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　　4. General requirements

　　一般要求

　　The guideline concerns specific requirements related to sterility, sterilisation processes and aseptic processing of sterile products and product components.

　　本指南包含與滅菌、滅菌工藝以及無菌產品和產品組份的無菌工藝相關的具體要求。

　　4.1. Requirements for the manufacture of sterile medicinal products and sterile components

　　無菌藥品和無菌組分生產的要求

　　The choice of sterilisation method or aseptic processing should be justified, see section 4.3 Selection of sterilisation method.

　　滅菌方法或無菌工藝的選擇應合理, 見第4.3 節滅菌方法的選擇。

　　All sterilisation processes should be carried out according to the instructions of the Ph. Eur. unless justified.

　　除非經過論證，否則所有滅菌工藝都應按照Ph. Eur.的規定進行。

　　All sterilisation procedures for the finished product, active substance, the excipient(s) or the containers and the name and address of the sterilisation site should be stated. A description of the sterilisation method and/or aseptic processing, including in-process controls and validation data should be provided.

　　應說明所有成品、活性物質、輔料或容器的滅菌工藝，以及滅菌地點的名稱和地址。應提供滅菌方法和/或無菌工藝的說明, 包括中控和驗證數據。

　　When parametric release of sterility is proposed, the Guideline on real time release testing (formerly Guideline on parametric release), EMA/CHMP/QWP/811210/2009-Rev1 (human products only), the Guideline on Parametric release, EMEA/CVMP/QWP/339588/2005 (veterinary products only) and the text of Ph. Eur. Chapter 5.1.1 should be taken into account.

　　當提出無菌參數放行時, 應考慮EMA/CHMP/QWP/811210/2009-Rev1《實時放行檢驗指南(僅適用於人用產品)》 (原《參數放行指南》)、EMEA/CVMP/QWP/339588/2005《參數放行指南(僅適用於獸藥產品)》和Ph. Eur. 5.1.1 章節的要求。

　　The bioburden control criteria should be specified prior to all sterilisation processes. High bioburden acceptance criteria should not be justified by the capacity of the sterilisation process or any bioburden reducing step before sterilisation. Acceptance criteria for bioburden are discussed under the relevant sub-sections of 4.1 below.

　　應明確滅菌前的生物負荷控制標準。高生物負荷接受標準不應依賴滅菌工藝的能力或滅菌前的任何生物清除步驟。以下章節4.1 的相關小節討論了生物負荷的接受標準。

　　The levels of bacterial endotoxins in the finished product can be impacted by the bioburden and bacterial endotoxins in the components (i.e. active substance, excipients and containers), and by microbiological contaminants introduced during manufacture. To ensure an acceptable level of bacterial endotoxins in the finished product, the level of microbiological contaminants of the components should be minimal. Acceptance criteria for bioburden and, where relevant, bacterial endotoxins in components and bulk solutions should be specified.

　　成品中細菌內毒素的水平可能會受到組件 (即活性物質、輔料和容器)中生物負荷和細菌內毒素的影響, 也會受到生產過程中引入的微生物汙染物的影響。為確保成品中細菌內毒素的可接受水平, 各組件的微生物汙染物水平應最低。應規定組件和待灌裝溶液的生物負荷和細菌內毒素（如適用）的接受標準。

　　All filters used in the manufacture of the finished product that come in contact with the finished product, or with any component (substance or intermediate product) incorporated in the finished product should be described and the information stated in Table3, section 4.1.5 should be provided in the quality dossier. The information should be in line with the requirements stated in Eudralex GMP Annex 1. For ATMPs, the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products should be followed.

　　應描述所有與成品接觸或與成品中任何組分 (活性成分或中間產品) 接觸的用於成品生產的過濾器，並在其質量檔案中提供章節4.1.5表3中要求的信息。這些資料應符合 Eudralex GMP 附錄1的要求。對於 ATMP, 應遵循《ATMP良好生產規範指南》。

　　If a secondary container (e.g. secondary pouch for infusion bags or blisters intended to keep the outside of the container sterile) is used to provide a specific protection to the medicinal product, the packaging process should be described, including a risk assessment, since it may affect the sterility of the finished product; for example, trapping moisture between the primary and secondary containers. Information should be provided as to when the packaging step is performed (before or after sterilisation) and any aseptic techniques employed. The proposed processes should be justified from a microbiological perspective. If the use of a secondary container means additional sterilisation of the finished product is performed, this should be justified with regard to sterility assurance and any potential impact on finished product quality.

　　如果使用二級容器 (例如用於保持輸液袋或泡罩外部無菌的外袋) 為醫藥產品提供特定保護, 則應說明包裝過程, 包括風險評估, 因為它可能會影響成品的無菌性;例如, 在內包裝容器和二級容器之間殘留水分。應提供關於何時 (滅菌前或滅菌後) 進行包裝步驟以及所採用的任何無菌技術的信息。工藝應從微生物的角度加以證明。如果使用二級容器意味著需要對成品進行額外的滅菌, 則應在無菌保證和對成品質量的任何潛在影響方面進行論證。

　　Documentation regarding sterilisation and aseptic processing to be included in the quality dossier is presented below. The documentation could, for practical reasons, be presented in connection with the item which is to be sterilised if a reference to the location of the documents is provided in section 3.2.P.3.3 or in Part 2 B. The documents may be provided for human products in sections 3.2.S.2 Manufacture, 3.2.P.2 Pharmaceutical development, 3.2.P.3 Manufacture, 3.2.P.4 Control of excipients, or 3.2.P.7 Container closure system, or for veterinary products in Part 2 A.4 Development pharmaceutics, Part 2 B.1 Manufacturing method, Part 2 C.1 Active substance, Part 2 C.2 Excipients or Part 2 C.3 Container closure systems. The documentation should be provided for all sites performing sterilisation or aseptic processing, regardless of whether the processes are performed in-house or outsourced.

　　需包含在質量檔案中的關於滅菌和無菌工藝的文件羅列如下。出於實際原因, 如果3.2.P.3.3 節或第2 b 部分提到文件的位置, 則文件可和待滅菌的物品放在一起。這些文件可在人用藥品的3.2.S.2 生產、3.2.P.2 藥品研發、3.2.P.3 生產、3.2.P.4 輔料控制，或3.2.P.7 容器封閉系統中提供；或獸藥第2部分 A.4 藥品研發, 第2部分 B.1 生產方法, 第2部分C.1活性物質, 第2部分 C.2 輔料或第2部分 C.3容器封閉系統中提供。所有進行滅菌或無菌工藝的場所都應提供文件, 無論操作是本廠執行或是外包。

　　Process parameters such as processing and holding times are assessed and agreed during the evaluation of the quality dossier. These may be further reviewed during GMP inspections, which may result in changes to the registered dossier being required.

