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[FDA国外警告信] FDA警告信:OOS,不能只怪色谱柱和分析员

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发表于 2021-4-26 16:30:03 | 显示全部楼层 |阅读模式

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来源:制药工程论坛
FDA公布一封针对印度一家注射剂生产企业(Shilpa Medicare Limited)的警告信。主要的缺陷项涉及:OOS和投诉调查不充分、未遵守投诉处理程序。同时FDA指出:该公司对于产品出现的重大潜在风险,未能及时通知FDA,涉及现场警报报告(FAR)违规。
对于OOS调查不充分,在警告信中给出了多个案例,包括:
  • HPLC结果出现未知色谱峰,公司将其简单归因为样品污染或色谱柱上样问题,并重复检验,直至得到可接受的结果;
  • 某注射液的三个不同批次中都获得了OOS含量结果,调查认定为分析错误所致。

在没有充分科学依据的情况下,该公司以对分析人员进行了培训为CAPA,结束调查,并放行了相关OOS批次。对此,FDA提出了诸多质疑,让我们看看这部分内容。



Warning Letter 320-21-01

October 9, 2020

Dear Mr. Bhutada:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility at Shilpa Medicare Limited, Unit-IV, FEI 3009876430, Plot No. S-20 to S-26, Pharm, Formulation SEZ, TSIIC, Green Industrial Park, Polepally (Village), Jadcherla (Mandal), District Mahabubnagar(Telangana), from February 13 to 20, 2020, and February 24 to 25, 2020.
美国FDA于2020年2月13日至20日和2月24日至25日检查了你们位于印度的Shilpa Medicare Limited, Unit-IV生产场所。
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).
本警告信总结了制剂生产严重违反CGMP的行为。参见21CFR第210与211部分。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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).
由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合CGMP要求,你们的药品根据FDCA的501(a)(2)(B)以及21 U.S.C. 351(a)(2)(B)被认为是掺假药品。
In addition, the inspection revealed that your firm failed to submit an (b)(4) Field Alert Report (FAR) to FDA within three working days of receipt of information concerning significant chemical, physical, or other change or deterioration in a distributed drug product, as required by section 505(k) of the FD&C Act, 21 U.S.C. 355(k) and stipulated by the regulation 21 CFR 314.81(b)(1)(ii).
此外,检查还发现你公司未能按FDCA第505(k)条款,21 U.S.C. 355(k)和21 CFR 314.81(b)(1)(ii)规定在收到已销售药品有严重化学、物理或其它变化或变质问题的信息之后3个工作日内向FDA提交FAR。
We reviewed your March 17, 2020, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司XXXX年XX月XX日的回复,并此告知已收到后续通信。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
检查期间,我们的调查人员发现的具体问题包括但不仅限于以下:



