预防无菌制剂微生物污染控制的规程中的无菌工艺没有经过合适的验证

Air flow visualization studies for the (b)(4) line used to aseptically fill (b)(4) for the US market did not meet the acceptance criteria of airflow that is unidirectional and free from turbulence or follow the established execution instructions in the study protocol.

用于美国市场的 (b)(4) 无菌灌装线 (b)(4) 的气流可视化试验不符合单向且无湍流的气流的验收标准，或不符合试验方案中已建立的执行说明。

a. In the area where empty (b)(4) are opened and exposed to the environment there is a gap between the overhead HEPA filters of approximately (b)(4) Raw video footage obtained during the smoke studies of this area show air turbulence and upward flowing air, The raw video footage showing this deficient air flow pattern was not included in the final edited versions of the videos discussed in the validation report

位于敞口容器上方，发现临近的HEPA过滤器之间有缝隙存在。这个位置的原始气流模型研究视频显示有湍流和向上气流出现，该原始视频素材未包含在验证报告中讨论的最终编辑版本的视频中。

b. The videos show upward flowing smoke along the RABS barrier near (b)(4) inside the filling and stoppering RABS. This area is below an approximately (b)(4) gap between the edge of the HEPA filter and the RABS barrier. The validation report did not identify any deficiencies in this area. A similar gap between the RABS barrier and the HEPA filters exists on all (b)(4) sides of the RABS filling barrier. The air flow visualization studies have not thoroughly evaluated this gap.

视频显示，在灌装和加塞RABS内部 (b)(4) 附近，烟雾是沿着RABS屏障向上流动的。该区域在HEPA过滤器的边缘与RABS屏障之间的间隙大约 (b)(4) 下方。验证报告没有发现这方面的任何缺陷。RABS屏障和HEPA过滤器之间的类似间隙存在于RABS灌装屏障的所有侧面 (b)(4) 上。气流可视化试验尚未彻底评估这一缝隙。

c. The videos show upward flowing and turbulent air flow near a gap between the HEPA filter edge and the barrier (b)(4) outside of the filling barrier, near (b)(4) There is an approximately (b)(4) gap between the edge of the HEPA filter and the RABS barrier, This Grade A classified area is used during (b)(4) assembly of the machine, and interventions, The raw video footage showing this deficient air flow pattern was not included in the final versions of the videos discussed in the validation report.

视频显示了HEPA过滤器边缘和灌装屏障外部的屏障 (b)(4) 之间的间隙附近的向上的气流和湍流，在 (b)(4) 附近。在HEPA过滤器的边缘和RABS屏障之间存在大约 (b)(4) 的间隙，该等级A分类区域在机器的组装和干预期间使用 (b)(4) ，验证报告中讨论的视频的最终版本中不包括显示该缺陷气流模式的原始视频片段。

d. The (b)(4) barrier used to open and load empty (b)(4) has a support for the (b)(4) positioned about (b)(4) below the HEPA filter, The smoke studies did not thoroughly evaluate the impact of this support on the air flow in this area.

用于打开和装载空的 (b)(4) 的 (b)(4) 屏障具有用于 (b)(4) 的支撑件，其位于HEPA过滤器下方大约 (b)(4) ，烟雾试验没有彻底评估这种支撑对该区域气流的影响。

e. Protocol (b)(4) OA/AFVP/017 for the (b)(4) line states the smoke needs to be introduced by placing the nozzle with the smoke upwards and the nozzle should be moved to cover the entire area of the filter. Raw video files show the smoke nozzle pointed in downward direction and in fixed locations. The final edited videos did not show the smoke from where it was introduced near the filter to the working location.

