培養(yǎng)基模擬灌裝驗(yàn)證時(shí)間點(diǎn)選擇
發(fā)布時(shí)間：
2022-12-27
作者：
微生物培養(yǎng)基哪家便宜
培養(yǎng)基模擬灌裝驗(yàn)證時(shí)間點(diǎn)選擇探討
《無(wú)菌附錄》第四十七條主要內(nèi)容如下：
1、無(wú)菌生產(chǎn)工藝的驗(yàn)證應(yīng)包括培養(yǎng)基模擬灌裝試驗(yàn)。
2、應(yīng)根據(jù)產(chǎn)品的劑型以及培養(yǎng)基的選擇性、澄清度、濃度和滅菌的適用性選擇培養(yǎng)基。
3、應(yīng)盡可能模擬常規(guī)的無(wú)菌生產(chǎn)工藝，包括所有對(duì)產(chǎn)品的無(wú)菌特性有影響的關(guān)鍵操作，及生產(chǎn)中可能出現(xiàn)的各種干預(yù)和最差條件。
4、培養(yǎng)基模擬灌裝試驗(yàn)的首次驗(yàn)證，每班次應(yīng)連續(xù)進(jìn)行3次合格的試驗(yàn)。
5、空氣凈化系統(tǒng)、設(shè)備、生產(chǎn)工藝及人員重大變更后，應(yīng)重復(fù)進(jìn)行培養(yǎng)基模擬灌裝試驗(yàn)。
6、培養(yǎng)基模擬灌裝試驗(yàn)通常應(yīng)按生產(chǎn)工藝每班次半年進(jìn)行1次，每次至少一批。
7、培養(yǎng)基模擬灌裝容器的數(shù)量規(guī)定。
（本文主要探討符合3、4、5、6要求的培養(yǎng)基模擬灌裝驗(yàn)證時(shí)間點(diǎn)的合理選擇。）
對(duì)于無(wú)菌生產(chǎn)工藝來(lái)說(shuō)，無(wú)菌工藝驗(yàn)證（培養(yǎng)基模擬灌裝驗(yàn)證）僅能證明無(wú)菌工藝系統(tǒng)（人機(jī)料法測(cè)環(huán)）的無(wú)菌保證能力在某一個(gè)時(shí)間點(diǎn)（或者培養(yǎng)基模擬灌裝驗(yàn)證這一個(gè)時(shí)間段）的表現(xiàn)，并不能保證在不同時(shí)間段會(huì)自始至終保持良好的無(wú)菌保證水平。
換句話(huà)說(shuō)，培養(yǎng)基模擬灌裝驗(yàn)證，僅能證明本次驗(yàn)證階段的無(wú)菌保證水平，間接反映了現(xiàn)階段無(wú)菌工藝系統(tǒng)的無(wú)菌保證能力。
即使所有與無(wú)菌產(chǎn)品的無(wú)菌性有關(guān)的廠(chǎng)房設(shè)施、設(shè)備部件、器具容器、原輔材料都經(jīng)過(guò)了有效的滅菌處理，但是當(dāng)把這些所有要素（人機(jī)料法測(cè)環(huán)）按照一定的工藝規(guī)程排列組合在一起的時(shí)候，仍有可能會(huì)出現(xiàn)無(wú)菌條件得不到保證甚至產(chǎn)品被污染的可能。
所以，無(wú)菌工藝驗(yàn)證（培養(yǎng)基模擬灌裝驗(yàn)證）是對(duì)整個(gè)無(wú)菌生產(chǎn)工藝過(guò)程中的無(wú)菌保證水平的驗(yàn)證。
首先，應(yīng)盡可能模擬常規(guī)的無(wú)菌生產(chǎn)工藝，也就是盡可能按照常規(guī)的生產(chǎn)工藝進(jìn)行培養(yǎng)基模擬灌裝驗(yàn)證。
其次，應(yīng)包括所有對(duì)產(chǎn)品的無(wú)菌特性有影響的關(guān)鍵操作，及生產(chǎn)中可能出現(xiàn)的各種干預(yù)和最差條件。
什么是“常規(guī)的無(wú)菌生產(chǎn)工藝”中的“最差條件”？
1、人，經(jīng)過(guò)良好的培訓(xùn)和資質(zhì)確認(rèn)的高素質(zhì)的人員，要耐受常規(guī)無(wú)菌生產(chǎn)工藝的生產(chǎn)過(guò)程時(shí)間、生產(chǎn)環(huán)境條件，尤其是夜班、倒班、加班、拖班……等生產(chǎn)過(guò)程容易出現(xiàn)的可能。并增加灌裝人員的數(shù)量超過(guò)正常灌裝生產(chǎn)所需的人員數(shù)量，包括人員操作最有可能出現(xiàn)的誤操作的干擾模擬狀況。
2、機(jī)，設(shè)備、器具、組件……清潔、消毒、滅菌后在無(wú)菌工藝區(qū)域保存時(shí)間（最好是使用時(shí)間）超出控制要求或者接近控制要求的時(shí)限。模擬設(shè)備故障、設(shè)備維修、部件調(diào)整、拆卸、替換。模擬設(shè)備工藝參數(shù)的較苛刻運(yùn)行條件（低速、高速、包裝容器的極限規(guī)格）。
3、料，使用促生長(zhǎng)培養(yǎng)基，無(wú)菌物料、藥液實(shí)際灌裝前在儲(chǔ)罐中保存放置的最長(zhǎng)時(shí)間，無(wú)菌物料需要除菌的時(shí)間間隔，無(wú)菌過(guò)濾到灌封加塞完成所需要的最大可能時(shí)間，灌裝后的儲(chǔ)存時(shí)間。
4、法，嚴(yán)格執(zhí)行所有的工藝規(guī)程、檢驗(yàn)方法、操作規(guī)程，并且選取SOP范圍內(nèi)的苛刻條件，證明“模擬常規(guī)的無(wú)菌生產(chǎn)工藝”中的最差條件的無(wú)菌保證水平。
