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2025年10月，美國(guó)注射劑協(xié)會(huì)（PDA）更新了第22號(hào)技術(shù)報(bào)告“無(wú)菌工藝模擬灌裝”。（PDA TR22培養(yǎng)基模擬灌裝指南（2025新版）正式發(fā)布?。┰摪嫖募^之前版本有較大的改變，總結(jié)更新了近些年的法規(guī)要求和無(wú)菌保證技術(shù)的發(fā)展。本文主要總結(jié)了部分變化的一些關(guān)鍵點(diǎn)進(jìn)行總結(jié)分析，希望大家以此為了解這個(gè)報(bào)告的起點(diǎn)，系統(tǒng)全面的梳理此報(bào)告全文的更新和變化內(nèi)容。

01、先決條件

1.1 CCS should be developed and implemented before executing an APS. 

結(jié)合最新的法規(guī)要求和行業(yè)發(fā)展，強(qiáng)調(diào)在APS前應(yīng)當(dāng)完成CCS的開發(fā)和應(yīng)用。

1.2 Prior to performing APS; engineering batches and/or water trials should be performed to understand any handling issues and the interventions required for the process.

更加貼合行業(yè)實(shí)際，在實(shí)際執(zhí)行APS前應(yīng)當(dāng)有工程批或者灌水實(shí)驗(yàn)批來(lái)確認(rèn)可能發(fā)生的事件和干預(yù)操作。

1.3 While itis allowed by regulations to combine dynamic environmental qualification with APS, this is not recommended for new facilities or in general when the reliability of the controls to ensure proper environmental conditions during operation is not yet known.

根據(jù)原文意思，雖然法規(guī)允許動(dòng)態(tài)環(huán)境確認(rèn)和APS一同進(jìn)行，但是對(duì)于新廠房不建議這么做，還是要在整體環(huán)境可控情況下再開始APS。

02、最差情況

2.1 However, in some situations, the worst case may include executing the process with fewer people if this results in excessive movement by the process operators, or if it complicates the process steps.

對(duì)于一些最差情況，不一定人數(shù)越多就是最差情況，如果一些操作，人數(shù)少時(shí)會(huì)產(chǎn)生更高風(fēng)險(xiǎn)的動(dòng)作或者會(huì)使一些操作更加復(fù)雜化，這種情況也是需要考慮的最差情況。

2.2 The risk assessment may also identify CAPA for reducing the "worst-case" situation such as improved operability leading to less interventions.

在做最差情況的風(fēng)險(xiǎn)評(píng)估時(shí)，也可以同時(shí)識(shí)別出一些CAPA措施來(lái)改進(jìn)一些干預(yù)操作，而不僅僅輸出哪些是最差情況。

03、干預(yù)操作

3.1 Companies should also establish clear instructions for the performance of each aseptic intervention with inputs from operators, line mechanics, supervisory staff, microbiology, engineering, and quality assurance. These instructions can be in the form of written procedures, visual aids, videos, other media such as virtual reality, or any combination thereof. The instructions must be periodically reviewed and updated to reflect the current processes and interventions.

Operators must demonstrate their ability to perform the aseptic interventions on the filling line prior to taking part in an APS or participating in a product fill.

在介紹干預(yù)操作的部分，首先要求對(duì)于所有干預(yù)操作要求有詳細(xì)的文件指導(dǎo)，包括一些視頻指導(dǎo)，在APS前要求完成人員的無(wú)菌操作確認(rèn)。這和之前很多公司的做法和理念是有差別的，行業(yè)內(nèi)很多還是在通過(guò)APS來(lái)證明干預(yù)操作符合要求，APS前沒有對(duì)人員的無(wú)菌操作進(jìn)行確認(rèn)。此處明確了，整個(gè)流程的思路，現(xiàn)有無(wú)菌操作的設(shè)計(jì)，建立對(duì)應(yīng)的指導(dǎo)文件，后續(xù)有煙霧實(shí)驗(yàn)進(jìn)行初步確認(rèn)，對(duì)操作人員的無(wú)菌操縱規(guī)范進(jìn)行確認(rèn)，最后通過(guò)APS進(jìn)行進(jìn)一步的證明。

3.2 If possible, the time of collection should be noted, which would allow contaminated units to be linked directly with the approximate time and activity being performed or simulated during the APS.

