近日，FDA 发布了浙江华海药业有限公司 Zhejiang Huahui Pharmaceutical Co., Ltd.的483表。

 

FDA本次检查安排在春节假期前夕，2025年1月16-17日和20-24日（中间1月18-19是周末），持续时间一周半，检查官是：Justin A. Boyd和Jeffrey P.Raimondi，检查过程包含对设备清洁极为细致的检查，烟雾试验（气流流型）、100%目视检查、偏差等。

 

包括提及：

 

烟雾试验过程中烟雾发生器朝下（与气流方向相同）进行的，而不是将烟雾发生器垂直于气流；

 

清洁验证仅两个取样点，未包含最难清洁的区域。例如：设备底部、内表面、垫圈、顶部区域或管道等难清洁区域

 

高效空气过滤器（HEPA）下方张贴非无菌胶带

 

翻译如下：

 

OBSERVATION #1

观察项 1

 

Equipment and utensils are not cleaned 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，以防止可能会改变药品安全性、鉴定、剂量、质量或纯度的污染。

 

Cleaning of non - dedicated xx used to manufacture US market products was not effective. There are xx non - dedicated xx used for US market products. The following was observed on cleaned equipment:

非专用 xx 清洁效果不佳。在已清洁非专用设备上观察到以下情况：

 

a. The non - dedicated GJC100 - 01 xx was not clean on January 16, 2025, immediately before it was intended to be used to manufacture batch xx of xx and xx Tablets USP xx (US market). The non - dedicated piece of equipment is used to manufacture xx different US market products.

a. 2025 年 1 月 16 日，在投入生产XX片剂之前，非专用设备 GJC100 - 01 xx 并不干净。

 

Prior to batch xx the equipment had undergone “Type C” changeover cleaning on January 15, 2025, that should have removed all product from the previous batch. On the morning of January 16, 2025, a production operator had visually inspected the equipment for cleanliness and approved the cleaning without identifying any xx residues.

在 xx 批次之前，该设备于 2025 年 1 月 15 日进行了 “类别C” 的清场，这本应清除上一批次的所有产品。2025 年 1 月 16 日上午，一名生产操作员对设备的清洁状况进行了目视检查，并在未发现任何 xx 残留的情况下批准了清洁。

 

When the equipment was inspected later in the morning, after initial xx for batch xx had already started, visible residues were observed in the following locations:

当天上午晚些时候，在 xx 批次的初始 xx 已经开始后，再次检查设备时，在以下位置发现了明显的残留物：

 

i. xx and xx residues were observed in the xx duct and on the valve of the xx duct. Swab sampling detected the presence of xx and xx in this area.

i. 在 管道及管道阀门处发现 xx 和 xx 残留。棉签取样检测到该区域存在 xx 和 xx。

 

xx was last manufactured December 21, 2024. Since that time, batches of xx Tablets, xx Tablets, xx Tablets, and xx and xx Tablets had been manufactured on this equipment.

xx（指被发现的残留物）的上次生产是在 2024 年 12 月 21 日。从那时起，在该设备上生产过 xx 片剂、xx 片剂、xx 片剂以及 xx 和 xx 片剂。

 

This site was previously cited on an FDA 483 for failing to appropriately clean the xx products of the xx

该场所此前曾因未能对 xx 产品进行适当清洁而被列入 FDA 483 表格。

 

ii. xx and xx residues were observed on equipment surfaces on the underside of the xx at the bottom of the product container. No sampling of this area was conducted before the equipment was cleaned.

ii. 在产品容器底部 xx 下方的设备表面观察到 xx 和 xx 残留。设备清洁前未对该区域进行取样。

 

iii. xx was observed on surfaces in the xx. No sampling of this area was conducted before the equipment was cleaned.

