缺陷提及：药品稳定性样品存放在QC实验室房间内，所有质量控制和研发人员均可进入。该公司质量控制分析人员称，没有实施程序化的系统来确保只有正确的样品和正确数量的样品被用于必要的稳定性测试。根据该公司的OOS调查，“检错样品”成为 OOS 事件根本原因的常客。此外，缺陷中还提及在未确认 CAPA 有效性的情况下关闭OOS。

缺陷还提及：QC人员可以访问 Empower 3.0 色谱数据系统（CDS）中的研发项目的缺陷。

缺陷还提及：稳定性试验未按照SOP和稳定性试验方案规定的时间点进行测试，测试在规定时间点之后的六个月才完成，尽管发起了偏差，依然落下缺陷。

缺陷还提及：质量保证（QA）部门未对所有生产记录和质量控制测试结果的单机版设备和网络版设备的原始生产和分析数据，包括审计追踪，进行全面审查（在生产批记录最终批准之前）。仅进行了生产记录的纸质审查以及对包括电子实验室笔记本（ELN）在内的质量控制试验报告的确认。

OBSERVATION 1

观察项1

QUALITY SYSTEM
质量体系

The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed.

适用于质量控制部门的职责和程序未形成书面文件，或未得到充分遵循。

Specifically,
具体而言：

a. Your drug product stability sample testing and control program is deficient. Drug product stability samples, including those that are pending testing or have completed testing, were placed on xx located in QC Analytical LAB - xx Room # xx which were accessible to all QC and R&D personnel. According to your QC analyst, no procedural system was implemented to ensure that only the right sample and the right amount of sample can be used to conduct the requisite stability testing. According to your OOS investigations, “error in sample selection is the likely cause of the initial out - of - specification (OOS) results” (OOS - AL2 - 24 - 0033, ) and “the root cause for the failure is due to selection of wrong samples” (OOS - AL2 - 25 - 0001) were concluded as the root causes of the respective OOS events. However, the proposed CAPA (CAP - AL2 - 25 - 0001) was to include a control measure (verification of samples) by revising the SOP (SOP - AL2 - QC - 0007 - 005). Both OOS investigations were for closed without verifying the effectiveness of the proposed CAPA.

a. 贵公司的药品稳定性样品测试和控制程序存在缺陷。药品稳定性样品，包括待测试或已完成测试的样品，被放置在质量控制分析实验室 - xx 房间内的 xx 处，所有质量控制和研发人员均可进入。据贵公司质量控制分析人员称，没有实施程序化的系统来确保只有正确的样品和正确数量的样品被用于必要的稳定性测试。根据贵公司的OOS调查，“样品选择错误可能是初始OOS结果的原因”（OOS - AL2 - 24 - 0033）以及 “失败的根本原因是选择了错误的样品”（OOS - AL2 - 25 - 0001）被判定为相应 OOS 事件的根本原因。然而，提议的纠正和预防措施（CAPA，CAP - AL2 - 25 - 0001）是通过修订标准操作规程（SOP，SOP - AL2 - QC - 0007 - 005）来纳入一项控制措施（样品核查）。两项 OOS 调查均在未确认 CAPA 有效性的情况下关闭。

b. Your firm failed to follow the Stability Program for Finished Products SOP - AL21204.05 Studies Procedure and established Stability Studies Protocols for xx and xx Ointment xx % and xx %. The Stability Program for Finished Products procedure establishes that stability samples should be completed within xx of sample receiving. However, it was documented in Deviation DEV - AL2 - 24 - 0058, that the stability samples were not tested within the requisite timeframe. In addition, in your documents provided in the submission for xx Ointment xx and xx % the dates of analysis provided are not accurate as to the dates testing was completed. In occasions, the testing was completed six (6) months after the specify timepoint. Similarly, for xx Ointment, stability samples were not completed within the established procedure and protocol. In addition, in your documents provided in the submission for xx Ointment xx and xx % the dates of analysis provided are not accurate as to the dates testing was completed. In occasions, the testing was completed six (6) months or over a year after the specify timepoint.
b. 贵公司未遵循成品稳定性程序 SOP - AL21204.05 试验程序以及已制定的稳定性试验方案。成品稳定性程序规定，稳定性样品应在接收样品后的 xx 内完成检测。然而，在偏差报告 DEV - AL2 - 24 - 0058 中记录，稳定性样品未在规定时间内进行检测。此外，在提交的关于 xx 软膏（xx 和 xx%）的文件中，所提供的分析日期与实际完成测试的日期不符。有时，测试在规定时间点之后的六个月才完成。同样，对于 xx 软膏，稳定性样品也未在既定程序和方案规定的时间内完成检测。另外，在提交的关于 xx 软膏（xx 和 xx%）的文件中，所提供的分析日期与实际完成测试的日期不符。有时，测试在规定时间点之后的六个月甚至一年多才完成。

