操作人员使用的洗手间污渍严重，且未提供洗手皂。

更衣室的储物柜、工作服和操作人员的鞋子都很脏。

在主管人员的抽屉里还发现了明显脏污的布手套，这些手套在生产过程中会与产品直接接触。

清洁验证缺乏清洁过程的详细信息（如溶剂或清洁剂的使用、关键清洁步骤的描述）。微生物残留的取样位置仅标注为设备 “不同部位”，缺乏具体采样位置及选择的科学依据。

检查人员发现了不可接受的记录管理问题，包括但不限于：批记录破损、在生产区域发现破损的分析色谱图、包装区域标签和放行记录管理失控，以及在未上锁的抽屉中发现未完成的标签和放行记录。

关于生产批记录，操作人员的做法是回填此前记录在非受控表格上的数据，这些非受控表格未留存。生产记录的非实时记录引发了FDA对该公司记录管理实践和记录的有效性及完整性的担忧。

计算机数据备份程序称数据数据归档至云服务器，但安捷伦 OpenLab 色谱数据系统（CDS）的数据却（b)(4）归档至同一计算机的第二个硬盘。检查期间，检查人员发现第二个硬盘已损坏。

方法验证不足，含量测定的分析方法验证方案未包含精密度验证（相对标准偏差百分比）的可接受限度，且每项测试仅进行了一次测定。

未进行强制降解研究以证明稳定性方法具有稳定性指示作用。

工艺验证中未包含所生产的最小批量，缺乏每个工艺阶段的取样计划，及所用原材料的测试要求。此外，报告中未对验证批次的关键工艺参数结果进行评估。

金属检测器的验证缺乏对不同金属类型的反应测试、对不同尺寸和类型（b)(4）颗粒的敏感性评估、剔除机制的功能测试，以及不同流动速度或产品流量下的操作条件评估。

 

缺陷翻译如下

 

During our inspection, our investigators observed specific deviations including, but not limited to, the following.
检查期间，我们的检查人员发现了以下具体违规情况（包括但不限于）：

 

1. Failure to properly maintain buildings and facilities used in the manufacture of API.
未能妥善维护用于生产原料药的厂房和设施。

 

Facility Conditions
设施条件

You failed to maintain your drug manufacturing facility in a good state of repair. The washroom used by operators was observed to be heavily soiled, and soap for handwashing was not available. In addition, the gowning room was observed to have dirty lockers, garments, and operator shoes. Visibly soiled cloth gloves, which come into direct product contact with the (b)(4) USP (b)(4) API, were also observed in a supervisor’s desk drawer to be used by operators during manufacturing. You reported that these gloves are cleaned after use; however, you lacked documentation to support their cleaning.
贵公司未能将药品生产设施保持在良好的维护状态。操作人员使用的洗手间污渍严重，且未提供洗手皂。此外，更衣室的储物柜、工作服和操作人员的鞋子都很脏。在主管人员的抽屉里还发现了明显脏污的布手套，这些手套在生产过程中会与（b)(4) USP（b)(4）原料药直接接触。贵公司称这些手套使用后会进行清洁，但缺乏清洁记录支持。

 

Equipment Cleaning and Maintenance
设备清洁与维护

You failed to have adequate procedures for cleaning and maintenance of manufacturing equipment. For example, our investigators observed manufacturing equipment labeled as “cleaned” but found with the following deficiencies.
贵公司缺乏足够的生产设备清洁和维护程序。例如，我们的检查人员发现标有 “已清洁” 的生产设备存在以下缺陷：

A (b)(4) was labeled as clean and ready to be used; however, it was observed with residual product and a fraying rope inside the (b)(4).
一台（b)(4）标有清洁完毕可使用，但内部发现有产品残留和一根磨损的绳子。

A (b)(4) and (b)(4) were identified as cleaned; however, a significant amount of (b)(4) was observed on both pieces of equipment.
一台（b)(4）和（b)(4）标识为已清洁，但两台设备上均发现大量（b)(4）残留物。

Equipment and utensils (e.g., (b)(4) and (b)(4)), used to (b)(4) the (b)(4) USP (b)(4) API, were found to be stored on a dirty (b)(4) during the manufacturing of lot (b)(4).
在生产批号为（b)(4）的API时，用于（b)(4）（b)(4) USP（b)(4）API的设备和器具（如（b)(4）和（b)(4））被发现存放在一个脏污的（b)(4）上。

(b)(4) were observed to be unclean, and these units lacked documentation of cleaning activities.
（b)(4）被发现未清洁，且这些设备缺乏清洁活动记录。