　　在質量檔案的評估過程中, 會對工藝參數,例如工藝和保留時間進行評估和商定。這些可能會在 GMP 檢查期間進一步審查, 並可能導致需要變更註冊檔案資料。

　　4.1.1. Steam sterilisation

　　蒸汽滅菌

　　All steam sterilisation processes require a minimum lethality of F0 ≥ 8 minutes and a minimum process hold temperature of 110 °C.

　　所有蒸汽滅菌工藝都要求最低殺滅力為 f0≥8分鐘, 最低工藝溫度為110°c。

　　Sterilisation processes of different levels of lethality are presented in Table 1, along with the documentation to be included in the quality dossier. The processes in the table are presented with decreasing lethality when read from top to bottom, thus the first feasible process should be selected.

　　表1列出了不同水平的殺滅力的滅菌過程, 以及需要列入質量檔案的文件。表中的工藝從上到下殺死力逐漸降低, 因此應優先選擇上一個可行的工藝。

　　For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (≥121 °C, ≥15 min in all units) validation data for the sterilisation cycle is not required to be submitted in the quality dossier.

　　對於使用 ph. eur. 5.1.1 的參考條件進行滅菌 (所有位置≥121°c,≥15分鐘), 則無需在質量檔案中提交滅菌周期的驗證數據。

　　If used as an additional control to measure the process lethality, F0, should be stated, together with the lowest temperature measured by the temperature sensors to determine F0.

　　如果使用f0作為監測工藝殺滅力的額外控制, 則應說明 f0, 並由溫度傳感器測得的最低溫度來確定 f0。

　　Steam sterilisation performed with finished product temperature below 115 °C during the holding phase is an exceptional case and should be scientifically justified and supported by additional data as described in Table 1. If temperatures below 110 °C are included (during heat-up and cool-down) in the determination of F0, this should be justified.

　　成品溫度低於115°c的蒸汽滅菌保持階段是一種特殊情況, 應進行論證, 並有表1所述的其他數據的支持。如果 f0 的測定中包括低於110°c 的溫度 (在加熱和冷卻過程中), 則應進行論證。

　　Information regarding the F0 concept and microbial reduction is provided in Ph. Eur. 5.1.5 Application of the F0 concept to steam sterilisation of aqueous preparations.

　　關於 f0 概念和微生物降低的信息載於 ph. eur. 5.1.5 f0 概念在水製劑蒸汽滅菌中的應用。

　　The bioburden limit should be in line with any pre-sterilisation bioburden reduction process capability (e.g. filtration). For aqueous solutions, the limits stated in Table 1 are acceptable for active substances and drug product formulations without further justification. Other testing regimes and limits to control bioburden at the defined level should be justified.

　　生物負荷限度應與任何預滅菌生物負荷降低工藝能力 (如過濾) 一致。在沒有特殊說的情況下，對於水溶液， 表1所述的限度對於活性物質和藥物產品製劑是可以接受的。其他控制生物負荷在既定水平的測試方法和限度應進行論證。

　　Moist heat processes with an F0 < 8 min may be suitable as a post-aseptic processing terminal heat treatment for formulations that cannot withstand a complete terminal sterilisation cycle. Such processes may further ensure a SAL of sterile filtered (or otherwise sterilised) bulk components, which have been aseptically filled. Post-aseptic processing terminal heat treatments are also presented in Table 1.

　　f0 < 8分鐘的溼熱處理工藝可作為無菌處理後的終端熱處理, 適用於無法承受完整的終端滅菌程序的情況。此類工藝可進一步確保無菌過濾 (或以其他方式滅菌) 的散裝組件經無菌分裝後的SAL。無菌處理後終端熱處理也見表1。

　　It is emphasised that this additional post-aseptic processing terminal heat treatment should not compensate for poor aseptic manufacturing practice. The same requirements for the aseptic part of the process apply as for finished products manufactured without such an additional post-aseptic processing terminal heat treatment.

　　需要強調的是, 這種額外的無菌加工終端熱處理不應作為不良無菌生產操作的補償。這與沒有額外無菌加工終端熱處理在無菌工藝部分的要求是一樣的。

　　Validation data to be provided in the quality dossier for all steam sterilisation processes that do not fulfil the requirements of Ph. Eur. 5.1.1 standard process (required information 7 in Table 1):

　　對於不符合 ph. eur. 標準工藝要求的所有蒸汽滅菌工藝, 需在質量檔案中提供的驗證數據 (表1中所需信息 7):

　　Load mapping of the chamber and load mapping distribution of the items in the chamber (including the slowest to heat locations); summary or confirmation of performance.

　　腔體的裝載布置和腔體中物品的裝載熱分布（包括加熱最慢的位置）; 性能確認總結。

　　Physical and biological cycle effect confirmation summary of at least three sterilisation runs demonstrating an SAL ≤10-6, as described in Ph. Eur. 5.1.1 ensuring:

　　至少三次滅菌程序的物理和生物效果確認總結, 顯示SAL≤10-6, 如 ph. Eur第5.1.1章節的要求:

　　Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle parameters, including time, temperature, pressure and F0, if applicable;

　　顯示滅菌腔室中的滅菌負荷達到規定的循環參數, 包括時間、溫度、壓力和 f0 (如適用);

　　Acceptable temperature differences between temperature sensors in the load;

　　裝載中溫度傳感器之間可接受的溫差;

　　Acceptable F0 variability within the load;

　　負載內可接受的 f0 波動;

　　Relationship between physical and biological validation.

　　物理驗證和生物驗證之間的關係。

　　For the biological validation, a biological indicator as described in Ph. Eur. chapter 5.1.2 Biological indicators and related microbial preparations used in the manufacture of sterile products with a D121-value of ≥1.5 minutes should be used.

　　對於生物驗證, 應使用Ph.Eur. 5.1.2章節 「用於無菌產品生產的生物指示劑和相關微生物製品無菌產品的相關微生物製劑」中規定的D121℃≥1.5分鐘的生物指示劑。

　　The SAL should be determined, its microbiological basis should be justified and details of calculations provided in the quality dossier. Preferably it should be calculated from the maximum bioburden per container and the D-value of the biological indicator used in the validation.