iii. 在 xx 内的表面观察到 xx。设备清洁前未对该区域进行取样。

 

iv. xx were observed on the surface of the xx zone. Swab sampling of this area detected xx

iv. 在 xx 区域的表面观察到 xx。该区域的棉签取样检测到 xx

 

v. xx were observed in the chute that transfers product from xx to the xx. Swab sampling of this area detected xx

v. 在将产品从 xx 输送至 xx 的斜槽中观察到 xx。该区域的棉签取样检测到 xx

 

vi. xx residues were observed on the rim of the product container. Swab sampling identified xx and xx

vi. 在产品容器边缘观察到 xx 残留。棉签取样识别出 xx 和 xx

 

vii. xx residues were observed on the gasket between the product container and xx zone. Swab sampling identified xx and xx

vii. 在产品容器与 xx 区域之间的垫圈上观察到 xx 残留。棉签取样识别出 xx 和 xx

 

viii. xx was observed on external surfaces of the equipment. No sampling of this area was conducted before the equipment was cleaned.

viii. 在设备外表面观察到 xx。设备清洁前未对该区域进行取样。

 

ix. During additional inspection of the equipment on January 20, 2025, the xx duct and valve were observed to have xx build - up on them.

ix. 在 2025 年 1 月 20 日对设备的额外检查中，观察到 xx 管道和阀门上有 xx 堆积。

 

b. On January 16, 2025, xx was observed on the xx valve on the xx of the cleaned xx GJC349 - 05. The investigation conducted by quality personnel was not going to include sampling of this visible xx or the area behind the xx valve on the xx duct. These areas were only swabbed after discussions during the inspection. When swab sampling of the xx residues was conducted and tested against the previous product, no peak was identified.

 

b. 2025 年 1 月 16 日，在已清洁的 xx GJC349 - 05 的 xx 上的 xx 阀门处观察到 xx。质量人员进行的调查不包括对这一可见位置或 xx 管道上 xx 阀门后面的区域。这些区域仅在检查期间讨论后才进行棉签取样。对 xx 残留进行棉签取样并与之前的产品进行测试时，未检测到峰值。

 

On January 20, 2025, a buildup of xx was observed on the xx duct and valve for this piece of equipment.

2025 年 1 月 20 日，在该设备的 xx 管道和阀门上观察到 xx 堆积。

 

c. On January 20, 2025, xx residues were observed on the xx valve on the xx of xx GJC348 - 05. The investigation conducted by quality personnel was not going to include sampling of this area. These areas were only swabbed after discussions during the inspection. When sampling was performed, the APIs xx and xx were detected.

c. 2025 年 1 月 20 日，在 xx GJC348 - 05 的 xx 上的 xx 阀门处观察到 xx 残留。质量人员进行的调查原本不包括对该区域取样。这些区域仅在检查期间讨论后才进行棉签取样。取样时，检测到了活性药物成分（APIs）xx 和 xx。

 

There was also stagnant liquid in the xx duct.

在 xx 管道中也有积液。

 

A buildup of xx was observed on the xx duct and valve.

在 xx 管道和阀门上观察到 xx 堆积。

 

Equipment surfaces on the top of the xx also appeared to have xx residues.

xx 顶部的设备表面似乎也有 xx 残留。

 

d. On January 20, 2025, xx was observed on the surfaces of the xx duct and valve of the xx GJC350 - 05.

d. 2025 年 1 月 20 日，在 xx GJC350 - 05 的 xx 管道和阀门表面观察到 xx。

 

The xx duct and valve was not sampled as part of the quality investigation before it was cleaned.

在清洁前，质量调查未对 xx 管道和阀门进行取样。

 

e. On January 20, 2025, xx was observed on the surfaces of the xx duct and valve on xx GJC101 - 01.

e. 2025 年 1 月 20 日，在 xx GJC101 - 01 的 xx 管道和阀门表面观察到 xx。

 

During investigation sampling by quality personnel, xx was detected in the xx duct and valve.

