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預(yù)防無菌制劑微生物污染控制的規(guī)程中的無菌工藝沒有經(jīng)過合適的驗證

 

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.

 

用于美國市場的 (b)(4) 無菌灌裝線 (b)(4) 的氣流可視化試驗不符合單向且無湍流的氣流的驗收標準，或不符合試驗方案中已建立的執(zhí)行說明。

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，發(fā)現(xiàn)臨近的HEPA過濾器之間有縫隙存在。這個位置的原始氣流模型研究視頻顯示有湍流和向上氣流出現(xiàn)，該原始視頻素材未包含在驗證報告中討論的最終編輯版本的視頻中。

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.

視頻顯示，在灌裝和加塞RABS內(nèi)部 (b)(4) 附近，煙霧是沿著RABS屏障向上流動的。該區(qū)域在HEPA過濾器的邊緣與RABS屏障之間的間隙大約 (b)(4) 下方。驗證報告沒有發(fā)現(xiàn)這方面的任何缺陷。RABS屏障和HEPA過濾器之間的類似間隙存在于RABS灌裝屏障的所有側(cè)面 (b)(4) 上。氣流可視化試驗尚未徹底評估這一縫隙。

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.

視頻顯示了HEPA過濾器邊緣和灌裝屏障外部的屏障 (b)(4) 之間的間隙附近的向上的氣流和湍流，在 (b)(4) 附近。在HEPA過濾器的邊緣和RABS屏障之間存在大約 (b)(4) 的間隙，該等級A分類區(qū)域在機器的組裝和干預(yù)期間使用 (b)(4) ，驗證報告中討論的視頻的最終版本中不包括顯示該缺陷氣流模式的原始視頻片段。

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.

用于打開和裝載空的 (b)(4) 的 (b)(4) 屏障具有用于 (b)(4) 的支撐件，其位于HEPA過濾器下方大約 (b)(4) ，煙霧試驗沒有徹底評估這種支撐對該區(qū)域氣流的影響。

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 針對#產(chǎn)線規(guī)定煙霧需要通過將噴嘴朝上放置引入，并且噴嘴應(yīng)移動以覆蓋過濾器的整個區(qū)域。原始視頻文件顯示煙霧噴嘴指向下方并固定在某些位置。 最終編輯的視頻未顯示從靠近過濾器到工作區(qū)域引入煙霧的過程。

 

工藝變更致混合不均，無工藝受控數(shù)據(jù)放行且隔離批次處置不當

 

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

為了減少三種對乙酰氨基酚和磷酸可待因片劑的生產(chǎn)工藝時間，你們實施了生產(chǎn)工藝變更。使用此新工藝，你們生產(chǎn)了 (b)(4) 個工藝性能確認批次。由于均勻性失?。ɡ?，混合、含量均勻性），你們拒絕放行了 (b)(4) 個批次，但放行了其余 (b)(4) 個批次。

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，你們沒有數(shù)據(jù)來支持你們的工藝處于受控狀態(tài)。

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.

在實施工藝變更后，你們的評估得出新的工藝導致混合不均勻的結(jié)論，之前的生產(chǎn)工藝更加穩(wěn)定且可靠，剩余批次應(yīng)暫停處理，等待進一步討論。在首次評估的八個月后，你們決定恢復(fù)舊工藝。然而，貴公司卻判定那些被隔離的批次產(chǎn)品可以進行銷售分發(fā)。

 

無菌工藝未經(jīng)驗證

 

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月開始生產(chǎn)運營以來，用于生產(chǎn) (b)(4) 小瓶 SurCord® 和 SurForce® 的無菌工藝尚未經(jīng)過驗證（例如通過執(zhí)行培養(yǎng)基灌裝模擬）。這些產(chǎn)品聲稱是無菌且預(yù)期是無菌的。

 

回顧性驗證代替再驗證

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.

貴司的回復(fù)不充分。未能提供一份詳細的工藝性能確認計劃，用于貴司的驗證或要實施的行動，以識別所有可變性來源。此外，貴司的回復(fù)沒有提供每個藥品前瞻性PPQ研究完成的時間表。使用回顧性驗證方法是不被接受的。最后，貴司沒有說明這一違規(guī)行為對目前在市場上銷售的藥品的影響。

 

不能證明生產(chǎn)工藝可以穩(wěn)定地生產(chǎn)出符合其預(yù)期質(zhì)量屬性的 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,

你們公司未能制定方案和實施計劃，以確保所有API的生產(chǎn)工藝、設(shè)備和設(shè)施都適合使用。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.