c. Your QC analysts have access to R&D projects in the Empower 3.0 chromatography data system (CDS).
c. 贵公司的质量控制分析人员可访问 Empower 3.0 色谱数据系统（CDS）中的研发项目。

d. The standard operating procedure (SOP) Change Control Procedure Document No. SOP - ABN - QA - 0002 Version No. 009, establishes changes would be classify as minor, major and critical, depending on its impact to the identity, safety, strength, quality, purity and efficacy of the product or validation status of process, equipment, utility, facility or GMP compliance/procedures and systems or regulatory filings. However, the firm does not follow the established procedure for example, changes that should be classify as major or critical are classified as minor. Change Control CC - AL2 - 23 - 0197 was initiated on 22 - Dec - 2023 for introduction of a xx to be installed in Room xx even when this change required introduction of xx to the room and may impact validated utilities, the change was classified as Minor. In another example, CC - AL2 - 21 - 0248 was initiated on 30 - Nov - 2021 for introduction of xx in the facility, however, the change which may impact the validation status of process, and impact other drug products was classified as minor.
d. 标准操作规程（SOP）变更控制程序文件（文件编号 SOP - ABN - QA - 0002，版本号 009）规定，根据变更对产品的属性、安全性、效力、质量、纯度和功效，或对工艺、设备、公用设施、设施或 GMP 合规性 / 程序和系统或法规申报的验证状态的影响，将变更分为微小、主要和关键变更。然而，贵公司未遵循既定程序，例如，应归类为主要或关键的变更被归类为微小变更。变更控制 CC - AL2 - 23 - 0197 于 2023 年 12 月 22 日发起，是为了在 xx 房间安装 xx，即便该变更需要向房间引入 xx 且可能影响已验证的公用设施，该变更仍被归类为微小变更。再如，CC - AL2 - 21 - 0248 于 2021 年 11 月 30 日发起，是为了在工厂引入 xx，然而，这种可能影响工艺验证状态并对其他药品产生影响的变更被归类为微小变更。

e. There are not procedures established for introduction of new drug products at the facility. The quality unit lacks a procedure to establish a process for introducing new products to the existing manufacturing lines which will need a risk assessment of the impact to existing validated processes and equipment.
e. 工厂未制定引入新药品的程序。质量部门缺乏为将新产品引入现有生产线制定流程的程序，而这需要对现有已验证工艺和设备所受影响进行风险评估。

f. Comprehensive reviews of raw manufacturing and analytical data including audit trails are not performed by the Quality Assurance (QA) unit for standalone and network equipment records/systems for all production records and QC testing results (prior to the final approval of manufacturing batch records (MBR)). According to your QA reviewers, comprehensive batch record review by QA – prior to final approval of such record – is limited to paper review of the manufacturing record and verification of QC study reports including ELN. You do not review and verify critical raw data including equipment process parameters and/or audit trails to ensure completeness and accuracy of the critical process parameters and test results. In addition, you do not conduct periodic QA review of the quality system including QC analytical data to ensure ongoing compliance and product quality.
f. 质量保证（QA）部门未对所有生产记录和质量控制测试结果的单机版设备和网络版设备记录 / 系统的原始生产和分析数据，包括审计追踪，进行全面审查（在生产批记录（MBR）最终批准之前）。据贵公司 QA 审核人员称，QA 在最终批准此类记录之前的全面批记录审查仅限于对生产记录的纸质审查以及对包括电子实验室笔记本（ELN）在内的质量控制试验报告的确认。贵公司未审查和确认关键原始数据，包括设备工艺参数和 / 或审计追踪，以确保关键工艺参数和测试结果的完整性和准确性。此外，贵公司未对质量体系（包括质量控制分析数据）进行定期 QA 审查，以确保持续合规和产品质量。

g. Temperature, humidity, and pressure differential in drug product manufacturing areas (Grade D) are not continuously monitored. According to your manufacturing manager and QA personnel, the above environmental controls are monitored and recorded only xx. The current monitoring system does not provide assurance that any excursions from the normal operating ranges during manufacturing operations would be monitored, corrected, and documented.
g. 药品生产区域（D 级）的温度、湿度和压差未得到持续监测。据贵公司生产经理和 QA 人员称，上述环境控制仅在 xx 进行监测和记录。当前的监测系统无法确保在生产操作过程中，对超出正常操作范围的情况进行监测、纠正和记录。