5、測(cè)，檢驗(yàn)檢測(cè)條件無(wú)須贅述，主要是環(huán)境監(jiān)測(cè)、無(wú)菌檢驗(yàn)……
6、環(huán)，無(wú)菌環(huán)境的清潔、消毒、滅菌后的最長(zhǎng)放置時(shí)間（最好是動(dòng)態(tài)生產(chǎn)的最長(zhǎng)使用時(shí)間），環(huán)境保護(hù)設(shè)施設(shè)備的故障、異常操作對(duì)環(huán)境的影響，比如開(kāi)關(guān)門(mén)等。初效、中效、高效的衰減對(duì)于送風(fēng)量影響的最差條件。最大人員數(shù)量對(duì)于環(huán)境的影響。
綜上所述，我們對(duì)于新項(xiàng)目建成后、重大偏差變更后、重大維修后、長(zhǎng)時(shí)間停產(chǎn)后的無(wú)菌工藝驗(yàn)證（培養(yǎng)基模擬灌裝驗(yàn)證）（或再驗(yàn)證），與正常連續(xù)生產(chǎn)的每半年周期的再驗(yàn)證分開(kāi)描述。
1、對(duì)于新項(xiàng)目建成后、重大偏差變更后、重大維修更換后、長(zhǎng)時(shí)間停產(chǎn)后的無(wú)菌工藝驗(yàn)證（培養(yǎng)基模擬灌裝驗(yàn)證），如果等同于首次驗(yàn)證，法規(guī)要求“每班次應(yīng)連續(xù)進(jìn)行3次合格的試驗(yàn)”，我覺(jué)得更準(zhǔn)確的描述應(yīng)該是“新項(xiàng)目建成后、重大偏差變更后、重大維修更換后、長(zhǎng)時(shí)間停產(chǎn)后”“再次投入生產(chǎn)運(yùn)行（或工藝驗(yàn)證）之前”“模擬常規(guī)的無(wú)菌生產(chǎn)工藝”“連續(xù)生產(chǎn)三個(gè)批次”的模擬灌裝試驗(yàn)，當(dāng)然，根據(jù)“偏差變更重要性、維修更換關(guān)鍵性、停產(chǎn)時(shí)間長(zhǎng)短”進(jìn)行必要的風(fēng)險(xiǎn)評(píng)估，完全可以規(guī)定“培養(yǎng)基模擬灌裝驗(yàn)證”1、2、3次都可以接受。
2、那么對(duì)于法規(guī)規(guī)定“培養(yǎng)基模擬灌裝試驗(yàn)通常應(yīng)按生產(chǎn)工藝每班次半年進(jìn)行1次，每次至少一批”，應(yīng)該理解成如果沒(méi)有“重大偏差變更、重大維修、長(zhǎng)時(shí)間停產(chǎn)”現(xiàn)象，應(yīng)當(dāng)“按生產(chǎn)工藝每個(gè)生產(chǎn)工藝每半年進(jìn)行1次每次至少一批”、而且盡可能在“正常生產(chǎn)產(chǎn)品的批次之間”進(jìn)行“最差條件”的培養(yǎng)基模擬灌裝試驗(yàn)。
3、周期性“培養(yǎng)基模擬灌裝試驗(yàn)”最差條件，仍然要滿(mǎn)足前面說(shuō)的各種條件！
那么，以下條件，可以不認(rèn)為是“常規(guī)的無(wú)菌生產(chǎn)工藝”中的“最差條件”：
1、設(shè)備、器具、組件……剛剛做完清潔、消毒、滅菌（SIP），即開(kāi)始培養(yǎng)基模擬灌裝試驗(yàn)。這不是最差條件，這是最優(yōu)條件。
2、無(wú)菌物料、藥液實(shí)際灌裝前在儲(chǔ)罐中保存沒(méi)有達(dá)到最長(zhǎng)時(shí)間，或者模擬灌裝過(guò)程沒(méi)有涵蓋最長(zhǎng)保存時(shí)限。
3、無(wú)菌環(huán)境剛剛進(jìn)行完清潔、消毒、滅菌，即開(kāi)始培養(yǎng)基模擬灌裝試驗(yàn)。這不是最差條件，這是最優(yōu)條件。
4、還有，HVAC系統(tǒng)剛剛更換過(guò)濾器、設(shè)備剛剛進(jìn)行日常的維護(hù)維修，理論上都不算“最差條件”，因?yàn)檫@些情況都屬于“常規(guī)的無(wú)菌生產(chǎn)工藝”中可能出現(xiàn)的情況。
但是很多時(shí)候培養(yǎng)基模擬灌裝試驗(yàn)時(shí)間點(diǎn)的選擇，大家還是沒(méi)有考慮這么多，也不可能同時(shí)兼顧各種最差情況的同時(shí)出現(xiàn)。
我們通常見(jiàn)到的是，為了保證無(wú)菌工藝驗(yàn)證（培養(yǎng)基模擬灌裝驗(yàn)證）的成功，大家都會(huì)不遺余力的去創(chuàng)造“最最優(yōu)化”的無(wú)菌生產(chǎn)條件（根本不是最差條件），根本不去考慮可能存在的“最差條件”！
Study on time point selection for validation by simulated filling of culture medium
Article 47 of the sterile appendix reads as follows:
1. Validation of aseptic production process shall include simulated filling test of culture medium.
