The quality control area is a particular focus of the inspectors during every FDA inspection. Here, violations of GMP regulations are found particularly frequently, as can be read in numerous warning letters.
质量控制领域是FDA检查员在每次检查中特别关注的焦点。在这里，违反GMP法规的行为尤其频繁，这可以从大量的警告信中看到。
This article describes the type and frequency of GMP deficiencies in the quality control laboratories of the inspected companies on the basis of a systematic review of the Warning Letters citations. The data scope of this analysis includes the published Warning Letters of the fiscal years 2017 to 2021 (Oct. 2016 to Sept. 2021), which were addressed to manufacturers of finished medicinal products and contract laboratories. The citations examined refer to the following sections of the Code of Federal Regulations (21 CFR):
本文在对FDA警告信进行系统性统计的基础上，介绍了被检查企业QC实验室GMP缺陷的类型和频率。本分析的数据范围包括2016年10月至2021年9月已公布的警告信，这些警告信是发给制剂成品生产商和合同实验室的。警告信引用的法规参考21 CFR的以下章节：
Subpart I – Laboratory Controls
子部分I - 实验室控制
211.160 General requirements 通用要求
211.165 Testing and release for distribution 检测和放行
211.166 Stability testing 稳定性测试
Subpart J – Records and Reports
子部分J -记录和报告
211.194 Laboratory records 实验室记录
The analysis of the frequency of GMP deficiencies assigned to the respective CFR paragraphs, considered over the period of 5 fiscal years, is shown in the following chart.
在5年期间，对各个GMP缺陷频率的分析展示在了下图中。
According to this, the most frequent GMP deficiencies in the quality control area concern the tests prior to release of the product as well as stability tests; the latter were cited particularly frequently in the last fiscal year (2021).
QC领域最常见的GMP缺陷涉及产品放行前的检测以及稳定性测试，后者在2021财年被提及的频率尤其高。
§211.160 General requirements 通用要求
Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.
你们公司未能建立实验室控制，包括科学合理和适当的规范、标准、取样计划和测试程序，以确保成分、药品容器、瓶盖、中间物料、标签和药品符合适当的鉴别、强度、质量和纯度标准。
Unsuitable or non-validated test methods without scientifically supported significance are used, especially for microbiological controls.
使用了不合适的或未经验证的没有科学意义支持的检测方法，特别是微生物控制方法。
Test specifications for incoming and final inspections are not available. Sampling plans are missing or unsuitable.
没有进场物料检验和最终检查的检测标准，取样计划缺失或不合适。
Testing is done against unsuitable specifications.
测试是针对不合适的标准进行的。
Critical changes to electronic equipment in the QC laboratory are made in an uncontrolled manner. Uncontrolled manipulation of electronic data is possible.
QC实验室中电子设备的重大变更是在不受控制的情况下进行的，有机会可以不受控制地操纵电子数据。
Appropriate routine monitoring is lacking for the water system.
对水系统缺乏适当的常规监测。
§211.165 Testing and release for distribution 检测和放行
Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. o Finished products are released for sale without testing for compliance with specifications. This is the most common violation of GMP rules cited in the Warning Letters with reference to 211.165. In isolated cases, this deficiency also affects active substances that are released for further processing without appropriate compliance testing. Non-validated test methods are used.
你们公司在放行前没有对每批药品进行适当的符合药品最终标准的实验室检测，包括每种活性成分的鉴别和强度。成品未经过符合标准的检测就放行销售。这是警告信中引用的最常见的违反GMP规范的行为。在个别情况下，这种缺陷也会影响未经适当合规性检测就被放行用于进一步加工的活性物质。使用未经验证的测试方法。
§211.166 Stability Testing 稳定性测试
Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products, and to use results of such stability testing to determine appropriate storage conditions and expiration dates.
你们公司未能建立和遵循充分的书面检测程序，以评估药品的稳定性特性，并使用该稳定性测试的结果来确定适当的储存条件和有效期。
The test methods used in the studies do not demonstrate stability.
研究中使用的测试方法没有证明其稳定性。
The stability studies do not include current container and closure systems.
稳定性研究不包括当前的容器和封闭系统。
Microbial stability or sterility of the products is not tested.
未检测产品的微生物稳定性或无菌性。
Only short-term stability studies are carried out;long-term studies to validate the declared shelf life are missing.
只进行短期稳定性研究，目前还缺乏验证所宣布的有效期的长期稳定性研究。
There is no analytical recording or quantitative measurement of impurities in the stability studies.
在稳定性研究中没有杂质的分析记录或定量测量。
OOS results occur several times during the stability study, but are not further investigated; nevertheless, the study data serve to validate the shelf life.
OOS结果在稳定性研究中多次出现，但没有进一步研究。然而，研究数据用于验证有效期。
The analytical methods for the stability tests are not validated.
稳定性试验的分析方法没有得到验证。
There is no on-going stability testing programme.
没有持续的稳定性测试计划。
Data from older studies are used to justify the shelf life; stabilitystudies involving the current supplier and the current production site do not exist.
使用旧的稳定性研究数据来证明有效期的合理性，不存在涉及当前供应商和当前生产场地的稳定性研究。
Stability studies are completely missing.
稳定性研究完全缺失。
§211.194 Laboratory Records 实验室记录
Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards.
你们公司未能确保实验室记录包含所需的所有测试的完整数据，以确保符合既定规范和标准。
Documentation is incomplete, missing
文档不完整，缺失
OOS results
OOS结果
Root cause analysis of OOS results
OOS结果的根本原因分析
Data from failed tests
失败测试的数据
Re-test data, data on which the information on the certificateof analysis is based
重测数据，数据用于产生COA
Data on microbiological tests as well as relevant information (e.g. incubation times, materials, etc.), data that should actually be documented according to the audit trail
微生物测试数据以及相关信息(如培养时间、物料等)，应根据审计追踪记录的数据
Batch numbers
批号
Data on shelf life of standards
标准品的有效期数据
Unofficial records are used (uncontrolled Excel files or notes accessible to everyone, which are later destroyed).
使用非正式的记录(不受控制的Excel文件或每个人都可以访问的笔记，后来被销毁)。
Records are falsified, data is "invented"; audit trails are not secured against manipulation.
记录是伪造的，数据是“虚构的”，审计追踪不能防止被操纵。
The analysis of the warning letters shows that in many cases, the basic requirements for GMP-compliant work in the quality control laboratory as well as special requirements, e.g. for the performance of stability studies, are violated; the frequency of the latter has increased significantly in recent years.
对警告信的分析表明，在许多情况下，QC实验室GMP合规工作的基本要求以及稳定性研究等特殊要求被违反，近年来，后者的频率显著增加。
All in all, this kind of insight into the deficiency reports that repeatedly appear in the warning letters and the scenarios described there, some of them in detail, can be useful for preparing for an upcoming FDA inspection.
总而言之，这种对警告信中反复出现的缺陷报告的观察和学习，其中一些的细节，可以为即将到来的FDA检查做准备。