OBSERVATION 2
观察项 2

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. Specifically, the following deviations were reviewed and found deficient:
对于任何无法解释的差异，无论批次是否已分发，均未进行彻底审查。具体而言，经审查发现以下偏差存在缺陷：

a. Investigation Report for Device Malfunction for xx Solution USP, xx Complaint Number A - PC2024 - 001 opened on 01/11/2024 is deficient. The investigation was initiated after complaint was received due to xx malfunction. During your investigation report, you didn't identify a root cause associated to manufacturing process. However, your investigation failed to mention that previously, investigations INV - NC - 018 - 015, INV - NCAL - 018 - 001, INV - NCAL - 019 - 004 and DEV - 19 - 013, were initiated for malfunction of the xx during the submission batches manufactured in 2018. It was identified a potential root cause as xx to the bottles prior to filling may disrupt the xx and inability of the xx to function, however, after changes to the process were implemented, your firm received over a hundred (100) of complaints for xx malfunction. Your investigation was deficient and corrective and preventive actions were not adequate to prevent recurrence of this issue.
a. 2024 年 1 月 11 日发起的关于 xx 溶液的设备故障调查报告（投诉编号 A - PC2024 - 001）存在缺陷。在收到因 xx 故障的投诉后展开调查。在贵公司的调查报告中，未确定与生产工艺相关的根本原因。然而，贵公司的调查未提及此前在 2018 年生产的提交批次中，曾针对 xx 故障发起过 INV - NC - 018 - 015、INV - NCAL - 018 - 001、INV - NCAL - 019 - 004 和 DEV - 19 - 013 等调查。已确定一个潜在根本原因，即在灌装前对瓶子进行 xx 操作可能会干扰 xx，且 xx 无法正常运行，然而，在对工艺进行变更后，贵公司仍收到了一百多起关于 xx 故障的投诉。贵公司的调查存在缺陷，纠正和预防措施不足以防止该问题再次发生。

b. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 23 - 0008, we noted the following deficiencies: in - process test for xx Solution USP, xx (Lot xx) testing for assay of in - process sample was out of specification. The % Assay of xx in xx was found to be xx ng xx (%). The result for the xx of xx Solution USP, xx was xx mg xx (%). The reportable limit for the xx of xx (s) xx ng xx (%) to xx ng xx (%). The in - process acceptance criteria is each should contain not less than xx ng and not more than xx ng xx (%) to xx (%) of labeled amount. Re - testing the original sample confirmed the out of specification. Your firm identified the root cause as a sampling issue; however, the same sampling approach was used for the validation batches manufactured in April 2023 and not out of specifications were reported. In addition, your firm did not propose a corrective and preventive action nor efficacy checks to prevent future recurrences. This batch of xx Solution USP, xx was released and distributed to the market.
b. 在审查OOS 调查 OOS - AL2 - 23 - 0008 时，我们注意到以下缺陷：xx 溶液 xx（批次 xx）的中间产品含量测试超标。在 xx 中 xx 的含量百分比被发现为 xx ng xx（%）。xx 美国药典溶液 xx 的 xx 结果为 xx mg xx（%）。xx（s）xx ng xx（%）至 xx ng xx（%）的报告限。中间产品接受标准是每个应包含不低于 xx ng 且不高于 xx ng xx（%）至 xx（%）的标示量。对原始样品重新测试证实了超标情况。贵公司将根本原因确定为取样问题；然而，2023 年 4 月生产的验证批次使用了相同的取样方法，却未报告超标情况。此外，贵公司未提出纠正和预防措施，也未进行有效性检查以防止未来再次发生。这批 xx 美国药典溶液 xx 被放行并投放市场。

c. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 22 - 0005, we noted the following deficiencies: testing for content of xx mg xx (Lot: xx) and xx mg xx (Lot: xx) release reported an out of specification. On December 21, 2022, the content of xx observed in the samples was xx % (specification xx %). Your firm could not identify a laboratory error and therefore decided to repeat the test in a new sample over xx after the OOS. As the results for the new sample were acceptable, the investigation was closed. Your firm did not initiate a Phase 2 investigation as required by the Handling and Investigation of Out of Specification Results in Quality control Laboratory Document No. SOP - AL21203.10 effective on 14Nov2022. Similarly, during the review of OOS Investigation Report INV - NCAL - 22 - 020, initiated in 03Nov2022, the OOS for xx mg (Lot: xx) was reported. The most probable root cause for this investigation was an analyst error during standard preparation, however, there was no indication that the standards prepared were not complying with your testing method acceptance criteria for percentage (9%) of recovery. Your firm invalidated the initial OOS results and continue repeating the test with new samples on 29DEC2022 with acceptable results. Your investigation approach and these out of the specifications cannot be considered thorough, as other root causes were not evaluated. In addition, your investigations do not extend to other batches, even when the same lot of xx is used for different xx strengths.
c. 在审查超标OOS 调查 OOS - AL2 - 22 - 0005 时，我们注意到以下缺陷：xx mg xx（批次：xx）和 xx mg xx（批次：xx）放行时的含量测试报告超标。2022 年 12 月 21 日，在样品中观察到的 xx 含量为 xx%（标准为 xx%）。贵公司未能确定实验室误差，因此决定在超标后 xx 时间对新样品重复测试。由于新样品的结果可接受，调查关闭。贵公司未按照 2022 年 11 月 14 日生效的《质量控制实验室超标结果的处理和调查》（文件编号 SOP - AL21203.10）的要求启动第二阶段调查。同样，在审查 2022 年 11 月 3 日发起的 OOS 调查报告 INV - NCAL - 22 - 020 时，报告了 xx mg（批次：xx）的 OOS 情况。此次调查最可能的根本原因是标准制备过程中的分析人员失误，然而，没有迹象表明所制备的标准品不符合贵公司回收率（9%）的测试方法验收标准。贵公司判定初始 OOS 结果无效，并于 2022 年 12 月 29 日使用新样品继续重复测试，结果可接受。贵公司的调查方法以及这些超标情况不能被认为是彻底的，因为未评估其他根本原因。此外，贵公司的调查未延伸到其他批次，即使同一批次的 xx 用于不同 xx 规格。

d. Investigation Reports for deviation investigation for Staphylococcus epidermidis found in microbial limit test of xx JSP (DEV - AL2 - 23 - 0009) and the associated CAPA (CAP - AL2 - 23 - 0009) are deficient. The deviation was opened on 03/24/2023 due to observation of microbial colony growth during microbial limit testing of the drug product。A CAPA was performed to investigate and pinpoint the potential source of contamination. Bacillus spp. and Paenibacillus amylolyticus were recovered from swabs of the area floor in the manufacturing area. No follow - up actions were taken and there was no data confirming that the xx did not support microbial growth. Subject CAPA was completed and approved by QA on 12/06/2023. These examples are not all inclusive but demonstrate that your investigations not always are conducted in a thoroughly manner and not all the potential root causes are evaluated.

d. 关于在 xx 日本药局方（JSP）微生物限度测试中发现表皮葡萄球菌的偏差调查（DEV - AL2 - 23 - 0009）报告及相关纠正和预防措施（CAPA，CAP - AL2 - 23 - 0009）存在缺陷。该偏差于 2023 年 3 月 24 日因在药品微生物限度测试中观察到微生物菌落生长而开启。已进行 CAPA 以调查并确定潜在污染源。从生产区域地面的拭子中回收到了芽孢杆菌属和淀粉水解类芽孢杆菌。未采取后续行动，也没有数据证实 xx 不支持微生物生长。相关 CAPA 于 2023 年 12 月 6 日由 QA 完成并批准。这些例子并非全部，但表明贵公司的调查并非总是彻底进行，且并非所有潜在根本原因都得到评估。

OBSERVATION 3
观察项 3

A xx field Alert Report was not submitted within three working days of receipt of information concerning a failure of one or more distributed batches of a drug to meet the specifications established for it in the application.

在收到有关一种或多种已分发药品批次不符合申请中既定规格的信息后，未在三个工作日内提交 xx 现场警报报告。

Specifically,
具体而言，

Your firm failed to submit a Field Alert Report (FAR) to the agency within three (3) working days. Your firm failed to follow standard operating procedure (SOP) APL - GP - GEN - 0039 Field Alert Reporting Version 1.0.0.0, which establishes that an event investigation that indicates potential/confirmed failure of one or more batches of the drug product that is distributed in market is a condition for filing FAR from manufacturing site. Your firm received a complaint for the distributed drug product xx Solution USP xx Lot Number xx on 01/11/2024 due to xx malfunction where the patient could not extract drug product from the bottle due to xx malfunction, however, not FAR was submitted. In addition, your firm received similar complaints for distributed drug product xx Solution USP xx Lot Number xx between February 7, 2024, and March 27, 2024. Your firm had received six (6) complaints due to xx malfunction, xx malfunction and initial FAR was submitted to the agency on March 28, 2024. Your firm submitted a FAR after seventy - seven (77) days has passed since your firm became aware of the product quality defect.

