冻干工艺六注意

2023-08-07

冷冻干燥是一个非常关键的工艺步骤，所有影响产品或物料无菌性的活动均认为是对已灭菌产品的无菌工艺的延伸。

Lyophilization is a critical process step and all activities that can affect the sterility of the product or material need to be regarded as extensions of the aseptic processing of the sterilized product. The lyophilization equipment and its processes should be designed to ensure that product or material sterility is maintained during lyophilization by preventing microbial and particle contamination between the filling of products for lyophilization, and completion of lyophilization process. All control measures in place should be determined by the site's CCS. 冷冻干燥是一个非常关键的工艺步骤，所有影响产品或物料无菌性的活动均认为是对已灭菌产品的无菌工艺的延伸。冻干设备及其工艺均应当设计以保证产品或物料的无菌性，防止在产品灌装到冻干完成之间的微生物或微粒污染。所有在线控制措施在工厂的 CCS 中确定。

The sterilisation of the lyophilizer and associated equipment (e.g. trays, vial support rings) should be alidated and the holding time between the sterilisation cycle and use appropriately challenged during APS。The lyophilizer should be sterilised regularly, based on system design. Re-sterilisation should be performed following maintenance or cleaning. Sterilised lyophilizers and associated equipment should be rotected from contamination after sterilisation. 冻干机和相关设备（例如托盘、西林瓶支撑环）的灭菌经过验证，在 APS 期间适当挑战灭菌循环和使用之间的保持时间。冻干机根据系统设计定期灭菌。在维护或清洁后进行再灭菌。保护灭菌后的冻干机和相关设备，防止污染。

Lyophilizes and associated product transfer and loading/unloading areas should be designed to minimize operator intervention as far as possible. The frequency of lyophilized sterilization should be determined based on the design and risks related to system contamination during use. Lyophilizes that are manually loaded or unloaded with no barrier technology separation should be sterilized before each load. For lyophilizes loaded and unloaded by automated systems or protected by closed barrier systems, the frequency of sterilization should be justified and documented as part of the CCS. 冻干机和相关产品转移和装载/卸载区域经过设计，尽可能减少操作人员的干预。冻干机灭菌的频率根据设计和使用过程中与系统污染相关的风险来确定。没有屏障技术隔离的手动装载或卸载的冻干机在每次装载前进行灭菌。对于通过自动化系统装载和卸载或由密闭的屏障系统保护的冻干机，对灭菌频率进行论证并，作为 CCS 的一部分记录在案。

The integrity of the lyophilizedshould be maintained following sterilization and during lyophilization. The filter used to maintain lyophilizer integrity should be sterilized before each use of the system and its integrity testing results should be part of the batch certification/release. The frequency of vacuum/leak integrity testing of the chamber should be documented and the maximum permitted leakage of air into the lyophilizer should be specified and checked at the start of every cycle. 灭菌后和冻干过程中保持冻干机的完整性。用于维持冻干机完整性的过滤器在系统每次使用前进行灭菌，其完整性测试结果作为批次认证/放行的一部分。记录冻干室的真空/检漏测试的频率，最大允许的空气泄漏有规定，并在每个循环开始时进行检查。

Lyophilization trays should be checked regularly to ensure that they are not misshapen or damaged. 定期检查冻干托盘以确保其没有变形或损坏。

Points to consider for the design of loading (and unloading, where the lyophilized material is still unsealed and exposed), include but are not limited to:装载（如果冻干后物料仍未密封并暴露，还包括卸载）的设计要点，包括但不限于：

i. The loading pattern within the lyophilized should be specified and documented. 规定并记录冻干机的装载方式。
ii. The transfer of partially closed containers to a lyophilized should be undertaken under grade A conditions at all times and handled in a manner designed to minimize direct operator intervention. Technologies such as conveyor systems or portable transfer systems (e.g. clean air transfer carts, portable unidirectional airflow workstations) should be used to ensure that the cleanliness of the system used to transfer the partially closed containers is maintained. Alternatively, where supported by validation, trays closed in grade A and not reopened whilst in the grade B area may be used to protect partially stoppered vials (e.g. appropriately closed boxes). 将半封闭容器转移到冻干机时，始终在 A 级条件下进行，并且采用可以最大程度减少操作员直接干预的传递方式。使用诸如传送带系统或便携式转移系统（例如，洁净空气传输车，便携式单向流工作台）等技术，以确保维持用于转移部分密闭容器的系统的洁净度。或者，在经过验证的情况下，在 A 级密封且在B 级区时不再重新打开的托盘可用于保护半压塞的西林瓶（例如，适当密封的箱子）。
iii. Airflow patterns should not be adversely affected by transport devices and venting of the loading zone. 转移装置和装载区的通风不对气流模式造成不良影响。
iv. Unsealed containers (such as partially stoppered vials) should be maintained under grade A conditions and should normally be separated from operators by physical barrier technology or any other appropriate measures. 未密封的容器（例如半压塞的西林瓶）在 A 级条件下，并且通常通过物理屏障技术或任何其它适用措施与操作员隔开。
v. Where seating of the stoppers is not completed prior to opening the lyophilizer chamber, product removed from the lyophilizer should remain under grade A conditions during subsequent handling.在冻干机打开前，产品处于半压塞状态的，则产品移出冻干机进行下一步操作的时维持在 A 级环境下。
vi. Utensils used during loading and unloading of the lyophilizer (e.g. trays, bags, placing devices, tweezers) should be sterile. 冻干机装载和卸载过程中使用的器具（例如托盘、袋子、定位装置、镶子）为无菌状态。

撰稿人 | 制药人职场加油站

责任编辑 | 胡静

审核人 | 何发

冻干工艺六注意

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