近日，FDA发布了对中国药企BBC Group Limited的警告信，为其恢复国外现场检查以来首次基于现场检查发布的对中国药企的警告信，缺陷包括如下：

FDA要求审查气相色谱仪(GC)的分析数据。然而，该公司表示，在检查开始之前大约一个月，所有2018年至2020年的检验数据都已丢失。这些数据已不可恢复。

该公司仅保留实验室记录的静态副本(即纸质记录)进行审查，FDA认为这是不够的，因为它们没有保留完整色谱的动态记录格式来支持测试结果，并且它们不包括完整原始记录的一部分的系统适应性记录。

FDA检查人员发现GC相关的计算机系统和软件缺乏访问限制。例如，使用GC执行药品分析的实验室员工都以“系统管理员”身份登录，不需要密码，并具有完全的系统管理权限。此外，没有启用GC上的审计追踪。

FDA发现该公司的黏度计和紫外线-可见光度计是能够在产品/物料测试过程中保存数据的。尽管有这种能力，但该公司分析人员未能保存完整的动态测试数据。

该公司还使用电子表格进行稳定性试验数据输入。但是，这些电子表格不受控，也没有保护措施来防止数据操纵、覆盖或删除。

分析测试方法没有得到充分验证。具体来说，没有系统适应性性要求，也没有确定对照标准。

FDA检查人员在生产现场发现设备产品接触表面上的锈迹，随后要求查看设备维护日志。这些文件仅提供中文。FDA翻译后发现所提供的文件与检查期间要求的设备不同。

缺陷翻译如下：

CGMP Violations

1. Your firm failed to exerciseappropriate controls over computer or related systems to assure that onlyauthorized personnel institute changes in master production and controlrecords, or other records (21 CFR 211.68(b)).

贵公司未能对计算机或相关系统实施适当的控制，以确保只有经授权的人员才能对主生产和控制记录或其他记录进行更改(21 CFR 211.68(b))。

Your firm manufactures over-the-counter (OTC) drug products,including alcohol-based hand sanitizers[1]. During the inspection of your facility, ourinvestigator attempted to review analytical data from your gas chromatograph(GC) supporting the release of drug products distributed to the United States.However, your firm stated that all testing data from 2018 to 2020 was lostapproximately one month prior to the initiation of our inspection. The GC isused to analyze the identity and strength of active ingredients and impuritiescontained in your OTC drug products, as well as other critical parameters.According to firm management, the data is unrecoverable. While your firmretained a static copy of laboratory records for review (i.e., paper record),they were inadequate as they did not preserve the dynamic record format of thefull chromatographs to support test results and they did not include systemsuitability documentation that are part of the complete, original record.

贵公司生产非处方(OTC)药品，包括含酒精洗手液[1]。在对你们工厂的检查期间，我们的检查人员试图审查你们气相色谱仪(GC)的分析数据。然而，贵公司表示，在我们开始检查之前大约一个月，所有2018年至2020年的检验数据都已丢失。气相色谱用于分析你们OTC药品中所含活性成分和杂质的鉴别和检测，以及其他关键参数。根据公司的管理，这些数据已不可恢复。而贵公司保留实验室记录的静态副本(即纸质记录)进行审查，这是不够的，因为它们没有保留完整色谱的动态记录格式来支持测试结果，并且它们不包括完整原始记录的一部分的系统适应性记录。

Additionally, our investigator observed that the computerizedsystem and software associated with your GC lacked restricted access. Forexample, your laboratory employees who used the GC to perform analyses of drugproducts all logged in as “System Administrator,” which does not require apassword, and had full system administration rights. In addition, audit trailson your GC were not enabled.

