FDA警告信：OOS未充分调查、分析方法未验证、记录不完整、稳定性数据不足

  摘 要 ▼  
美国FDA于2024年03月22日对Antaria Pty.Ltd.签发了警告信，主要包括了如下重大缺陷：
超标结果(OOS)重复发生，调查未确定根本原因，纠正预防措施无法确认有效性。
警告信中提到，该公司对 API 实验室测试（包括含量和炽灼失重(LOI) 测试）期间获得的大量 OOS 结果缺乏充分的调查和纠正措施。根本原因未得到明确定义，且未充分记录，并且质量部门 (QU) 放行了 OOS 结果批次。
企业的回复没有得到FDA认可，主要体现在没有描述对所有调查的根本原因分析和纠正措施充分性的整体审查，没有通知收到 OOS 批次的客户进行检测，也没有对留样样品进行回顾性评估。同时，给出了需要进一步开展的工作与需要提供的资料，值的充分研究和学习。（该条缺陷很有代表性，OOS调查是企业的难点，FDA不仅阐明了具体问题，并且给出了解题思路，值得深入研究和学习）
产品检测的分析方法未进行验证，无法确认企业自身的分析方法相当于或优于USP方法。
警告信提到，该公司未能按照美国药典 (USP) 专论现行版本对产品进行适当的分析测试（含量和炽灼失重），也没有数据支持其测试方法相当于或优于 USP 方法。（既没有按USP方法执行测试，又没有进行相关分析方法验证，与USP的方法进行对比研究）
实验室控制记录信息不完整，缺少部分检测过程中的信息数据。
警告信中提到，该公司未能在实验室记录中纳入所有实验室分析项目的完整数据，并且依赖不完整的信息来确定产品是否符合质量标准。例如，缺少在 API 测试期间使用的储备溶液、样品溶液、稀释剂、流动相和试剂的制备记录。还未能记录进行分析测试时所使用的仪器和设备。（该问题在国内的公司还是比较常见的，体现了实验室记录设计存在不足，违背了记录可追溯性的原则）
未能设计充分书面的、持续的稳定性测试程序来监控 API 的稳定性特性，并使用结果来确认适当的存储条件和复验期或有效期。
警告信中提到，该公司的稳定性计划不够充分。在2019 年、2020 年或 2021 年生产的API，未能进行年度至少一批稳定性考察。稳定性程序缺乏有关适当测试方法的具体要求。此外，稳定性研究仅包括 2015 年生产的批次，并且仅在 2022 年建立了年度持续稳定性计划。
该公司的回复是不充分的，因为没有讨论对流通中已经生产而未经适当稳定性测试的 API 批次的回顾性审查。（不能仅仅是“我目前符合要求”了，而且要证明与确认之前的做法是否已经产生了风险！）
从缺陷可以看到此封警告信的关注点主要为超标结果调查和纠正措施实施的有效性、实验室控制模块工作存在不足，无法确保销售产品的质量可控。
【基础信息:】
Posted Date：2024.4.9
Letter lssue Date：2024.3.22
FEI：3025978151
Firm name：Antaria Pty.Ltd.
Type establishment inspected：Drug Manufacturing Facility
Investigator：N/A

  警告信正文  ▼   
The U.S.Food and Drug Administration (FDA) inspected your drug manufacturing facility, Antaria Pty.Ltd., FEI 3025978151, at 81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia, from November 13 to 17, 2023.
美国食品药品监督管理局 (FDA) 于2023 年11月13日至17日检查了你们位于81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia的药品生产工厂Antaria PtyLtd.，FEI 3025978151。
This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (API)
本警告信总结了原料药（API）现行良好生产规范（CGMP）的重大偏差。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are 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).
由于你们的生产、工艺、包装或贮存的方法、设施或控制不符合 CGMP， 依据《联邦食品、药品和化妆品法案》（FD&C 法案）501(a)(2)(B) 节、21 U.S.C. 351(a)(2)(B) 的规定，你们的 API被判定为掺假。
We reviewed your December 7, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们详细审查了你们公司于 2023 年 12 月 7 日对我们的 FDA 483 表的回复，并确认收到了你们后续的应对。
During our inspection, our investigator observed specific deviations including, but not limited to, the following.