　　應確定SAL，其微生物基礎應合理，並在質量檔案中提供計算細節。最好是根據每個容器的最大生物負荷和驗證中使用的生物指示劑的D值計算。

　　Additional validation data to be provided in the quality dossier for low energy steam processes or where a bio-indicator with a D121-value of <1.5 minutes is used in the validation of the sterilisation process (required information 8 in Table 1):

　　在低殺滅率蒸汽滅菌工藝的質量檔案中提供的補充驗證數據,或在滅菌過程的驗證中使用D121值<1.5分鐘的生物指示劑的情況下需提供的補充驗證數據(表1中所需信息 8):

　　The following additional data should be provided:

　　應提供以下補充數據:

　　A justification for the start point of the sterilisation phase, that is the temperature when the temperature sensors record the F0 from the start to end of the process;

　　論證滅菌階段的起點，即滅菌開始至結束溫度探頭用於記錄f0的溫度;

　　Biological indicators with suitable resistance at the actual temperature range as described in Ph. Eur. 5.1.2 should be included in the validation to demonstrate sensitivity to the process.

　　驗證應包括在 Ph.Eur.第5.1.2章中所述的實際溫度範圍內具有適當阻力的生物指示劑，以證明對工藝的敏感性。

　　More detailed validation data is requested to ensure that the proposed sterilisation process is suitable for low temperature processes and for processes using biological indicators of low heat resistance because:

　　需要更詳細的驗證數據, 以確保建議的滅菌工藝適用於低溫工藝和使用低耐熱性生物指示劑的工藝, 因為:

　　The change in lethal effect in relation to the process temperature may not be log linear at lower sterilisation temperatures.

　　在較低的滅菌溫度下, 殺滅效率與工藝溫度的變化可能不是對數線性的。

　　The SAL demonstrated in the validation of a sterilisation process is dependent on the heat resistance of the biological indicator used in the validation of the process. When a biological indicator of low D-value is used in the validation of the sterilisation process, the SAL demonstrated becomes numerically higher, but does not provide as high a safety margin as where a more resistant biological indicator is used. The SAL should always be established in relation to a D-value that is higher than that of the normal bioburden at routine production.

　　在滅菌工藝的驗證中顯示的SAL取決於在驗證過程中使用的生物指示劑的耐熱性。當在滅菌過程的驗證中使用低D值的生物指示劑時， 所顯示的SAL會變得更高，但不能提供與使用更耐熱的生物指示劑那樣高的安全係數。SAL應該始終與D值相關，D值高於常規生產中的正常生物負荷。

　　4.1.2. Dry heat sterilisation

　　乾熱滅菌

　　Time and temperature of the sterilisation cycle and a bioburden limit should always be stated.

　　通常應說明滅菌周期的時間和溫度以及生物負荷限度。

　　For sterilisation using a reference condition of the Ph. Eur. 5.1.1 (a minimum of 160 °C for at least 2 h), the validation data for the sterilisation cycle is not required to be submitted in the quality dossier. For sterilisation cycles with time and/or temperature lower than the reference conditions of the Ph. Eur., physical and biological validation of the sterilisation cycle should be provided to demonstrate an SAL of ≤10-6, as described in Ph. Eur. 5.1.1. The SAL of such a sterilisation process should be calculated from the maximum bioburden per container.

　　對於使用 ph. eur. 5.1.1 的參考條件 ( ≥160℃至少2小時 ) 進行滅菌, 滅菌周期的驗證數據不需要在質量檔案中提交。對於時間和溫度低於藥典參考條件的滅菌周期，應提供滅菌周期的物理和生物驗證, 以證明 SAL≤10-6。這種滅菌工藝的SAL應根據每個容器的最大生物負荷計算。

　　Where required, sufficient validation data should be submitted to demonstrate that an SAL of ≤10-6 is obtained for all containers. The data submitted should include at least, but is not limited to:

　　必要時，應提交足夠的驗證數據, 以證明所有容器都能獲得≤10-6 的 sal。提交的數據至少應包括但不限於:

　　腔體負載分布和箱體中物品負載的分布 (包括最慢加熱位置)--性能的總結或確認;

　　Physical and biological cycle effect confirmation summary of at least three sterilisation runs ensuring:

　　至少3次的物理和生物性能確認總結, 以確保:

　　Demonstration that the sterilisation load in the steriliser chamber achieves the specified cycle parameters, including time, temperature, and, lethality;

　　證實滅菌器腔體中的滅菌負載達到規定的循環參數, 包括時間、溫度、殺滅力等;

　　負載中溫度傳感器之間可接受的溫差;

　　Acceptable lethality variability within the load;

　　負載內殺滅率的可接受波動範圍;

　　物理和生物驗證之間的關係。

　　For the biological validation, a biological indicator as described in Ph. Eur. chapter 5.1.2 should be used.

　　對於生物驗證, 應使用5.1.2 所述的生物指示劑。

　　A maximum bioburden limit of 100 CFU/100 g or 100 CFU/100 ml would be acceptable for parenteral finished product formulations without further justification. For active substances and finished products that are not used for parenteral administration, a maximum total bioburden limit of 10 CFU/g or 10 CFU/ml is acceptable without further risk based justification. Other testing regimes and limits to control bioburden at the defined level should be justified. A justified bioburden limit should also be established for empty containers.

　　對於腸外成品配方, 在沒有進一步說明的情況下, 最大生物負荷限制為 100 cfu/100 g 或 100 cfu/100 毫升是可以接受的。對於不用於腸外給藥的活性物質和成品, 最大總生物量限制為 10 cfu/g或 10 cfu/ml 是可以接受的, 沒有進一步基於風險說明。其他用以控制生物負荷在規定水平內的方法和限度應進行論證。對於空的容器，也應建立合理的生物負荷限度。

　　Dry heat at temperatures of greater than 220 °C for a validated time is frequently used for both sterilisation and depyrogenation of glassware and other heat-resistant container materials e.g. aluminium crimps. In this case, demonstration of a 3 log reduction in heat-resistant endotoxins can be used as validation criteria.

　　在溫度大於220°c 的情況下, 在經過驗證的時間內進行乾熱, 通常用於玻璃器皿和其他耐熱容器材料的滅菌和去熱原。在這種情況下, 可將耐熱內毒素下降3個log作為驗證標準。

　　4.1.3. Ionization radiation sterilisation

　　電離輻射滅菌

　　For this method of sterilisation, the reference absorbed dose is ≥25 kGy. Other doses may be used to achieve an SAL ≤106, if justified and validated.

　　對於這種滅菌方法, 參考吸收劑量≥25 kGy。如經論證和驗證，也可以使用其他劑量以達到 sal≤10-6。

　　Data as requested in Note for Guidance 「The use of Ionization Radiation in the Manufacture for Medicinal Products」 and in compliance with Ph. Eur. chapter 5.1.1 should be provided. Relevant guidance in establishing the radiation dose other than 25 kGy is available in ISO standard 11137.

　　應提供指南《藥品生產中使用電離輻射》中要求的數據, 並符合 ph. eur 5.1.1 章的要求。ISO 標準11137提供了確定 25 kgy 以外的輻射劑量的相關指導。

　　Where any requirements in ISO 11137 are in contradiction to requirements stated in any Note for Guidance issued by the EMA or Ph. Eur. monograph, the requirements of the Ph. Eur. and the Note for guidance apply.