贵公司未能在三个工作日内向本机构提交现场警报报告（FAR）。贵公司未遵循标准操作规程（SOP）APL - GP - GEN - 0039《现场警报报告》（版本 1.0.0.0），该规程规定，对表明一种或多种在市场上分发的药品批次存在潜在 / 已确认不合格情况的事件调查，是生产场地提交 FAR 的条件。贵公司于 2024 年 1 月 11 日收到关于已分发药品 xx 美国药典溶液（批次编号 xx）的投诉，原因是 xx 故障，患者因 xx 故障无法从瓶中取出药品，但未提交 FAR。此外，贵公司在 2024 年 2 月 7 日至 3 月 27 日期间收到了关于已分发药品 xx 美国药典溶液（批次编号 xx）的类似投诉。贵公司共收到六起因 xx 故障、xx 故障的投诉，最初的 FAR 于 2024 年 3 月 28 日提交给本机构。贵公司在意识到产品质量缺陷 77 天后才提交 FAR。

FACILITIES AND EQUIPMENT SYSTEM

OBSERVATION 4
观察项 4

Equipment and utensils are not cleaned, maintained, and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

设备和器具未按适当间隔进行清洁、维护和消毒，以防止污染改变药品的安全性、属性、效力、质量或纯度。

Specifically,
具体而言：

a. Compounding Room xx of the xx manufacturing area, where compounding unit operation for commercial production of xx is performed, houses xx pieces of equipment – xx. Until December 2024, this xx equipment collectively shared the same equipment ID number MF - EOP - 18 as evidenced by xx.
a. 在 xx 生产区域的配料室 xx，进行 xx 商业化生产的配料单元操作，此处有 xx 件设备 - xx 。截至 2024 年 12 月，如 xx 所示，这些 xx 设备共用设备编号 MF - EOP - 18 。

Concurrently with the commercial production of xx drug products were performed in the Compounding Room xx. This was evidenced by logbook entries in Log Book #: xx.
在配料室 xx 同时进行 xx 药品的商业化生产。这在日志编号 xx 的日志条目中有体现。

Multiple manufacturing equipment were shared during the manufacturing production of the above products including xx.
在上述产品的生产过程中，共用了多种生产设备，包括 xx 。

According to Equipment Cleaning Verification Protocol for Manufacturing Equipment (SOP - AL2 - PR - 0007, which governs xx manufacturing equipment cleaning) and Cleaning Validation Protocol for xx, the effectiveness of the equipment cleaning is demonstrated by 1) visual inspection of the equipment, and 2) analytical testing with an acceptance limit of not more than xx ppm of the residual drug substance content. There were no scientific justification or data to demonstrate that potential safety risks of carryover contamination of the previous drug products are adequately mitigated. The protocols did not consider or justify, with data, the hardest to clean areas. Equipment specific cleaning programs were not evaluated or validated as part of the validation or verification protocols. No dirty and clean hold time limits were defined and validated. There was also no evidence that the analytical method for xx residue detection was validated under the actual condition of use.
根据《生产设备清洁验证方案》（SOP - AL2 - PR - 0007，用于管理 xx 生产设备的清洁）和 xx 的《清洁验证方案》，设备清洁的有效性通过以下方式证明：1）对设备进行目视检查；2）分析测试，残留药物物质含量的可接受限度不超过 xx ppm 。没有科学依据或数据证明先前药品的残留污染所带来的潜在安全风险已得到充分缓解。这些方案没有用数据考虑或证明最难清洁的区域。作为验证或核查方案的一部分，未对设备特定的清洁程序进行评估或验证。未定义和验证脏污和清洁的保留时间限制。也没有证据表明用于 xx 残留检测的分析方法在实际使用条件下经过了验证。

b. According to AuroLife xx Preventive Maintenance (PM) Checklist (Form FE - 1201 - F02.00), xx Equipment ID #: MF - EQP - 18 preventive maintenance was performed on the equipment on July 31, 2024. The same information was not recorded in the Cleaning and Usage Log Book (Log Book #: xx from 02Jan2024 to 31Dec2024). No cleaning action was recorded in the Log Book following the preventive maintenance. During this period, xx was manufactured using the same equipment: xx.

b. 根据 AuroLife xx 预防性维护（PM）检查表（表格 FE - 1201 - F02.00），2024 年 7 月 31 日对设备 ID 为 MF - EQP - 18 的 xx 设备进行了预防性维护。同样的信息未记录在 2024 年 1 月 2 日至 12 月 31 日的《清洁和使用日志》（日志编号 xx）中。预防性维护后，日志中未记录清洁操作。在此期间，使用同一设备生产了 xx：xx 。

OBSERVATION 5
观察项 5

Buildings used in the manufacture, processing, packing or holding of drug products are not maintained in a clean and sanitary condition and are free of infestation by insects and other vermin.