OOS调查不充分

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
你公司未彻底调查已销售和未销售批次产品或其组份未经解释的差异或不符合其标准(21 CFR 211.192)。
Your firm manufactures (b)(4) sterile injectables and solid dosage drug products. You failed to conduct adequateout-of-specification (OOS) and complaint investigations, including the identification of the root cause and timely implementation of effective corrective action and preventive action (CAPA) plans.
你公司生产XX无菌注射剂和固体制剂。你们未进行充分的OOS和投诉调查,包括识别根本原因,及时执行有效的CAPA计划。
a. On June 29, 2019, (b)(4) Tablets batch (b)(4) obtained OOS results for impurity-(b)(4).
2019年6月29日,XX片剂XX批次杂质XX结果为OOS.
Your Phase I investigation confirmed the initial OOS result when the original sample was re-injected and re-filtered. Noprobable root cause was identified. Also, you did not thoroughly investigate an unknown chromatographic peak observed adjacent to the impurity (b)(4) peak in the High-Performance Liquid Chromatographic (HPLC) run.
你们的第一阶段调查确认了初始OOS结果,然后原样重新进样重新过滤。未发现可能的根本原因。你们亦未对HPLC运行过程中发现的杂质XX峰旁边的未知色谱峰进行彻底调查。
You attributed the unknown chromatographic peak to sample contamination or HPLC column load problem, without supporting documentation. You made no meaningful effort to determine if the sample was contaminated. The initial HPLC run that generated the OOS result met the method system suitability requirements and no column or equipment malfunction was reported. Your analyst also reported that the column had been properly flushed. Based on your investigation, the unknown peak was not observed in either the blank or the placebo injections.
你们将未知色谱峰归因于样品污染或HPLC柱负载问题,但并没有支持性文件。你们没有做出有意义的工作来确定样品是否被污染。初始得出OOS结果的HPLC运行符合方法的系统适用性标准,没有报告色谱柱或设备故障。你们的化验员亦报告说色谱柱进行了正常冲洗。根据你们的调查,在空白和不加样基质进样中并没有发现未知峰。
During your Phase II laboratory investigation, the HPLC column was reconditioned (i.e., washed for (b)(4)). With no explanation of your rational, on July 9, 2019, you retested batches(b)(4),(b)(4), and (b)(4) using the reconditioned column. The three batches complied with the specification for the impurity-(b)(4).However, you did not include batch (b)(4), which had the original OOS result, in the retest.
在你们第二阶段实验室调查中,HPLC色谱柱进行了恢复(即冲洗XX)。2019年7月9日,没有解释什么原因,你们采用恢复过的色谱柱对3个批次进行了复测。这三批符合XX杂质标准。但是复测中并未包括原始结果为OOS的XX批。
Later, batch (b)(4) was retested using a new sample preparation with the reconditioned column. However, this chromatographic run was aborted: reportedly, there was a system communication error. You again reconditioned the HPLC column by washing it with water for(b)(4),followed by (b)(4) washing (b)(4). Batch (b)(4) was retested after the HPLC column was reconditioned multiple times. The impurity-(b)(4)met the specification and product was released.
后来,XX批采用恢复过的色谱柱和新的样品制备溶液进行了复测。但是,报告说此次色谱运行过程因系统通讯故障被中断了。你们又使用XX水再次冲洗了色谱柱,然后用XX冲洗。在HPLC色谱柱冲洗多次之后,你们对XX批次进行了复测。XX杂质符合标准,产品被放行。
Your response is inadequate. You did not provide sufficient scientific justification to demonstrate the HPLC column was the root cause ofthe original confirmed OOS. You did not explain why the unknown chromatographic peak was not observed in the blank or standard solutions. Your investigation is unclear as to why the original sample was not retested using a new HPLC columnto rule out sample contamination as the root cause. Your investigation also lacked information about the history and use of the HPLC column, and an evaluation of the analytical method and equipment-column performance.
你们的回复是不充分的。你们并没有提交足够的科学论证来证明HPLC色谱柱是原始已确认OOS的根本原因。你们并未解释为何未知色谱峰在空白和基质溶液中均未发现。你们的调查并未说明为何原始样品未采用新的HPLC柱进行复测来排除样品污染的根本原因。你们的调查亦缺乏关于HPCL色谱柱的历史和使用的信息,缺乏对分析方法和设备—柱性能的评估。
b. You obtained OOS assay results in three different batches of (b)(4) Injection. The specification is (b)(4)-(b)(4)% for both solution and suspension assay.
你们有3批XX注射剂的含量检测结果为OOS,溶液和混悬液含量标准均为XX-YY%。
i. On April 30, 2018, you reported an OOS assay result for batch (b)(4), which failed to meet the (b)(4) solution and suspension specifications. The OOS results reported were (b)(4)% insolution and (b)(4)% in suspension. You concluded that the most probable cause was an error in the preparation of the stock solution, and released the batch based on the average of a (b)(4) retest.
2018年4月30日,你们报告XX批含量结果为OOS,不符合XX溶液和混悬液标准。溶液OOS结果报告为XX%,混悬液OOS结果报告为YY%。你们结论说最可能的原因是贮备液配制错误,然后根据XX复测结果的平均值放行该批次。
ii. On October 12, 2019, you obtained an OOS assay result for batch (b)(4), which failed to meet (b)(4) solution specifications. The OOS result reported was (b)(4)%. You concluded the OOS was “due to analytical error” and the batch was released.
2019年10月12日,你们报告XX批含量结果为OOS,不符合XX溶液的标准,结果为XX%。你们结论说该OOS结果是“由于分析错误”,然后放行了该批次。
iii. On October 16, 2019, you obtained an OOS assay result for batch (b)(4), which failed to meet (b)(4) solution specification. The OOS reported was (b)(4)%. You concluded the OOS was due to analytical error, and the batch was released.
2019年10月,你们报告XX批含量结果为OOS,不符合XX溶液标准,结果为XX%。你们结论说该OOS是由于分析错误,然后放行了该批次。
In all three investigations you concluded, without adequate scientific justification, that analytical error was the most probable root cause for the original OOS results. Your firm opened CAPA where analysts were retrained to avoid reoccurrence. Your investigations lacked sufficient details of the CAPA implemented and how you will measure the effectiveness of the CAPA. Although you conducted a Phase 2 production review, you did not conduct a comprehensive evaluation of the product development, manufacturing validation, previous failing results obtained, and analytical test method. All three batches were released based on passing retest results.
在所有你们得出结论的三次调查中,都是在没有充分的科学理由情况下,将分析错误作为了初始OOS结果的最可能根本原因。你公司启动了CAPA,对化验员重新培训以避免重复发生。你们的调查中没有所实施CAPA以及你们要如何评测CAPA有效性的详细信息。虽然你们进行了第二阶段生产审核,但你们并没有对产品开发、生产验证、之前不合格结果以及分析方法进行全面评估。所有3批产品均根据合格的复测结果放行。