　　如果 ISO 11137 中的任何要求與 ema 或 ph. eur. 專論發布的任何指導說明中的要求相牴觸, 則應使用 ph. eur. 和指南的要求。

　　4.1.4. Gas sterilisation

　　氣體滅菌

　　4.1.4.1 General considerations

　　一般考慮

　　Generally, gas sterilisation is only acceptable if no other method of sterilisation is possible. Gas sterilisation provides sterilisation of the surface of materials. It is mainly employed for sterilising packaging materials and equipment, and has therefore only been included in the decision tree for containers. To ensure adequate sterility, sufficient penetration by gas and moisture is essential. This should be followed by a purging process to ensure that any residues of gas or related transformation by-products are below concentrations that could give rise to toxic effects during use of the finished product. The effectiveness of the purging process should be demonstrated.

　　一般來說, 只有在沒有其他滅菌方法的情況下, 氣體滅菌才是可以接受的。氣體滅菌可對材料表面進行滅菌。它主要用於對包裝材料和設備進行滅菌, 因此只包括在容器的決策樹中。為了確保足夠的無菌性, 氣體和水分的充分滲透是必不可少的。氣體滅菌結束後應採取清除工藝, 以確保氣體或相關轉化副產品的任何殘留物低於可能導致成品使用過程中產生毒性影響的濃度。應證明清除過程的有效性。

　　Gas sterilisation of porous compounds, such as dry powders, is not acceptable unless other methods of sterilisation are not feasible and its use is scientifically justified. Prior to the gas sterilisation, the active substance or excipient should be sterile filtered and crystallised under aseptic conditions to minimise bioburden and entrapment of micro-organisms within the crystals. Convincing evidence should be provided demonstrating that the material to be sterilised is not susceptible to compression preventing gas and moisture penetration during sterilisation.

　　對多孔化合物 (如乾粉體) 進行氣體滅菌是不可接受的, 除非其他滅菌方法不可行且使用該方法經科學論證。在氣體滅菌之前, 活性物質或輔料應在無菌條件下進行無菌過濾和結晶, 以最大限度地減少微生物在晶體中的吸收和包裹。應提供令人信服的證據, 證明待滅菌的材料在滅菌過程中不易擠壓，防止氣體和水分滲透。

　　A description of the apparatus, quantitative data on gas(es) to be used, the bioburden prior to sterilisation, the time of exposure to the gas, the temperature and humidity prior to and during each step of the sterilisation cycle, and, if applicable, the conditions for the removal of any toxic gas residues should be provided. Humidity used for the preconditioning and/or conditioning of the material to be sterilised shall be generated by clean steam. These conditions should be monitored by appropriate in-process controls with justified acceptance criteria. The process should be developed and validated in compliance with Ph. Eur. 5.1.1 and 5.1.2. A risk assessment with regards to residual toxic impurities should be conducted and a control strategy should be provided where applicable. The requirements should be in accordance with the requirements of ICH M7 「Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk」. Even if the relevant product is outside the scope of that guideline, its limits for highly toxic impurities could be applied.

　　應提供設備說明、要使用的氣體的定量數據、滅菌前的生物負荷、接觸氣體的時間、滅菌周期每一步開始前和期間的溫度和溼度, 以及，適當時，清除任何有毒氣體殘留的條件。用於對待滅菌材料進行預處理和/或調節的溼度應通過清潔蒸汽產生。這些條件應通過適當的過程控制和合理的接受標準進行監測。應按照 ph. eur. 5.1.1 和5.1.2 制定和驗證這一程序。應對殘留有毒雜質進行風險評估, 並酌情提供控制戰略。這些要求應符合 ich m7 「評估和控制藥品中的 dna 反應性 (誘變) 雜質以限制潛在致癌風險」。即使相關產品超出了該準則的適用範圍, 也可以使用其對劇毒雜質的限度。

　　Results of the process validation should demonstrate an SAL of ≤10-6.

　　工藝驗證的結果應證明 sal ≤10-6。

　　The effectiveness of the process should be routinely checked for every batch confirming that the process parameters and biological indicators are all within their acceptance criteria and by sterility testing. Parametric release is not acceptable for gas sterilisation (according to Ph. Eur. chapter 5.1.1).

　　應檢查每一批工藝的有效性, 確認工藝參數和生物指示劑都在其接受標準範圍內, 並通過無菌測試。參數放行對於氣體滅菌是不可接受的 (根據5.1.1 頁)。

　　4.1.4.2 Ethylene oxide sterilisation

　　環氧乙烷滅菌

　　Ethylene oxide (ETO) sterilisation processes should be developed and validated in compliance with Ph. Eur. 5.1.1 and 5.1.2. Relevant guidance in establishing the sterilisation process cycle parameters and validation is available in ISO standard 11135.

　　應按照 ph. eur 5.1.1 和5.1.2 開發和驗證環氧乙烷 (eto) 滅菌工藝。iso 標準11135提供了在確定滅菌工藝循環參數和驗證方面的相關指導。

　　ETO is a gas which is highly toxic. ETO sterilisation is generally only acceptable if no other method of sterilisation is possible. The risk assessment should consider the residual known genotoxic impurities (such as ETO and halogenated ethylenehydrines). This should be evaluated in accordance with the requirements of ICH M7 「Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk」, unless the relevant product is outside the scope of that guideline. For products outside the scope of ICH M7, the applicant should apply limits for highly toxic impurities in accordance with ICH M7, or the acceptance criteria stated in Table 2, whichever is most appropriate.

　　eto 是一種劇毒氣體。eto 滅菌通常只有在沒有其他滅菌方法的情況下才可接受。風險評估應考慮已知的殘留遺傳毒性雜質 (如 eto 和滷化乙二氫)。應根據 ich m7 "評估和控制藥品中的 dna 反應性 (誘變) 雜質以限制潛在致癌風險" 的要求對此進行評估, 除非相關產品不在該指南的範圍之內。對於 ich m7 範圍以外的產品, 申請人應根據 ich m7 或表2中規定的接受標準對劇毒雜質實施限制, 以最適當者為準。

　　For empty containers intended to be filled with aqueous products, (e.g. prefilled syringes), the need to justify the use of ETO in the sterilisation of the container prior to filling can be waived, as the degradation kinetics of ETO in an aqueous medium have been sufficiently demonstrated. However, the levels of toxic residues (ETO and halogenated ethylenehydrines) in the finished product need to fulfil the requirements of ICH M7, or the limits stated in Table 2 below, as applicable.

