第一部分：廠(chǎng)房設施部分的強制性條款

       4.4-The maintenance of unidirectional airflow should be demonstrated and qualified across the whole of the grade A area.

       解析：應該在整個(gè)A級區域內部證明和確認對單向流的維護。通過(guò)這句話(huà)可以看出，A級區域的內部驗證和測試不能只測試某個(gè)位置，應該基于A(yíng)級區域面積和A級區域內部的關(guān)鍵工位的評估，來(lái)選擇足夠測試點(diǎn)，來(lái)證明A級區域內部的單向流。

       4.4-Air pressure differences should be continuously monitored.

       解析：應該對壓差進(jìn)行持續監控。從這句可以看出，應該對關(guān)鍵位置壓差，進(jìn)行持續監控。這些關(guān)鍵位置的壓差指的是A級-B級區域之間的壓差，以及B級-C級區域之前的壓差。

       4.6-Sliding doors may be undesirable for this reason.

       解析：在無(wú)菌車(chē)間不能使用推拉門(mén)，也不能使用懸吊門(mén)。因為這樣類(lèi)型的門(mén)，存在更多不易清潔的死角。

       4.9-Sinks and drains should be prohibited in the grade A and grade B areas.

       解析：在A(yíng)級和B級區域不能出現水池和地漏。這個(gè)問(wèn)題，不需要解釋?zhuān)@是GMP基本原則和無(wú)菌制藥特征決定的。

       4.10-The transfer of materials, equipment, and components into the grade A or B areas should be carried out via a unidirectional process. The removal of items from the grade A and B areas (e.g. materials, waste, environmental samples) should be carried out via a separate unidirectional process.

       解析：將物料、設備和部件傳遞進(jìn)入A級區域或者B級區域，應該采用單向流程。將物料、廢棄物、環(huán)境監控樣品從A級區域和B級區域轉移出來(lái)時(shí)，應該從一個(gè)單獨的單向流通道轉移出來(lái)。從這句要求可以看出，進(jìn)入A/B級區域的通道應該單獨設置，進(jìn)入通道和生產(chǎn)廢棄物退出通道，應該分開(kāi)。

       4.11-The final stage of the airlock should, in the "at rest" state, be of the same cleanliness grade (viable and total particle) as the cleanroom into which it leads.

       解析：人流物流通道最后一個(gè)階段的房間，應該和擬進(jìn)入區域在靜態(tài)下保持相同的標準（微生物項目和懸浮粒子項目）。

       4.12-Personnel airlocks: Areas of increasing cleanliness used for entry of personnel (e.g. from the grade D area to the grade C area to the grade B area). In general hand washing facilities should be provided only in the first stage of the changing room and not be present in changing rooms directly accessing the grade B area.

       解析：人流通道氣鎖房間：這些氣鎖房間是用于人員進(jìn)入的房間，采用逐級提升潔凈度的方式來(lái)實(shí)現人員進(jìn)入（例如從D級進(jìn)入C級，然后再進(jìn)入B級）。通常，洗手設施應該僅僅在更衣室通道的第一個(gè)房間設置，而不應該出現在緊靠B級區域的房間設置洗手裝置。

       從上面這段要求，相信制藥企業(yè)明白無(wú)菌車(chē)間更衣通道設置的一般性要求。雖然措辭沒(méi)有使用必須，但是歐盟GMP附錄1采用舉例的方式告訴制藥行業(yè)，這是最常見(jiàn)和最推薦的方式之一。

       4.12-Only materials and equipment that have been included on an approved list and assessed during validation of the transfer process should be transferred into the grade A or grade B areas via an airlock or pass-through hatches.

       解析：只有納入批準清單的物料和設備才可以通過(guò)傳遞窗或者緩沖間傳遞進(jìn)入A級或者B級區域。從這句可以看出，凡是進(jìn)入A級或者B級區域的物料和設備，必須納入一個(gè)特定的批準目錄中。

       4.13-For pass-through hatches and airlocks (for material and personnel), the entry and exit doors should not be opened simultaneously.