Your response is inadequate. Although you suggested possible root causes, you provided no scientific evidence to support your conclusions that laboratory errors had occurred. Your firm also failed to provide details of the CAPA implemented and how you measure the effectiveness of CAPA.
你们的回复是不充分的。虽然你们提出了最可能的根本原因,但你们并未提出科学证据来支持你们的化验室发生错误的结论。你公司亦未提交所实施CAPA以及你们要如何评估CAPA有效性的详细信息。
c. Your complaint investigation related to (b)(4) Injection (b)(4) mg/(b)(4) mL, batch (b)(4), produced in January 2019 with an expiration date of (b)(4), was inadequate.
你们对2019年1月生产的XX批次的XX注射剂有关的投诉调查不充分。
On October 2, 2019, a complaint received reported that the “(b)(4) enclosure” system separated from the glass vial. During the manufacture of this batch an unplanned deviation was initiated due to several filled vials showing sealing defects. About an hour after the filling operation started “bad cap rejections” (improper (b)(4)) was observed. The deviation record indicated that the (b)(4) were misplaced/misaligned and that the (b)(4) was not properly locked. According to your complaint investigation a breakdown of the sealing machine had occurred when the product was manufactured and “there might be the probability that few vials with loose sealing might have missed out during visual inspection.” Despite this you released the batch.
2019年10月2日,收到投诉报告说“XX封闭”系统与玻璃瓶脱开。在该批次生产期间有一个计划外偏差是几个灌装后的小瓶出现密封缺陷。灌装操作开始约一小时之后发现有“轧盖不良拒收”(不当XX)。该偏差记录显示XX被放错位置/未对齐,XX未恰当锁定。根据你们的投诉调查,在产品生产时有一个密封机出故障了,“存在几个小瓶密封较松的情况,在目视检查时可能未发现”。尽管如此,你们仍将该批次放行了。
We acknowledge that your firm conducted a study after the inspection to assess the integrity of the seal of vials as part of assessment into this issue.
我们知晓你公司在检查之后进行了研究,作为对该问题评估的一部分,评估了小瓶密封的完整性。
Your response is inadequate. You provide no justification for having released the batch of (b)(4) Injection batch #(b)(4), including the portion filled during the first hour of sealing, when a machine breakdown occurred. In addition, your investigation is silent regarding thevials filled prior to noting the equipment breakdown.
你们的回复是不充分的。你们未提交放行XX批次注射剂的论证,包括机器发生故障时在密封的第一个小时内灌装的那部分小瓶。另外,你们的调查没有提到注意到设备故障之前所灌装小瓶的情况。
d. You received multiple consumer complaints for batches of (b)(4) Injection related to the presence of foreign particles; these complaints have not been properly evaluated to prevent reoccurrence.
你们收到了XX注射剂多个批次有异物出现的投诉。你们未对这些投诉进行恰当评估从而防止再次发生。
Your investigation concluded, with no scientific evidence, that the root cause was related to the use of a (b)(4) by the end user. You indicated that you evaluated the drug product using(b)(4) and observed no problem, while the complainants used an (b)(4). You do not have sufficient scientific data, including but not limited to functionality test data, to support your root cause that the foreign particles and stopper separations or “seal coring” defects are caused by the use of a (b)(4).
你们的调查在没有科学证据的情况下得出结论说根本原因与最终用户使用了XX有关。你们指出你们评估了使用XX的药品,发现没有问题,而投诉者使用的是XX。你们并没有科学的数据,包括但不仅限于功能测试数据,来支持你们所认为的外来颗粒物和胶塞分离或“密封掉芯”缺陷的根本原因是使用了XX。
Inadequate OOS investigations is a repeat CGMP violation from the 2017 FDA inspection.
OOS调查不充分是2017年FDA检查发现CGMP缺陷的重复。
We acknowledge your efforts to remediate your investigation program and your decision to initiate a protocol-based study to evaluate the (b)(4) used by the end user on Shilpa-supplied products.
我们知道你们努力补救你们的调查程序,你们决定启动基于方案的研究来评估最终用户在Shilpa 供应的药品中使用XX的情况。
However, your response lacks adequate details regarding the scope and extent of the remediation.
但是你们的回复缺乏补救范围和程度方面足够详细的内容。
In response to this letter, provide the following:
在回复本函时请提交以下内容:
•      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, quality assurance unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• 一份对你们偏差、不符合、投诉、OOS结果和不合格调查的整个体系的全面独立评估。提交一份补救该系统的详细行动计划。你们的行动计划应包括但不仅限于对调查完整性、范围确定、根本原因评估、CAPA有效性、质量部门监管和书面程序的重大改进。说明你公司要如何确保正常执行所有调查阶段。
• Provide your market action plan for the batches referenced in this letter and other batches found out of compliance as part of your independent retrospective assessment.
•  提交本函中提及的批次及其它发现在你们独立回顾评估中发现的不合格批次的市场行动计划
•  An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates if staff with proper investigation competencies effectively conducts root cause analysis, assures CAPA effectiveness, regularly reviews investigations trends, implements improvements to the CAPA program when needed, ensures appropriate quality assurance unit decision rights, and is fully supported by executive management.
• 提交一份你们CAPA程序的独立评估和补救计划。提交一份报告评估你们员工是否具备适当的调查能力,可以有效执行根本原因分析,确保CAPA有效性、定期审核调查趋势、必要时改进CAPA程序,确保适当的QA部门决定权,并得到高级管理层的全力支持
• A management strategy including the interim measures describing the actions you have taken or will take to protect patientsand to ensure the quality of your drugs, such as notifying your customers,recalling product, conducting additional testing, adding batches to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
• 提交一份管理策略,包括你们已采取或准备采取的保护患者,确保你们药品质量的临时措施,如通知你们的客户、召回产品、执行附加检测、增加批次到稳定性计划中以确保稳定性,药品申报措施,以及强化投诉监督
•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 U.S. and a report summarizing the findings of the analysis, includingthe following for each OOS:
•提交一份对美国产品(无论该批次最后是否销至美国)所有宣布无效的OOS的独立回顾审核(包括中控和放行/稳定性检测),报告分析结果摘要,包括所有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.
  • 确定是否有科学论证和证据来得出结论宣布OOS结果无效,或无法得出结论证明可归因的实验室错误
  • 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.
  • 如果调查可以得出结论认为是实验室根本原因的,请提交理由,确保识别并补救所有会受到相同或类似根本原因影响的其它实验室方法
  • 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). Summarize potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
  • 如果回顾审核发现OOS结果的根本原因没有证据支持或未找到实验室根本原因,提交一份对生产的彻底审核(例如,批生产记录、生产步骤的充分性、设备/设施的适用性、原料波动性、工艺能力、偏差历史、投诉历史、批不合格历史)。汇总每个调查得出的潜在的生产根本原因,以及所有生产操作改进要求

