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培養(yǎng)基模擬灌裝（也稱無菌工藝模擬，APS）需要檢查裝量嗎？或者需要從灌裝線將樣品取出來測(cè)試嗎？

近日，F(xiàn)DA發(fā)給 Ner PharMa S.r.l.的483缺陷報(bào)告中提及培養(yǎng)基模擬灌裝過程中進(jìn)行重量檢查的缺陷，該公司在培養(yǎng)基模擬灌裝中使用實(shí)際取樣檢查的方式從無菌灌裝線取樣以進(jìn)行重量檢查（顯然這些樣品不會(huì)被培養(yǎng)）。此外該公司還將每次模擬灌裝的前xx瓶樣品進(jìn)行無菌檢查，對(duì)此，F(xiàn)DA批評(píng)無菌檢查的培養(yǎng)條件與培養(yǎng)基模擬灌裝不一致，沒有倒置培養(yǎng)。

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

旨在防止聲稱無菌的藥品受到微生物污染的程序，未包含對(duì)無菌及滅菌工藝的充分驗(yàn)證。

A) Inherent and corrective interventions and the times/durations in which they occur, are not always documented within batch production records as required by procedure TB021, Injectables: Allowed Interventions During Aseptic Processing on ×× Line, Version: 3. There is no assurance the maximum number of times and durations they are performed during routine production are accurately simulated during media fills.

A) 固有及糾正性干預(yù)及其發(fā)生的時(shí)間/時(shí)長(zhǎng)，并未始終按照TB021程序（《注射劑：××生產(chǎn)線無菌工藝過程中的允許干預(yù)》，版本：3）的要求記錄在批生產(chǎn)記錄中。無法保證日常生產(chǎn)中這些干預(yù)執(zhí)行的最大次數(shù)和時(shí)長(zhǎng)，在培養(yǎng)基模擬灌裝過程中得到了準(zhǔn)確模擬。

B) Media fills are performed using a split batch approach, where some units of the batch are transferred to the ×× (to represent the ×× process) and the remaining vials are filled as ×× This media fill approach is not representative of routine operations.

B) 培養(yǎng)基模擬灌裝采用分批拆分的方式進(jìn)行：將批次中的部分單元轉(zhuǎn)移至××（以模擬××工藝），剩余西林瓶則按××方式灌裝。這種培養(yǎng)基模擬灌裝方式無法代表日常操作。

C) During Aseptic Process Simulations, Step ×× states to simulate the sampling “without taking any vials from the filling line”. However, during the December 2023 and the subsequent six media fills performed in 2024 for the vial filling line, vials were removed ×× for performing weight checks. 

C) 在無菌工藝模擬過程中，××步驟規(guī)定模擬取樣應(yīng)“不從灌裝線上取任何西林瓶”。然而，在2023年12月及2024年后續(xù)開展的6次培養(yǎng)基模擬灌裝中，均實(shí)際從灌裝線抽取樣品進(jìn)行重量檢查。

D)The initial ×× vials filled on day 1 and the initial ×× vials filled on day 2 of each media fill are removed for sterility testing. These vials are not subject to the inverted incubation condition required by media fill.

D) 每次培養(yǎng)基模擬灌裝中，第1天灌裝的前××個(gè)樣品、第2天灌裝的前××個(gè)樣品會(huì)被取出用于無菌測(cè)試。這些樣品均未遵循培養(yǎng)基模擬灌裝要求的倒置培養(yǎng)條件。

而在FDA對(duì)Alvotech HF（安沃泰克）的483中，則提及未確認(rèn)每個(gè)無菌操作人員在無菌工藝模擬期間均已執(zhí)行所有常規(guī)和糾正性關(guān)鍵干預(yù)操作的缺陷：

Aseptic personnel qualification does not require inclusion of all critical interventions during aseptic process simulation (media fill). Currently, (b)(4) aseptic operators are certified for Grade A interventions. No evaluation was conducted to verify that each certified operator has performed all routine and corrective critical interventions, including the complete aseptic set-up processes of filling and stopping parts, during aseptic process simulation.

無菌人員資質(zhì)確認(rèn)在培養(yǎng)基模擬灌裝期間未要求涵蓋所有關(guān)鍵干預(yù)操作。目前，xx 名無菌操作人員已通過 A 級(jí)干預(yù)操作的資質(zhì)確認(rèn)。未開展評(píng)估以確認(rèn)每位經(jīng)確認(rèn)的操作人員在無菌工藝模擬期間均已執(zhí)行所有常規(guī)和糾正性關(guān)鍵干預(yù)操作，包括灌裝和壓膠塞部件的完整無菌裝機(jī)過程。

在FDA對(duì)賽諾菲Sanofi S.p.A的483中，該公司使用替代設(shè)備用于培養(yǎng)基模擬灌裝，F(xiàn)DA對(duì)此也不接受：

Aseptic process simulations do not fully represent drug product manufacturing in the ××(s)(s)

無菌工藝模擬未充分代表××（場(chǎng)所）中藥品的生產(chǎn)情況。

Specifically,

具體而言，

The firm does not use ××(s)(s) used in production for any products filled in the ××(s)(s)

該公司在××（場(chǎng)所）灌裝任何產(chǎn)品時(shí)，未使用生產(chǎn)中所用的××（設(shè)備/部件）。

Rather, all ××(s) aseptic simulations are conducted with like-for-like ××(s)(s) dedicated solely to media fills.

相反，所有××（類型）無菌模擬均使用僅專用于培養(yǎng)基灌裝的同類××（設(shè)備/部件）進(jìn)行。