Can the ventilation of GMP clean rooms be switched off overnight?

GMP潔凈室的通風系統(tǒng)是否可以在夜間關閉？

The ventilation systems of clean rooms consume a lot of energy, especially power for the ventilating fan, refrigerating capacity for cooling and dehumidification in summer as well as heating for warming and steam for humidification in winter. Therefore, the question comes up again and again whether one might switch off the ventilation of the rooms overnight or when they are not used in order to save energy.

潔凈室的通風系統(tǒng)耗費巨大能源，特別是通風系統(tǒng)的風扇、夏天致冷和除濕以及冬天加熱和加濕用蒸汽。因此，一直就有這個問題：公司是否可以在晚上或不用的時候關閉房間的通風，以節(jié)約能源？

It is not advised to switch off the ventilation system completely, it is rather advised not to do it. Premises, pressure conditions, microbiology, everything would be out of control during that time. This would make the subsequent measures for the restoration of the GMP-compliant state very complex because each time a requalification would be necessary to reach the normal GMP-compliant state.

一般不建議完全關閉通風系統(tǒng)，事實上最好不要這樣做。設施、壓差條件、微生物，在此期間所有東西都有可能失控。這會讓之后的恢復GMP符合狀態(tài)所需的措施非常復雜，因為每次都要做再確認，來達到正常的GMP符合狀態(tài)。

But a reduction in the performance of the ventilation systems (reduction of the air volume by reducing the performance of the ventilation system) is possible, and is already carried out in some companies. Here too, however, the GMP-compliant state must be achieved prior to using the clean room again and this procedure must be validated.

但是，可以降低通風系統(tǒng)的頻率（通過減少通風系統(tǒng)的頻率來減少換氣量），已經(jīng)有一些公司在這么做了。但是，在重新使用潔凈室之前還是必須達到GMP符合狀態(tài)，并且該程序必須經(jīng)過驗證。

For this purpose the following points must be observed:

為此必須要觀察以下幾點：

The reduction can only be carried out so far that the clean room specific limits prescribed for the relevant case are not violated in general. These limits have to be defined in each case for the operating status and the reduction mode including permissible minimum and maximum values, such as clean room class (particle count with equivalent particle size), product specific values (temperature, relative humidity), pressure conditions (pressure difference between the rooms). Note that the values in reduction mode have to be chosen in such a way that the facility has reached the GMP-compliant state in due time before production begins (integration of a time program). This state depends on different parameters such as building material and performance of the system etc. The pressure conditions should be maintained all the time, this means that a reversion of the flow direction is not allowed.

降低通風系統(tǒng)的頻率只能達到一個指定的程度，以確保維持特定個例中的潔凈室的特定限度。在每個個例中，這些運行狀態(tài)下的和降低頻率狀態(tài)下的限度必須定義，其中包括允許的最小和最大值，例如潔凈室級別（粒子數(shù)和相關的粒徑）、產(chǎn)品特定的值（溫度、相對濕度）、壓差條件（房間之間的壓差）。注意，在降低頻率的模式下的值的選擇必須使得設施在生產(chǎn)開始之前的規(guī)定時間內(nèi)（時間計劃結(jié)合在其中）達到GMP符合狀態(tài)。此狀態(tài)取決于不同的參數(shù)，例如建筑材料和系統(tǒng)性能等。應在所有的時間內(nèi)都維持壓差條件，這表示不允許氣流逆向。

Furthermore, the installation of an independent clean room monitoring system is recommended in any case in order to constantly monitor and document the above mentioned clean room specific parameters. Thus, the conditions of the area concerned can be monitored and documented at any time. In the case of deviations (reaching of a limit) and in the individual case it is possible to access the measurement and control technology of the ventilation system and to carry out the relevant adjustments.

還有，建議安裝一個獨立的潔凈室監(jiān)測系統(tǒng)，這樣可以連續(xù)監(jiān)測并記錄上述潔凈室指定參數(shù)。這樣，所關注的區(qū)域的條件應可以在任何時間進行監(jiān)測和記錄。如果有偏差發(fā)生（達到限度），在個案中有可能具備測量和通風系統(tǒng)控制技術，進行相關調(diào)整。

During the reduction attention should be paid to ensuring that no unpredicted external interfering influences such as the entry of persons are allowed. For this the installation of a corresponding entry control is advised. In the case of an electronic locking system the entry authorisation can be linked with the above mentioned time program as well as with the independent clean room monitoring system so that entry is authorised only subject to compliance with the predefined requirements.

