MHRA曾發(fā)表對(duì)汽化過(guò)氧化氫（VHP）熏蒸消毒的局限性的文章，該文章表示，盡管在理想條件下，VHP可以使生物指示孢子減少多達(dá)6個(gè)對(duì)數(shù)，但是鑒于許多部件結(jié)構(gòu)難以實(shí)現(xiàn)VHP穿透，或者由于非常小的阻塞會(huì)導(dǎo)致的VHP失敗，甚至來(lái)自指紋的脂肪酸可以“保護(hù)”微生物免受VHP，VHP熏蒸過(guò)程是非常脆弱的，不能用于直接和間接接觸產(chǎn)品部件的“滅菌”。“VHP在良好控制和驗(yàn)證的情況下，對(duì)于周?chē)ぷ骺臻g的消毒凈化是非常有效的。但是，我們目前的立場(chǎng)是VHP不能用于對(duì)重要物品進(jìn)行滅菌。”
原文翻譯如下：
I have been the chairperson for the revision of Annex 1 of the EU and PIC/S GMPS for the manufacture of sterile medicinal products for a couple of years now. As such I engaged with stakeholders and other regulators to understand their wishes and concerns. One particular topic that has come up as a discussion point at a number of the more recent conferences that gives me great concern, and this is around how to sterilise direct and indirect product contact items in an isolator. I therefore felt it was time to go into print regarding the agency’s view.
我負(fù)責(zé)主持修訂EU和PIC/S GMP附錄1《無(wú)菌藥品生產(chǎn)》多年。因此，我與利益相關(guān)方和其他機(jī)構(gòu)商洽以理解他們的期望和關(guān)注點(diǎn)。在最近的一些會(huì)議上討論了一個(gè)特別的話(huà)題，這個(gè)話(huà)題引起了我的極大關(guān)注，這涉及到如何對(duì)隔離器中直接和間接接觸產(chǎn)品的物品進(jìn)行消毒。因此，我覺(jué)得是時(shí)候?qū)⒐俜降挠^點(diǎn)公諸于眾了。
A number of manufacturers are looking at isolator technology in new or existing facilities, which is great to hear, but the fly in the ointment, is that the consideration of how to sterilise direct and indirect contact parts does not always form part of the design process. But before I go further I will clarify what I mean by indirect and direct product contact parts:
許多廠商正在新設(shè)備或現(xiàn)有設(shè)備中考慮隔離技術(shù)，這聽(tīng)起來(lái)很棒，但美中不足的是，設(shè)計(jì)過(guò)程中并沒(méi)有考慮如何對(duì)直接和間接接觸產(chǎn)品的部件進(jìn)行滅菌。在我進(jìn)一步討論之前，我會(huì)澄清我的意思是間接和直接接觸產(chǎn)品的部件：
Indirect product contact parts, as the name implies, are equipment parts that come into contact with items and components, such as stoppers. So, although the equipment itself does not contact the product the items that are “processed” by the equipment do.
間接接觸產(chǎn)品的部件，顧名思義，為接觸物品和組件（如膠塞）的設(shè)備部件。因此，盡管設(shè)備本身并不接觸產(chǎn)品，但該設(shè)備加工了產(chǎn)品部件。
Direct contact parts are those that the product passes through, such as filling needles or pumps.
直接接觸產(chǎn)品的部件為產(chǎn)品經(jīng)過(guò)，如分裝針頭或泵。
The issue that is arising is that a number of manufacturers are not including robust systems of sterilisation, such as autoclaves, dry heat or offsite irradiation in their facility designs. This leaves a situation where the Agency is being asked, why Vapour Hydrogen Peroxide (VHP) cannot be used for “sterilisation” of these direct and indirect product contact parts. After all, pharmacopeias refer to VHP as a sterilising agent. However, our concern is that although under ideal conditions, VHP can achieve a reduction of biological Indicator spores of up to 6 logs, the process itself is incredibly fragile.