　　對於打算裝滿水性產品的空容器 (例如預填充注射器), 可以免除對灌裝前使用ETO對容器滅菌的論證，因為ETO在水介質中的降解動力學已經充分證明。但是, 成品中毒性殘留物 (ETO 和滷化乙基氫) 的含量需要滿足 ich m7 的要求，或者適當時，滿足下文表2所述的限度。

　　Table 2 Limits for toxic gas residues fromethylene sterilisation where the ICH M7 limits do not apply

　　在不適用 ich m7 限度的情況下, 乙烯滅菌產生的有毒氣體殘留限值

　　

　　4.1.5. Sterile filtration

　　除菌過濾

　　The integrity of the sterilised filter should be verified by testing before use unless specifically justified and validated, and should be verified by on line testing immediately after use. Nominal pore sizes of 0.22 m or less are acceptable without further justification, in accordance with Ph. Eur.

　　除非有明確的證明和驗證，除菌過濾器的完整性應在使用前通過測試進行確認, 並應在使用後立即通過在線測試進行確認。根據 ph. eur., 在沒有進一步理由的情況下, 可以接受0.22μm 或以下的公稱孔徑。

　　For routine commercial manufacturing, bioburden testing should be performed on the bulk solution immediately before sterile filtration.

　　對於日常的商業生產, 應在除菌過濾前立即對溶液進行生物負荷測試。

　　In most situations, a limit of NMT 10 CFU/100 ml (TAMC) would be acceptable for bioburden testing. If a pre-filter is added as a precaution only and not because the unfiltered bulk solution has a higher bioburden, this limit is applicable also before the pre-filter and is strongly recommended from a GMP point of view. A bioburden limit of higher than 10 CFU/100 ml before pre-filtration may be acceptable if this is due to starting material known to have inherent microbial contamination. In such cases, it should be demonstrated that the first filter is capable of achieving a bioburden of NMT 10 CFU/100 ml prior to the last filtration. Bioburden should be tested in a bulk sample of 100 ml in order to ensure the sensitivity of the method. Other testing regimes to control bioburden at the defined level should be justified.

　　在大多數情況下, 生物負荷測試可以接受 ≤ 10 cfu/100 ml (總需氧菌計數) 的限度。如果添加預過濾器僅為預防措施, 而不是因為待過濾溶液生物負荷過高， 則此限度也適用於預過濾器之前，並且從GMP角度考慮也是強烈建議如此。如果由於起始材料已知具有固有微生物汙染, 在預過濾前生物負荷限度高於 10 cfu/100 ml 可能是可以接受的。在這種情況下, 應證明第一個過濾器能夠達到在後一個過濾器之前達到≤10 cfu/100 ml 的生物負荷。生物負荷應該在100毫升的溶液中進行測試, 以確保該方法的敏感性。其他用以控制生物負荷在規定水平的測試方法應進行論證。

　　The maximum time between the start of bulk solution preparation and sterile filtration should be stated, minimised and appropriately supported by data. Filtration times longer than 24 hours should be justified.

　　應說明和最大限度減少從溶液配製到除菌過濾之間的最長時間間隔，並有數據支持。過濾時間超過24小時應進行論證。

　　If a sterile filtered bulk solution is not filled into the final product containers within 24 hours, the sterile filtration should, unless justified, be repeated immediately before filling. An additional bioburden test should be performed before any further bioburden reduction step after the holding time. The holding time should be adequately justified.

　　如果無菌過濾溶液未在24小時內灌入最終產品容器, 除非經論證, 否則應立即重新進行無菌過濾才能灌裝。一旦超出保持時間，在任何進一步減少生物負荷的步驟之前， 應進行額外的生物負荷檢驗。保持時間應進行充分論證。

　　4.1.6. Aseptic processing

　　無菌工藝

　　Aseptic processing is not considered to be a sterilisation process but concerns the usage of technologies to process sterile components avoiding addition of microbiological contaminants, e.g. use of an isolator or Restricted Access Barrier System (RABS).

　　無菌處理不被認為是滅菌過程, 但涉及使用無菌部件進行加工的技術，需要避免引入微生物汙染，例如使用隔離器或受限進入屏障系統 (rabs)。

　　For aseptic processing, information on the bulk holding time before filling and on the filling time should be stated and appropriately supported by data. The times should be minimised. The grounds for holding and filling times longer than 24 hours should be justified and supported by a risk assessment. It should be verified that the results of the media simulations support the proposed holding and processing times. The actual results of media simulations fall within the field of GMP and need not be presented routinely, but may be requested by the competent authorities in certain circumstances since such data are important to justify proposed holding and filling times.

　　對於無菌處理, 應說明灌裝前的保持時間和灌裝時長的信息, 並有適當的數據支持。時間應儘量減少。保持時間和灌裝時長超過24小時的理由應得到風險評估的論證和支持。應當核實的是, 培養基模擬灌裝的結果支持了擬議的保持時間和處理（灌裝）時長。培養基模擬灌裝的實際結果屬於GMP領域， 不需要例行提出，但在某些情況下, 主管當局可能會提出要求, 因為這類數據對於證明擬議的保持時間和灌裝時長的合理性是很重要的。

　　Sterile containers should be used for aseptically treated active substances, excipients and finished products.

　　經無菌處理的活性物質、輔料和成品應使用無菌容器。

　　Where blow-fill-seal technology is used for aseptically treated products, a summary of the validation data should be provided to confirm that the container produced is sterile. The validation should, using a biological indicator with a suitable resistance, demonstrate a SAL of ≤10-6 for the surface of the container. The bioburden of the material(s) used for the manufacture of the blow-fill-seal container should be controlled. The limit should be justified in relation to the lethality of the validated blow-fill-seal process. The bioburden limit should also include a safety margin as a for any possible bioburden enclosed within the material.

　　當吹-灌-封技術用於在無菌處理產品時，應提供驗證數據總結, 以確認所生產的容器是無菌的。驗證應使用具有適當耐受性的生物指示劑, 證明容器表面的 SAL≤10-6。應控制用於製造吹-灌-封容器的材料的生物負荷。生物負荷的限度應結合吹-灌-封工藝的殺滅力進行論證。生物負荷限度還應包括安全係數，以防止材料中包含的任何可能的生物負荷。

　　The majority of ATMPs cannot be terminally sterilised. In such cases, the manufacturing process should be conducted aseptically. Further details on aseptic manufacturing for ATMPs can be found in the Guidelines on Good Manufacturing Practice for Advanced Therapy Medicinal Products.

