GMP缺陷分析解读—质量体系

问题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)
你们公司对未解释的差异或任一批次的失败或原辅料不符合其任一质量标准的情况未进行彻底调查，不管该批次是否已经放行销售。(21 CFR 211.192)
You failed to conduct adequate investigations into out-of-specification (OOS) test results for critical product attributes, such as assay, for your (b)(4) drug products. Your investigations into the OOS results did not determine root causes and include effective corrective action and preventive action (CAPA) to prevent their recurrence. In addition, your rationales for invalidating the testing failures lacked a substantive scientific evaluation.
你们没有对XX药品关键产品属性的检测结果超标（OOS）进行充分调查。你们没有确定OOS结果的根本原因，也没有制定有效的纠正措施和预防措施（CAPA）以防止其再次发生。此外，最后评价为无效OOS的结果缺乏实质性的科学评价依据。
In your response, you committed to reviewing and revising your OOS, deviation, complaints, and CAPA management systems. You also provided an assessment of the impact of the OOS results to consumer safety, and you concluded that there was no impact. However, your response was inadequate because you failed to provide a comprehensive investigation including, but not limited to, an adequate evaluation of root causes of the OOS results and the scope of the failures.
在回复中，你们承诺会审核并修订OOS，偏差，投诉和CAPA的管理系统。你们还提供了一份针对OOS结果对消费者安全性影响评估，你们得出的结论是没有影响。但是，你们的回复是不充分的，因为未能提供全面的调查，包括但不限于对OOS结果的根本原因以及不合格范围的充分评估均不充分。
In response to this letter, provide the following.
在对此函的回复中，请提供以下内容：
A retrospective, independent review of all invalidated OOS (in-process and finished testing) results obtained for products currently on the U.S. market and within expiry. Assess whether the scientific justification and evidence for each invalidated OOS result was conclusive. For investigations that conclusively establish laboratory root cause, determine effectiveness of the CAPA, and ensure that other laboratory methods vulnerable to the same root cause are identified for remediation. For any OOS results with 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, raw materials, process capability, deviation history, batch failure history). Provide a CAPA plan that identifies manufacturing root causes and specifies meaningful improvements.
一份回顾性的独立审查，针对目前美国市场上在有效期内的所有涉及无效OOS的产品（中控和成品检验）。对每一个被视为无效OOS结果是否基于科学判断和有效证据证明。对于最终结论归因为实验室原因的调查，请确定CAPA的有效性，并确保易受相同根本原因影响的其它实验室方法被识别且进行整改。对于不能得出结论或未发现是实验室的根本原因的所有OOS，请提供一份彻底的生产情况的审查（例如，批生产记录、生产步骤的合理性、原料、工艺性能、偏差历史、不合格批历史）。请提供一份识别的生产根本原因并制定有效改善措施的CAPA计划。
Review and remediate your overall system for investigating OOS results. Provide a CAPA plan to improve OOS handling. Your CAPA plan should ensure that your revised OOS investigations procedure includes enhanced quality unit oversight of laboratory investigations, identification of adverse laboratory control trends, resolution of causes of laboratory variation, and investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified.
对OOS调查系统进行审核和整改。提供一份OOS的处理程序改进的CAPA计划。你们的CAPA计划应确保修订后的OOS调查规程包括质量部门对实验室调查的强化监督、不良实验室控制趋势的识别、实验室偏差根源的解决方案、以及无法最终确定为实验室原因时对潜在生产原因的调查。
·A comprehensive, independent assessment of your system for investigating deviations, atypical events, complaints, OOS results, and failures. Your CAPA plan should include, but not be limited to, improvements in investigations, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA plan effectiveness.
一份针对调查偏差、异常事件、投诉、OOS结果和不合格的整体系统的综合独立评估。CAPA计划应包括但不限于对调查、根本原因分析、书面规程和质量部门监督的改进。还应包括评估CAPA计划有效性的流程。
·A full evaluation of scope and magnitude to determine the impact of the failing results on the batches that had OOS results and additional drug products you manufacture.
一份对OOS影响范围和程度的全面评估，以确定不合格结果对受影响批次以及企业生产的其它药品的影响。
——摘自FDA 2018年对法国某公司开出的警告信。

