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7.0 Cleaning Validation Protocols
7.0 清洁验证方案
Cleaning validation protocols have many of the same elements as process validation protocols. For reasons of clarity, the format of a cleaning validation protocol usually follows the same approach (as appropriate) as used for process validation protocols for a given company. Common elements include purpose, scope, responsibilities, applicable product(s) and equipment, cleaning SOP, acceptance criteria and a requirement for a final report. Key elements for cleaning validation protocols include residue limits (see Section 4.0), sampling procedures (see Section 5.0) and analytical methods (see Section 6.0). The organization and rationale for cleaning validation protocols for biotechnology manufacturers is fundamentally the same as for other pharmaceutical manufacturers.
清洁验证方案具有与工艺验证方案相同的要素。为使清晰易懂，清洁验证方案的版式通常遵循工艺验证方 案所用的版式（若适用） 。共同要素包括目的、范围、职责、试用产品和设备、清洁 SOP、可接受限度及 对最终报告的要求。清洁验证方案的关键要素包括残留限度（参见 4.0） 、取样程序（参见 5.0）及分析 方法（参见 6.0） 。对于生物制剂厂来说，清洁验证方案的组织规则和基本原理本质上与其它制剂厂相同。
7.1 清洁验证方案
7.1 Cleaning Verification Protocols
Protocols for cleaning verification purposes are the same as for cleaning validation, except that the protocol is specific to one cleaning event. From a compliance perspective, the protocol applies only to the one cleaning event (although from a scientific perspective the data may suggest similar performance if the cleaning event were repeated). Another difference is that because a verification protocol is typically performed on a unique cleaning event, there may be limited cleaning development before execution of that protocol. Alternatively, companies might use a concept that defines explicit requirements for cleaning verification in an SOP and documents the specific activities, sample positions, etc., on a form, which will be approved.
清洁确认 方案与清洁验证的目的相同，但这个方案特指一次清洁活动。从合规角度看，这个方案仅仅适用 于一次清洁活动（尽管从科学角度看，若重复进行这个清洁活动，数据资料可以显示出类似的性能） 。另 一个差异是，因为一个确认方案通常是一次唯一的清洁活动，所以方案中针对清洁的研究可能是有限的。或者，公司可能会这样做，在一个 SOP 中详细规定了清洁确认的要求，并在一个需要批准的表格上规定一 些特殊活动，取样位置等。
7.2 基于法规变更的关键问题
7.2 key Issues Based on Regulatory Changes
It is assumed that the validation protocol is not written and approved until the cleaning process has been designed and developed (see Section 3.0). This is particularly important as it relates to a life cycle approach to validation. Two key issues for protocols, each of which is in a state of flux because of regulatory changes, are discussed below.
一般认为，清洁工艺的设计和开发完成后才形成书面的验证方案并被批准（参见 Section3.0） ，因其与验 证的生命周期方法相关，所以这一点尤其重要。方案有两个关键问题，其中每一个都会随着法规的变化而 变化，讨论如下：
7.2.1 方案中清洁验证的批次数量
7.2.1 Number of Runs in a Protocol
The traditional approach for cleaning validation protocols has been to require an evaluation of a minimum of three consecutive runs of the cleaning processes. By consecutive, it has meant that no cleaning events of that same process are skipped without appropriate rationale. This practice is in flux because of changes in approach by the U.S. FDA; the Agency no longer suggests a minimum of three runs. (17,18) Rather, the manufacturer must provide a rationale (based on its understanding of the process) for determining the number of runs. Providing such a rationale is not straightforward for cleaning processes, and some companies specify in their master plans that three runs will be required unless there is a written rationale for a different number. It should be noted that as of publication of this Technical Report, the question of the “number of runs” remains a significant issue in terms of applicability to cleaning validation and global harmonization for cleaning Validation.
清洁验证方案的传统方式要求评估至少三个连续批次的清洁过程。连续性是指在没有适当依据的支持下， 不得有忽略相同操作过程的清洁事件发生。这一操作惯例会随着 U.S.FDA 清洁方法的改变而不断变化；FDA 不再建议至少三个批次，而是要求生产商需提供关于实施批次数量的证明（基于对清洁过程的理解） 。提 供这样一个清洁过程证明并不直观，公司需要在他们的主计划中明确规定进行三次清洁验证，除非另有书 面证明证实不同验证次数的合理性。应该指出，至本技术报告发表时，从清洁验证的适用范围及清洁验证 的各国协调来看，这个“数量”问题仍是一个重要的议题。
7.2.2 最差条件
7.2.2 Worst-Case Process Conditions
The traditional approach for cleaning validation protocols has been to include worst-case process conditions in the three protocol runs. Worst-case process conditions may include maximum dirty hold time, maximum batches in a campaign, use of different operators for manual cleaning, shortest allowed time for manual cleaning steps, lowest allowed temperature for manual cleaning processes, and worst-case circuits for CIP skid selection. Parameters such as temperature, cleaning agent concentration, and process step times for automated cleaning processes are generally controlled in a narrow range such that challenging the cleaning process at the lower or upper end of the specification is not appropriate. In this traditional approach, worst-case process conditions may be addressed in each of the three required validation runs, unless there is adequate data from the design and development of the cleaning process to support worst-case conditions in fewer runs.
清洁验证方案的传统做法是已在三次清洁验证中包含了最差过程条件。最差条件可能包括最大“dirty hold time”(指生产结束至清洁开始的时间)、批组最大批次、手动清洁中不同操作人员的使用、手动清洁步骤的 最短允许时间、 手动清洁过程的最低允许温度及 CIP （在线清洗） SKID 的最差回路。通常将参数如温度、 清洁剂浓度及自动清洁程序的过程步骤时间设定在一个狭窄的控制范围内，如此在较低或较高标准上挑战 清洁程序是不适当的。在传统方法中，三次验证中的每一批都可能描述最差条件，除非有充分的清洁程序 设计与研发资料可以支持较少批次。
文章来源：允咨生物GMP学苑
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