在检查过程中，我们的调查人员发现的具体偏差包括但不限于以下内容。
1.Failure to adequately investigate and document out-of-specification results and implement appropriate corrective actions.
未能充分调查和记录超标结果(OOS)并实施适当的纠正措施。
Your firm manufactures API (b)(4) USP, labeled in part to be the active ingredient used in (b)(4).You failed to adequately investigate out-of-specification (OOS) test results.Specifically, your firm lacked adequate investigations and corrective actions for numerous OOS results obtained during laboratory testing of your API, including assay and loss on ignition (LOI) testing.The root causes were not clearly defined nor adequately documented, and lots with OOS results were released by your quality unit (QU).
你公司生产 API (b)(4) USP，部分标签显示其为 (b)(4) 中使用的活性成分。你们未能充分调查超标（OOS）的测试结果。具体来说，你们公司对在 API 实验室测试（包括含量和炽灼失重(LOI) 测试）期间获得的大量 OOS 结果缺乏充分的调查和纠正措施。根本原因未得到明确定义，且未充分记录，并且你们的质量部门 (QU) 放行了 OOS 结果批次。
In your response, you state that staff turnover and insufficient staff training attributes to the lack of competency in good laboratory practices.Additionally, you state that you will revise your OOS procedures.You also state that you will review historical LOI OOS to identify a root cause and retrain your laboratory staff. Your response is inadequate because you failed to describe a holistic review of all investigations’ root cause analyses and corrective actions for adequacy.In addition, you did not inform your customers who received OOS lots for assay nor perform a retrospective assessment of retain samples.
在你们的回复中，你们指出员工流动和员工培训不足导致缺乏良好的实验室实践能力。此外，你们表示将修改您的 OOS 程序。你们还表示，你们将回顾历史LOI OOS数据，以识别根本原因并重新培训你们的实验室工作人员。你们的回复不充分，因为你们没有描述对所有调查的根本原因分析和纠正措施充分性的整体审查。此外，你们没有通知收到 OOS 批次的客户进行检测，也没有对留样样品进行回顾性评估。
Inadequate investigations can lead to unidentified root causes, ineffective corrective action and preventive action (CAPA), and recurring problems that compromise the ability to manufacture safe and effective drugs.
调查不充分可能导致无法确定根本原因、无效的纠正措施和预防措施 (CAPA) 以及影响生产安全有效药物能力的反复出现的问题。
For more information about handling OOS results and documentation of your investigations, please refer to the FDA guidance for industry publication Investigating Out-of-Specification at https://www.fda.gov/media/158416/download
有关处理 OOS 结果和调查文件的更多信息，请参阅 FDA 行业出版物《超标调查》指南，网址为 https://www.fda.gov/media/158416/download
In response to this letter, provide:
在回复此信时，请提供：
A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products irrespective of whether the batch was ultimately distributed in the United States and a report summarizing the findings of the analysis, including the following for each OOS:
对美国注册的产品所有无效的OOS（包括中控和放行/稳定性测试）结果进行回顾性的、独立的审查，无论该批次最终是否在美国分销，并提交一份总结分析结果的报告，包括针对每项 OOS 的以下内容：
※ Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
对于无效的 OOS 结果，确定相关的科学依据和证据是否确凿或不确凿地证明了导致实验室错误的原因。
※ For investigations that conclusively establish laboratory root cause, provide rationale, and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.

对于最终确定实验室根本原因的调查，提供合理依据，并确保被认为所有其他易受相同或类似根本原因影响的实验室方法已进行补救。
※ For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history).Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
对于回顾性审查发现的所有 OOS 结果，如果其在实验室中没有确定的根本原因或没有发现根本原因，则需要对生产进行彻底审查（例如，批生产记录、生产步骤的充分性、设备/设施的适用性、原材料的变化、过程能力、偏差历史、投诉历史、批次不合规历史）。汇总每次调查的潜在生产根本原因和任何的生产操作改进。
A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system.Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures.Address how your firm will ensure all phases of investigations are appropriately conducted.
对你们的整个系统进行全面、独立的评估，以调查偏差、异常情况、投诉、OOS 结果和不合格事件。提供详细的行动计划来改进该系统。你们的行动计划应包括但不限于调查能力、范围确定、根本原因评估、CAPA 有效性、QU 监督和书面程序方面的重大改进。说明你们公司将如何确保调查的所有阶段均得到适当执行。
2.Failure to ensure that, for each batch of API, appropriate laboratory tests are conducted to determine conformance to specifications.
