什么是高效過濾器的接受標準?

　　What is the Acceptance Criteria of HEPA?

　　大多數(shù)測試標準關(guān)于高效過濾器泄漏率的接受標準是，可接受的泄漏限度最終由客戶和供應商共同確定。但是，對于使用HEPA過濾器或不同級別潔凈室的許多應用，大多數(shù)采用≤0.01%的掃描測試泄漏標準。盡管0.01%的泄漏率在歷史上已經(jīng)使用過，并且其起源與早期的光度計測試設(shè)備精度有關(guān)，但在沒有進行科學和基于風險的評估的情況下，將0.01%的泄漏率標準作為可接受標準將導致與泄漏測試有關(guān)的問題，并且如果在低風險區(qū)域發(fā)現(xiàn)超限或失敗情況，將可能會帶來巨大的運營成本。過濾器不是100%截留的，并且預計MPPS附近的粒子在過濾器局部或整體可以穿透。當使用較低級別的HEPA過濾器時，工廠進行的MPPS或MPPS附近粒子的可接受泄漏率標準可能等于或大于現(xiàn)場泄漏率測試的接受標準，測試接受標準會變得更具爭議和困難。在可能發(fā)生泄漏的地方尤其如此。因此，在購買過濾器時，考慮過濾器的等級以及安裝后如何進行測試非常重要，以避免不必要的現(xiàn)場測試失敗。

　　The approach most test standards take regarding acceptance criteria isthat the acceptable leak size limitsare ultimately determined by the customerand supplier. However, a scan test leak size limit of greater than or equal to0.01% has generally been adopted for many applications utilizing HEPA flters orclean areas of varying classifcations. Although the 0.01% leak size has beenused historically and has its origins linked to early generation analog photometertest equipment, establishing a leak size limit of 0.01% as an acceptancecriteria without performing a science and risk-based assessment can result inissues relating to leak testing and can contribute to signifcant operationalcosts if an out of tolerance or failed condition is identifed in a low riskarea. As previouslynoted in Section 6.5, flters are not 100% efcient and areexpected to have some natural or integral penetration of particles near theMPPS. Test acceptance limits become more controversial or problematic whenutilizing lower-rated HEPA flters where the acceptable factory penetration ator near MPPS can be comparable to or larger than the feldtest leak sizeacceptance criteria. This is especially true where the bleed through e?ectcan occur (see Section 6.9).When purchasing a flter, it is thereforeimportant to consider a flter’s rating as well as how it will be tested after installationin order to avoid unnecessary feld test failures.

　　ISO 14644-3 [33]提供了有關(guān)如何實施泄漏替代標準的指南。 在基于風險的方法中，理想的接受標準是，該接受標準可以反映所使用過濾器的效率或所測試房間的潔凈度。 ISO 14644-3使用工廠過濾效率等級作為接受標準協(xié)商的基礎(chǔ)。光度計泄漏測試和基于粒子計數(shù)器的泄漏測試的泄漏接受標準應該相同，因為兩種方法背后的理論和方法是相同的。如果執(zhí)行得當，使用光度計和粒子計數(shù)器進行的泄漏測試將得到相同的泄漏率結(jié)果(Meek等，2011 [121])。

　　ISO 14644-3 [33] gives guidance on how alternative leak acceptancecriteria can be implemented. In a risk-based approach, it may be ideal to haveacceptance criteria that trends with the eficiency of the flters being used orthecleanliness of the room being tested. ISO 14644-3 uses the factory flter efciency rating as the basis of acceptancecriteria negotiation. The leak acceptancecriteria for a photometer leak test and a particle counter based leaktestshould be the same, as the theory and methodology behind leak sizing isidentical for both methods. If performedproperly, a leak test with a photometerand a particle counter will result in the same leak size (Meek, et al., 2011[121]).

　　如果檢測到的泄漏量超過上游濃度的0.01%，一般認為該泄漏率超過最大允許標準。但是，對于整體效率MPPS≥99.95%且小于99,995%的過濾器系統(tǒng)(如H13過濾器)，接受標準為0.1%。

　　A leak detected in excess of 0,01 % of the upstream massconcentration is deemed to exceed themaximum allowable penetration. However,for filter systems of an integral efficiency at MPPS ≥ 99,95 %and less than99,995 %, the acceptance criterion is 0,1 %.

　　如果要測試 MPPS 整體效率低于 99.95% 的過濾系統(tǒng)，則根據(jù)客戶和供應商之間的協(xié)議，需要不一樣的接受標準。

　　If filter systems of an integral efficiency lower than 99,95 %at MPPS are to be tested, a different acceptance criterion are necessary, basedon agreement between customer and supplier.