质量人员在调查取样期间，在 xx 管道和阀门中检测到 xx。

 

2. Cleaning of non - dedicated xx equipment used to manufacture US market products was not effective. There are xx non - dedicated xx used for US market products. On January 21, 2025, the following was observed on cleaned equipment:

2. 用于生产美国市场产品的非专用 xx 设备清洁效果不佳。有 xx 非专用 xx 用于美国市场产品。2025 年 1 月 21 日，在已清洁设备上观察到以下情况：

 

a. There appeared to be residues where the xx connect to the product bowl on xx GJC104, GJC105, and GJC106.

a. 在 xx GJC104、GJC105 和 GJC106 上，xx 与产品料斗连接处似乎有残留。

 

b. There appeared to be residues on the xx equipment and on the gasket of the door with the xx equipment on xx GJC105.

b. 在 xx GJC105 的 xx 设备上以及带有 xx 设备的门的垫圈上似乎有残留。

 

c. There were residues on equipment surfaces inside the xx equipment that surrounds the product drum on xx GJC104, GJC105, and GJC106.

c. 在 xx GJC104、GJC105 和 GJC106 上，围绕产品转鼓的 xx 设备内部的设备表面有残留。

 

d. There was buildup of unidentified material in the xx duct in xx GJC104, GJC105, GJC106, and GJC201.

d. 在 xx GJC104、GJC105、GJC106 和 GJC201 的 xx 管道中有不明物质堆积。

 

e. It appeared that pieces of unidentified material from the xx duct had fallen onto the xx that attaches to the xx bowl on xx GJC104, GJC105, and GJC106.

e. 看起来，来自 xx 管道的不明物质碎片落到了 xx GJC104、GJC105 和 GJC106 上连接到 xx 料斗的 xx 上。

 

3. Cleaning validation studies did not identify the hardest - to - clean areas of equipment. For example:

3. 清洁验证研究未确定设备最难清洁的区域。例如：

 

a. Cleaning validation for xx in Workshop xx Initial xx did not include sampling of difficult - to - clean areas like the bottom of the product xx, surfaces in the xx, gaskets, areas at the top of the xx, or xx ducts to evaluate cleaning effectiveness.

a. 某车间 xx 初始 xx 的清洁验证未对产品 xx 底部、xx 内表面、垫圈、xx 顶部区域或 xx 管道等难清洁区域进行取样，以评估清洁效果。

 

b. Cleaning validation for the Workshop xx Unit xx was limited to two sampling points, including the product bowl and a xx. It did not consider other difficult - to - clean areas including the xx, the xx, the door of the equipment outside of the product bowl, or xx ducts.

 

b. 某车间 xx 单元 xx 的清洁验证仅限于两个取样点，即产品料斗和一个 xx。它未考虑其他难清洁区域，包括 xx、xx、产品料斗外设备的门，或 xx 管道。

 

OBSERVATION #2

观察项 2

 

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

 

旨在防止声称无菌的药品受到微生物污染的程序，未对灭菌工艺进行充分验证。

 

1. Smoke studies regarding Workshop xx used for aseptically filling xx injection, USP xx ng xx ng/mL and xx ng/mL vials for the US Market:

关于用于无菌灌装注射液的 xx 车间的烟雾试验：

 

a. Air turbulence was observed for the following interventions:

a. 在以下操作过程中观察到了气流紊乱：

 

i. Installation of xx for Stoppers

i. 安装胶塞xx

 

ii. Installation of Stopper Bowl into Line

ii. 安装胶塞料斗

 

b. The following dynamic interventions were not evaluated in the smoke studies:

b. 以下动态操作在烟雾研究中未进行评估：

 

i. The xx of stopper bags from Grade B onto the Grade A filling line platform, which occurs routinely during filling operations and up to xx bags at a time.

