Interpretations of the FDA's CGMP rules can often be read from Warning Letters as well as guidelines. A current Warning Letter describes the FDA's expectations of the Quality Control Unit for validations, among other things.
我们经常可以从警告信和指南中读到对FDA的CGMP法规的解释。现有一份警告信中描述了FDA对质量部门关于验证的期望。
With reference to 21 CFR 211.22, the FDA criticises in the Warning Letter that the quality control unit is not fulfilling its responsibility to ensure that drugs are manufactured in compliance with CGMP. The FDA understands that there must be written procedures on the tasks and responsibilities of the Quality Control Unit. These should show that the Quality Control Unit also has the "authority" to review and approve quality-related functions that have an impact on product quality.
关于21 CFR 211.22，FDA在警告信中批评质量部门没有履行其职责，确保药品的生产符合CGMP。FDA解释到，质量部门的任务和责任必须有书面程序。这些应该表明质量部门也有“权力”来审查和批准对产品质量有影响的质量相关职能。
And this includes process monitoring, which shows that the processes are stable and consistently deliver quality products. On this point, the FDA refers to 21 CFR 211.100 (a). In particular, the missing stage 3 in the FDA's process life cycle, "Continued Process Verification", is admonished here.
这包括过程监控，以表明过程稳定并始终如一地提供高质量的产品。在这一点上，FDA引用了21 CFR 211.100（a）。特别是，这里提出了（该公司）缺乏FDA工艺生命周期中的第3阶段“持续工艺确认”。
As a further (missing) responsibility of the Quality Control Unit, the FDA criticises in the Warning Letter, written, validated, reviewed and approved cleaning processes. These must be capable of removing residues from the surfaces that come into contact with the product in equipments that are used with several different products ("non-dedicated"). The FDA refers in this regard to 21 CFR 211.67 (b).
作为质量部门的进一步（缺失）责任，FDA在警告信中批评了经验证，审查和批准的书面清洁工艺。应能够去除多产品（“非专用”）共用设备中与产品接触的表面上的残留物。在这方面，FDA引用了21 CFR 211.67（b）。
With reference to the same paragraph, the FDA also criticises the lack of equipment maintenance procedures. These must also be established, reviewed and approved in writing in order to enable robust device operating conditions.
同时，FDA还批评了缺乏设备维护程序。应以书面形式建立、审查和批准，以实现稳健的设备操作条件。
In detail, the FDA wants to see an overview of the validation programme and timelines for the process performance qualification (PPQ) runs of each individual product. Furthermore, the FDA expects a data-based and scientifically verifiable programme regarding process variability.
详细地说，FDA希望看到每个产品的工艺性能确认（PPQ）运行的验证计划和时间表的概述。此外，FDA期望有一个关于工艺可变性的基于数据和科学可验证的计划。
Also urged is a cleaning validation programme with special emphasis on worst case conditions with regard to:
还敦促制定清洁验证计划，特别强调以下方面的最坏情况：
Drugs with higher toxicities
毒性最大的药物
Drugs with higher active ingredient contents
含有较高活性成分的药物
Drugs with low solubility in the cleaning reagent
在清洗剂中溶解度低的药物
Drugs with characteristics that make them difficult to clean
具有难以清洁的特性的药物
Swab sampling sites at locations that are most difficult to clean
在最难清洁的位置进行擦拭采样
maximum holding times before cleaning
清洁前的最长保持时间
The FDA also requires an update of the change management system with regard to the introduction of new manufacturing equipment and new products.
FDA还要求在新生产设备和新产品的引入方面，更新变更管理系统。
警告信原文翻译如下：
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)
贵公司的质量部门未能履行其职责以确保所生产的药品符合CGMP，并符合特性，含量，质量和纯度的既定规范（21 CFR 211.22）
Your firm failed to establish an adequate Quality Unit (QU) to ensure that:
贵公司未能建立充分的质量部门（QU）来确保：
Adequate procedures were established and written for roles and responsibilities of the QU to have the responsibility and authority to review and approve quality related functions that impact product quality (21 CFR 211.22(d)).
为QU的角色和职责建立并编写了适当的程序，以负责和授权审查和批准影响产品质量的质量相关功能（21 CFR 211.22（d））。
An ongoing written program for monitoring process control was established to ensure stable manufacturing operations and consistent drug quality (21 CFR 211.100(a)).