未能确保对每批 API 进行适当的实验室测试以确定符合质量标准。
Based on review of your laboratory results, you failed to appropriately perform analytical testing (assay and LOI) of your (b)(4) USP in accordance to the current version of United States Pharmacopeia (USP) monograph, nor did you have data to support that your test method was equivalent or better than the USP method.In your response, you state that you will revise your (b)(4) USP assay and LOI test methods to better align with the USP.
根据对你们实验室结果的审查，你们未能按照美国药典 (USP) 专论现行版本对你们的 (b)(4) USP 进行适当的分析测试（含量和炽灼失重），也没有数据支持你们的测试方法相当于或优于 USP 方法。在你们的回复中，你们表示将修改 (b)(4) USP 的含量和 LOI 检测方法，以更好地与 USP 保持一致。
Without adequate testing, there is no scientific evidence to assure that your APIs conform to appropriate specifications before release.
如果没有经过充分的测试，就没有科学证据来保证您的 API 在放行之前符合适当的质量标准。
See FDA’s guidance document, Analytical Procedures and Methods Validation for Drugs and Biologics, for general principles and approaches that FDA considers appropriate elements of analytical method validation at https://www.fda.gov/media/87801/download.
请参阅 FDA 的指导文件《药品和生物制品的分析程序和方法验证》，了解 FDA 认为适合分析方法验证要素的一般原则和方法，网址为https://www.fda.gov/media/87801/download
In response to this letter provide:
在回复此信时请提供：
A list of chemical and microbial test methods and specifications used to analyze each lot of your API before making a lot disposition decision, and the associated written procedures.
在做出批次处置决定之前，用于分析每批 API 的化学和微生物测试方法和质量标准的列表，以及相关的书面程序。
A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
对你们的实验室实践、程序、方法、设备、文档和分析人员能力进行全面、独立的评估。根据此审查，提供详细的计划来改进并评估你们公司实验室系统的有效性。
3.Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure your API complies with established specifications and standards.
未能提供包含所有实验室测试的完整数据的实验室控制记录，以确保你们的 API 符合既定的规范和质量标准。
You failed to include complete data in your laboratory records for all laboratory analyses, and accordingly relied on incomplete information to determine whether your (b)(4) USP met established specifications.For example, you lacked documentation of the preparation of stock solutions, sample solutions, diluents, mobile phases, and reagents used during testing of your API.You also failed to document the instruments and equipment used when performing analytical testing.
你们未能在实验室记录中纳入所有实验室分析项目的完整数据，并且依赖不完整的信息来确定你们的 (b)(4) USP 是否符合既定的质量标准。例如，你们缺少在 API 测试期间使用的储备溶液、样品溶液、稀释剂、流动相和试剂的制备记录。你们还未能记录进行分析测试时所使用的仪器和设备。
In your response, you acknowledge that your laboratory records lack complete testing information.You also state that you update your worksheets to record pertinent information.Your response is inadequate because it does not address the overall lack of traceability of previous analytical data, nor does it include a comprehensive strategy to confirm the validity of the previous analytical data used to release your (b)(4) USP.
在你们的回复中，承认你们的实验室记录缺乏完整的测试信息。你们还声明你们更新了工作表以记录相关信息。你们的回复是不充分的，因为它没有解决先前分析数据整体缺乏可追溯性的问题，也没有包括一个全面的策略来证实用于放行你们 (b)(4) USP 的先前分析数据的有效性。
Without adequate documentation of analytical tests and equipment used, you lack basic data to support that each API product batch conforms to appropriate specifications before release and distribution.
如果没有足够的分析测试和所用设备的记录，你们将缺乏基本数据来支持每个批次API 产品在放行和分销之前符合适当的质量标准。
In response to this letter provide a complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient.Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
在回复此信时，请提供对你们整个生产和实验室操作过程中使用的文件系统的完整评估，以确定哪些地方的文档记录不足。包括一份详细的 CAPA 计划，全面补救你们公司的文件记录规范性，以确保你们在整个运营过程中保留可追溯、清晰、完整、原始、准确、同步的记录。
4.Failure to design an adequate documented, on-going stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.