用于药品生产、加工、包装或储存的建筑物未保持清洁卫生，且未杜绝昆虫和其他害虫侵扰。

Specifically,
具体而言：

a. Filth, spider web, and insects are found on xx pallets used to stack and store boxes containing packaging/xx such as xx in the warehouse.
a. 在仓库中，用于堆放和储存包含包装 /xx（如 xx）的箱子的 xx 托盘上发现了污垢、蜘蛛网和昆虫。

SOP for Pest and Rodent Control (SOP - HS 1203.00) describes that the Pest and Rodent Control are outsourced to outside contractors. The SOP did not describe how your firm would evaluate the effectiveness of the pest control services to ensure that the manufacturing process, testing, and storage areas are free from infestation of vermin. Upon request, your firm provided xx pest and rodent finding reports generated by the outside contractor. However, there is no documented evidence that such reports were reviewed by your quality unit and that the effectiveness of the pest control was evaluated, maintained, and trended on a regularly basis.
《虫害和鼠害控制标准操作规程》（SOP - HS 1203.00）规定虫害和鼠害控制工作外包给外部承包商。该 SOP 未说明贵公司将如何评估虫害控制服务的有效性，以确保生产、测试和储存区域无虫害侵扰。经要求，贵公司提供了外部承包商生成的 xx 虫害和鼠害检查报告。然而，没有书面证据表明质量部门审查了这些报告，也没有证据表明定期对虫害控制的有效性进行了评估、维护和趋势分析。

b. According to the SOP for Cleaning of All Manufacturing Rooms and Clearance (SOP - MF 1202.02), xx water xx is used to clean the floor of the manufacturing rooms including those in Grade D area. Effectiveness of the cleaning/sanitization using such cleaning agents was not established.
b. 根据《所有生产车间清洁和清理标准操作规程》（SOP - MF 1202.02），使用 xx 水 xx 清洁包括 D 级区域在内的生产车间地面。未确定使用此类清洁剂进行清洁 / 消毒的有效性。

OBSERVATION 6
观察项 6

Routine calibration of automatic equipment is not performed according to a written program designed to assure proper performance.

自动设备的定期校准未按照旨在确保正常运行的书面程序进行。

Specifically,
具体而言，

The balance with Equipment Id. MF - BS - 11 (Serial No. xx) used for in - process controls in the xx manufacturing area Room: xx is not calibrated within the range of use. For example, the weight balance is use for the in - process controls of xx all strengths. The xx calibration of balance is conducted using standard weights between the range of xx, however, the in - process controls for xx to determine xx weight ranges from xx. Inaccurate weight of in process samples can lead to acceptance of xx with a variance greater than the established for the xx weight and discrepancies in drug content.

设备编号为 MF - BS - 11（序列号 xx）的天平，用于 xx 生产区域 xx 房间的中间控制，其校准范围不符合使用要求。例如，该天平用于所有规格 xx 的中间控制。天平的 xx 校准使用的标准砝码范围为 xx，但用于确定 xx 重量的中间控制范围为 xx 。中间样品的重量不准确可能导致接受 xx 时的偏差大于既定的 xx 重量偏差，并造成药物含量差异。

LABORATORY CONTROL SYSTEM

OBSERVATION 7
观察项 7

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release. Specifically,
药品分发的测试和放行，在放行前未通过适当的实验室检测来确定其是否符合最终规格。具体而言：

a. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 24 - 0003, we noted the following deficiencies: testing for xx in xx Solution (Lot xx) an out of specification was reported with results of xx % (Acceptance criteria xx % to xx %). Your investigation could not identify a root cause in the laboratory, and therefore, continue to repeat the test with other bottles as the original sample could not be located. The new tested samples complied with the acceptance criteria and therefore the lot was released for distribution.
a. 在审查超标（OOS）调查 OOS - AL2 - 24 - 0003 时，我们注意到以下缺陷：xx 溶液（批次 xx）中 xx 的测试结果超标，结果为 xx%（验收标准为 xx% 至 xx%）。贵公司的调查未能确定实验室中的根本原因，由于无法找到原始样品，因此继续用其他瓶进行重复测试。新测试的样品符合验收标准，因此该批次被放行分发。