方案(b)(4) QA/AFVP/017 针对#产线规定烟雾需要通过将喷嘴朝上放置引入，并且喷嘴应移动以覆盖过滤器的整个区域。原始视频文件显示烟雾喷嘴指向下方并固定在某些位置。 最终编辑的视频未显示从靠近过滤器到工作区域引入烟雾的过程。

工艺变更致混合不均，无工艺受控数据放行且隔离批次处置不当

To reduce the manufacturing process time for three strengths of acetaminophen and codeine phosphatetablets, you implemented a manufacturing process change Using this new process,you manufactured(b) (4)process performance qualification(PPQ)batches.You rejected (b)(4) batches for uniformity failures(e g,blend,content uniformity)and released the remaining (b)(4) batches

为了减少三种对乙酰氨基酚和磷酸可待因片剂的生产工艺时间，你们实施了生产工艺变更。使用此新工艺，你们生产了 (b)(4) 个工艺性能确认批次。由于均匀性失败（例如，混合、含量均匀性），你们拒绝放行了 (b)(4) 个批次，但放行了其余 (b)(4) 个批次。

You did not have data to support that your process was in a state of control prior to releasing those (b)(4) batches.

在放行那些 (b)(4) 批次之前，你们没有数据来支持你们的工艺处于受控状态。

Your evaluation of the process change after implementation concluded that the new process resulted in a non-uniform blend,your previous manufacturing process was more consistent and robust, and there maining batches should be held pending further discussion.Eight months after this initial evaluation you made the decision to revert to the old process.However,your firm determined that the quarantined batches could be distributed.

在实施工艺变更后，你们的评估得出新的工艺导致混合不均匀的结论，之前的生产工艺更加稳定且可靠，剩余批次应暂停处理，等待进一步讨论。在首次评估的八个月后，你们决定恢复旧工艺。然而，贵公司却判定那些被隔离的批次产品可以进行销售分发。

无菌工艺未经验证

The aseptic processes used to manufacture (b)(4) of vials of SurCord® and SurForce® have not been validated （e.g.， by performing media fi ll simulations） since your fi rm’s manufacturing operations began in June 2017. These products purport to be sterile and are expected to be sterile.

自你公司于2017年6月开始生产运营以来，用于生产 (b)(4) 小瓶 SurCord® 和 SurForce® 的无菌工艺尚未经过验证（例如通过执行培养基灌装模拟）。这些产品声称是无菌且预期是无菌的。

回顾性验证代替再验证

Your response is inadequate. You failed to provide a detailed process performance protocol for your validations or actions to be implemented to identify all sources of variability. Furthermore, your response did not provide a timeline for completion of prospective PPQ studies for each of your drug products. The use of a retrospective validation approach is not acceptable. Lastly, you did not address the impact this violation has on your drug products currently in the market.

贵司的回复不充分。未能提供一份详细的工艺性能确认计划，用于贵司的验证或要实施的行动，以识别所有可变性来源。此外，贵司的回复没有提供每个药品前瞻性PPQ研究完成的时间表。使用回顾性验证方法是不被接受的。最后，贵司没有说明这一违规行为对目前在市场上销售的药品的影响。

不能证明生产工艺可以稳定地生产出符合其预期质量属性的 API

Your firm failed to establish a protocol and implement a plan to ensure all API manufacturing processes, equipment and facilities are fit for use. For example,

你们公司未能制定方案和实施计划，以确保所有API的生产工艺、设备和设施都适合使用。例如，

Your firm could not provide records that process performance qualification (PPQ) had been performed for any of your APIs (e.g., (b)(4) ) manufacturing processes.