此外，我们的检查人员发现与你们的GC相关的计算机系统和软件缺乏访问限制。例如，使用GC执行药品分析的实验室员工都以“系统管理员”身份登录，不需要密码，并具有完全的系统管理权限。此外，没有启用GC上的审计追踪。

Furthermore, you did not retain all original, dynamic records,obtained during the course of testing on other laboratory equipment. Yourviscometer and UV-Vis spectrophotometer had the capability to save data fromproduct/material testing. Despite having this capability, your analysts failedto save the complete, dynamic testing data, and therefore the data was notavailable for review by the FDA investigator. The viscometer is used to measurethe viscosity of finished drug products during release testing and the UV-Visspectrophotometer is used to measure ethanol content during raw materialtesting.

此外，你们亦没有保留在其他实验室设备测试过程中获得的所有原始动态记录。你们的黏度计和紫外线-可见光度计是能够在产品/物料测试过程中保存数据的。尽管有这种能力，你们的分析人员未能保存完整的动态测试数据，因此数据无法供 FDA 检查人员查看。黏度计用于检测成品放行测试的黏度，紫外线-可见光度计用于检测原料乙醇含量。

Your firm also utilizes electronic spreadsheets to input datafor your stability program. However, these spreadsheets are not controlled andthere is no protection to prevent data manipulation, overwriting, or erasure.

贵公司还使用电子表格进行稳定性试验数据输入。但是，这些电子表格不受控，也没有保护措施来防止数据操纵、覆盖或删除。

In your response, you indicated that you purchased and/orinstalled additional equipment to address this violation, including, but notlimited to, an uninterrupted power source, remote hard drive, electricalequipment, and new software. Your response also states that you have updatedand developed associated procedures, created individual accounts for allpersonnel that utilize laboratory equipment, and conducted accompanyingtrainings. However, your response is inadequate because it lacked supportingdocumentation, including evidence to support that the computer securitycontrols were effective at preventing data and document manipulation.Additionally, you did not perform a retrospective risk assessment into howsystem vulnerabilities may have impacted data integrity.

在回复中，你们表示你们购买和/或安装了其他设备来解决此不合规问题，包括但不限于UPS电源、远程硬盘、电气设备和新软件。你们的答复还指出，你们已更新并开发了相关程序，为所有使用实验室设备的人员创建了个人帐户，并进行了相应的培训。但是，你们的回复是不充分的，因为它缺乏支持性文档，包括支持计算机安全控制有效防止数据和记录操纵的证据。此外，你们没有对系统性缺陷如何影响数据完整性进行追溯性风险评估。

Your firm does not adequately ensure the accuracy and integrityof data to support the safety, effectiveness, and quality of the drugs youmanufacture. See FDA’s guidance document Data Integrity and Compliance WithDrug CGMP for guidance on establishing and following CGMP compliant dataintegrity practices at https://www.fda.gov/media/97005/download.

贵公司没有充分确保数据的准确性和完整性，以支持你们生产的药品的安全性、有效性和质量。有关建立和遵循符合CGMP的数据完整性规范的指导，请参见FDA指南《数据完整性与药品CGMP符合性》：https://www.fda.gov/media/97005/download。

2. Your firm failed to establishlaboratory controls that include scientifically sound and appropriatespecifications, standards, sampling plans, and test procedures designed toassure that components, drug product containers, closures, in-processmaterials, labeling, and drug products conform to appropriate standards ofidentity, strength, quality, and purity (21 CFR 211.160(b)).

贵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，以确保原辅料、药品容器、密封部件、过程物料、标签和成品符合适当的鉴别、强度、质量，和纯度标准(21 CFR 211.160(b))。

Your analytical test methods were not adequately validated,including those for the active ingredient ethanol, which is used to manufactureyour alcohol-based hand sanitizers, and analysis for the impurity (b)(4).Specifically, no system suitability requirements were present and referencestandards were not identified. Data must be available to establish that theanalytical procedures used in testing meet proper standards of accuracy,sensitivity, specificity, and reproducibility and are suitable for theirintended purpose.