問(wèn)題是多數(shù)廠家在其設(shè)施設(shè)計(jì)中不包括強(qiáng)壯的無(wú)菌體系，如滅菌柜、干熱或場(chǎng)外輻照。這就產(chǎn)生了藥監(jiān)機(jī)構(gòu)被問(wèn)及的問(wèn)題：為什么過(guò)氧化氫（VHP）不能用于這些直接和間接接觸產(chǎn)品部件的“滅菌”？畢竟，藥典將VHP作為滅菌劑。然而，我們擔(dān)心的是，盡管在理想條件下，VHP可以使生物指示孢子減少多達(dá)6個(gè)對(duì)數(shù)，但該過(guò)程本身是非常脆弱的。
If we cast our minds back a number of years, when VHP was being used to decontaminate the internal surfaces of isolators (not the indirect or direct contact parts) there were a number of issues seen with biological indicators failing the process due to clumping of spores at a microscopic level. This led to a number of papers being written (such as “Biological indicators don’t lie, but in sporicidal gassing disinfection cycles do they sometimes confuse the truth?”, European Journal of Parenteral & Pharmaceutical Sciences 2009; 14(1): 5-10 © 2009 Pharmaceutical and Healthcare Sciences Society) that justified biological indicator failure at one or two locations based on statistical analysis. The papers also recommended that a number of indicators (usually 3) be placed at each location to demonstrate a 3 log reduction (which is not a sterilisation process). This, along with other evidence, such as VHP failure due to very minor occlusion, even to the degree that fatty acids from a fingerprint may “protect” contaminating organisms from the VHP demonstrate the true fragility of the process as a sterilant.
如果我們回想幾年，當(dāng)VHP被用于凈化隔離器內(nèi)表面（而不是間接或直接接觸部件）時(shí)，出現(xiàn)了許多生物學(xué)指標(biāo)因孢子結(jié)塊而失敗的問(wèn)題在微觀層面。這導(dǎo)致了許多論文的撰寫(xiě)（例如“生物指標(biāo)不說(shuō)謊，但在殺菌消毒循環(huán)中它們有時(shí)會(huì)混淆事實(shí)真相？”，European Journal of Parenteral＆Pharmaceutical Sciences 2009; 14（1）：5 -10©2009 Pharmaceutical and Healthcare Sciences Society），根據(jù)統(tǒng)計(jì)分析，在一個(gè)或兩個(gè)地點(diǎn)證明生物指標(biāo)失效。文件還建議在每個(gè)地點(diǎn)放置若干指標(biāo)（通常為3個(gè)）以顯示3個(gè)對(duì)數(shù)減少量。這與其他證據(jù)一樣，例如由于非常小的阻塞導(dǎo)致的VHP失敗，甚至到來(lái)自指紋的脂肪酸可以“保護(hù)”微生物免受VHP，證明了該過(guò)程作為滅菌劑的真正脆弱性。
If we then consider the design of some of the indirect and direct product contact parts, we find that a number of them are either difficult to achieve VHP penetration, or, damage and wear and tear can leave surfaces that lead to difficulty to clean and therefore potential occlusion.
如果我們考慮一些間接和直接的產(chǎn)品接觸部件的設(shè)計(jì)，我們發(fā)現(xiàn)其中一些難以實(shí)現(xiàn)VHP穿透，或者破損和磨損和撕裂留下難以清潔并可能阻塞VHP的表面。
VHP, when well controlled and validated, is a useful method for the decontamination of the surrounding workspace, e.g. an isolator environment. However, given the above concerns, our current stance is that VHP cannot be used to sterilise critical items. Even if some of the concerns can be removed by well thought out processes, this still leaves the sterilisation at risk of the vagaries of manual process during set up. For instance, how many of us see ‘human error’ as a high percentage of root cause errors during deviation investigations? Therefore, it would be a high risk option and potentially leave the patient at risk from such a fragile process.
