什么是高效過(guò)濾器的接受標(biāo)準(zhǔn)?

　　What is the Acceptance Criteria of HEPA?

　　大多數(shù)測(cè)試標(biāo)準(zhǔn)關(guān)于高效過(guò)濾器泄漏率的接受標(biāo)準(zhǔn)是，可接受的泄漏限度最終由客戶(hù)和供應(yīng)商共同確定。但是，對(duì)于使用HEPA過(guò)濾器或不同級(jí)別潔凈室的許多應(yīng)用，大多數(shù)采用≤0.01%的掃描測(cè)試泄漏標(biāo)準(zhǔn)。盡管0.01%的泄漏率在歷史上已經(jīng)使用過(guò)，并且其起源與早期的光度計(jì)測(cè)試設(shè)備精度有關(guān)，但在沒(méi)有進(jìn)行科學(xué)和基于風(fēng)險(xiǎn)的評(píng)估的情況下，將0.01%的泄漏率標(biāo)準(zhǔn)作為可接受標(biāo)準(zhǔn)將導(dǎo)致與泄漏測(cè)試有關(guān)的問(wèn)題，并且如果在低風(fēng)險(xiǎn)區(qū)域發(fā)現(xiàn)超限或失敗情況，將可能會(huì)帶來(lái)巨大的運(yùn)營(yíng)成本。過(guò)濾器不是100%截留的，并且預(yù)計(jì)MPPS附近的粒子在過(guò)濾器局部或整體可以穿透。當(dāng)使用較低級(jí)別的HEPA過(guò)濾器時(shí)，工廠進(jìn)行的MPPS或MPPS附近粒子的可接受泄漏率標(biāo)準(zhǔn)可能等于或大于現(xiàn)場(chǎng)泄漏率測(cè)試的接受標(biāo)準(zhǔn)，測(cè)試接受標(biāo)準(zhǔn)會(huì)變得更具爭(zhēng)議和困難。在可能發(fā)生泄漏的地方尤其如此。因此，在購(gòu)買(mǎi)過(guò)濾器時(shí)，考慮過(guò)濾器的等級(jí)以及安裝后如何進(jìn)行測(cè)試非常重要，以避免不必要的現(xiàn)場(chǎng)測(cè)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(shí)施泄漏替代標(biāo)準(zhǔn)的指南。 在基于風(fēng)險(xiǎn)的方法中，理想的接受標(biāo)準(zhǔn)是，該接受標(biāo)準(zhǔn)可以反映所使用過(guò)濾器的效率或所測(cè)試房間的潔凈度。 ISO 14644-3使用工廠過(guò)濾效率等級(jí)作為接受標(biāo)準(zhǔn)協(xié)商的基礎(chǔ)。光度計(jì)泄漏測(cè)試和基于粒子計(jì)數(shù)器的泄漏測(cè)試的泄漏接受標(biāo)準(zhǔn)應(yīng)該相同，因?yàn)閮煞N方法背后的理論和方法是相同的。如果執(zhí)行得當(dāng)，使用光度計(jì)和粒子計(jì)數(shù)器進(jìn)行的泄漏測(cè)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(cè)到的泄漏量超過(guò)上游濃度的0.01%，一般認(rèn)為該泄漏率超過(guò)最大允許標(biāo)準(zhǔn)。但是，對(duì)于整體效率MPPS≥99.95%且小于99,995%的過(guò)濾器系統(tǒng)(如H13過(guò)濾器)，接受標(biāo)準(zhǔn)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(cè)試 MPPS 整體效率低于 99.95% 的過(guò)濾系統(tǒng)，則根據(jù)客戶(hù)和供應(yīng)商之間的協(xié)議，需要不一樣的接受標(biāo)準(zhǔn)。