2. The media shall be selected according to the dosage form of the product and the selectivity, clarification, concentration and applicability of sterilization medium.
3. As far as possible, routine aseptic production processes should be simulated, including all key operations that affect the aseptic characteristics of the product, as well as all kinds of interventions and worst conditions that may occur in production.
4. For the first verification of the simulated filling test of culture medium, the qualified test should be carried out three times successively for each shift.
5. After major changes in air purification system, equipment, production process and personnel, the simulated filling test of culture medium shall be repeated.
6. The simulated filling test of culture medium should be carried out once every half a year according to the production process, at least one batch at a time.
7. The medium simulates the number of filling containers.
(this paper mainly discusses the reasonable selection of time points for validation of simulated filling of medium according to the requirements of 3, 4, 5 and 6.)
For aseptic production process, the aseptic process validation (medium filling simulation validation) can only show aseptic process system (man-machine material to measure ring) sterile guarantee ability at a certain point in time (or medium filling simulation verify this time), and cannot be guaranteed that at different times from beginning to end will keep good aseptic guarantee level.
In other words, the simulated filling verification of the culture medium can only prove the level of aseptic guarantee in this verification stage, which indirectly reflects the aseptic guarantee ability of the present aseptic process system.
Even if all related to sterile product aseptic workshop facilities, equipment, components, equipment container, raw and auxiliary materials are through the effective sterilization processing, but when all these elements to measure ring (man-machine material) according to certain procedure permutation and combination together of the time, still possible sterile conditions are not guaranteed, and even the possibility of contaminated products.