你们公司无法提供已对所有 API（例如 (b)(4) ）生产工艺执行了工艺性能确认 (PPQ) 的记录。

工艺验证完成前未完成设备设施确认

Specifically, your firm does not have approved protocol driven equipment performance qualification (PQ) studies with pre-approved acceptance criteria and which describes all aspects of the testing performed, and with a final summary report of the data generated and a determination of whether equipment qualification status was achieved. The process validation report titled "Process Performance Qualification Report of (b)(4) API" MVD-000146683, ver 3.0, was executed using equipment that was not fully qualified (IQ/OQ/PQ). The following are some examples of production equipment that lacks protocol-based equipment qualifications:

具体地说，贵公司没有经过批准的、包含预先批准的验收标准的设备性能确认方案，该方案描述了所进行的测试，并附有所生成数据的最终总结报告，以及设备是否达到确认状态的决定。名为“(b)(4) APl 的工艺性能确认报告”MVD-000146683（3.0 版）的工艺确认报告是使用未完全确认（IQ/OQ/PQ）的设备执行的。以下是一些缺乏基于方案的设备确认的生产设备的例子：

A.xxx (EquipmentID# PB1xxx -001), utilized in thexxx stage ofxxx USP production.

xxx (设备 ID# PB1xxx -001)，用于xxx USP 生产的xxx 阶段。

B.xxx Vessel (Equipment ID# PB1xxx -009), utilized in thexxx stage ofxxx USP production.

xxx容器（设备 ID# PB1xxx -009），用于xxx USP 生产的xxx 阶段。

C.xxx (PB2 xxx 001), utilized in the xxx stage of xxx USP production.

xxx (PB2 xxx 001)，用于xxx USP生产的xxx阶段。

D.xxx Equipment ID # PB3-xxx001), utilized in th exxx stage of xxx USP production.

xxx设备 ID # PB3- (b)(4) 001），用于xxx USP 生产的 xxx 阶段。

E.xxx )(Equipment ID # PB4xxx001), utilized in the xxx stage of xxx USP production.

xxx(Equipment ID # PB4xxx001),用于xxx USP 生产的xxx 阶段。

F.xxx Equipment ID # PB4xxx001), utilized in the xxx stage of xxx USP production.

xxx设备 ID # PB4xxx001), 用于xxx USP 生产的xxx阶段。

无菌模拟灌装不足

Your firm manufactures (b)(4) batches of sterile USP, API. Your firm calculated that one batch of (b)(4) USP API can be filled into (b)(4) drug product vials. Media fill study # MF/CPMD/22/04/01, conducted in May 2021 and simulating the manufacture of sterile (b)(4) API, failed due to recovering (b)(4) CFU for the (b)(4) simulation, and (b)(4) CFU for the (b)(4) simulation (DV/22/046). Spore forming bacteria such as Basileus subtilis, Basileus pumihs, Bacilhs oceanisediminis, and Basileus megaterium, were isolated from the recovered CFUs. Instead of performing re-validation via three consecutive media fills, your fim performed only one repeat media fill.

贵公司计算得出，一批 (b)(4) 美国药典标准的原料药可灌装到 (b)(4) 个药品小瓶中。于2021年 5月开展的培养基模拟灌装试验# MF/CPMD/22/04/01，模拟了无菌 (b)(4) 原料药的生产过程，该试验失败，原因是在 (b)(4) 模拟过程中检测到 (b)(4) 个菌落形成单位（CFU），在 (b)(4) 模拟过程中检测到 (b)(4) 个菌落形成单位（文件编号：DV/22/046）。从检测到的菌落形成单位中分离出了诸如枯草芽孢杆菌、短小芽孢杆菌、海洋解盐芽孢杆菌和巨大芽孢杆菌等产芽孢细菌。贵公司并未通过连续进行三次培养基模拟灌装试验来重新验证，而仅进行了一次重复的培养基模拟灌装试验。