GMP咨询顾问观点：
首先该公司的主要问题是发生OOS时没有进行充分调查，找不到根本原因，然后归结为无效OOS。有两种可能，一个是调查的方法不正确，实在找不到根本原因，第二是公司内部已经知道是什么原因，但是由于某种原因不愿意落到纸面上，所以找个实验室操作误差即无效OOS的理由搪塞过去。
其次该公司没有对相同根本原因造成其他的批次产品的影响程度进行扩大调查，这个结果通常也是因为故意隐瞒某种原因导致编写的“根本原因”不是真实原因，所以也没有考虑过要扩大调查。
这个公司的最大问题还是没有正视公司的根本问题，没有从根本上考虑解决问题，所以才会出现上述一系列的问题，作为制药企业，应正视每一个OOS，充分调查其根本原因，针对根本原因提出有效的整改措施，这样才能帮助企业提升整体质量管理水平，如果老是掩盖问题，就很难正确地解决问题的根源。

问题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)).
你们公司未制订详细的书面的生产和工艺控制的规程，不能保证你们生产的药品的一致性、规格、质量和纯度达到预期。(21 CFR 211.100(a))。
You failed to validate your processes and qualify equipment used to manufacture your (b)(4) drug products. Specifically, you did not perform process qualification studies, nor did you have a rigorous ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.
你们没有对生产(b)(4)药品的工艺和设备进行验证。特别是你们没有进行工艺确认研究，而且你们对保证稳定生产操作和产品质量一致的过程监控也没有严格的控制规程。
In your response, you committed to pursuing an improved process validation program for new drug products, to assessing the manufacturing processes for existing products, and to qualifying your current and future manufacturing equipment. However, you failed to provide assurance that your manufacturing equipment is suitable for its intended uses and that your manufacturing processes are reproducible and capable of meeting all predetermined quality attributes.
在回复中，你们承诺会有针对新药进行改进的工艺验证计划，以评估现有产品的生产工艺，以及确认当前和未来的生产设备。但是，你们不能保证你们的生产设备适合其预期用途以及你们生产工艺可以重复生产符合预定质量属性的产品。
In response to this letter, provide the following.
在对此函的回复中，请提供以下内容：
· A validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for each of your drug products. Describe your program for monitoring batch-to-batch variation to ensure an ongoing state of control.
提供一份确保产品在整个生命周期内处于受控状态的验证计划。包括每种药品执行适当的工艺验证的时间列表。描述为保证持续的受控状态而制定的批与批之间差异的监控计划。
· The process performance protocols and studies that evaluate whether your manufacturing equipment and processes are reliable. This includes but is not limited to determining whether your production parameters are consistently met and whether your process is capable of reproducibly yielding a product that meets its quality attributes.
提供生产设备和工艺是可靠的性能确认方案和研究计划，包括但不限于确定你们的生产工艺参数是否始终符合要求、你们的生产工艺是否能够重复生产出符合其质量属性的产品。
——摘自FDA 2018年对法国某公司开出的警告信。


GMP咨询顾问观点：
这家公司的问题比较严重，第一没有对生产设备进行性能确认，不能确认设备能否达到预期的性能期望。第二没有进行工艺验证研究，没有对工艺参数和范围进行验证，不能确认最佳工艺参数和范围。
对于这方面的问题，其实咱们国内基本都有设备验证和确认及做工艺验证确定工艺参数的理念，但是设备的确认和工艺验证的实际执行仍有做的不够完善的，现有的指南和法规已经提供了充分的思路，所以广大药品生产企业还是需要参考国内外的法规和指南进行执行，不断完善，落到实处，不流于形式。