i. 在灌装操作期间，通常会将胶塞袋子从 B 级区域转移到 A 级灌装线平台，一次最多转移 xx 袋。

 

ii. The xx of stoppers into the xx with the remaining bags of previously xx stopper bags on the filling line platform. Stoppers are xx  Smoke studies did not evaluate this entire intervention and how the airflow during stopper xx might be impacted by the remaining bags stored on the platform.

ii. 将胶塞装入 xx，同时灌装线平台上还留有之前已 xx 的胶塞袋子。胶塞是 xx  烟雾研究未对这一整套操作以及在瓶塞 xx 过程中气流可能因平台上存放的剩余袋而受到的影响进行评估。

 

c. Smoke studies for dynamic xx intervention of xx Disassemble and Installation was performed with the smoke generator pointing down, in the same direction as the airflow. It was not performed with the smoke generated pointing perpendicular to the airflow.

c. 关于 xx 拆卸和安装的动态 xx 操作的烟雾研究，是将烟雾发生器朝下（与气流方向相同）进行的，而不是将烟雾发生器垂直于气流方向进行的。

 

2. Smoke studies regarding Workshop xx used for aseptically filling xx Injection, USP xx ng vial for the US market:

2. 关于用于美国市场无菌灌装美国药典 xx ng 小瓶 xx 注射液的某车间的烟雾研究：

 

a. The dynamic xx loading of the xx vials into the xx was not evaluated as part of smoke studies.

a. 将 xx 小瓶动态 xx 装入 xx 的过程未作为烟雾研究的一部分进行评估。

 

b. Smoke studies for dynamic xx interventions were performed with the smoke generator pointing down, in the same direction as the airflow. It was not performed with the smoke generated pointing perpendicular to the airflow. These include:

 

b. 动态 xx 操作的烟雾研究是将烟雾发生器朝下（与气流方向相同）进行的，而不是将烟雾发生器垂直于气流。这些操作包括：

 

i. Calibration of Scale prior to filling

i. 灌装前秤的校准

 

ii. Calibration of Scale after being filled

ii. 灌装后秤的校准

 

iii. Adjustment of xx

iii. xx 的调整

 

iv. Adjustment of xx

iv. xx 的调整

 

v. Removing Vials at xx

v. 在 xx 处移除小瓶

 

vi. Adjustment leading to xx

vi. 导致 xx 的调整

 

3. Smoke studies for Workshop xx and xx were performed using xx generated from xx. There has been no evaluation of whether this produces neutrally buoyant smoke.

 

3. 某车间 xx 和 xx 的烟雾研究使用了由 xx 产生的 xx。尚未评估这是否能产生中性浮力烟雾。

 

OBSERVATION #3

观察项 3

 

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

 

没有为确保药品具有其声称或表示所具有的属性、效力、质量和纯度而设计的生产和工艺控制书面程序。

 

1. The visual inspection qualification process for 100% manual visual inspection is deficient in the following ways:

1. 100% 人工目视检查的目视检查确认过程存在以下缺陷：

 

a. The visual inspection kits for liquid vials do not contain glass, metal, elastomer material, and fiber of known size.

a. 液体小瓶目视检查套件中不包含已知尺寸的玻璃、金属、弹性体材料和纤维。

 

b. The visual inspection kits for liquid vials do not contain defect for precipitate (critical defect), group of particles (critical defect), smoke - like particle deposit (critical defect), protein floccule (critical defect), appearance defect with impact on container closure system (critical), and significant appearance xx (major defect), which are defect categories listed in the visual inspection record of each batch. There is no assurance operators can adequately identify these type of defects, where applicable, during manual visual inspection process.

b. 液体小瓶目视检查套件中没有沉淀（关键缺陷）、颗粒群（关键缺陷）、烟状颗粒沉积（关键缺陷）、蛋白絮凝物（关键缺陷）、对容器密封系统有影响的外观缺陷（关键缺陷）以及显著外观 xx（主要缺陷）等缺陷样本，而这些是每批目视检查记录中列出的缺陷类别。无法保证操作人员在人工目视检查过程中能够充分识别这些类型的缺陷（如适用）。

