3.5Cleaning Process Scale-Up

清洁工艺放大

Followingselection of cleaning agents and cleaning parameter ranges (such astemperature, contact time, cleaning agent concentration, and flow streamhydrodynamics) from historical plant data (if available) and laboratorydevelopment work, the cleaning process can be implemented for use on larger scalemanufacturing equipment. Determination of soil and cleaning agent residue removalis generally performed prior to formal cleaning validation protocols.Adjustments to cleaning parameters may be made during the scale-up processbased on plant experience and laboratory development studies.

依据历史数据（如果有）和实验室开发结果，确定清洁剂和清洁参数（如温度、接触时间、浓度、流体力学）后，可将清洁工艺应用到更大规模的生产设备上。在制订正式的清洁验证方案前，应先确定污物和清洁剂残留可被清除。根据工厂经验和实验室开发结果，可以在清洁工艺放大时调整清洁参数。

3.5.1Setting Process Controls

设定过程控制

Itis both prudent and consistent with current Good Manufacturing Practice (CGMP)to establish control ranges for the cleaning process operational andperformance parameters. As appropriate, operational parameters for cleaningprocesses include:

应建立清洁工艺参数的控制范围以严格、持续符合GMP要求。清洁工艺的操作参数如下：

·Dirty hold time for equipment (time between completion of use and initiation ofcleaning)

生产后保持时间（完成生产和开始清洁之间的时间）

·Clean hold time for equipment (time between completion of cleaning and nextuse)

清洁保持时间（完成清洁至下次使用之间的时间）

·Flow rate and/or delivery pressure of the cleaning stream (proof of flow forany parallel flow paths)

清洁溶液的流速和压力（确认流体流型是否为平行流的证据）

·Cleaning agent concentration

清洁剂浓度

·Duration of each step in the cleaning process (by time or volume)

清洁工艺中每个步骤的持续时间（以时间或体积表示）

·Temperature of washing solutions and rinses

冲洗和淋洗液的温度

·Air flow verification during any water removal or drying steps

干燥或除水过程中，气流的确认

Instrumentationfor each of these parameters should be included in the system design. Alertand/or action levels can be set for each critical cleaning process parameter inorder to maintain proper operation. Parameters may be significant for businessor economic reasons, as well as for patient and product quality reasons, aslong as the parameters set for business and economic reasons are more“stringent”than for patient and product quality reasons. Alert levels may be set based onexpected variability of the equipment and instrumentation in the cleaningsystem. Action levels should be set at values that permit adjustment to theequipment to avoid jeopardizing acceptable operation. Both alert and actionlevels should be within the acceptable ranges for each parameter. It is alsoreasonable to establish check times, so that if parameters do not reach theirset points (e.g., volume flow, conductivity) within that time, then an alarm ornotification occurs.

在设计系统时，应考虑这些参数的检测。可为关键清洁工艺参数订立警告/行动水平来维持正确的操作。参数可能因为经济/商业考虑、患者安全、产品质量而定，只要因商业/经济考虑建立的参数比比因患者/产品质量建立的参数更严格。警告水平可根据清洁系统中设备、仪表的预期变动来设立。行动水平的设定应能够允许对设备进行调整，避免出现不符合要求的结果。警告水平和行动水平都应该在每一参数的可接受范围内。同时亦可以设定检查时间，如果参数该检查时间内未达到设定值（如流量、电导率），便发出警告或通知。

Performanceparameters should also be evaluated during scale-up. As applicable, performanceparametersmay include:

在清洁工艺放大时应评估清洁效果，指示清洁效果的参数可以包括：

·Final rinse solvent analysis for active ingredients/degradants

最终淋洗液有效成份/分解物的检测

·Final rinse solvent analysis for cleaning agent

最终淋洗液清洁剂检测

·Final rinse water bioburden

最终淋洗液生物负载

·Final rinse water endotoxin

最终淋洗液内毒素含量