未能设计充分书面的、持续的稳定性测试程序来监控 API 的稳定性特性，并使用其结果来确认适当的存储条件和复验期或有效期。
Your firm’s stability program is inadequate.Your firm failed to place at least one lot of your API manufactured in 2019, 2020, or 2021 on stability annually.
你们公司的稳定性计划不够充分。你们公司在2019 年、2020 年或 2021 年生产的API，未能进行年度至少一批稳定性考察。
In your response, you acknowledge that your stability procedure lacks specificity regarding appropriate testing.Additionally, you acknowledge that your stability study only consists of lots manufactured in 2015 and that you only establish your annual, ongoing stability program in 2022.Your response is inadequate because you did not discuss a retrospective review of API lots in distribution that were manufactured without appropriate stability testing
在你们的回复中，你们承认你们的稳定性程序缺乏有关适当测试方法的具体要求。此外，你们承认，你们的稳定性研究仅包括 2015 年生产的批次，并且你们仅在 2022 年建立了年度持续稳定性计划。你们的回复是不充分的，因为你们没有讨论对流通中已经生产而未经适当稳定性测试的 API 批次的回顾性审查。
Without an adequate stability program, you cannot ensure that your APIs meet established specifications and all pre-determined quality criteria throughout the APIs’ assigned shelf-life.
如果没有适当的稳定性程序，你们就无法确保你们的 API 在指定的货架期内符合既定的质量标准和所有预定的质量要求。
In response to this letter provide:
在回复此信时请提供：
A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
全面、独立的评估和 CAPA 计划可确保你们的稳定性计划的充分性。你们的补救计划应包括但不限于：
※ Stability-indicating methods
稳定性指示方法
※ Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
在允许分销之前，对每种药品在其上市容器封闭系统中进行稳定性研究。
※ An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
这是一项持续进行的计划，每年都会将每种产品的代表性批次添加到计划中，以确定声称的货架期是否仍然有效。
※ Detailed definition of the specific attributes to be tested at each station (timepoint).
详细定义每个站点（时间点）要测试的具体属性。
All procedures that describe these and other elements of your remediated stability program.
描述这些内容以及稳定性补救计划的其他要素的所有程序。
Additional API CGMP Guidance
其他 API CGMP 指南
FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP.See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.gov/media/71518/download.
在确定 API 是否符合 CGMP条件下生产时，FDA 会考虑 ICH Q7 中概述的期望。有关 API 制造的 CGMP 指导，请参阅 FDA 指南 Q7原料药良好生产规范指南，网址为https://www.fda.gov/media/71518/download
Conclusion
结论
The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility.You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.
本信中引用的偏差并非你们工厂存在的所有偏差的完整列表。你们公司有责任调查并确定任何偏差的原因，并防止其再次发生或发生其他偏差。
Correct any deviations promptly.FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP.We may re-inspect to verify that you have completed corrective actions to any deviations.
及时纠正任何偏差。FDA 可能会拒绝批准将你们公司列为药品制造商的新申请或补充申请，直到所有偏差得到彻底解决且我们确认你们公司符合 CGMP。我们可能会重新检查以验证你公司是否完成所有偏差的纠正措施。
Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Antaria Pty.Ltd.81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3).Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C.351(a)(2)(B).
根据联邦食品、药品和化妆品法案第 801(a)(3) 节,21 U.S.C. 381(a)(3)，未能解决所有违规行为也可能导致 FDA 拒绝接纳 Antaria Pty.Ltd.81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia生产的物品到美国。根据该授权，如果物品疑似掺假，则可能被扣留或拒绝入境。因为其制造过程中使用的方法和控制疑似不符合 FD&C 法案（21 U.S.C. 351(a)(2)(B)）第 501(a)(2)(B) 条 CGMP 的规定。
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies.After you receive this letter, respond to this office in writing within 15 working days.Specify what you have done to address any deviations and to prevent their recurrence.In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices.If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
这封信函告知你们我们的调查结果并为您提供解决上述缺陷的机会。收到此信后，请在15个工作日内以书面形式回复本办公室。详细说明你们为解决偏差并防止其再次发生所做的努力。在回复此信时，你们可以提供更多信息供我们考虑，因为我们会继续评估你们的活动和做法。如果您无法在 15 个工作日内完成纠正措施，请说明延迟的原因和完成计划。
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