 

c. The visual inspection kits for xx vials do not contain defect vials for xx (critical defect), xx (major defect), and xx (major defect), which are defect categories listed in the visual inspection record of each batch.

c. xx 小瓶的目视检查套件中没有 xx（关键缺陷）、xx（主要缺陷）和 xx（主要缺陷）等缺陷小瓶样本，而这些是每批目视检查记录中列出的缺陷类别。

 

d. There is no complete defect library containing all defects for the liquid and xx vials.

d. 没有包含液体和 xx 小瓶所有缺陷的完整缺陷库。

 

e. Visual inspectors are required to be able to identify the defect vials during qualification and record the vial number in the corresponding defect row (such as critical, major, minor). The qualification records do not indicate what specific defect (such as glass, metal, etc.) was observed for each of these vials.

e. 目视检查人员需在确认过程中能够识别缺陷小瓶，并在相应的缺陷类别（如关键、主要、次要）栏中记录小瓶编号。但确认记录未注明针对每个小瓶所观察到的具体缺陷（如玻璃、金属等）。

 

f. There is no answer key for the current set of liquid test kits used to qualify operators for 100% visual inspection. After the most recent visual inspection qualification, the vial numbers were changed, but there is no record identifying the vial which contains what defect after the change.

f. 目前用于 100% 目视检查操作人员确认的液体检测套件没有参考答案。在最近一次目视检查确认后，小瓶编号发生了变化，但没有记录标明变更后每个小瓶所含的缺陷。

 

2. The xx used during visual inspection of sterile liquid drug products distributed to the US market in workshop xx is not qualified. The original qualification performed in 2018 required a two - stage qualification. The second stage of the qualification has never been performed, and to date, there is no active protocol or schedule to complete Stage 2.

2. 某车间用于美国市场无菌液体药品目视检查的 xx 未通过确认。2018 年进行初始确认要求分两阶段进行。但第二阶段的确认从未开展，至今也没有有效的方案或计划来完成第二阶段。

 

Additionally, prior to use of this equipment for commercial batches, a pre - and post - rejection test, using standard vials, is required to be performed. These standard vials do not contain glass, metal, elastomer material, and fiber of known size.

此外，在将该设备用于商业批次生产前，需使用标准小瓶进行拒收前和拒收后测试。这些标准小瓶中不包含已知尺寸的玻璃、金属、弹性体材料和纤维。

 

3. Acceptable ranges have not been established for operating the tablet compression machines. Examples include, but are not limited to xx Tablets and xx Tablets for the US market:

3. 尚未确定压片机操作的可接受范围。以美国市场的 xx 片剂和 xx 片剂为例（但不限于这些）：

 

a. Studies have not been completed to establish the reject rates for reject compression of tablets. There are no limits set in batch records and there is no process for setting the reject limits described in procedures used by the compression operators. Additionally, the operators have the ability to change the values for reject limits for each batch and to make changes during the batch. There has been no review of the electronic data to see what values were used during US market batches and to evaluate whether these values would have appropriately rejected non - conforming tablets.

a. 尚未完成确定片剂不合格压缩拒收率的研究。批次记录中未设定拒收限，压片操作人员使用的程序中也未描述设定拒收限的流程。此外，操作人员可针对每个批次更改拒收限数值，且在批次生产过程中也能进行更改。尚未对电子数据进行审查，以了解美国市场批次生产中使用的拒收限数值，也未评估这些数值是否能恰当拒收不合格片剂。

 

b. Acceptable ranges for compression machine parameters that the operators can change have not been established. For example: feeder speed, fill depth, or target main compression force.

b. 尚未确定操作人员可更改的压片机参数（如进料速度、填充深度或目标主压压力）的可接受范围。

 