VHP在良好控制和驗(yàn)證的情況下，對(duì)于周?chē)ぷ骺臻g的消毒凈化，例如隔離環(huán)境，是一種有用的方法。但是，鑒于上述擔(dān)憂(yōu)，我們目前的立場(chǎng)是VHP不能用于對(duì)重要物品進(jìn)行滅菌。即使一些問(wèn)題可以通過(guò)經(jīng)過(guò)深思熟慮的流程來(lái)解決，但這仍然會(huì)導(dǎo)致滅菌工藝設(shè)計(jì)人為調(diào)節(jié)不受控。例如，在偏差調(diào)查期間，我們有多少人將“人為錯(cuò)誤”看作是高比例的根本原因錯(cuò)誤？因此，這將是一個(gè)高風(fēng)險(xiǎn)的選擇，并有可能使患者面臨這樣一個(gè)脆弱工藝的風(fēng)險(xiǎn)。
So, what are we expecting?
那么，什么是我們的期望？
Our expectation is that the contact parts (direct and indirect) are sterilised using a robust sterilisation method that meets the current requirements of annex 1. This means that:
我們的期望是，接觸部件（直接和間接）使用符合附錄1當(dāng)前要求的高效的滅菌方法進(jìn)行滅菌。這意味著：
the sterilising agent reaches all of the critical surfaces in a consistent and repeatable manner, typically requiring processes such as moist or dry heat sterilisation.
滅菌劑接觸所有關(guān)鍵表面，并以一種一致的和可重復(fù)的方式，通常要求濕熱或干熱滅菌。
the item is unloaded from the sterilisation process either wrapped in integral covering or container, or is transferred under grade A conditions, such as a transfer isolator into the manufacturing isolator.
物品從滅菌程序中取出，應(yīng)使用完整包裹或密閉容器，或在A級(jí)條件下轉(zhuǎn)運(yùn)，如轉(zhuǎn)運(yùn)隔離器進(jìn)入生產(chǎn)隔離器。
We also expect that the parts are not exposed to the isolator environment until the isolator has been closed and after completion of the work zone decontamination VHP cycle.
我們還期望，在隔離器關(guān)閉并完成工作區(qū)VHP凈化消毒程序之前，部件不會(huì)暴露在隔離環(huán)境中。
相關(guān)缺陷：
歐盟eudraGMDP曾發(fā)布關(guān)于臺(tái)灣展旺生命科技股份有限公司的GMP不符合報(bào)告，其中包括VHP裝載模式設(shè)計(jì)和應(yīng)用不當(dāng)?shù)娜毕?，摘譯如下：
The manufacturer : SAVIOR LIFETEC CORPORATION
生產(chǎn)商：臺(tái)灣展旺生命科技股份有限公司
Site address : 29, KE-JHONG ROAD, CHUNAN CHEN, MIAOLI COUNTY, TW-350, Taiwan
臺(tái)灣苗栗縣竹南鎮(zhèn)科中路29號(hào)
Nature of non-compliance : The inspection identified a critical deficiency relating to the aseptic processing of Meropenem and Meropenem/Sodium Carbonate blend. The deficiency related to a lack of technical knowledge regarding sterile processing and included elements such as, autoclave and dry heat sterilisation of equipment, inadequate VHP load pattern design and application, media fills and environmental monitoring.
不符合情況：檢查發(fā)現(xiàn)一個(gè)與美羅培南和美羅培南/碳酸鈉混合物無(wú)菌加工相關(guān)的嚴(yán)重缺陷。缺陷與缺乏無(wú)菌處理技術(shù)知識(shí)有關(guān)，包括設(shè)備的高壓滅菌和干熱滅菌，VHP裝載模式設(shè)計(jì)和應(yīng)用不當(dāng)，培養(yǎng)基模擬灌裝和環(huán)境監(jiān)測(cè)等因素。
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