当提出无菌参数放行时, 应考虑EMA/CHMP/QWP/811210/2009-Rev1《实时放行检验指南(仅适用于人用产品)》 (原《参数放行指南》)、EMEA/CVMP/QWP/339588/2005《参数放行指南(仅适用于兽药产品)》和Ph. Eur. 5.1.1 章节的要求。

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.

应明确灭菌前的生物负荷控制标准。高生物负荷接受标准不应依赖灭菌工艺的能力或灭菌前的任何生物清除步骤。以下章节4.1 的相关小节讨论了生物负荷的接受标准。

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.

成品中细菌内毒素的水平可能会受到组件 (即活性物质、辅料和容器)中生物负荷和细菌内毒素的影响, 也会受到生产过程中引入的微生物污染物的影响。为确保成品中细菌内毒素的可接受水平, 各组件的微生物污染物水平应最低。应规定组件和待灌装溶液的生物负荷和细菌内毒素（如适用）的接受标准。

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.

应描述所有与成品接触或与成品中任何组分 (活性成分或中间产品) 接触的用于成品生产的过滤器，并在其质量档案中提供章节4.1.5表3中要求的信息。这些资料应符合 Eudralex GMP 附录1的要求。对于 ATMP, 应遵循《ATMP良好生产规范指南》。

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.

如果使用二级容器 (例如用于保持输液袋或泡罩外部无菌的外袋) 为医药产品提供特定保护, 则应说明包装过程, 包括风险评估, 因为它可能会影响成品的无菌性;例如, 在内包装容器和二级容器之间残留水分。应提供关于何时 (灭菌前或灭菌后) 进行包装步骤以及所采用的任何无菌技术的信息。工艺应从微生物的角度加以证明。如果使用二级容器意味着需要对成品进行额外的灭菌, 则应在无菌保证和对成品质量的任何潜在影响方面进行论证。

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.

需包含在质量档案中的关于灭菌和无菌工艺的文件罗列如下。出于实际原因, 如果3.2.P.3.3 节或第2 b 部分提到文件的位置, 则文件可和待灭菌的物品放在一起。这些文件可在人用药品的3.2.S.2 生产、3.2.P.2 药品研发、3.2.P.3 生产、3.2.P.4 辅料控制，或3.2.P.7 容器封闭系统中提供；或兽药第2部分 A.4 药品研发, 第2部分 B.1 生产方法, 第2部分C.1活性物质, 第2部分 C.2 辅料或第2部分 C.3容器封闭系统中提供。所有进行灭菌或无菌工艺的场所都应提供文件, 无论操作是本厂执行或是外包。

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.

在质量档案的评估过程中, 会对工艺参数,例如工艺和保留时间进行评估和商定。这些可能会在 GMP 检查期间进一步审查, 并可能导致需要变更注册档案资料。

4.1.1. Steam sterilisation

蒸汽灭菌

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

所有蒸汽灭菌工艺都要求最低杀灭力为 f0≥8分钟, 最低工艺温度为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列出了不同水平的杀灭力的灭菌过程, 以及需要列入质量档案的文件。表中的工艺从上到下杀死力逐渐降低, 因此应优先选择上一个可行的工艺。

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.

对于使用 ph. eur. 5.1.1 的参考条件进行灭菌 (所有位置≥121°c,≥15分钟), 则无需在质量档案中提交灭菌周期的验证数据。

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作为监测工艺杀灭力的额外控制, 则应说明 f0, 并由温度传感器测得的最低温度来确定 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.

成品温度低于115°c的蒸汽灭菌保持阶段是一种特殊情况, 应进行论证, 并有表1所述的其他数据的支持。如果 f0 的测定中包括低于110°c 的温度 (在加热和冷却过程中), 则应进行论证。

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.

关于 f0 概念和微生物降低的信息载于 ph. eur. 5.1.5 f0 概念在水制剂蒸汽灭菌中的应用。

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.

生物负荷限度应与任何预灭菌生物负荷降低工艺能力 (如过滤) 一致。在没有特殊说的情况下，对于水溶液， 表1所述的限度对于活性物质和药物产品制剂是可以接受的。其他控制生物负荷在既定水平的测试方法和限度应进行论证。

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分钟的湿热处理工艺可作为无菌处理后的终端热处理, 适用于无法承受完整的终端灭菌程序的情况。此类工艺可进一步确保无菌过滤 (或以其他方式灭菌) 的散装组件经无菌分装后的SAL。无菌处理后终端热处理也见表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.

需要强调的是, 这种额外的无菌加工终端热处理不应作为不良无菌生产操作的补偿。这与没有额外无菌加工终端热处理在无菌工艺部分的要求是一样的。

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):

对于不符合 ph. eur. 标准工艺要求的所有蒸汽灭菌工艺, 需在质量档案中提供的验证数据 (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.

腔体的装载布置和腔体中物品的装载热分布（包括加热最慢的位置）; 性能确认总结。

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:

至少三次灭菌程序的物理和生物效果确认总结, 显示SAL≤10-6, 如 ph. Eur第5.1.1章节的要求:

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

显示灭菌腔室中的灭菌负荷达到规定的循环参数, 包括时间、温度、压力和 f0 (如适用);

Acceptable temperature differences between temperature sensors in the load;

装载中温度传感器之间可接受的温差;

Acceptable F0 variability within the load;

负载内可接受的 f0 波动;

Relationship between physical and biological validation.

物理验证和生物验证之间的关系。

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.

对于生物验证, 应使用Ph.Eur. 5.1.2章节 “用于无菌产品生产的生物指示剂和相关微生物制品无菌产品的相关微生物制剂”中规定的D121℃≥1.5分钟的生物指示剂。

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.

应确定SAL，其微生物基础应合理，并在质量档案中提供计算细节。最好是根据每个容器的最大生物负荷和验证中使用的生物指示剂的D值计算。

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