4. During process validation, sampling plans have not been established that would allow for evaluation of variation that could be caused by different parameters used to operate equipment or evaluate variability within a batch. For example:

在工艺验证过程中，尚未制定抽样计划，以评估因设备操作参数不同而可能导致的变化，或评估批次内的变异性。例如：

 

a. Different compression speeds were used during process validation studies for xx Tablets and xx Tablets. There was no plan to establish acceptable ranges for commercial batches. Tablets manufactured at the different speeds were not separately sampled and tested to evaluate whether the different speeds led to variability within the batch.

a. 在 xx 片剂和 xx 片剂的工艺验证研究中使用了不同的压片速度。没有制定确定商业批次可接受范围的计划。以不同速度生产的片剂未分别进行抽样和测试，以评估不同速度是否会导致批次内的变异性。

 

b. During xx Tablets process validation, xx sampling was used for xx during the compression, xx and finished product testing stages. xx content testing during xx Tablets process validation was based on xx sampling.

b. 在 xx 片剂的工艺验证过程中，在压片、xx 以及成品测试阶段，xx 抽样用于 xx。在 xx 片剂工艺验证过程中的 xx 含量测试是基于 xx 抽样。

 

OBSERVATION #4

观察项 4

 

There is a failure to thoroughly review any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

 

对于任何无法解释的差异，或批次及其任何组件未能符合其任何规格要求的情况，无论该批次是否已分发，均未进行彻底审查。

 

1. Deviation DF - 23012 was opened when foreign matter was observed in xx of batch xx of xx Tablets (US Market). The batch was rejected. The investigation failed to perform any identification of the foreign matter or take any pictures. During the investigation, foreign matter similar in appearance was observed in the xx duct of the xx GZ5029. The area was cleaned without any analytical evaluation of the observed residues and no pictures were taken.

当在 xx 批次的美国市场 xx 片剂的 xx 中观察到异物时，启动了偏差 DF - 23012。该批次被拒收。调查未能对异物进行任何鉴定，也未拍摄任何照片。在调查过程中，在 xx GZ5029 的 xx 管道中观察到外观类似的异物。该区域在未对观察到的残留物进行任何分析评估的情况下被清洁，且未拍摄照片。

 

The investigation did not thoroughly assess whether contamination in this area could have impacted other batches made on this equipment. Additional batches made as part of the same campaign were not thoroughly inspected for the presence of foreign particles.

调查未彻底评估该区域的污染是否会影响在该设备上生产的其他批次。作为同一生产批次一部分的其他批次，未对异物颗粒的存在进行彻底检查。

 

The investigation was not expanded to inspect the xx ducts and document findings in other xx used for the US market products.

The cleaning procedures were not re - evaluated to consider cleaning of this area during changeover between products. The area is cleaned during maintenance xx but there is no requirement for the maintenance personnel to document if they observe residues during maintenance activities.

调查未扩大范围以检查用于美国市场产品的其他 xx 管道并记录结果。未重新评估清洁程序，以考虑在产品转换期间对该区域的清洁。该区域在维护 xx 期间进行清洁，但未要求维护人员记录在维护活动期间是否观察到残留物。

 

2. Complaint investigation CF - 23274 was opened when a customer obtained an OOS for dissolution on xx and xx of retain samples. The Tablet xx mg batch xx (EU market). The OOS was confirmed during the testing of retain samples. The investigation identified higher main compression force during tableting, which had no established limits, as well as increased disintegration times during storage. The cause of the higher compression force for the identification in the investigation as batch - to - batch variation, without further investigation of causes for the variation.

The investigation was not extended to US market tablet products, which similarly had no established ranges for the main compression force, to determine whether portions of batches were subject to variation leading to higher compression forces that could have produced non - conforming tablets.