       解析：對于人員和物料進(jìn)出的傳遞窗和緩沖間，進(jìn)出的門(mén)不能同時(shí)打開(kāi)。這是為了控制污染提出的基本要求，不需要過(guò)多解釋。

       4.14-Adjacent rooms of different grades should have an air pressure difference of a minimum of 10 Pascals (guidance value).

       解析：潔凈區內部不同級別相鄰房間之間的壓差應該保持最低10Pa（指導值）。從這條可以看出，具體保持多大的壓差數據，需要結合更具體的QRM來(lái)判斷，而不是一律保持10Pa就算可以。

       4.15 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contamination to the higher grade areas.

       解析：應該對潔凈區和潔凈室的氣流模式進(jìn)行可視化研究，以證明沒(méi)有空氣從低級別區域向高級別區域侵入，以及空氣不會(huì )從較低潔凈區域（例如地面）攜帶污染物越過(guò)人員或者設備向較高等級區域傳遞。

       從這句要求看，潔凈區內部送風(fēng)、回風(fēng)、排風(fēng)設置要非常精細的設計才可以實(shí)現這樣的工藝目的。而且驗證要求也提到很高程度，需要證明這些風(fēng)險是不存在的。

       4.19-Negative pressure isolators should only be used when containment of the product is considered essential (e.g. radiopharmaceutical products) and specialized risk control measures should be applied to ensure the critical zone is not compromised.

       解析：當產(chǎn)品的污染風(fēng)險（例如放 射 性藥品）被認為是基本問(wèn)題時(shí)，才允許使用負壓隔離器，采用采用特定的風(fēng)險控制措施，以確保關(guān)鍵區域不被污染。這句話(huà)描述了負壓隔離器使用的特定情況。

       4.20-The background environment for open isolators should generally correspond to a minimum of grade C. The background for closed isolators should correspond to a minimum of grade D.

       解析：O-隔離器的背景環(huán)境通常最低是C級。而C-隔離器的背景環(huán)境通常最低是D級。這句描述了在為隔離器設置背景環(huán)境是的特定要求。

       4.21-Isolators-Generally glove integrity testing should be performed at a minimum frequency of the beginning and end of each batch or campaign.

       解析：對于隔離器上面的手套完整性測試最低頻率是每個(gè)批次或者每個(gè)生產(chǎn)周期的開(kāi)始和結束，各測試一次。

       RABS-Gloves should be visually examined with each use, and integrity testing should be performed at periodic intervals.

       解析：對于RABS，應該每次使用是目視檢查手套的完整性，并且應該在周期性間隔測試手套完整性。

       4.30-Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 - 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.

       解析：在工作位置，單向流系統應該提供均一的空氣風(fēng)速，范圍是0.36 - 0.54 m/s，除非在CCS中對于風(fēng)速另有論證。氣流可視化研究應該和風(fēng)速測量相互關(guān)聯(lián)。

       通過(guò)上面這段描述，我們知道，具體單向流風(fēng)速要求，應該和工藝和具體位置相關(guān)，而不是必須采用0.36 - 0.54 m/s。

       4.32-The maximum time interval for requalification of grade A & B areas, is 6 months. The maximum time interval for requalification of grade C & D areas, is 12 months.

       解析：A/B級區域的再確認周期最短是6個(gè)月。C/D級區域再確認周期最短是12個(gè)月。上面描述無(wú)菌制藥企業(yè)對于潔凈區再確認的最低周期要求。

       4.35 Disinfectants and detergents used in grade A and grade B areas should be sterile prior to use.

       解析：用于A(yíng)級和B級區域的消毒劑和清潔劑應該在使用前滅菌或者除菌。從這條可以看出，A/B級是無(wú)菌區域，必須嚴格控制微生物污染。

       第二部分：設備部分的強制性條款

       5.2-The frequency at which alarms are assessed should be based on their criticality (with critical alarms reviewed immediately).

       解析：對于報警信息的審核應該基于它們的關(guān)鍵程度（關(guān)鍵報警信息必須立即審核）。從這段可以看出，如果制藥公司對于某些報警信息列為關(guān)鍵信息，應該安排人員24小時(shí)值班來(lái)處理。

       5.8-A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).