问题3. 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, and purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).
你们公司未根据药品特性对设备和容器具进行定期清洁、维护、消毒和/或灭菌，以防止设备故障与影响产品的安全性、一致性、规格、质量和纯度超出注册标准或其它既定要求。(21 CFR 211.67(a))
You failed to demonstrate that your cleaning and disinfection practices are adequate to remove contaminants from equipment you use to manufacture your (b)(4) drug products. Your determination of the adequacy of your cleaning and disinfection process is limited to a visual examination of the surfaces to detect any contaminants.
你们未能证明清洁和消毒活动足以清除用于生产XX药品的设备中的污染物。你们判断清洁和消毒的效果只有对设备表面进行目检来发现是否有污染物。
In your response, you provide an outline for your cleaning validation strategy and timeframes for completion. However, your response was inadequate because you failed to provide the specifics of your plan and rationale for your approach. Further, you provided no data to ensure that your cleaning and disinfection practices are sufficient to reproducibly remove contaminants from equipment product surfaces between manufacturing runs.
在回复中，你们提供了一份清洁验证策略概述和完成时间。但是，你们的回复不充分，因为未能提供计划的细节以及清洁方法的依据。此外，企业没有提供数据证明清洁和消毒行为可以重复清除与设备表面直接接触的污染物。
In response to this letter, provide the following.
在对此函的回复中，请提供以下内容：
· A comprehensive plan to evaluate cleaning and disinfection procedures and practices. Your plan should include the cleaning and disinfection techniques, agents used, agents’ application times, testing methods, and respective testing criteria to effectively address potential chemical or microbiological contaminants.
一份评估清洁和消毒程序和方法的综合计划。计划应包括清洁和消毒技术，使用的试剂，试剂施用时间，检验方法以及相应的检验标准，以有效清洁潜在的化学或微生物污染物。
· Scientific rationale for your cleaning and disinfection validation strategy to ensure your cleaning and disinfection procedures are effective.
清洁和消毒验证策略的科学依据，以确保清洁和消毒程序有效。
· A summary of updates to your cleaning and disinfection validation protocols incorporating conditions identified as worst case. This should include, but not be limited to:
一份更新的清洁和消毒验证方案，包括已鉴定的最差条件。应包括但不限于：
Evaluating drugs of the highest toxicity
评估毒性最高的药物;
Assessing drugs of the lowest solubility in their cleaning solvents
评估清洁溶剂中溶解度最低的药物;
Evaluating drugs with characteristics that make them difficult to clean
评估难清洁的特性的药物;
Swabbing equipment locations that are most difficult to clean
最难擦拭清洁的设备位置。
· A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning and disinfection procedures for new products, processes, and equipment.
一份已更新的SOP的概述 , 确保新产品、工艺和设备的清洁和消毒程序进行适当地确认和验证。
Out-of-Specification Test Results 检测结果超标
For more information about handling failing, out-of-specification, 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 at url.
关于不合格、OOS、OOT或其它非预期结果的处理和调查文件等更多信息, 请参加FDA指南Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production , url.
Process Controls 工艺控制
Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at url.
你们公司缺乏一个确保稳定的生产操作和始终如一的药品质量的持续工艺监控计划。关于FDA工艺验证指南General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at url。
CGMP Consultant Recommended 建议聘请CGMP顾问
Based upon the nature of the violations we identified at your firm and because you failed to correct repeat observations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
鉴于我们在你们公司发现的违规行为和因为你们不能纠正重复发生的缺陷，我们强烈建议你们公司聘请有资质的顾问（根据 21 CFR 211.34规定）来帮助你们公司符合CGMP要求。你们聘请顾问并不能减轻你们符合CGMP的责任。你们公司的高层管理者有责任全面解决所有缺陷、持续确保CGMP合规性。
Conclusion结论
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
此信中所引述的违规行为并非涵盖全部。企业有责任对这些违规行为进行调查 , 确定原因，防止其再次发生 , 防止其它违规行为的再次发生。
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
在你们全部整改所有违规行为我们确认符合CGMP之前，FDA可能暂停批准该企业作为药品生产商的任何新的申请或补充申请。
Failure to correct these violations may also result in FDA refusing admission of articles manufactured at Laboratoires Clarins at 5 rue Ampére, Pontoise into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of 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).
按照FD&CA第801(a)(3) 节 [21 U.S.C. 381(a)(3)] , 未能纠正这些违规可能还会导致FDA拒绝接受公司（Laboratoires Clarins at 5 rue Ampére, Pontoise）生产的产品进入美国。依据上述法案，因为生产中使用的方法和控制不符合FD&C Act, 21 U.S.C. 351(a)(2)(B) 第501(a)(2)(B)节中的CGMP要求，产品可能会被拒绝入境。
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
在收到此函后 , 请在15个工作日内给本办公室回复。在回复中说明自从检查后企业做了哪些工作来纠正违规行为，防止其再次发生。如果不能在15个工作日内完成的纠正措施，说明延迟的原因以及完成计划。
——摘自FDA 2018年对法国某公司开出的警告信


GMP咨询顾问观点：
对生产设备进行有效的清洁和消毒是防止产品之间产生交叉污染的重要途径，如果设备清洁消毒未有效执行也会直接导致产品之间的交叉污染，根据交叉污染的不同程度和药品治疗方向的不同，这种交叉污染有时会对患者带来不同程度的伤害，甚至造成严重不良反应或者死亡。
因此当新增一个产品共线时，应进行多产品共线的风险评估，另外进行清洁消毒验证以确定有效的清洁消毒方法，如果要连续批生产，应进行清洁有效期的验证工作，以确定最长连续批生产的时间。
在警告信的最后总结了上述问题，并建议该公司聘有资质的顾问帮助该公司进行相关整改和CGMP符合性工作。另外也提出警告在他们公司完整整改之前，FDA有可能禁售该公司药品和暂停新的申请和补充申请，问题很严重，所以药品生产企业应尽量避免出现类似的问题。

       文章来源： 允咨GMP制药技术

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