当客户在保留样品的 xx 和 xx 中获得溶出度超标（OOS）结果时，启动了投诉调查 CF - 23274。涉及的是欧盟市场的 xx 毫克片剂批次 xx。在保留样品测试中确认了 OOS 结果。调查发现压片过程中主压压力较高（该压力没有既定限度），以及储存期间崩解时间增加。调查将较高压缩力的原因确定为批次间变异，但未对变异原因作进一步调查。

调查未扩展到美国市场的片剂产品（这些产品同样没有确定主压压力的范围），以确定批次的某些部分是否因变异而导致压缩力过高，进而产生不合格片剂。

 

3. Investigation OOT - FQC22020 was opened during stability testing of process validation batches of xx Tablets for the US market at the xx timepoint. The product is labeled with a xx expiration date and has a specification for unknown impurities of not more than xx %. Batch xx had a result of xx % and batch xx had a result of xx % for unknown impurities. The production investigation identified inter - batch variability as the reason for higher impurities in these batches, but failed to understand what was causing this variation or what caused the impurity to form. The investigation did not thoroughly evaluate whether a xx expiration date was appropriate for ongoing commercial manufacturing given this data and the lack of understanding of the cause of variability that generated this impurity.

在美国市场 xx 片剂工艺验证批次的稳定性测试中，在 xx 时间点启动了调查 OOT - FQC22020。该产品标注的 xx 有效期，且对未知杂质的规格要求为不超过 xx%。xx 批次的未知杂质结果为 xx%，xx 批次为 xx%。生产调查将批次间变异性确定为这些批次中杂质含量较高的原因，但未能弄清楚导致这种变异的原因或杂质形成的原因。鉴于这些数据以及对产生该杂质的变异性原因缺乏了解，调查未彻底评估 xx 有效期对于正在进行的商业生产是否合适。

 

A different unknown peak was detected in some xx Tablets stability batches. For example, batches xx and xx each had a result of xx % at xx compared to a specification of not more that xx %. The peak was attributed to an excipient, but the specific excipient was not identified. No investigation was evaluated if this was a risk to not be in all stability tablets if it is coming from an excipient, which should be present in all batches.

在一些 xx 片剂稳定性批次中检测到不同的未知峰。例如，xx 批次和 xx 批次在 xx 时的结果均为 xx%，而规格要求不超过 xx%。该峰被归因于一种辅料，但未确定具体是哪种辅料。未评估如果该峰来自一种应存在于所有批次中的辅料，是否会对所有稳定性片剂构成风险。

 

4. Investigation OOS - FQC23008 was opened for a batch uniformity OOS result for batch xx of xx Tablets (US market). The batch was rejected. The investigation concluded the operators did not properly reject tablets at the end of the batch, resulting in lower assay results for tablets at the end of the batch, which caused the failure. No confirmatory testing of tablets from the end of the batch was conducted to support this conclusion. The investigation concluded the incident was isolated to this batch.

针对美国市场 xx 片剂 xx 批次的批次均匀度 OOS 结果，启动了调查 OOS - FQC23008。该批次被拒收。调查得出结论，操作人员未正确在批次结束时剔除片剂，导致批次末尾片剂的检测结果偏低，从而导致不合格。未对批次末尾的片剂进行验证性测试以支持这一结论。调查得出结论，该事件仅局限于该批次。

 

Another batch in the campaign xx had a content uniformity stage one AV of xx and stage two of xx compared to an AV limit not more than xx. This was higher than historical data. The investigation included additional xx testing for this batch, but no testing specific to the end of the batch to evaluate whether a similar incident had occurred.