       解析：傳送帶不能在A(yíng)級區域之外運行，或者不能在B級和較低級別區域之間運行，除非傳送帶自身可以持續滅菌，例如隧道烘箱。

       這句告訴我們，在設置傳送帶的時(shí)候，必須遵守這些基本原則。

       5.9-Tube length should typically be no longer than 1m unless justified and the number of bends should be minimized.

       解析：懸浮粒子計數器取樣管長(cháng)度通常不能超過(guò)1米，除非另有說(shuō)明。而且，取樣管上面的彎曲數量應該最小化。這個(gè)要求應該是行業(yè)共識了，請牢記山東省某企業(yè)被歐盟警告的案例。

       第三部分：公用系統部分的強制性條款

       6.10 Water for injections (WFI) should be produced from water meeting specifications that have been defined during the qualification process, stored and distributed in a manner which minimizes the risk of microbial growth (e.g. by constant circulation at a temperature above 70°C).

       解析：注射用水 (WFI) 應使用符合在確認過(guò)程中定義的標準的水生產(chǎn)，以將微生物生長(cháng)風(fēng)險降至最低的方式儲存和分配（例如在高于 70°C 的溫度下持續循環(huán)）。從這條可以看出，WFI循環(huán)溫度是硬性要求。

       6.12-Chemical testing results should be approved before the water system is returned to use and microbiological/endotoxin results verified to be within specification and approved before batches manufactured using water from the system are considered for certification/release.

       解析：在水系統恢復使用之前，應該對于化學(xué)測試結果進(jìn)行審核批準；使用相關(guān)工藝用水生產(chǎn)的藥品在放行之前，微生物項目和內毒素項目應該被確認符合標準并得到批準。從這條要求看，應該對于WFI進(jìn)行批次劃分，在生產(chǎn)記錄上面記錄生產(chǎn)使用的WFI批號，并按照規定完成放行。

       6.13-Sample plans should be based on the qualification data, should consider the potential worst case sampling locations and should ensure that at least one representative sample is included every day of the water that is used for manufacturing processes.

       解析：對于工藝用水的取樣計劃應該基于確認數據，應該考慮潛在的最差取樣位置，應該確保每天至少取樣一個(gè)代表性的取樣點(diǎn)，來(lái)評估用于生產(chǎn)的工藝用水的質(zhì)量。根據上面這段要求，對于水系統取樣計劃，應該采用常見(jiàn)的3+N或者4+N方法。

       6.15 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling.

       解析：應該對于WFI系統采用持續監控，測試TOC和電導率項目，因為這樣可以及時(shí)反饋整個(gè)系統的性能，比離線(xiàn)測試要更好。從這句看，對于WFI系統，在線(xiàn)監控TOC和電導率是必須項目。

       第四部分：人員管理部分的強制性條款

       7.5 Unqualified personnel should not enter grade B cleanrooms or grade A in operation. If needed in exceptional cases, manufacturers should establish written procedures outlining the process by which unqualified personnel are brought into the grade B and A areas.

       解析：未經(jīng)過(guò)無(wú)菌更衣確認的人員，不能進(jìn)入A級或者B級區域。如果需要設置額外情況，制造商應該建立書(shū)面規程，來(lái)描述未經(jīng)過(guò)更衣確認人員如何進(jìn)入A/B級區域，如何被管控。

       第五部分：生產(chǎn)和特定技術(shù)部分的強制性條款

       8.3 Filling of products for terminal sterilisation should be carried out in at least a grade C environment.

       解析：最終滅菌產(chǎn)品的灌裝區域應該至少設置在C級區域。

       8.22- Glass ampoules, BFS units and small volume containers (≤100 ml) closed by fusion should be subject to 100% integrity testing using validated methods.

       解析：采用融封工藝生產(chǎn)的玻璃安瓿、BFS工藝生產(chǎn)的單元包裝、小容量容器（≤100ml）應該采用驗證的方法進(jìn)行100%的完整性檢測。

       8.67- 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.