在降低風機頻率時，要注意確保沒有非預期的外來干擾影響，例如，人員進入。這種情況建議使用相應的人員進出控制。如果使用的是電子鎖系統(tǒng)，進出權(quán)限可以與上述時間計劃相關聯(lián)，以及與獨立的潔凈室監(jiān)測系統(tǒng)相關聯(lián)，這樣，進出授權(quán)必須要符合預定的要求。

In principal, both states must be qualified first and then requalified in regular intervals and the customary measurements for the regular operating status such as the recovery time measurement in case of a complete failure of the facility must be carried out. In the case a clean room monitoring system exists it is in principal not required - as mentioned above - to carry out further measurements at the start of operations after reduction mode if the procedure is validated. Special focus should be put on the procedure of restarting since temporary reversions of the flow direction are possible, for instance.

原則上來說，兩種狀態(tài)都必須先確認，然后進行定期再確認。通常，常規(guī)運行狀態(tài)下的測量，例如設備完全失效情形下恢復時間測量是必須要進行的。如果存在有潔凈室監(jiān)測系統(tǒng)，程序經(jīng)過驗證的話，原則上不需要---如上所述---在降低通風頻率后重新開始運行時進行進一步測量。特別要注意的是重新開始運行時的程序，因為，比如氣流方向短時逆向是有可能發(fā)生的。

All in all about 30 % of the energy costs can be saved depending on the mode of operation and the shift model but additional investment costs might have to be offset.

總體來說，根據(jù)運行模式和當班模式的不同，大概能節(jié)約30%左右的能源，但可能會被額外的投資成本所抵消。

WHO 非無菌空調(diào)GMP指南

GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS: PART 2 INTERPRETATION OF PART 1 – GMP FOR HVAC SYSTEMS

非無菌制劑暖通空調(diào)GMP指南：第二部分——HVAC系統(tǒng)的GMP要求

It is recommended that the HVAC system be operational on an ongoing basis. Where a manufacturer decides to use energy saving modes or switch some selected AHUs off at specified intervals such as overnight, weekends or extended periods of time, care should be taken to ensure that materials and products are not affected. In such cases, the decision, procedures and records should be sufficiently documented and should include risk assessment, standard operating procedures (SOPs), records and validation. This includes procedures and records for the start-up and shut-down sequence of air handling units.

建議HVAC系統(tǒng)持續(xù)運行。當決定在特定時間使用節(jié)能模式或選擇關閉部分AHU，如夜間、周末或很長時間，應關注確保物料和產(chǎn)品不受影響。這種情況下，應充分記錄該決定、規(guī)程和記錄，并包括風險評估、標準操作規(guī)程（SOP）、記錄和驗證。這包括風機處理單元（AHU）的開啟和關閉順序的規(guī)程和記錄。

GB 50457-2019

醫(yī)藥工業(yè)潔凈廠房設計標準

9.2.15 無菌藥品生產(chǎn)的潔凈區(qū)凈化空氣調(diào)節(jié)系統(tǒng)應保持連續(xù)運行，維持相應的潔凈級別。在非生產(chǎn)期間，凈化空氣調(diào)節(jié)系統(tǒng)可以采用低頻運行等模式，但仍應保持醫(yī)藥潔凈室相應級別和對周圍低級別潔凈區(qū)的正壓。因故停機再次開啟空氣凈化系統(tǒng)，應當進行必要的測試以確認滿足其規(guī)定的潔凈度級別要求。

GB 50457-2019

醫(yī)藥工業(yè)潔凈廠房設計標準

條文說明

“在非生產(chǎn)時間，由于潔凈室內(nèi)主要污染源(操作人員)的撤離，室內(nèi)的發(fā)塵量大大降低，為了節(jié)省運行費用，在滿足潔凈級別和正壓的前提條件下，可以采用降低空氣凈化系統(tǒng)風量方法。”

“對于無菌生產(chǎn)核心區(qū)建議維持正常生產(chǎn)運行時的關鍵參數(shù)，對于其他醫(yī)藥潔凈室需維持的正壓值應根據(jù)產(chǎn)品特性、生產(chǎn)運行時的情況，QA部門質(zhì)量驗證的結(jié)果及企業(yè)自身生產(chǎn)管理水平而定。”