你们的分析测试方法没有得到充分验证，包括用于生产成品的活性物质乙醇的分析方法，以及杂质(xx)的分析方法。具体来说，没有系统适应性性要求，也没有确定对照标准。应有数据来确定用于检测的分析方法在准确性、灵敏性、特异性和重现性方面符合适当的标准，并适合于其预期用途。

In your response, you indicated that you updated test methods, establishedmethod validation protocols, and completed test method evaluation. However,your response is inadequate for the following reasons.

在你们的回复中，你们指出你们更新了测试方法，建立了方法验证方案，并完成了分析方法评估。然而，由于以下原因，你们的回复是不充分的。

The response lacked information on the analyte reference standards used forthe method validation.

缺乏用于方法验证的分析物对照标准的信息。

The response lacked method validation details on identity of the testedanalytes, system suitability, method specificity data, preparations of theanalyte stock solutions, and accuracy and precision data from spike andrecovery experiments at different concentration levels.

缺乏方法验证细节，包括被测试的分析物的鉴定、系统适应性、方法特异性数据、分析溶液的准备，以及不同浓度下的峰和回收率实验的准确性和精密度数据。

The response lacked an assessment of drug products manufactured utilizing thedeficient methods.

缺乏对已使用有缺陷方法生产的药品的评估。

3. Your firm failed to clean, maintain,and, as appropriate for the nature of the drug, sanitize and/or sterilizeequipment and utensils at appropriate intervals to prevent malfunctions orcontamination that would alter the safety, identity, strength, quality, orpurity of the drug product beyond the official or other establishedrequirements (21 CFR 211.67(a)).

贵公司没有根据药品的性质以适当的时间间隔对设备和用具进行清洁、维护和消毒，以防止故障或污染，从而改变安全性、特性、强度、质量，或药品纯度超过官方或其他既定要求(21 CFR 211.67(a))。

During our inspection, the investigator observed rust on (b)(4) andproduct contact surfaces of four of the (b)(4) used tomanufacture drug products, including the manufacture of your OTC handsanitizers. Upon request, you provided our investigator with manufacturingequipment maintenance logs for the aforementioned (b)(4).These documents were only available in Chinese. After the conclusion of theinspection, the FDA had the document translated and found that the documentprovided was for equipment identified as “liquid washing pan” with serialnumber WJB-001, which is located in Workshop (b)(4) onthe (b)(4) floor, and not the (b)(4) withequipment ID’s 12 through 15 located in Workshop (b)(4) onthe (b)(4) floor that were observed with rust. FDA isconcerned that you provided maintence records for different equipment thanthose requested during the inspection.

在我们的检查中，检查人员观察到用于制造药物产品的四种（b）（4）的锈迹（b）（4）和产品接触表面，包括制造您的OTC洗手液。应要求，您向我们的调查人员提供了上述（b）（4）的制造设备维护日志。这些文件仅提供中文。检查结束后，FDA翻译了文件，发现所提供的文件用于编号为WJB-001的"液体洗涤锅"的设备，该设备位于（b）（4）楼的车间（b）（4），而不是设备ID的12至15的设备，位于（b）（4）楼层的车间（b）（4）中，这些车间位于用铁锈观察到的车间（b）（4）楼。FDA担心您提供的主记录与检查期间要求的设备不同。

In your response, you indicated that you replaced all the (b)(4) inyour (b)(4). However, your response failed to address the rustdocumented in other parts of the (b)(4). Additionally, your response isinadequate as you failed to revise your cleaning and maintenance procedures toprevent recurrence of this issue, you failed to perform a risk assessment ofdrug products manufactured in the four (b)(4) thatcontained rust, and you did not determine the root cause of why employees whoperform (b)(4) inspections of manufacturing equipment did notobserve the rust in the (b)(4).

在你们的回复中，你们表示你们更换了你们xx中的所有xx。然而，你们的回复没有解决xx其他部分的生锈问题。此外，你们的回复是不充分的，因为你们未能修改你们的清洁和维护程序以防止该问题的再次发生，你们未能对生锈的4个xx所生产的药品进行风险评估，你们没有确定对生产设备进行xx检查的员工没有在xx中发现生锈的根本原因。