       解析：針對干熱滅菌，供應到隧道的所有空氣都應至少通過(guò)HEPA，并且應進(jìn)行定期測試（至少每?jì)赡暌淮危┮宰C明空氣過(guò)濾器的完整性。

       從這條可以看出，用于干熱隧道烘箱的過(guò)濾器必須是HEPA，不能采用非HEPA。而且完整性測試頻率也進(jìn)行詳細規定。

       8.68 When a thermal process is used as part of the depyrogenation process for any component or product contact equipment/material, validation studies should be performed to demonstrate that the process provides a suitable Fh value and results in a minimum 3 log10 reduction in endotoxin concentration.

       解析：當干熱工藝被用作任何部件或產(chǎn)品接觸設備/材料的去熱原過(guò)程時(shí)，應進(jìn)行驗證研究以證明該工藝提供了合適的Fh值并導致內毒素濃度至少降低3個(gè)log10。

       8.79 If the product cannot be sterilised in its final container, solutions or liquids should be sterilised by filtration through a sterile sterilising grade filter (with a nominal pore size of a maximum of 0.22 μm that has been appropriately validated to obtain a sterile filtrate) and subsequently aseptically filled into a previously sterilised container.

       解析：如果產(chǎn)品不能在其最終容器中滅菌，溶液或液體應通過(guò)無(wú)菌級過(guò)濾器（標稱(chēng)孔徑最大為0.22 μm，經(jīng)適當驗證以獲得無(wú)菌濾液）過(guò)濾來(lái)除菌，隨后填充到已經(jīng)預先滅菌的容器中。

       第六部分：環(huán)境和工藝監控部分的強制性條款

       9.16 For grade A, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly.

       解析：對于A(yíng)級區域，應在關(guān)鍵加工的整個(gè)過(guò)程中進(jìn)行懸浮粒子監測，包括設備組裝操作。

       9.17 The grade A area should be monitored continuously (for particles ≥0.5 and ≥5 μm) and with a suitable sample flow rate (at least 28 litres (1ft3) per minute) so that all interventions, transient events and any system deterioration is captured.

       解析：應連續監測A級區域（對于 ≥0.5um和 ≥5 μm的顆粒）并以合適的采用速度（至少28升（1ft3）每分鐘的流速），以便捕獲所有干預、瞬態(tài)事件和任何系統惡化信息。從這句可以看出，A級區域懸浮粒子監控的采樣流速，需要符合上面的硬性要求。

       第七部分：質(zhì)量控制部分的強制性條款

       10.3 The bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilised products and the results considered as part of the final batch review.

       解析：對無(wú)菌灌裝產(chǎn)品和最終滅菌產(chǎn)品的每批產(chǎn)品都應進(jìn)行生物負荷量測定，并將結果視為最終批次審核的一部分。根據這句，應該在每批次無(wú)菌產(chǎn)品生產(chǎn)時(shí)，在合適位置取樣測試生物負荷量。

       總結

       根據上面匯總和梳理的信息可以看出，剛發(fā)布的EU GMP附錄1對于無(wú)菌藥品提出了明顯的嚴苛要求。因此說(shuō)，想進(jìn)軍歐盟市場(chǎng)的中國企業(yè)，要提前準備，才可以取得預期的成績(jì)。

       說(shuō)明：本文不構成價(jià)值判斷和投資建議。

       作者簡(jiǎn)介：zhulikou431，高級工程師、PDA會(huì )員、ISPE會(huì )員、ECA會(huì )員、PQRI會(huì )員、資深無(wú)菌GMP專(zhuān)家，在無(wú)菌工藝開(kāi)發(fā)和驗證、藥品研發(fā)和注冊、CTD文件撰寫(xiě)和審核、法規審計、國際認證、國際注冊、質(zhì)量體系建設與維護領(lǐng)域，以及無(wú)菌檢驗、環(huán)境監控等領(lǐng)域皆具有較深造詣。近幾年開(kāi)始著(zhù)力關(guān)注制藥宏觀(guān)領(lǐng)域趨勢分析和制藥企業(yè)并購項目的風(fēng)險管理工作。