　　大多數ATMP不能進行最終滅菌。在這種情況下, 生產過程應無菌。有關 ATMP無菌生產的更多詳細信息，請參見《先進治療藥品良好生產規範指南》。

　　4.2. Good manufacturing practice for sterile active substances, sterile excipients and sterile containers

　　無菌活性物質、無菌輔料和無菌容器GMP

　　Volume 4 of "The rules governing medicinal products in the European Union" contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively. For Advanced Therapy Medicinal Products, the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products should be followed.

　　《歐盟藥品管理法》第4卷載有解釋委員會規定的人用和獸用醫藥產品GMP的原則的指南。對於高級治療藥品, 應遵循《高級治療藥品的良好生產規範指南》。

　　4.2.1. Active substances

　　活性成分

　　The basic GMP requirements for active substances used as starting materials (European Union (EU) GMP guide part II) apply to the manufacture of sterile active substances up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not covered by EU GMP Part II but should be performed in accordance with the principles and guidelines of GMP as laid out in the relevant EU Directive and interpreted in the GMP Guide including its Annex 1.

　　作為起始物料的活性物質的基本GMP要求 (歐盟 (EU) GMP指南 第二部分 ) 適用於無菌活性物質在進入無菌步驟之前的生產。無菌活性成分的滅菌和無菌處理不在歐盟 GMP 第二部分的範圍內, 但應按照歐盟相關指令中的規定和 GMP指南中 解釋的GMP 原則和指南進行, 包括其附錄1。

　　The sterilisation and aseptic processing of active substances is considered to be a step in the manufacture of the medicinal product. This implies that for any active substance manufacturer who performs sterilisation and subsequent aseptic handling of the active substance, a valid manufacturing authorisation or GMP certificate from an EEA authority or from an authority of countries where mutual recognition or other Community arrangements apply has to be submitted.

　　活性物質的滅菌和無菌加工被認為是藥品生產的一個步驟。這意味著，對活性物質進行滅菌及隨後無菌處理的任何活性物質生產商，需要提交EEA藥監局，或MRA國家藥監局頒發的有效的生產許可或GMP證書。

　　The same GMP and data requirements also apply to sterile active substances supported by a Certificate of Suitability issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM) or described in an Active Substance Master File (ASMF).

　　同樣的GMP 和數據要求也適用於由EDQM頒發的符合性證書支持的無菌活性物質, 或在活性物質主文件 (ASMF) 中描述的無菌活性物質。

　　4.2.2. Excipients

　　輔料

　　All the excipient sterilisation sites should be stated by name and address in the dossier.

　　所有的輔料滅菌工廠都應在檔案中註明名稱和地址。

　　For excipients required to be sterile (i.e. those subsequently used in an aseptic manufacturing process), the site where sterilisation of the excipients takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity. Nevertheless the sterilisation of an excipient is a critical process and the sterility of the excipient is a critical quality attribute to ensure the sterility of the finished product. When a GMP certificate is not available, a statement should be provided confirming that the finished product manufacturer has evaluated all the manufacturers of sterile excipients with regards to their quality system related to the sterilisation of the excipient. For products for human use this evaluation should be conducted in line with the (GMP) Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use by taking into account the specific requirements of Annex 1 of EU GMP-Guidelines.

　　對於需要無菌的輔料 (例如，直接用於無菌生產過程的輔料)， 對輔料進行滅菌的工廠可能沒有經過歐盟當局的檢查, 因此可能無法持有與此活動相關的歐盟GMP證書。然而, 輔料的滅菌是一個關鍵的過程, 輔料的無菌性是確保成品無菌的一個關鍵的質量屬性。在沒有GMP證書的情況下, 應提供一份聲明, 確認成品生產商已對所有無菌輔料生產商進行了與輔料滅菌相關的質量體系評價。對於人用藥品，這一評價應按照2015年3月19日發布的關於正式風險評估的 (GMP) 指南進行，考慮歐盟GMP附錄1的具體要求，以確定所適用的人用藥品輔料的GMP。

　　4.2.3. Containers

　　容器

　　For containers required to be sterile (i.e. those subsequently used in an aseptic manufacturing process), the site where sterilisation of the containers takes place may not have undergone inspection by an EU authority and consequently may not hold an EU GMP certificate in relation to this activity1. When a GMP certificate is not available, certification that the sterilisation has been conducted and validated in accordance with the following ISO standards would be considered sufficient to provide an acceptable level of sterility assurance for the empty container:

　　對於需要無菌的容器 (例如直接用於無菌生產過程容器)， 對容器進行滅菌的工廠可能沒有經過歐盟當局的檢查, 因此可能沒有持有與此活動相關的歐盟GMP證書。在沒有GMP證書的情況下, 證明已按照以下 ISO標準進行滅菌和驗證，將被視為足以提供適當無菌保證水平的容器：

　　1.I.S. EN ISO 20857 Sterilization of Health Care Products - dry Heat - Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices;

　　2.I.S. EN ISO 11135 Sterilization of Health-care Products - Ethylene Oxide - Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices;

　　3.I.S. EN ISO 17665-1 Sterilization of Health Care Products - Moist Heat - Part 1: Requirements for the Development, Validation and Routine Control of a Sterilization Process for Medical Devices, and, ISO/TS 17665-2 Sterilization of health care products -- Moist heat -- Part 2: Guidance on the application of ISO 17665-1;

　　4.I.S. EN ISO 11137-1 Sterilization of Health Care Products - Radiation - Part 1: Requirements for Development, Validation and Routine Control of a Sterilization Process for Medical Devices;

　　5.I.S. EN ISO 11137-2 Sterilization of Health Care Products - Radiation - Part 2: Establishing the Sterilization Dose;

　　6.I.S. EN ISO 11137-3 Sterilization of Health Care Products - Radiation - Part 3: Guidance on Dosimetric Aspects.

　　It is the responsibility of the manufacturer of the medicinal product, to ensure the quality, including sterility assurance, of containers. The site where QP certification of the finished product takes place, and other manufacturing sites which are responsible for outsourcing this sterilisation activity, should have access to the necessary information to demonstrate the ongoing qualification status of suppliers of this sterilisation service. This may be checked during inspections of the manufacturer of the finished product. The Competent Authorities may also decide, based on risk, to carry out their own inspections at the sites where such sterilisation activities take place.

　　藥品生產商有責任確保容器的質量，包括無菌保證。對成品進行QP的工廠，以及負責將這一滅菌活動外包的其他製造工廠, 應能獲得必要的信息, 以證明此滅菌服務供應商的持續確認狀態。這可能會在成品生產商的檢查過程中進行檢查。主管當局還可根據風險決定對進行此類滅菌活動的工廠進行自己的檢查。

　　Quality Dossier requirements

　　質量檔案要求

　　The following details regarding the sterilisation of the container components should be included in the quality dossier:

　　關於容器部件滅菌的以下細節應包括在質量檔案中:

　　1.The sterilisation method and sterilisation cycle;

　　滅菌方法和滅菌周期

　　2.Validation of the sterilisation cycle if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.;

　　如果滅菌周期不使用 ph. Eur 中規定的參考條件, 則驗證滅菌周期;

　　3.The name and address of the site of sterilisation and, where available*, details of GMP certification of the site.