　　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(guò)濾器

　　The flters for depyrogenation tunnel

　　安裝到去熱原隧道中的過(guò)濾器需要經(jīng)受長(zhǎng)時(shí)間的高溫操作，因此不適用標(biāo)準(zhǔn)過(guò)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(duì)0.3 μm顆粒的效率為99.99%的特殊過(guò)濾器(注，F(xiàn)DA對(duì)HEPA的定義為> 99.97%@0.3 μm)。最近，可用的材料有了進(jìn)步，并且引入了柔性密封劑，可以減少加熱時(shí)間并降低密封劑開(kāi)裂的風(fēng)險(xiǎn)。傳統(tǒng)的過(guò)濾器需要具有受控的加熱和冷卻速度(通常不超過(guò)1℃/分鐘;應(yīng)與過(guò)濾器供應(yīng)商確認(rèn)該速率)，以防止熱應(yīng)力損壞密封件。通常，在不使用期間，系統(tǒng)會(huì)保持高溫，以減少過(guò)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(guò)濾器通常是H14。這些過(guò)濾器可以在安裝時(shí)進(jìn)行全面掃描泄漏測(cè)試，但是在首次加熱循環(huán)之后(過(guò)濾器會(huì)燃燒，通常會(huì)導(dǎo)致該過(guò)濾器等級(jí)與H13相當(dāng))，不建議再進(jìn)行傳統(tǒng)測(cè)試。因?yàn)闅馊苣z油(如聚α烯烴(PAO))將被截留到過(guò)濾器上并燃燒，從而產(chǎn)生不健康的煙霧，并可能堵塞過(guò)濾介質(zhì)。由于將過(guò)濾器介質(zhì)粘合在一起的粘合劑在燃燒會(huì)放氣，通常導(dǎo)致過(guò)濾器變脆。DEHS(癸二酸二乙基己酯)是一種可能會(huì)更快蒸發(fā)的替代油。

　　EU-GMP附錄1《無(wú)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(yīng)配置干熱滅菌/去熱原隧道以確保氣流通過(guò)維持適當(dāng)?shù)乃淼缐翰詈蜌饬鱽?lái)保護(hù)A級(jí)滅菌區(qū)域的完整性和性能。應(yīng)評(píng)估壓差曲線(xiàn)。應(yīng)評(píng)估任何氣流變化的影響，以確保維持加熱曲線(xiàn)。所有供應(yīng)到隧道的空氣應(yīng)至少通過(guò)HEPA過(guò)濾器，并應(yīng)進(jìn)行定期測(cè)試(至少每半年一次)以證明空氣過(guò)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(duì)內(nèi)包裝組件、起始物料或活性物質(zhì)進(jìn)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(gè)滅菌和滅菌后存放過(guò)程中，應(yīng)對(duì)較低潔凈等級(jí)區(qū)域保持相對(duì)正壓。所有進(jìn)入烘箱的空氣都應(yīng)通過(guò)HEPA過(guò)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?zhuān)?/span>

　　1、新版EU-GMP附錄1《無(wú)菌藥品生產(chǎn)》要求滅菌隧道至少安裝HEPA過(guò)濾器，HEPA過(guò)濾器即H13級(jí)和H14級(jí)高效過(guò)濾器，可通過(guò)在加熱段安裝H14過(guò)濾器(MPPS泄漏率≤0.01%)，并在安裝時(shí)進(jìn)行全面掃描檢漏測(cè)試，以使過(guò)濾器在首次加熱后能夠至少符合H13級(jí)標(biāo)準(zhǔn)(MPPS泄漏率≤0.05%)。

　　2、新版EU-GMP附錄1《無(wú)菌藥品生產(chǎn)》要求：對(duì)于干熱滅菌隧道的HEPA過(guò)濾器，至少每半年進(jìn)行一次測(cè)試以證明過(guò)濾器完整性，其他地方的過(guò)濾器則未在文件中作出具體規(guī)定，可按照ISO14644標(biāo)準(zhǔn)執(zhí)行。