•A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing:
• 提交一份你们OOS结果调查系统的全面审核和补救计划。CAPA应包括但不仅限于解决:
  • Quality unit oversight of laboratory investigations
  • 质量部门对实验室调查的监管
  • Identification of adverse laboratory control trends
  • 找出不良实验室控制趋势
  • Resolution of causes of laboratory variation
  • 实验室波动原因的解决方案
  • Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
  • 只要实验室原因无法得出结论,则启动对潜在生产原因的彻底调查
  • Adequately scoping of each investigation and its CAPA
  • 充分界定每个调查及其CAPA的范围
  • Revised OOS investigation procedures with these and other remediations
  • 根据这些和其它补救情况修订OOS调查程序

For more information about handling failing, OOS, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification(OOS) Test Results for Pharmaceutical Production athttps://www.fda.gov/media/71001/download.
更多关于不合格、OOS、OOT或其它非预期结果处理的信息,以及你们调查的文件要求,参见FDA的OOS指南。

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药徒
发表于 2021-4-26 16:50:50 | 显示全部楼层
学习,国内现在都是这么干的,国家给个重大缺陷项,后面都学乖了
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发表于 2021-4-27 16:19:40 | 显示全部楼层
国内药企的常规做法,调查都不充分
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药徒
发表于 2021-7-24 21:24:46 来自手机 | 显示全部楼层
进来参观一下,顺便看看情况
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