　　滅菌現場的名稱和地址, 以及現場 GMP 認證的詳細信息（如適用） *。

　　*Where the container component is a CE-marked Class Is sterile device (e.g. sterile syringe), a declaration from the device manufacturer that the component is a Class Is sterile device, together with a copy of the certificate of conformity from the Notified Body will suffice. In the absence of a GMP certificate or declaration that the component is a CE-marked Class Is medical device, confirmation by finished product manufacturer that the sterilisation process has been conducted and validated in accordance with the relevant ISO standards should be provided.

　　* 如果容器組件是 CE標誌等級I的無菌器械 (例如無菌注射器)，則一份來自該器械生產商聲明該組件是等級I無菌器械的聲明，以及認證機構提供的符合性證書副本，足夠。在沒有 GMP 證書或聲明組件是CE標誌等級I 醫療器械的情況下, 應提供成品製造商確認已按照相關 ISO 標準滅菌和驗證的證明。

　　4.3. Selection of sterilisation method

　　滅菌方法的選擇

　　Finished products intended to be sterile should be terminally sterilised in their final container whenever possible, as clearly stated in the Ph. Eur., general chapter 5.1.1. Similarly, active substances, excipients and containers when required to be sterile should be packed before they are sterilised whenever possible. When terminal sterilisation by heat is not possible, the application of an alternative method of terminal sterilisation, sterilising filtration and/or aseptic processing may be considered. It is recognised that terminal sterilisation processes utilising conditions other than the Ph. Eur. reference conditions may be developed to provide satisfactory SALs and such alternative processes may be acceptable when properly designed, validated and controlled.

　　歐洲藥典通論5.1.1 中明確指出, 無菌成品應儘可能在其最終容器中進行最終滅菌。同樣, 需要無菌時, 活性物質、輔料和容器應包裝好，然後儘可能進行滅菌。當不可能用熱進行終端滅菌時, 可以考慮採用一種替代的方法，如終端滅菌、除菌過濾和/或無菌處理。應認識到可以開發歐洲藥典參考條件以外的其他終端滅菌工藝，以提供令人滿意的SAL，這種替代工藝如經適當設計、驗證和使用，是可以接受的。

　　If a sterilisation process using principles other than those described in the Ph. Eur. (steam, dry heat, ionising radiation, gas sterilisation and sterilising filtration) is intended to be used for the sterilisation of an active substance, excipient, container or finished product, the applicant may consider seeking scientific advice regarding the acceptability of the method and the documentation required.

　　如果使用歐洲藥典中(蒸汽、乾熱、電離輻射、氣體滅菌和除菌過濾)以外的其他滅菌方法對活性物質、輔料、容器或成品進行滅菌，申請人可考慮就該方法的可接受性和所需文件尋求科學意見。

　　During the manufacturer’s evaluation of whether a terminal sterilisation cycle is possible, substantial efforts should be made to enable terminal sterilisation. If the active substance or another component of the finished product is shown to degrade significantly or an impurity limit is exceeded during shelf-life under even the least stressful terminal sterilisation conditions, the efforts made to develop a formulation and container capable of undergoing terminal sterilisation should be presented in the development section. Such efforts could be selection of optimal pH, choice of excipients (qualitative and quantitative), container, optimisation of sterilisation method and manufacturing conditions.

　　在生產商評估是否有可能進行最終滅菌的過程中，應儘可能使用終端滅菌。如果即使在最緩和的最終滅菌條件下, 活性物質或成品的其他成分在其有效期內仍會明顯下降或雜質超標，則應在開發部分展示為開發耐受最終滅菌配方和容器所做的努力。這些努力可以包括選擇最佳 ph 值、選擇輔料 (定性和定量)、容器、優化滅菌方法和生產條件。

　　In case of medicinal products containing highly sensitive active substances, (e.g. proteins or other heat labile biological substance), where it is well known that terminal sterilisation is not possible, a justification based on a scientific rationale is generally acceptable and further justification of the choice of aseptic processing discussed later in section 4.3 may not be needed.

　　如果是含有高敏感性的活性物質 (如蛋白質或其他熱不穩定的生物物質) 的醫藥產品, 眾所周知, 不可能進行最終滅菌, 基於科學合理的論證通常是可以接受的，不需要進一步論證選擇第4.3 節無菌加工的理由。

　　The principles for the choice of sterilisation process for finished products and containers are presented in the form of decision trees in section 5 of this guideline. The principles of the decision trees may also be applied for the sterilisation of active substances and excipients.

　　本指南第5節以決策樹的形式介紹了成品和容器滅菌工藝選擇的原則。決策樹的原則也可適用於活性物質和輔料的滅菌。

　　For finished products where terminal sterilisation is not possible and aseptic processing is proposed, the decision trees should be applied to individual components or mixtures of components in the formulation. An impact on the shelf-life or storage conditions caused by a terminal sterilisation process is not in itself a reason to exclude terminal sterilisation, unless the new storage condition or shelf-life would cause significant problems for the user.

　　對於不可能進行最終滅菌並擬進行無菌處理的成品，決策樹應應用於配方中的單個組件或組件組合。最終滅菌過程對有效期或儲存條件造成的影響本身並不是排除最終滅菌的理由, 除非新的儲存條件或有效期會給用戶帶來重大問題。

　　Terminal sterilisation should not be ruled out purely on the basis of an increase in degradation products above the qualification thresholds in ICH Q3A/VICHGL10 (active substances), ICH Q3B/ VICH GL11 (finished products) or the impurity limits in ICH M7 for products in the scope of that guideline without additional justification. If impurities are either metabolites or are generated at levels already qualified, then terminal sterilisation is still considered feasible. However, if the degradation products are not qualified at the level at which they occur, then sterile filtration and aseptic processing may be selected. For medicinal products for human use impurities which occur above the identification threshold should be specified in the finished product specification.

　　不應僅僅因為降解產物增加超過 ICH Q3A/VICHGL10 (活性物質)、ICH Q3B/VICH GL11 (成品) 中的限度或ICH M7指導範圍中的產品的雜質限度，就排除最終滅菌而不進行論證。如果雜質都是代謝產物或是其產生水平經確認, 那麼最終滅菌仍然被認為是可行的。然而, 如果降解產物在發生的水平上不合格, 則可以選擇除菌過濾和無菌工藝。對於人用藥產品, 超過識別閾值的雜質應在成品標準中明確規定。

　　The risk induced by the degradation should be balanced by the risk induced with an aseptic manufacturing method, also taking in account the posology of the finished product and the nature of the degradation products. Attempts to find terminal sterilisation conditions adjusted to give acceptable impurity levels based on degradation mechanisms of the active substance and the actual bioburden should be described in the quality dossier.