這個(gè)也是行業(yè)內(nèi)現(xiàn)在容易的忽視的問(wèn)題，雖然APS里設(shè)計(jì)了很多的干預(yù)操作，但是每個(gè)干預(yù)操作涉及哪些灌裝瓶是沒法關(guān)聯(lián)的。在出現(xiàn)APS陽(yáng)性后，沒法回溯到陽(yáng)性瓶發(fā)生的時(shí)間和這個(gè)時(shí)間段涉及的相關(guān)的干預(yù)操作。

04、需要培養(yǎng)的部分

Processes involving materials that come into contact with product contact surfaces but are then discarded (e.g., product flushes) and should be simulated with nutrient media and incubated as part of the APS. This requirement may be waived only if it is clearly demonstrated that the waste process does not impact product sterility.

此條和歐盟無(wú)菌附錄要求一致，對(duì)于生產(chǎn)中要和產(chǎn)品接觸的部件表面接觸，而后要廢棄的，也要進(jìn)行模擬和培養(yǎng)。如，對(duì)于PUPSIT會(huì)做滅菌后使用前的完整性，此處會(huì)用到無(wú)菌水的沖洗，此處需要模擬這類操作，并進(jìn)行對(duì)應(yīng)的培養(yǎng)。

05、無(wú)菌保存時(shí)限

Additionally, the APS should not be used to qualify or establish holding times for sterilized materials, components, or equipment. These holding times should be independently qualified based on production requirements and environmental conditions.

行業(yè)內(nèi)很多將多個(gè)設(shè)備、物料、容器等的無(wú)菌保存時(shí)限結(jié)合在APS中一起做，而此處要求應(yīng)當(dāng)單獨(dú)做這類的保存時(shí)限。

06、清潔確認(rèn)

To prevent contamination risk product-contact parts must be cleaned by a validated cleaning procedure to remove any growth-media residues. Cleaning may require removing gaskets and valves after an APS to avoid media contamination of commercial product.

Defined procedures should be in place, and cleaning validation should account for the effective removal of residual media from direct and indirect product-contacting equipment surfaces. Procedures on how to handle spillage during filling should be in place to avoid media entering difficult to clean areas. Where it is not possible to clean surfaces that may have been contacted by media, such as for gaskets and seals, these should be replaced.

APS后的清潔確認(rèn)，由于APS期間會(huì)使用大量的促進(jìn)微生物生長(zhǎng)的培養(yǎng)基。需要在APS進(jìn)行對(duì)應(yīng)的清潔確認(rèn)，采取一些如更換閥門或墊片的操作，避免潛在的微生物的污染。

07、批次Abort

Any units that have been filled prior to the event that led to the discontinuation should be incubated and evaluated. If positive units are found (and are unrelated to the discontinuation event), then the APS may be considered as failed, regardless of the number of units filled and would need to be investigated as such. However, if an aborted APS shows no positive units, then the aborted APS should not be considered as a passing, unless the requisite number of units have been filled and all other conditions and requirements of the APS have been met.

對(duì)于一些意外情況需要abort的批次，在意外發(fā)生前已經(jīng)灌裝的產(chǎn)品都需要培養(yǎng)，出現(xiàn)陽(yáng)性也需要調(diào)查。不能因?yàn)槌霈F(xiàn)意外了，生產(chǎn)不再進(jìn)行，整批產(chǎn)品廢棄。

CONCLUSION

以上只是列出部分的一些變化項(xiàng)目，通過(guò)列舉的這些項(xiàng)目，大家可以看到此版技術(shù)報(bào)告，提出了很多新的理念和要求，希望大家可以仔細(xì)研讀，系統(tǒng)梳理變化內(nèi)容，不斷完善自己公司內(nèi)容的APS的管理。