You also failed to adequately document and validate cleaning procedures. For example, your cleaning validation lacked details of the cleaning process (e.g., use of solvent or detergent, and description of critical cleaning steps). Sampling performed for microbial residues was identified to be from “different places” on the equipment and lacked specific sample locations and scientific rationale for their selection. In addition, you did not adequately document your equipment cleaning as part of the batch record or a cleaning record.
贵公司还未能充分记录和验证清洁程序。例如，清洁验证缺乏清洁过程的详细信息（如溶剂或清洁剂的使用、关键清洁步骤的描述）。微生物残留的取样位置仅标注为设备 “不同部位”，缺乏具体采样位置及选择的科学依据。此外，设备清洁未作为批记录或清洁记录的一部分进行充分记录。

 

It is essential that your facility is in a good state of repair and sanitary conditions are maintained to avoid product contamination. Inadequately cleaned and maintained manufacturing equipment can lead to potential cross-contamination that could compromise your API’s quality and safety.
保持设施良好维修状态和卫生条件以避免产品污染至关重要。清洁和维护不足的生产设备可能导致潜在的交叉污染，进而影响原料药的质量和安全性。

 

2. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.

质量部门未能履行确保贵公司生产的API符合 CGMP 的职责。

 

Poor Documentation Practices
记录管理缺陷

Your firm manufactures (b)(4) USP (b)(4) API. Your quality unit (QU) failed to implement adequate controls to ensure the integrity of data generated at your facility. Our investigators observed unacceptable documentation practices, including, but not limited to, the following: torn batch records, a torn testing chromatogram found in the manufacturing area uncontrolled labeling and clearance forms in the packaging area, and a partially completed labeling and clearance form in an unlocked desk drawer.
贵公司生产（b)(4) USP（b)(4）原料药。质量部门（QU）未能实施足够控制以确保贵公司生成数据的完整性。我们的检查人员发现了不可接受的记录管理问题，包括但不限于：批记录破损、在生产区域发现破损的分析色谱图、包装区域标签和放行记录管理失控，以及在未上锁的抽屉中发现未完成的标签和放行记录。

In addition, manufacturing batch records were initiated after the (b)(4) stage of the crude (b)(4) was completed. Your operators’ practice was to backfill data that had previously been recorded on uncontrolled sheets for this initial API processing stage. These uncontrolled sheets were not maintained.
此外，生产批记录在（b)(4）的（b)(4）阶段完成后才开始填写。操作人员的做法是回填此前在API初始加工阶段记录在非受控表格上的数据，这些非受控表格未留存。

CGMP activities must be documented at the time of performance. Non-contemporaneous documentation on manufacturing records raises concerns about the validity and integrity of your firm’s documentation practices and records.
CGMP 活动必须在执行时记录。生产记录的非实时记录引发了对贵公司记录管理实践和记录的有效性及完整性的担忧。

 

Inadequate Electronic Data Controls
电子数据控制不足

You failed to follow adequate controls for your computerized systems. For example, your computerized data backup procedure states that data is (b)(4) archived to a cloud server; however, data from the Agilent OpenLab Chromatographic Data System (CDS) was instead being archived (b)(4) to a second hard drive on the same computer. During the inspection, our investigators documented that the second hard drive was corrupted, and chromatographic data, obtained from February to September 2024, may have been affected.
贵公司未能对计算机系统实施足够控制。例如，计算机数据备份程序称数据（b)(4）归档至云服务器，但安捷伦 OpenLab 色谱数据系统（CDS）的数据却（b)(4）归档至同一计算机的第二个硬盘。检查期间，我们的检查人员发现第二个硬盘已损坏，2024 年 2 月至 9 月的色谱数据可能已受影响。

You provided a document stating that the hard drive was sent to an external contractor for data recovery; however, you did not conduct a thorough investigation into this incident. Additionally, you failed to identify the specific data that may have been affected, including an evaluation of the potential impact on product quality.
贵公司提供文件称硬盘已送外部承包商进行数据恢复，但未对此事件进行彻底调查。此外，贵公司未能确定可能受影响的具体数据，包括对产品质量潜在影响的评估。

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.
贵公司的质量体系未能充分确保数据的准确性和完整性，以支持所生产药品的安全性、有效性和质量。有关建立和遵循符合 CGMP 的数据完整性实践的指南，请参见 FDA 指导文件《数据完整性与药品 CGMP 合规性》，网址：https://www.fda.gov/media/119267/download。

 

3. Failure to test the identity of each batch of incoming production material and to appropriately qualify suppliers to rely upon their certificate of analysis.
未能对每批进厂物料进行鉴定，也未能适当确认供应商以依赖其COA。

 