培养基模拟灌装失败，未能彻底调查原因

Investigation APL-AN-PNC-22-0125 was opened when one turbid vial in (b)(4) #64, produced during the aseptic process simulation for the (b)(4) Line, performed in July 2022, was found on (b)(4) of incubation. The organism was identified as Staphylococcus haemolyticus. This line is used to aseptically fill the U.S. marketed drug product, (b)(4) gram and (b)(4) mg vials. Your investigation references the time frame of 13:43 to 14:39 when you believe the (b)(4) containing the turbid vial was filled. Your investigation documented that 14 of the 15 interventions performed during that time frame were (b)(4) interventions. It attributes the root cause to be (b)(4) intervention C-37, "Replacement of the (b)(4) using the rational that this is a non-routine intervention.” In your investigation you did not fully assess the other 13 (b)(4) interventions performed during that time frame. You also did not address the risk to commercial product as this intervention was observed in the media fill recording to include the same manual manipulations as those observed while reviewing commercial production, machine assembly, specifically intervention I-1.3 "Assembly of the (b)(4) . Your corrective action was elimination of the intervention, "Replacement of the (b)(4) but it failed to include an assessment of the current interventions that are performed during set up and filling, which require the same or similar manual manipulations, including ways to augment those similar inventions to reduce risk to the product.

当在2022年7月对 (b)(4) 线进行无菌工艺模拟灌装生产的 (b)(4) #64 中发现培养的一个小瓶浑浊时就开启了调查 APL-AN-PNC-22-0125。该病原体被鉴定为溶血性葡萄球菌。该生产线用于无菌灌装美国销售的药品， (b)(4) 克和 (b)(4) 毫克小瓶。您的调查参考了13：43 到 14：39的时间范围，当时您认为装有浑浊小瓶的 (b)(4) 已灌装。您的调查表明，在这段时间内进行的 15 项干预措施中有14项是 (b)(4) 干预措施。它将根本原因归因于 (b)(4) 干预 C-37，“使用非常规干预的理由替换 (b)(4) ”。在您的调查中，您没有充分评估在该时间段内进行的其他 13个 (b)(4) 干预措施。您也没有解决商业产品的风险，因为在培养基灌装记录中观察到的这种干预包括与审查商业生产、机器组装时观察到的相同的手动操作，特别是干预I-1.3 “ (b)(4) 的组装”。您的纠正措施是取消了该干预措施，“替换了 (b)(4) ”，但它没有评估调试和灌装过程中执行的当前干预措施的影响，这些干预需要相同或类似的手动操作，也没有评估增强这些类似干预的方法以降低对产品的风险。

培养基模拟灌装中存在额外干预操作

An operator performed an (b)(4) intervention at approximately (b)(4) for (b)(4) tubing adjustment (Intervention C43). The operator was supposed to perform the instead (b)(4) which required them to lean over the conveyor. The operator did not first sanitize their hands before entering the filling barrier. The operator leaned over open vials that were still present on the line at the time of the intervention. Not all exposed vials were removed. This intervention was not documented and performing this intervention from (b)(4) has not been evaluated in smoke studies or media fills.

一名操作人员在大约 (b)(4) 的时间进行了一次 (b)(4) 干预操作，目的是调整 (b)(4) 管道（干预措施 C43）。该操作人员本应进行 (b)(4) 操作，这要求他们俯身到传送带上。在进入灌装隔离区之前，该操作人员没有对手部进行消毒。在干预操作时，该操作人员俯身越过了生产线上仍放置着的敞口小瓶。并非所有暴露的小瓶都被移除。此次干预操作未记录在案，而且从 (b)(4) 进行此项干预操作，既未在烟雾模拟研究中评估过，也未在培养基灌装试验中评估过。

培养基灌装测试不充分

Regarding media fill,the insufficient simulation of interventions was criticized.Among other things, a cutting device in aseptic filling was replaced about 15 times during the past six months with out being included in the media fill programme.The company's solutions to these issues-including the product recall of the batch affected, the involvement of a third party to improve the media fill programme,as well as the plan to adjust procedures and revalidate,were not satisfactory to the FDA.

在培养基灌装方面，干预措施模拟不足遭到了批评。在过去六个月里，无菌灌装过程中的一个切割装置更换了约15次，但这一情况并未纳入培养基灌装方案。该公司针对这些问题所采取的解决措施，包括召回受影响批次的产品、引入第三方来改进培养基灌装方案，以及调整程序和重新验证的计划，都未能让FDA满意。