b. During the review of Out of Specification (OOS) Investigation OOS - AL2 - 23 - 0007, initiated on 06Jun2023 after xx test was out of specifications for 6 - month stability time point 25°C/60%RH xx batch). The Content of xx (%Label Claim) in sample (sample ID xx) was found to be xx %. The result for the xx (sample ID xx) for 6 Month stability timepoint, 25°C/60% was xx %. The reportable xx for the xx was xx %. Which is below the acceptance criteria of NLT xx %. Your firm could not identify a root cause for the OOS in the laboratory or in the documentation associated with the analysis, therefore, repeating the test with a new sample was authorized since the original sample solution was expired. During the review of raw data that supported this analysis and investigation the following I noted the OOS investigation was initiated on 29Jun2023, over three (3) weeks of the sample analysis therefore the original sample was not available. In addition, during the review of the raw data I observed that other results reported as passing for xx xx ng xx 6 - month 40°C/75RH % Lot: xx but individual results were xx % and xx %, however, because xx was over xx % xx %) it was accepted.
b. 在审查超标（OOS）调查 OOS - AL2 - 23 - 0007 时（该调查于 2023 年 6 月 6 日在 xx 测试在 25°C/60% 相对湿度 6 个月稳定性时间点超标后启动，涉及 xx 批次）。样品（样品 ID xx）中 xx 的含量（标示含量百分比）为 xx% 。在 25°C/60% 相对湿度 6 个月稳定性时间点，xx（样品 ID xx）的结果为 xx% 。xx 的可报告 xx 为 xx% ，低于不低于 xx% 的验收标准。贵公司无法确定实验室或与分析相关文件中 OOS 的根本原因，由于原始样品溶液已过期，因此授权用新样品重复测试。在审查支持该分析和调查的原始数据时，我注意到 OOS 调查于 2023 年 6 月 29 日启动，此时距样品分析已超过三周，因此原始样品已不可用。此外，在审查原始数据时，我观察到其他报告为合格的 xx xx ng xx 40°C/75 相对湿度 6 个月（批次：xx）的结果，但个别结果为 xx% 和 xx% ，然而，因为 xx 超过了 xx% xx%），所以结果被接受。

In addition, your firm analyzed other samples for xx xx ng xx 6 - month 25°C/60RH % Lot: xx in the same analytical run but because xx was NLT xx %, result was accepted. Your testing procedure does not indicate that this practice is acceptable.
此外，贵公司在同一分析运行中分析了 xx xx ng xx 25°C/60 相对湿度 6 个月（批次：xx）的其他样品，但因为 xx 不低于 xx% ，结果被接受。贵公司的测试程序未表明这种做法是可接受的。

c. During the review of analytical raw data xx xx ng xx Lot: xx assay determination I observed an unidentified peak eluting at around xx of the chromatographic run. Your firm could not provide scientific evidence of what the unknown peak was as it was not observed during the establishing of standard testing procedure. Similarly, the peak was observed in other chromatographic runs for assay in stability samples. In addition, your firm confirmed that there is no procedure for investigating unknown peaks.

此外，贵公司在同一分析运行中分析了 xx xx ng xx 25°C/60 相对湿度 6 个月（批次：xx）的其他样品，但因为 xx 不低于 xx% ，结果被接受。贵公司的测试程序未表明这种做法是可接受的。

OBSERVATION 8
观察项 8

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that components and drug products conform to appropriate standards of identity, strength, quality and purity. Specifically,
实验室控制未包括建立科学合理且适当的测试程序，以确保组分和药品符合适当的属性、效力、质量和纯度标准。具体而言：

a. Your firm failed to establish a scientifically sound method to test related substances in xx Drug Substance. The method transfer of the Related Substance by HPLC method for xx was completed and effective on 03Aug2023, however, testing for xx Drug Substance batches (Batch No. xx, No. xx) used in the submission of xx was released by Quality Assurance in July 2022 and September 2022 for usage in submission batches manufactured on August 2022 and November 2022. Your testing of drug substances is conducted by a method that has not been implemented.
a. 贵公司未能建立科学合理的方法来测试 xx 原料药中的有关物质。xx 的高效液相色谱（HPLC）法有关物质方法转移于 2023 年 8 月 3 日完成并生效，然而，用于 xx 申报的 xx 原料药批次（批号 xx、xx）的测试，已于 2022 年 7 月和 9 月由质量保证部门放行，用于 2022 年 8 月和 11 月生产的申报批次。贵公司对原料药的测试所使用的方法并未得到实施。

b. In addition, as documented in Method Transfer of Related Substances by HPLC method for xx protocol TFR01 - 198RP - 21.00, the percentage of difference (%error) between the results for xx from your firm and the certificate of analysis from the vendor was xx % (Acceptance Criteria NMT xx %), nevertheless, the method was implemented by adjusting the acceptance criteria without a scientific sound justification.
b. 此外，如 xx 的 HPLC 法有关物质方法转移协议 TFR01 - 198RP - 21.00 中所记录，贵公司的 xx 结果与供应商分析证书之间的差异百分比（误差百分比）为 xx%（验收标准不超过 xx%），然而，在没有科学合理依据的情况下，通过调整验收标准实施了该方法。