You failed to conduct an identity test on each lot of raw material used in the manufacture of your API. You instead relied on the certificates of analysis (COAs) from your suppliers without adequately qualifying them. You tested (b)(4), received as your primary raw material, for some quality attributes; however, an identity test was not performed before use in manufacturing.
贵公司未能对用于生产原料药的每批原材料进行鉴定，在未充分确认供应商的情况下依赖其分析证书（COA）。贵公司对作为主要原材料的（b)(4）进行了某些质量属性测试，但未能在用于生产前进行鉴定测试。

In addition, your procedure for vendor qualification states that critical vendors, such as suppliers of active raw materials, are required to be qualified. You did not qualify your suppliers of primary raw material and failed to establish the reliability of each of your suppliers’ COA for raw material specifications and characteristics.
此外，供应商确认程序规定，关键供应商（如活性原材料供应商）需通过确认。贵公司未对主要原材料供应商进行确认，也未能确认每个供应商关于原材料规格和特性的 COA 的可靠性。

Without adequate testing, there is no scientific evidence to assure that your raw materials conform to appropriate specifications before release.
缺乏足够的测试，就没有科学证据确保原材料在放行前符合适当的规格。

 

4. Failure to ensure that all specifications and test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality.
未能确保所有规程和测试程序科学合理且适当，以确保API符合既定质量标准。

 

Inadequate Testing of (b)(4) API
API测试不足

You failed to adequately test your (b)(4) USP (b)(4) API per the current USP monograph. For example, you did not conduct testing for “(b)(4)” and “(b)(4).” These tests are not required in your API specification. As a result, you distributed lots of (b)(4) API to the U.S. market without assurance that they meet the current USP standards. This may also render your (b)(4) USP adulterated under section 501(b) of the FD&C Act.
贵公司未能根据现行 USP 专论对（b)(4) USP（b)(4）API进行充分测试。例如，未进行 “（b)(4）” 和 “（b)(4）” 测试，这些测试在原料药标准中未作要求。因此，贵公司将多批（b)(4）原料药销往市场时，无法确保其符合现行 USP 标准。这也可能导致（b)(4) USP 原料药根据 FD&C 法案第 501 (b) 条被认定为掺假。

Inadequate Method Verification
方法验证不足

You failed to perform an adequate analytical method verification for (b)(4) assay. Your protocol did not include an acceptance limit for the verification of the precision (percent relative standard deviation). The verification exercise included a single determination of each test.
贵公司未能对（b)(4）含量测定进行充分的分析方法验证。验证方案未包含精密度验证（相对标准偏差百分比）的可接受限度，且每项测试仅进行了一次测定。

Inadequate Stability Method Validation
稳定性方法验证不足

You failed to ensure that the analytical method used for stability testing of (b)(4) USP (b)(4) API is suitable for its intended use. For example, you did not perform forced degradation studies to demonstrate that the method is stability-indicating.
贵公司未能确保用于（b)(4) USP（b)(4）原料药稳定性测试的分析方法适合其预期用途。例如，未进行强制降解研究以证明该方法具有稳定性指示作用。

 

5. Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes.
未能证明生产工艺可 reproducibly 生产出符合预定质量属性的原料药。

 

Inadequate Process Validation
工艺验证不足

You failed to adequately validate your (b)(4) API manufacturing process. For example, your process validation lacked a scientific rationale for not including the smallest batch size your firm manufactures, a defined sampling plan for each stage, and testing requirements for raw materials used. In addition, your report lacked an evaluation of critical processing parameters results for the validation batches.
贵公司未能对（b)(4）API的生产工艺进行充分验证。例如，工艺验证中未包含贵公司所生产的最小批量，未提供科学理由，缺乏每个工艺阶段的取样计划，及所用原材料的测试要求。此外，报告中未对验证批次的关键工艺参数结果进行评估。

 

Equipment Qualification
设备确认

You lacked qualification for major equipment, such as the (b)(4) tank, (b)(4) machine, and (b)(4). In addition, the qualification of the (b)(4) lacked testing of the (b)(4) response to different types of metal, evaluation of its sensitivity to different sizes and types of (b)(4) particles, functionality of rejection mechanisms, and evaluation of operating conditions for different flow rates or product throughput. Furthermore, the qualification of the (b)(4) lacked a comprehensive range of operating parameters.
贵公司缺乏对主要设备的确认，如（b)(4）储罐、（b)(4）设备和（b)(4）。此外，（b)(4）的确认缺乏对不同金属类型的反应测试、对不同尺寸和类型（b)(4）颗粒的敏感性评估、剔除机制的功能测试，以及不同流动速度或产品流量下的操作条件评估。此外，（b)(4）的确认缺乏全面的操作参数范围。