你們公司無法提供已對所有 API（例如 (b)(4) ）生產(chǎn)工藝執(zhí)行了工藝性能確認 (PPQ) 的記錄。

 

工藝驗證完成前未完成設(shè)備設(shè)施確認

 

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:

具體地說，貴公司沒有經(jīng)過批準的、包含預(yù)先批準的驗收標準的設(shè)備性能確認方案，該方案描述了所進行的測試，并附有所生成數(shù)據(jù)的最終總結(jié)報告，以及設(shè)備是否達到確認狀態(tài)的決定。名為“(b)(4) APl 的工藝性能確認報告”MVD-000146683（3.0 版）的工藝確認報告是使用未完全確認（IQ/OQ/PQ）的設(shè)備執(zhí)行的。以下是一些缺乏基于方案的設(shè)備確認的生產(chǎn)設(shè)備的例子：

 

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

xxx (設(shè)備 ID# PB1xxx -001)，用于xxx USP 生產(chǎn)的xxx 階段。

 

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

xxx容器（設(shè)備 ID# PB1xxx -009），用于xxx USP 生產(chǎn)的xxx 階段。

 

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

xxx (PB2 xxx 001)，用于xxx USP生產(chǎn)的xxx階段。

 

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

xxx設(shè)備 ID # PB3- (b)(4) 001），用于xxx USP 生產(chǎn)的 xxx 階段。

 

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

xxx(Equipment ID # PB4xxx001),用于xxx USP 生產(chǎn)的xxx 階段。

 

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

xxx設(shè)備 ID # PB4xxx001), 用于xxx USP 生產(chǎn)的xxx階段。

 

無菌模擬灌裝不足

 

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.

貴公司計算得出，一批 (b)(4) 美國藥典標準的原料藥可灌裝到 (b)(4) 個藥品小瓶中。于2021年 5月開展的培養(yǎng)基模擬灌裝試驗# MF/CPMD/22/04/01，模擬了無菌 (b)(4) 原料藥的生產(chǎn)過程，該試驗失敗，原因是在 (b)(4) 模擬過程中檢測到 (b)(4) 個菌落形成單位（CFU），在 (b)(4) 模擬過程中檢測到 (b)(4) 個菌落形成單位（文件編號：DV/22/046）。從檢測到的菌落形成單位中分離出了諸如枯草芽孢桿菌、短小芽孢桿菌、海洋解鹽芽孢桿菌和巨大芽孢桿菌等產(chǎn)芽孢細菌。貴公司并未通過連續(xù)進行三次培養(yǎng)基模擬灌裝試驗來重新驗證，而僅進行了一次重復(fù)的培養(yǎng)基模擬灌裝試驗。

 

培養(yǎng)基模擬灌裝失敗，未能徹底調(diào)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.

當在2022年7月對 (b)(4) 線進行無菌工藝模擬灌裝生產(chǎn)的 (b)(4) #64 中發(fā)現(xiàn)培養(yǎng)的一個小瓶渾濁時就開啟了調(diào)查 APL-AN-PNC-22-0125。該病原體被鑒定為溶血性葡萄球菌。該生產(chǎn)線用于無菌灌裝美國銷售的藥品， (b)(4) 克和 (b)(4) 毫克小瓶。您的調(diào)查參考了13：43 到 14：39的時間范圍，當時您認為裝有渾濁小瓶的 (b)(4) 已灌裝。您的調(diào)查表明，在這段時間內(nèi)進行的 15 項干預(yù)措施中有14項是 (b)(4) 干預(yù)措施。它將根本原因歸因于 (b)(4) 干預(yù) C-37，“使用非常規(guī)干預(yù)的理由替換 (b)(4) ”。在您的調(diào)查中，您沒有充分評估在該時間段內(nèi)進行的其他 13個 (b)(4) 干預(yù)措施。您也沒有解決商業(yè)產(chǎn)品的風險，因為在培養(yǎng)基灌裝記錄中觀察到的這種干預(yù)包括與審查商業(yè)生產(chǎn)、機器組裝時觀察到的相同的手動操作，特別是干預(yù)I-1.3 “ (b)(4) 的組裝”。您的糾正措施是取消了該干預(yù)措施，“替換了 (b)(4) ”，但它沒有評估調(diào)試和灌裝過程中執(zhí)行的當前干預(yù)措施的影響，這些干預(yù)需要相同或類似的手動操作，也沒有評估增強這些類似干預(yù)的方法以降低對產(chǎn)品的風險。

 

培養(yǎng)基模擬灌裝中存在額外干預(yù)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.

一名操作人員在大約 (b)(4) 的時間進行了一次 (b)(4) 干預(yù)操作，目的是調(diào)整 (b)(4) 管道（干預(yù)措施 C43）。該操作人員本應(yīng)進行 (b)(4) 操作，這要求他們俯身到傳送帶上。在進入灌裝隔離區(qū)之前，該操作人員沒有對手部進行消毒。在干預(yù)操作時，該操作人員俯身越過了生產(chǎn)線上仍放置著的敞口小瓶。并非所有暴露的小瓶都被移除。此次干預(yù)操作未記錄在案，而且從 (b)(4) 進行此項干預(yù)操作，既未在煙霧模擬研究中評估過，也未在培養(yǎng)基灌裝試驗中評估過。

 

培養(yǎng)基灌裝測試不充分

 

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.

在培養(yǎng)基灌裝方面，干預(yù)措施模擬不足遭到了批評。在過去六個月里，無菌灌裝過程中的一個切割裝置更換了約15次，但這一情況并未納入培養(yǎng)基灌裝方案。該公司針對這些問題所采取的解決措施，包括召回受影響批次的產(chǎn)品、引入第三方來改進培養(yǎng)基灌裝方案，以及調(diào)整程序和重新驗證的計劃，都未能讓FDA滿意。