建立监控工艺控制的持续书面程序，以确保稳定的生产操作和一致的药物质量（21 CFR 211.100（a））。
Cleaning processes were written, validated, reviewed, and approved for cleaning nondedicated manufacturing equipment to ensure that residues are adequately removed from the product contact surfaces of manufacturing equipment during cleaning (21 CFR 211.67(b)).
已编写、验证、审查和批准用于清洁非专用制造设备的清洁工艺，以确保在清洁过程中充分去除制造设备产品接触表面上的残留物（21 CFR 211.67（b））。
Equipment maintenance procedures were established, written, reviewed, and approved for your drug manufacturing equipment to ensure robust equipment operations (21 CFR 211.67(b)).
已建立、编写、审查和批准药品制造设备的维护程序，以确保设备稳健运行（21 CFR 211.67（b））。
Your response is inadequate. You intend to establish and implement procedures to comply with CGMPs. However, you did not provide detailed corrective action and preventive actions (CAPA) plan to systematically address the deficiency.
你们的回复是不充分的。你们打算建立和实施这些程序以符合CGMP。但是，你们没有提供详细的纠正措施和预防措施 （CAPA） 计划来系统地解决缺陷。
Your firm’s quality systems are inadequate. 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.
贵公司的质量体系是不充分的。请参阅FDA的指导文件药品CGMP法规的质量体系方法，以帮助实施质量体系和风险管理方法，以满足CGMP法规21 CFR，第210和211部分的要求，https://www.fda.gov/media/71023/download。
In response to this letter, provide the following:
回复此函，请提供：
A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
全面的评估和补救计划，以确保你们的QU获得有效运作的权力和资源。评估还应包括但不限于：
A determination of whether procedures used by your firm are robust and appropriate
确定贵公司使用的程序是否稳健和适当
Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
规定在整个操作过程中进行QU监督，以评估对适当做法的遵守情况
A complete and final review of each batch and its related information before the QU disposition decision
在作出QU处置决定之前，对每批产品及其相关信息进行全面和最终审查
Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
监督和批准调查并履行所有其他QU职责，以确保所有产品的特性，含量，质量和纯度
A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
验证程序的详细摘要，以确保整个产品生命周期中的控制状态以及相关程序。描述你们的工艺性能确认计划，以及对批次内和批次间变异的持续监控，以确保持续的控制状态。
A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.
为你们的每种已上市药品执行适当的工艺性能确认 （PPQ） 的时间表。
An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
对每个药品工艺进行评估，以确保有一个数据驱动且科学合理的程序来识别和控制所有可变性来源，以使你们的生产工艺始终符合适当的标准和生产标准。这包括但不限于评估设备对其预期用途的适用性、监控和测试系统中可检测性的充分性、输入物料的质量以及每个生产工艺步骤和控制的可靠性。
See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation athttps://www.fda.gov/regulatory-information/search-fda-guidancedocuments/process-validation-general-principles-and-practices.
请参阅FDA的指导文件《工艺验证：一般原则和实践》，了解FDA在 https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/process-validation-general-principles-and-practices 中认为工艺验证的适当要素的一般原则和方法。
Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
适当改进你们的清洁验证计划，特别强调在你们的药物生产操作中纳入被确定为最坏情况的条件。这应包括但不限于识别和评估所有最坏情况：
drugs with higher toxicities
毒性较高的药物
drugs with higher drug potencies
含有较高活性成分的药物
drugs of lower solubility in their cleaning solvents
在清洁剂中溶解度较低的药物
drugs with characteristics that make them difficult to clean
具有难以清洁的特性的药物
swabbing locations for areas that are most difficult to clean
擦拭最难清洁区域的位置
maximum hold times before cleaning
清洁前的最长保持时间
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
此外，请描述在引入新制造设备或新产品之前必须在变更管理系统中采取的步骤。
A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
更新的SOP摘要，确保有适当的程序来验证和确认产品，工艺和设备的清洁程序。
Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
你们的 CAPA 计划对设施和设备实施常规、警惕的运营管理监督。除其他事项外，该计划应确保迅速发现设备/设施性能问题，有效执行维修，遵守适当的预防性维护计划，及时对设备/设施基础设施进行技术升级，并改进不断进行管理审查的制度。