新版GMP指南（2023版）

廠房設施和設備分冊

3.6.2.4 節(jié)能模式下的風量平衡

非生產(chǎn)模式作為凈化空調(diào)系統(tǒng)的一個運行模式，應保持連續(xù)運行，維持相應的凈化級別和對周圍區(qū)域的正壓，維持良好的氣流方向。凈化空調(diào)系統(tǒng)的送風量變化、不同潔凈區(qū)域的風量變化、潔凈室風量的變化，都需要凈化空調(diào)系統(tǒng)來實現(xiàn)機組風量、區(qū)域風量及潔凈室風量的再平衡。

無菌區(qū)風量可維持規(guī)范范圍內(nèi)的下限運行。

其他潔凈區(qū)可以較大幅度降低運行風量。

說明：由于凈化空調(diào)系統(tǒng)送風管道內(nèi)壓力的差異，不同區(qū)域風量變化存在差異，當系統(tǒng)總風量降低時，不同區(qū)域風量的降低存在區(qū)別，凈化空調(diào)系統(tǒng)的風量平衡就會被破壞，從而造成潔凈室的壓力梯度紊亂。同時，為維持區(qū)域正壓，凈化空調(diào)系統(tǒng)的新風量應依據(jù)正壓需要進行調(diào)整。

凈化空調(diào)系統(tǒng)生產(chǎn)模式動態(tài)工藝運行、非生產(chǎn)模式運行都需要再平衡系統(tǒng)風量區(qū)域的風量。

實施方式：

首先完成非生產(chǎn)模式下凈化空調(diào)系統(tǒng)的系統(tǒng)送風量、潔凈區(qū)域送風量的測算設置好非生產(chǎn)模式下的需求風量；

凈化空調(diào)系統(tǒng)采用設置好的非生產(chǎn)模式風量運行，進行相關的環(huán)境參數(shù)測試并通過測試的參數(shù)對風量進行調(diào)整；

通過測試確認在滿足環(huán)境凈化級別及正壓需求下的各風量，確認非生產(chǎn)模式下凈化空調(diào)系統(tǒng)的運行設定參數(shù)；

采用非生產(chǎn)模式運行，再次確認潔凈環(huán)境的凈化級別和參數(shù)，并確認生產(chǎn)模式與非生產(chǎn)模式的自動切換過程。

經(jīng)過確認后的非生產(chǎn)模式可以作為凈化空調(diào)系統(tǒng)的一個運行模式，在生產(chǎn)結(jié)束后，自動切入非生產(chǎn)模式運行。

ISPE無菌生產(chǎn)設施（第三版）

Any regular shutdown of HVAC systems for the purpose of energy savings is strongly discouraged, as it can lead to a loss of control and may increase the potential for product contamination. While HVAC shutdowns of short duration may be shown to not endanger the state of environmental control (via system and facility specific studies), shutdownsof multiple hours or days generally do endanger environmental control andrequire increasingly laborious cleaning disinfection and monitoring efforts tobring the cleanroom environments back into control.
注意： 非常不建議任何以節(jié)能為目的定期關停 HVAC 系統(tǒng)的行為， 因為這樣可能導致控制失控，并可能增加產(chǎn)品污染的可能性。 雖然 HVAC 短時間關停可能不會危及環(huán)境控制狀態(tài)（ 通過系統(tǒng)和設施的具體研究） ， 停機數(shù)小時或數(shù)天通常會危及環(huán)境控制， 要使?jié)崈羰噎h(huán)境恢復控制， 需要更加費力的清潔消毒和監(jiān)測工作。

結(jié)論

回到我們最初的問題：潔凈室的通風系統(tǒng)是否可以在夜間關閉？

答案是：不可以完全關閉，但允許在嚴格控制和充分驗證的前提下，采用降頻運行的節(jié)能模式。

如藥企需要在保證產(chǎn)品質(zhì)量和尋求節(jié)能方案之間尋找平衡。通過科學的方法和嚴格的驗證，降頻運行為這一平衡提供了可行的解決方案，既滿足GMP合規(guī)要求，又能實現(xiàn)顯著的節(jié)能效果。

在質(zhì)量管理中，沒有簡單的"是"或"否"，只有基于風險的科學決策和嚴謹驗證后的合理安排。

本文由廣州佳譽醫(yī)療器械有限公司/佛山浩揚醫(yī)療器械有限公司聯(lián)合編輯