　　降解引入的風險應與無菌生產方法引入的風險相平衡, 同時考慮到成品的劑量和降解產物的性質。在質量檔案中, 應說明試圖根據活性物質的降解機制和實際生物負荷，找到最終滅菌條件，調整到可接受的雜質水平。

　　In certain cases, as described in the bullet points below, the use of aseptic processing may be accepted, even if the formulation itself can be terminally sterilised. The approach should be clearly documented, explained and scientifically justified. Such cases could be justified by:

　　在某些情況下, 如下文要點所述, 即使工藝本身可以最終滅菌, 也可以使用無菌工藝。應明確記錄、解釋和科學論證這一方法。這種情況的通過以下方式論證：

　　User benefit provided by a container that cannot be terminally sterilised such as:

　　不能最終滅菌的容器有利於用戶利益, 例如:

　　Eye drop containers enabling administration of single drops to the eye;

　　能實現單滴液滴滴到眼睛裡的滴眼容器；

　　Containers enabling non parenteral multi-dose preservative free medicinal products for human use;

　　能實現人用注射劑無防腐劑的容器;

　　Enhanced ease of administration;

　　增強易管理性;

　　Safer handling of toxic products, for instance plastic vials instead of glass vials for cytotoxic medicinal products.

　　更安全地處理有毒產品，例如使用塑料瓶而不是玻璃瓶至細胞毒性藥品。

　　The choice to use a heat-labile container cannot in itself be the sole reason for not applying a terminal sterilisation process and alternative materials should be investigated. Thus, a discussion regarding the efforts made to develop a container that may be terminally sterilised should be included.

　　選擇使用熱不穩定容器本身不能成為不採用最終滅菌工藝的唯一理由，應研究替代材料。因此，應包含關於努力研究可以最終滅菌的容器的討論。

　　Enabling as long a shelf-life as possible for radiopharmaceutical medicinal products with a shelf-life of less than one week.

　　為放射性藥物醫藥產品提供不超過一周的儘可能長的保質期。

　　The acceptability of aseptic processing should be based on the application of the decision tree and a risk assessment. The bullet points below are not intended to be used to justify aseptic processing as such, but are only intended to provide guidance on issues that are considered when evaluating the acceptability of a sterilisation or aseptic processing. Considerations include (but are not limited to):

　　無菌工藝的可接受性應基於決策樹的應用和風險評估。下面的要點並非旨在用於證明無菌工藝的合理性，而僅旨在為評估滅菌或無菌工藝的可接受性時需考慮的問題提供指導。考慮因素包括（但不限於）：

　　Evidence that the proposed container with enhanced user benefits is fit for purpose;

　　提出具有增強的用戶利益的推薦容器符合目的的證據;

　　Stability of the active substance, the degradation mechanism(s) and the toxicity of impurities formed during the sterilisation process;

　　活性物質的穩定性，降解機理和滅菌過程中產生的雜質的毒性;

　　The volume to be administered per dose.

　　每劑給藥的體積

　　In conclusion, the justification for the chosen sterilisation or aseptic processing should include a thorough benefit risk evaluation and it should be demonstrated that suitable development efforts have been made.

　　總之，所選擇的滅菌或無菌工藝的理由應包括徹底的利益風險評估，並且應該證明已經進行了適當的研發工作。

　　For advanced therapy medicinal products, the microbiological quality of all components, process equipment and the aseptic techniques of the manufacturing processes are of utmost importance when the finished product cannot be sterilised. For those medicinal products that cannot be sterilised, such as cell based medicinal products, a detailed risk assessment with regards to microbial contamination should be provided. A risk based approach is already foreseen for these ATMP (see Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products, EMA/CAT/CPWP/686637/2011).

　　對於先進的治療藥品，當成品不能滅菌時，所有組分的微生物質量，工藝設備和生產工藝的無菌技術都是至關重要的。對於那些不能滅菌的藥品，如基於細胞的藥品，應提供有關微生物汙染的詳細風險評估。已經預見到這些ATMP的基於風險的方法（參見基於風險的方法指南，根據適用於高級治療藥物的指令2001/83 / EC的第IV部分附錄I，EMA / CAT / CPWP / 686637/2011）。

　　5. Decision trees

　　決策樹

　　The decision trees in Figures 1 and 2 are intended to assist in the selection of the optimal sterilisation method taking into account the various issues to be considered. When moving down the decision trees, the methods generally show a decreasing assurance of sterility and therefore, the first feasible option should normally be chosen.* The decision trees have been elaborated primarily for finished products containing chemical active substances, but may be applicable also to other types of products (including active substance and excipients). Figure 3 provides the corresponding information for empty containers. The decision tree is not applicable to sterile empty containers that are CE marked medical devices. In the case of biological products, an alternative approach may be appropriate.

　　圖1和圖2中的決策樹旨在幫助選擇最佳的滅菌方法,同時考慮到需要考慮的各種問題。決策樹越向下的方法，無菌性保證越低, 因此, 通常應選擇第一個可行的選擇. 決策樹主要針對含有化學活性物質的成品進行了詳細闡述，但也可適用於其他類型的產品（包括活性物質和輔料）。圖3提供了空容器的相應信息。決策樹不適用於有CE標記的醫療器械的無菌空容器。對於生物產品,可採用替代辦法。

　　*While sterilisation by heat and sterilisation by ionising irradiation provide the same assurance of sterility, sterilisation by heat has lower risk (e.g. radiolysis impurities) and is more easily controlled than sterilisation by ionising irradiation. For these reasons, heat is given priority over ionising irradiation in the decision trees.

　　雖然通過加熱滅菌和通過電離輻射滅菌提供了同樣的無菌保證, 但加熱滅菌的風險較低(例如輻射雜質)，也比電離輻射滅菌更容易控制。因此, 在決策樹中, 加熱滅菌優先於電離輻射滅菌。

　　Figure 1 Decision tree for sterilisation choices for aqueous products

　　對於溶液劑型產品滅菌方法選擇的決策樹：

　　

　　Figure 2 Decision tree for sterilisationchoices for dry powder products, non-aqueous liquid or semi-solid products

　　非溶液劑型、半固體或乾粉產品滅菌方法選擇的決策樹：

　　

　　Figure 3 Decision tree for sterilisationchoices for containers

　　容器滅菌工藝選擇的決策樹

　　

　　來源：網絡

　　編輯整理：德斯特cGMP

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