　　用于去熱原隧道的高效過濾器

　　The flters for depyrogenation tunnel

　　安裝到去熱原隧道中的過濾器需要經(jīng)受長時間的高溫操作，因此不適用標準過濾器。廠家使用陶瓷材料用于濾材與邊框的密封可提供耐受350℃的對0.3 μm顆粒的效率為99.99%的特殊過濾器(注，F(xiàn)DA對HEPA的定義為> 99.97%@0.3 μm)。最近，可用的材料有了進步，并且引入了柔性密封劑，可以減少加熱時間并降低密封劑開裂的風險。傳統(tǒng)的過濾器需要具有受控的加熱和冷卻速度(通常不超過1℃/分鐘;應與過濾器供應商確認該速率)，以防止熱應力損壞密封件。通常，在不使用期間，系統(tǒng)會保持高溫，以減少過濾器的加熱循環(huán)。

　　The flters ftted to a depyrogenation tunnel are subject toprolonged periods of high temperature operation, so standard flters are notsuitable. Special flters rated to 350°C are available with a manufacturerguaranteed efciency of 99.99% for 0.3 μm particles (note that the FDA defnitionof a HEPA is > 99.97% at 0.3 μm) at a temperature of 350°C) with a ceramicmaterial used for the media to frame seal. Recently there have been advances inthe materials available and ?exible sealants are being introduced that canreduce the heat up time and reduce the risk of sealant cracking. Traditionalflters need to have a controlled heat up and cool down time (typically not toexceed 1°C per minute; the rate should be confrmed with the flter supplier) toprevent heat stress damage to the seals. Often the systems are maintained hotduring periods of non-use to reduce the heat cycling on the flter.

　　用于去熱原隧道的過濾器通常是H14。這些過濾器可以在安裝時進行全面掃描泄漏測試，但是在首次加熱循環(huán)之后(過濾器會燃燒，通常會導致該過濾器等級與H13相當)，不建議再進行傳統(tǒng)測試。因為氣溶膠油(如聚α烯烴(PAO))將被截留到過濾器上并燃燒，從而產(chǎn)生不健康的煙霧，并可能堵塞過濾介質(zhì)。由于將過濾器介質(zhì)粘合在一起的粘合劑在燃燒會放氣，通常導致過濾器變脆。DEHS(癸二酸二乙基己酯)是一種可能會更快蒸發(fā)的替代油。

　　EU-GMP附錄1《無菌藥品生產(chǎn)》-2022最終版

　　Filters used for depyrogenation tunnel are generally H14. Theseflters can be full face scan leak tested on installation, but after the initialheating cycle (burning in the flter, which usually results in the flter gradebecoming equivalent to H13) traditional testing is not recommended. The oilaerosol (if it is Polyalphaolefn (PAO)) will load onto the flter and burn o?,giving o?unhealthy fumes, and may load the flter media; this is usually more fragileafter burn in as the binder holding the media together has o?-gassed.DEHS (Diethylhexyl Sebacate) is an alternative oil that may evaporatefaster.

　　應配置干熱滅菌/去熱原隧道以確保氣流通過維持適當?shù)乃淼缐翰詈蜌饬鱽肀ＷoA級滅菌區(qū)域的完整性和性能。應評估壓差曲線。應評估任何氣流變化的影響，以確保維持加熱曲線。所有供應到隧道的空氣應至少通過HEPA過濾器，并應進行定期測試(至少每半年一次)以證明空氣過濾器的完整性...

　　8.67 Dry heat sterilisation/depyrogenation tunnels should be configured to ensure that airflow protects the integrity and performance of the grade A sterilising zone by maintaining appropriate pressure differentials and airflow through the tunnel. Air pressure difference profiles should be assessed. The impact of any airflow change should be assessed to ensure the heating profile is maintained. All air supplied to the tunnel should pass through at least a HEPA filter and periodic tests (at least biannually) should be performed to demonstrate air filter integrity...

　　干熱烘箱通常用于對內(nèi)包裝組件、起始物料或活性物質(zhì)進行滅菌或去熱原，但也可用于其他工藝。除非保持了包裝的完整性，否則在整個滅菌和滅菌后存放過程中，應對較低潔凈等級區(qū)域保持相對正壓。所有進入烘箱的空氣都應通過HEPA過濾器...

　　8.70 Dry heat ovens are typically employed to sterilise or depyrogenate primary packaging components, starting materials or active substances but may be used for other processes. They should be maintained at a positive pressure relative to lower grade clean areas throughout the sterilisation and post sterilisation hold process unless the integrity of the packaging is maintained. All air entering the oven should pass through a HEPA filter...

　　注釋：

　　1、新版EU-GMP附錄1《無菌藥品生產(chǎn)》要求滅菌隧道至少安裝HEPA過濾器，HEPA過濾器即H13級和H14級高效過濾器，可通過在加熱段安裝H14過濾器(MPPS泄漏率≤0.01%)，并在安裝時進行全面掃描檢漏測試，以使過濾器在首次加熱后能夠至少符合H13級標準(MPPS泄漏率≤0.05%)。

　　2、新版EU-GMP附錄1《無菌藥品生產(chǎn)》要求：對于干熱滅菌隧道的HEPA過濾器，至少每半年進行一次測試以證明過濾器完整性，其他地方的過濾器則未在文件中作出具體規(guī)定，可按照ISO14644標準執(zhí)行。