OBSERVATION 9
观察项 9

In - process samples are not representative. Specifically,
中间产品样品不具代表性。具体而言，

Batch manufacturing record for xx Solution USP xx (Batch No. xx) requires that xx samples are collected for in - process testing xx by the manufacturing associates and xx samples are collected xx by quality assurances. The xx dated 22SEP2022, requires that xx samples are collected for in - process testing xx by the manufacturing associates and xx samples are collected xx by quality assurances. There is no assurance that the sampling approach is a statistically representative of each product and each lot and has a precise representation of the quality attributes purposed to have.

xx 美国药典溶液 xx（批号 xx）的批次生产记录要求，由生产人员采集 xx 样品用于中间控制测试 xx，由质量保证人员采集 xx 样品 xx。2022 年 9 月 22 日的 xx 要求，由生产人员采集 xx 样品用于中间控制测试 xx，由质量保证人员采集 xx 样品 xx。无法保证该抽样方法在统计上能代表每种产品和每个批次，也无法精确体现预期的质量属性。

OBSERVATION 10
观察项 10

Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in - process material and the drug product.

未建立控制程序来验证那些可能导致中间物料和药品特性出现变异性的生产工艺的性能。

Specifically,
具体而言，

According to the Operation Instruction of xx Machine (4.6.2018) xx in which “the machine must be stored or operated (mandatory)” included room quality requirements for the xx room “in which the front part of machine is positioned”. The requirements included xx. However, a review of your xx Log Book for Manufacturing Log Books revealed that the above xx controls including xx were not controlled to always meet the xx machine requirements in Room xx.
根据 xx 机器操作说明（4.6.2018）xx，其中 “机器必须存放或操作（强制性）” 包含了对 xx 房间（机器前部所在房间）的环境质量要求。这些要求包括 xx 。然而，对贵公司生产日志中的 xx 日志审查显示，上述包括 xx 在内的 xx 控制措施并不能始终满足 xx 房间内 xx 机器的要求。

According to the same logbooks xx during the period of August 2022 to January 2023 and on the days when the xx operations were performed for xx exhibit batches manufacturing xx were outside of the above xx control ranges. A review of xx mg xx exhibit batch assay testing OOS investigations (OOS number OOS - AL2 - 22 - 0002) revealed that you experienced aberration in the manufacturing process which caused variability in weight xx of the product xx.

根据同一批日志，在 2022 年 8 月至 2023 年 1 月期间，以及在进行 xx 展示批次生产的 xx 操作日，xx 超出了上述 xx 控制范围。对 xx 毫克 xx 展示批次含量测试超标（OOS）调查（OOS 编号 OOS - AL2 - 22 - 0002）的审查显示，生产过程中出现偏差，导致产品 xx 的重量 xx 出现变异性。

OBSERVATION 11
观察项 11

Procedures for corrective and preventive action have not been adequately established.

纠正和预防措施程序未得到充分建立。

Specifically,
具体而言，

Investigation Report for Device Malfunction for xx Solution USP, xx Complaint Number A - PC2024 - 001 opened on 01/11/2024 is deficient. The investigation was initiated after complaint was received due to xx malfunction. During your investigation report, you didn't identify a root cause associated to manufacturing process. However, your investigation failed to mention that previously, investigations INV - NC - 018 - 015, INV - NCAL - 018 - 001, INV - NCAL - 019 - 004 and DEV - 19 - 013, were initiated for malfunction of the xx during the submission batches manufactured in 2018. It was identified a potential root cause as xx of xx to the bottles prior to filling may disrupt the xx however, after changes to the process were implemented, your firm has received over a hundred (100) of complaints for xx malfunction. The corrective and preventive actions implemented were inadequate in that the condition for the malfunction of the xx was not corrected before the batches were released for distribution.
2024 年 1 月 11 日开启的关于 xx 美国药典溶液的设备故障调查报告（投诉编号 A - PC2024 - 001）存在缺陷。在收到因 xx 故障的投诉后展开调查。在贵公司的调查报告中，未确定与生产工艺相关的根本原因。然而，贵公司的调查未提及此前在 2018 年生产的提交批次中，曾针对 xx 故障发起过 INV - NC - 018 - 015、INV - NCAL - 018 - 001、INV - NCAL - 019 - 004 和 DEV - 19 - 013 等调查。已确定一个潜在根本原因，即在灌装前对瓶子进行 xx 的 xx 操作可能会干扰 xx，然而，在对工艺进行变更后，贵公司仍收到了一百多起关于 xx 故障的投诉。所实施的纠正和预防措施并不充分，因为在批次放行分发前，xx 故障的状况并未得到纠正。