components1 include a limit test in the USP to ensure that the component meets the relevant safety limits for levels of (b)(4). Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture of your drug products.
然而，在此次檢查中，與之前的承諾相悖，貴公司未能證明已對每批存在（b)(4) 污染高風(fēng)險(xiǎn)的進(jìn)貨成分進(jìn)行了充分檢測。這些成分包括但不限于用于生產(chǎn)藥品的（b)(4) 溶液，貴公司未對其進(jìn)行適當(dāng)?shù)纳矸輽z測。對于這些及其他某些高風(fēng)險(xiǎn)藥品成分 1 ，身份檢測包括美國藥典中的一項(xiàng)限度測試，以確保成分的（b)(4) 含量符合相關(guān)安全限值。由于貴公司未使用美國藥典中能檢測這些有害雜質(zhì)的身份測試方法對每批進(jìn)貨成分進(jìn)行檢測，因此無法保證這些成分可用于藥品生產(chǎn)。
The use of ingredients contaminated with(b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4) to help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for (b)(4) contamination at (b)(4).
使用受（b)(4) 污染的成分已在全球范圍內(nèi)導(dǎo)致多起人類致命中毒事件。有關(guān)在生產(chǎn)含有高風(fēng)險(xiǎn)（b)(4) 污染成分的藥品時(shí)如何滿足 CGMP 要求，請參閱 FDA 的指導(dǎo)文件（b)(4) ，文件鏈接為（b)(4)。
Additionally, you failed to perform identity testing on the component(b)(4) and lacked adequate impurities testing on (b)(4) before being used in manufacturing. Furthermore, (b)(4) was not adequately monitored for (b)(4).
此外，你們沒有對（b)(4) 成分進(jìn)行身份檢測，在將其用于生產(chǎn)前也缺乏足夠的雜質(zhì)檢測。而且，對于（b)(4) 中的（b)(4) 也沒有進(jìn)行充分監(jiān)測。
In your response on October 18, 2024, you indicate that you have updated your procedures to mandate the testing of identity and purity of active ingredients and the testing of identity of nonactive ingredients. Your response is inadequate because you did not address your plans for qualification of your component suppliers, did not address your previous commitments to perform identity testing on high-risk components, and failed to clarify whether your firm tested all lots of drug products that you distributed to the United States for risk of(b)(4). You also failed to adequately address quality attributes of your components.
在 2024 年 10 月 18 日的回復(fù)中，你們表示已更新程序，要求對活性成分的身份和純度以及非活性成分的身份進(jìn)行檢測。但你們的回復(fù)并不充分，因?yàn)槟銈儧]有提及對組件供應(yīng)商進(jìn)行資質(zhì)審核的計(jì)劃，沒有回應(yīng)之前對高風(fēng)險(xiǎn)成分進(jìn)行身份檢測的承諾，也沒有說明貴公司是否對運(yùn)往美國的所有批次藥品進(jìn)行了（b)(4) 風(fēng)險(xiǎn)檢測。此外，你們也沒有充分說明組件的質(zhì)量屬性。
2.Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
貴公司的質(zhì)量控制部門未能履行其職責(zé)，以確保所生產(chǎn)的藥品符合藥品生產(chǎn)質(zhì)量管理規(guī)范（CGMP），并達(dá)到既定的關(guān)于藥品身份、含量、質(zhì)量和純度的標(biāo)準(zhǔn)。
Your QU did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to:
你們的質(zhì)量部門未能為你們的藥品的制造提供足夠的監(jiān)督。例如，你們的質(zhì)量部門未能：
Perform assay testing for the strength of the active ingredient in(b)(4) drug products (21 CFR 211.165(b)).
對(b)(4)藥品中活性成分的含量進(jìn)行檢測。
Ensure an adequate stability program (including assessment of product potency over the shelf life) to support your claimed(b)(4) expiry for (b)(4) drug products (21 CFR 211.166).
確保有足夠的穩(wěn)定性計(jì)劃（包括產(chǎn)品有效期內(nèi)的效力評估），以支持你們聲稱的藥品有效期（21 CFR 211.166）。
Ensure that personnel had adequate training and experience for the production and analysis of(b)(4) drug products (21 CFR 211.25(a)).
確保工作人員在(b)(4)藥品的生產(chǎn)和檢驗(yàn)方面有足夠的培訓(xùn)和經(jīng)驗(yàn)（21 CFR 211.25(a)）。
Testing is essential to ensure that the drug products you manufacture conform to all pre-determined quality attributes appropriate for their intended use. Because you lacked adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished product specifications and are suitable for release to consumers.
檢驗(yàn)是必要的，以確保你們生產(chǎn)的藥品符合所有既定的質(zhì)量屬性，適合他們的預(yù)期用途。由于你們未對每一批藥品進(jìn)行充分的測試，因此你們不知道它們是否符合所有適當(dāng)?shù)某善窐?biāo)準(zhǔn)，是否適合放行。
You did not ensure that your QU implemented its basic functions. Your management should immediately and comprehensively assess your company’s manufacturing operations to ensure that your systems, processes, and products meet CGMP.
你們沒有確保質(zhì)量部門實(shí)現(xiàn)了其基本職能。你們的管理層應(yīng)該立即和全面地評估貴公司的生產(chǎn)業(yè)務(wù)，以確保你們的系統(tǒng)、工藝和產(chǎn)品符合CGMP的要求。
See FDA’s guidance documentQuality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.
