Processing 生产
40. Precautions to minimise contamination should be taken during all processing stages including the stages before sterilisation.
在所有生产阶段,包括灭菌前各阶段,要注意采取措施预防和减少污染。
41. Preparations of microbiological origin should not be made or filled in areas used for the processing of other medicinal products; however, vaccines of dead organisms or of bacterial extracts may be filled, after inactivation, in the same premises as other sterile medicinal products.
微生物制品不能在其他药品生产使用的区域进行处理或灌装,但是死的微生物或细菌提取物的疫苗在灭活后可以在其他无菌产品生产的设施中进行灌装。
42. Validation of aseptic processing should include a process simulation test using a nutrient medium (media fill). Selection of the nutrient medium should be made based on dosage form of the product and selectivity, clarity, concentration and suitability for sterilisation of the nutrient medium. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical subsequent manufacturing steps. It should also take into account various interventions known to occur during normal production as well as worst case situations. Process simulation tests should be performed as initial validation with three consecutive satisfactory simulation tests per shift and repeated at defined intervals and after any significant modification to the HVAC-system, equipment, process and number of shifts. Normally process simulation tests should be repeated twice a year per shift and process. The number of containers used for media fills should be sufficient to enable a valid evaluation. For small batches, the number of containers for media fills should at least equal the size of the product batch. The target should be zero growth but a contamination rate of less than 0.1% with 95% confidence limit is acceptable. The manufacturer should establish alert and action limits. Any contamination should be investigated.
无菌生产过程的验证,要包括利用营养培养基进行的模拟试验。要根据产品的剂型和培养基的选择性、澄明度、浓度和灭菌的适应性来选择使用培养基。过程模拟试验要尽可能地接近正常的无菌生产程序,包括随后的各个关键生产步骤。同时要考虑在正常生产过程中的各种干预和挑战性状况。过程模拟试验在验证的开始阶段,要每个班次连续做三次满意的试验,在规定的时间间隔或空气处理系统、设备、生产方法和班次的任何重要改变后,重复进行。通常每班和每个工艺每年重复两次过程模拟试验。试验中用于培养基灌装的容器的数量要足够进行有效的评估。对一个小批量,用于培养基灌装的容器数量至少等于产品的批量。目标是零生长,但在污染率低于0.1%,可信度在95%时是可以接受的。生产商要设置警戒限度和措施限度。所有的污染都要进行调查。
43. Care should be taken that any validation does not compromise the processes.
要注意任何验证都不会影响生产。
44. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken.
水源、水处理设备和处理过的水,要定期在化学和微生物污染方面、可能的情况下包括内毒素进行监控。对监控结果和采取的任何措施都要进行记录。
44. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken.
在洁净区内,特别是当无菌生产在进行中,活动要尽可能少,人员的活动要受到控制并按照方法,避免由于过多活动带来尘埃颗粒和微生物的扩散。周围环境的温度和湿度不能高到不舒服,因为工作服是相当密封的。
46. Microbiological contamination of starting materials should be minimal. Specifications should include requirements for microbiological quality when the need for this has been indicated by monitoring.
原料的微生物污染必须低。当指明该项目需要控制时,标准里要包括微生物方面的质量要求。
47. Containers and materials liable to generate fibres should be minimised in clean areas.
容易产生纤维的容器和原料要尽量少进入洁净区。
48. Where appropriate, measures should be taken to minimise the particulate contamination of the end product.
适当的条件下,要采取措施,减少对终产品的尘埃粒子的污染。
49. Components, containers and equipment should be handled after the final cleaning process in such a way that they are not recontaminated.
原辅料、容器和设备在进行清洁后,在处理过程中要避免再次污染。
50. The interval between the washing and drying and the sterilisation of components, containers and equipment as well as between their sterilisation and use should be minimised and subject to a time-limit appropriate to the storage conditions.
原辅料、容器、和设备的清洗和干燥以及灭菌之间的间隔时间,灭菌和使用之间的间隔时间,在规定的储存条件下要尽可能缩短,并控制在时间限度内。
51. The time between the start of the preparation of a solution and its sterilisation or filtration through a micro-organism-retaining filter should be minimised. There should be a set maximum permissible time for each product that takes into account its composition and the prescribed method of storage.
溶液的开始配制到灭菌或微孔过滤处理的时间间隔要尽可能短。应该根据产品的组分和规定的储存方法,设定最长允许时间。
52. The bioburden should be monitored before sterilisation. There should be working limits on contamination immediately before sterilisation which are related to the efficiency of the method to be used. Where appropriate the absence of pyrogens should be monitored. All solutions, in particular large volume infusion fluids, should be passed through a micro-organism-retaining filter, if possible sited immediately before filling.
在灭菌前要对微生物的含量进行监控。对于同灭菌方法的效果相关的灭菌前的步骤的污染,要有工作限度。适当的情况下,要对无热源进行监控。所有溶液,特别是大剂量注射液,要通过微生物过滤器,如果可能,过滤步骤紧接着灌装。
53. Components, containers, equipment and any other article required in a clean area where aseptic work takes place should be sterilised and passed into the area through double-ended sterilisers sealed into the wall, or by a procedure which achieves the same objective of not introducing contamination. Non-combustible gases should be passed through micro-organism retentive filters.
原辅料、容器、和设备以及其他无菌操作的洁净区内需要的物品,应该灭菌并且通过穿墙安装的两端开门的灭菌柜,或通过能够达到同样目的,不带进污染的程序。非易燃气体要通过微生物过滤器。
54. The efficacy of any new procedure should be validated, and the validation verified at scheduled intervals based on performance history or when any significant change is made in the process or equipment.
任何一个新程序的效果都要进行验证,要根据运行历史定期地,或当生产工艺或设备有重大改变时,对验证的结果进行再确认。