 

该生产活动中的另一个 xx 批次，其含量均匀度第一阶段的 AV 值为 xx，第二阶段为 xx，而 AV 限度要求不超过 xx。这高于历史数据。调查对该批次进行了额外的 xx 测试，但未针对批次末尾进行特定测试，以评估是否发生了类似事件。

 

OBSERVATION #5

观察项 5

 

Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

无菌加工区域在维护用于控制无菌条件的设备系统方面存在缺陷。

 

On 16 - Jan - 2025, a 2 x 126 cm piece of non - sterile tape was observed between xx sharing xx. These sit below the HEPA filters and above where empty vials enter the line from the xx before being aseptically filled within Workshop xx. The tape was placed between these xx to seal an approximate 3mm gap, which was observed sometime after the HEPA filters had been replaced around April 2024. This aseptic filling line is used to fill xx Injection xx mg for the US Market.

 

2025 年 1 月 16 日，在共享 xx 的 xx 之间观察到一块 2×126 厘米的非无菌胶带。这些位于高效空气过滤器（HEPA）下方，以及在无菌灌装车间 xx 内空小瓶从 xx 进入生产线的上方。该胶带被放置在这些 xx 之间，以密封一个约 3 毫米的缝隙，该缝隙是在 2024 年 4 月左右更换 HEPA 过滤器后的某个时间被观察到的。这条无菌灌装线用于灌装美国市场的 xx 毫克 xx 注射液。

 

There is no record documenting when the gap was observed, who it was observed by, and if the gap was reported to the appropriate department including the Quality Unit. No investigation and subsequent CAPA plan into the cause of the gap has been made.

没有记录表明何时发现该缝隙、由谁发现，以及该缝隙是否已报告给包括质量部门在内的相关部门。未对缝隙产生的原因进行调查并制定后续的纠正和预防措施（CAPA）计划。

 

There is no record documenting the approval and use of the non - sterile tape to seal the gap within the Grade A filling line, and there is no workorder or documentation detailing the installation, and subsequent replacement (if performed) of the tape.

没有记录证明对使用非无菌胶带密封 A 级灌装线内缝隙的批准情况，也没有工作订单或文件详细说明胶带的安装及后续更换情况（如有更换）。

 

An assessment was not performed to evaluate how the gap between the HEPA filter xx in the aseptic filling line and the use of the non - sterile tape within the area might impact airflow, cleaning, environmental monitoring, and product quality.

未对无菌灌装线中 HEPA 过滤器 xx 之间的缝隙以及该区域内非无菌胶带的使用可能对气流、清洁、环境监测和产品质量产生的影响进行评估。

 

OBSERVATION #6

观察项 6

 

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.

实验室控制未包括建立科学合理且适当的测试程序，以确保药品符合适当的属性、效力、质量和纯度标准。

 

Analytical method validation studies have not included forced degradation studies for methods used for stability testing. For example, the US market products: xx Tablets, xx Tablets, xx Tablets, and xx Tablets.

 

分析方法验证研究未包括对用于稳定性测试的方法进行强制降解研究。例如美国市场的产品：xx 片剂、xx 片剂、xx 片剂和 xx 片剂。

 

OBSERVATION #7

观察项 7

 

The quality control unit lacks authority to review production records to assure that no errors have occurred.

 

质量控制部门缺乏审查生产记录以确保未出现错误的权限。

 

Procedures for audit trail reviews for production equipment have not been established:

尚未建立生产设备审计追踪审查程序：

 

a. Production operators can make changes to compression settings. Quality personnel do not review audit trails that document parameters and changes.

a. 生产操作员可以更改压片设置。质量人员不审查记录参数和更改情况的审计追踪。

 

b. Production personnel can make changes to recipes for production and xx in the Workshop xx. Quality personnel do not review audit trails that document this information.

b. 生产人员可以更改生产配方以及车间 xx 内的 xx。质量人员不审查记录这些信息的审计追踪。

 

xx GJC100 - 01 and GJC101 - 01 do not have an audit trail, do not save data, and requires personnel to manually input operating parameters for production and xx. There is no quality unit verification of the manually entered information.

xx GJC100 - 01 和 GJC101 - 01 没有审计追踪功能，不保存数据，且需要人员手动输入生产和 xx 的操作参数。质量部门未对人工输入的信息进行核实。