請參閱FDA指南：關(guān)于藥品CGMP法規(guī)的質(zhì)量體系方法，以幫助實(shí)施質(zhì)量體系和風(fēng)險(xiǎn)管理方：https://www.fda.gov/media/71023/download。
3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). Your laboratory records lacked complete and original data to support the analyses performed. For example:
貴公司未能確保實(shí)驗(yàn)室記錄包含來自所有必要測試的完整數(shù)據(jù)，以確保符合既定的規(guī)范和標(biāo)準(zhǔn)（21 CFR 211.194(a)）。 你們的實(shí)驗(yàn)室記錄缺乏完整的和原始的數(shù)據(jù)來支持所執(zhí)行的分析。例如：
Your laboratory records included missing data. Furthermore, there were discrepancies between the original and re-written versions of testing records and COAs pertaining to active and non-active ingredients used in the manufacture of OTC drug products.
你們的實(shí)驗(yàn)室記錄數(shù)據(jù)缺失。此外，關(guān)于藥品生產(chǎn)中使用的活性成分和非活性成分的檢驗(yàn)記錄的原始版本和謄抄版本與COAs之間存在差異。
Your firm did not retain original data to support testing of components used to manufacture OTC drug products for the U.S. market. During our inspection, you confirmed that original data, including balance printout slips,(b)(4) times, (b)(4), sample preparations, and equipment logs were not maintained.
貴公司沒有保留原始數(shù)據(jù)來支持所生產(chǎn)藥品的部件的檢驗(yàn)。在我們的檢查過程中，你們確認(rèn)沒有保存原始數(shù)據(jù)，包括天平打印單、(b)(4)時(shí)間、(b)(4)、樣品準(zhǔn)備和設(shè)備日志。
The use of correction fluid (white-out) was also observed to make corrections on paper records documenting microbial analyses of finished products and raw materials. These documentation practices raise concerns about the integrity, authenticity, and reliability of all your data, and quality of your drug products. Document control is essential to maintaining an adequate quality system.
還觀察到使用涂改液來對成品和原輔料的微生物檢驗(yàn)記錄進(jìn)行涂改。這些做法引起了對所有數(shù)據(jù)的完整性、真實(shí)性和可靠性以及藥品質(zhì)量的關(guān)切。文件控制對于保持一個(gè)適當(dāng)?shù)馁|(zhì)量體系是至關(guān)重要的。
In your response, you acknowledge that “QA management did not have a sound understanding of CGMP requirements.” You also commit to performing retrospective testing of “materials,” and state that you have updated procedures and re-trained personnel. Your response is inadequate, as you fail to fully consider comprehensive data integrity (DI) remediation to address the gaps and uncertainties caused by a significant adverse pattern of data that was discarded, lost, or not recorded contemporaneously. Additionally, your response did not consider plans to assess your manufacturing operation’s documentation system to determine where they are insufficient.
在你們的回復(fù)中，你們承認(rèn)“QA經(jīng)理對CGMP要求沒有很好的理解”，你們還承諾對“物料”進(jìn)行回顧性測試，并聲明已經(jīng)更新了SOP并重新培訓(xùn)了人員。你們的回復(fù)是不充分的，因?yàn)闆]有充分考慮全面的數(shù)據(jù)完整性（DI）補(bǔ)救措施，以解決由被丟棄、丟失或未同時(shí)記錄的重大不利數(shù)據(jù)模式所造成的差距和不確定性。此外，你們的回復(fù)沒有考慮評估的你們的生產(chǎn)操作文件體系以確定其不足的計(jì)劃。
Reliability of data is fundamentally compromised when there is a failure to record or maintain complete and accurate records of test results, or conditions associated with all tests. Furthermore, the lack of reliable data compromises the quality unit’s (QU) ability to exercise its function of ensuring compliance to applicable standards.
當(dāng)未能記錄或維護(hù)與所有測試相關(guān)的測試結(jié)果或條件的完整和準(zhǔn)確的記錄時(shí)，數(shù)據(jù)的可靠性將從根本上受到損害。此外，由于缺乏可靠的數(shù)據(jù)，也損害了質(zhì)量部門（QU）行使其確保遵守適用標(biāo)準(zhǔn)的功能的能力。
Data Integrity Remediation
數(shù)據(jù)完整性修正
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant DI practices at https://www.fda.gov/media/119267/download.
你們的質(zhì)量體系不能充分確保數(shù)據(jù)的準(zhǔn)確性和完整性，以支持所生產(chǎn)藥物的安全性、有效性和質(zhì)量。關(guān)于建立和遵循符合CGMP的DI實(shí)踐的指導(dǎo)，請參閱FDA指南：藥物CGMP數(shù)據(jù)完整性和符合：https://www.fda.gov/media/119267/download
We acknowledge that you are using an independent third-party consultant to perform DI training. However, we strongly recommend that you retain an independent third-party qualified consultant to audit your operation and assist in your DI remediation to meet FDA requirements.
我們知道，你們正在使用一個(gè)獨(dú)立的第三方顧問來進(jìn)行DI培訓(xùn)。然而，我們強(qiáng)烈建議你們聘請一名獨(dú)立的第三方合格顧問來審計(jì)你們的操作，并協(xié)助你們的DI補(bǔ)救，以滿足FDA的要求。
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