Therefore, aseptic process verification (culture medium simulation filling verification) is the verification of aseptic guarantee level in the whole process of aseptic production.
First of all, the conventional aseptic production process should be simulated as much as possible, that is, the culture medium should be simulated and filled as much as possible according to the conventional production process.
Secondly, all key operations that affect the aseptic properties of the product should be included, as well as all kinds of interventions and worst conditions that may occur in production.
What are the "worst conditions" in the "conventional aseptic manufacturing process"?
1, who, after a good training and qualification confirmation of qualified personnel, to tolerate regular aseptic production process of the production process time, production conditions, especially the night shift, shift work, overtime, drag class... Wait for the production process easy to appear possible. Moreover, the number of filling personnel exceeds the number of personnel required for normal filling production, including the interference simulation of the most likely misuse of personnel operations.
2. Machine, equipment, apparatus, components After cleaning, disinfecting and sterilizing, the storage time (preferably using time) in the aseptic process area exceeds the control requirements or is close to the control requirements. Simulate equipment failure, equipment maintenance, component adjustment, disassembly, replacement. Simulation equipment process parameters of the more stringent operating conditions (low speed, high speed, packaging container limit specifications).
3, material, the use of the growth medium, aseptic filling material, the solution actual before a place for the longest time, and kept in a tank of aseptic materials need to be aseptic interval, sterile filtration to potting gasser needed to complete the maximum possible time, storage time after filling.
4, law, strictly carry out all the technical process, inspection method, operating rules, and select the SOP within the scope of the harsh conditions, prove that "simulation of the conventional aseptic production process" in the worst condition of sterile guarantee level.
5. Test and test conditions need not be repeated, mainly environmental monitoring and aseptic testing
6, ring, a sterile environment after the cleaning, disinfection and sterilization of the longest place time dynamic production for the longest time (preferably), environmental protection facilities of failure, abnormal operation of environmental impact, such as doors, etc. The worst condition for the effect of initial, medium and high efficiency attenuation on the air volume. Maximum personnel impact on the environment.
To sum up, for our new, big deviation change after the completion of the project, after major repair, production for a long time after the aseptic process validation of filling simulation validation (medium) (or verification), and normal continuous production every half cycle of revalidation described separately.
1, for the new, significant deviation change after the completion of the project, after major repair replacement, after long time after the production of aseptic filling simulation validation (medium) for process validation, if is equal to the first time validation, regulatory requirements "per shift shall be qualified test for 3 times in a row", I think a more accurate description should be "new, significant deviation change after the completion of the project, after major repair replacement, after a long period of time after shutdown" "again production run (or process validation)" before "simulation routine aseptic production process" "continuous three batches produced" filling simulation test, of course, According to the importance of "deviation change, repair and replacement key, length of time of production", the necessary risk assessment can completely rules "medium filling simulation validation" 1, 2, 3 are acceptable.
2, so the rules and regulations "medium filling simulation test should be according to the production process usually once per half a year, every time a batch of" at least, should understand as if there is no "significant deviation changes, major maintenance, production for a long time" phenomenon, should be "according to the production process for each production process every six months for one time at least one batch of" as much as possible, and in "between the normal production of the product batch" medium filling simulation test of the worst "condition".
3. The worst condition of periodic "medium simulated filling test" shall still meet all the conditions mentioned above!
Therefore, the following conditions may not be considered as the "worst conditions" in the "conventional aseptic production process" :
1. Equipment, equipment, components Just finished cleaning, disinfection, sterilization (SIP), that is to start the simulated filling test of culture medium. This is not the worst case, this is the best case.
2. The maximum storage time of sterile materials and liquid did not reach before the actual filling, or the maximum storage time was not covered in the simulated filling process.
3. The sterile environment has just been cleaned, sterilized and sterilized, that is, the simulated filling test of culture medium is started. This is not the worst case, this is the best case.
Just replace filters, 4, and HVAC system equipment just for routine maintenance, in theory is not the worst "condition", because it belongs to the "regular aseptic production process" in the situation that may occur.
However, most of the time, the choice of time point of filling test is not considered, and it is impossible to take all kinds of worst cases into consideration at the same time.
We usually see is, in order to ensure that aseptic filling simulation validation (medium) for process validation of success, we will spare no efforts to create "the most optimization of aseptic production conditions (not the worst conditions), not to think about possible" worst condition "!