中英对照APIC原料药厂清洁验证指南70分组法括号法.docx

1、中英对照APIC原料药厂清洁验证指南70分组法括号法APIC 201405原料药厂清洁验证指南：7.0 分组法（括号法）和最差情况分级（中英文）2014-07-15 julia翻译 蒲公英 7.0 Bracketing and Worst Case Rating 分组法（括号法）和最差情况分级7.1 Introduction 介绍The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The va

2、lidation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used. 原料药工厂中的多产品设备清洁要求进行清洁验证。清洁工作量会比较大。为了减少验证的工作量，可以采用最差情形方法进行验证。By means of a bracketing procedure the substances are grouped. 采用分组法时，物质按类进行分组。A worst case rating p

3、rocedure is used to select the worst case in each group. 然后在每组中采用最差情形分级法选择各组中最差的情况。Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists. 对最差情形进行验证。至关重要的是，选择最差情形的科学合理性要进行记录。This chapter gives an

4、 overview of the suggested work to be carried out, the acceptance criteria and the methodology for evaluation of the data. It should be emphasized that this is only an example to give guidance. The equipment, the substances produced and the procedures in place may vary; and this results in other sol

5、utions than those given in this example. 本章介绍了所需要进行的工作、可接受标准和数据评估方法。需要强调的是，这只是一个指导性的例子，而实际情况下，设备、生产的物质和清洁程序可能有所不同，则可能需要采用与例中不同的解决方案。The worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances and other chemicals within the bracket,

6、 including those not individually tested. 最差情形分级优先性是用来支持清洁方法对组内所有原料药和化学物均有效的结论的，包括那些并没有进行单独检测的物质。7.2 Bracketing Procedure 分组法The objective of a bracketing project, is for the company to demonstrate that it has a scientific rationale for its worst case rating of the substances in the cleaning validat

7、ion program. The first thing to do is to make groups and sub groups - which we will term “bracketing”, from which worst cases will later be selected based on the results from the rating. The bracketing procedure should be included in a company policy, or an SOP or an equivalent document on cleaning

8、validation. A multipurpose facility, Clean Company, is presented as an example we will follow. 分组法的目的是让公司可以证明清洁验证方案中，对原料药进行最差情形分级具有科学合理性。首先要做的是进行分组和分小组-我们称为“分组法（括号法）”，在一个组中，再根据分级结果选择一个最差情形。分组流程应包括在公司方针中，或在SOP或相当清洁验证文件中。以下的例子中我们假定有一个多功能工厂、一个清洁公司。a) Equipment Train The Clean Company is a multipurpose

9、site for synthesis and isolation of organic substances (see figure 1). It is divided into six equipment trains separated from each other and intended for different use (earlier API steps, final API purification, drying etc.). In TrainA 9 substances can be produced, in TrainB 9 substances can be prod

10、uced, in TrainC 8 substances can be produced, in TrainD 8 substances can be produced, in TrainE 10 substances can be produced, and in TrainF 11 substances can be produced. With no bracketing and worst case rating, cleaning validation studies would be required for each of the 55 substances. 设备链：清洁公司是

11、一个多功能场所，生产有机物质合成和分离步骤（参见图1）。其设备被分为6条生产设备链，相互独立，用于不同用途（较早的原料药步骤、最终原料药精制、干燥等）。在A链中，可以生产9种物质，在B链中，可以生产9种物质，在C链中可以生产8种物质，在D链中，可以生产8种物质，在E链中可以生产10种物质，在F链中可以生产11种物质。如果不采用分组法和最差情形法的话，则需要对55种物质分别进行清洁验证。The first grouping criteria is that the substances in a group are produced in identical equipment trains a

12、nd cleaned out following the same cleaning procedure/SOP. The ideal with regard to cleaning validation (as will be discussed in 7.3) each train could be considered as a group. Then 6 worst cases would ideally be identified. In reality, the number of worst cases identified will often be something bet

13、ween these two extremes (more than 6, but less than 55). 进行分组的第一个标准是组内的物质是在同一条设备链中生产，并采用同一个清洁程序/SOP进行清洁。理想状态是每条链可以作为一个组来进行清洁验证（如7.3中讨论的一样）。这样，理想状态下需要识别出6种最差情形。现实中，最差情形的识别可能会是两个极端情况（多于6个，但少于55个）。CleanCompany 清洁公司Figure 1 Clean Companys ideal example (1 train considered as 1 group) gives 6 worst cases

14、. In this example the main classes in this bracketing are based on the different Trains. The following equipment classes are maintained: 图1：清洁公司的理想案例（设备链1被作为第一组）给出了6个最差情形。在此例中，组内主要级别是基于不同生产链的。以下设备分级不变：? TrainA ? TrainB ? TrainC ? TrainD ? TrainE ? TrainF b) Substances 物质If the company has two or mor

15、e trains used for the same purpose (such as earlier API steps, final API purification, drying etc.) a choice of which products to be produced in each of the trains used for the same purpose is done. The combination of substances (starting materials, intermediates or APIs) in a train can be chosen ba

16、sed on one or more of the following strategies, or combinations of them: 如果公司有2个或更多设备链用于同一个生产目的（例如，更早的原料药生产步骤、最终原料药精制、干燥等），已选好了在每个设备链中生产哪个产品。在一个设备链生产哪些物质（起始物料、中间体或原料药）可以采用以下策略或联合策略来做选择： Produce in the same train substances with the same cleaning procedure; 在同一设备链里生产可以采用相同的清洁程序的物质 Produce in the same

17、 train substances with very low therapeutic doses and/or low batch sizes (and the opposite); 在同一设备链中生产治疗剂量很低和/或批量很小（以及相反情况）的物质 Produce in the same train substances with very low ADE values (and the opposite). 在同一设备链中生产ADE值非常低（以及相反情况）的物质Also a choice of maximum flexibility can be used, but this could

18、 result in low limits for residues (for example if the substance to be cleaned out has a very low therapeutic dose, and the following substance has a small batch size and/or a very high daily dose) and thus longer cleaning times. Advantages and disadvantages with several cleaning procedures, compare

19、d to one cleaning procedure, will be discussed in section 7.3. More explanations on effects of different strategies will be evident from section 7.4. 也可以选用具有最大灵活性的方式，但这样可能会使得残留限度非常低（），导致清洁时间会很长。在7.3中讨论了选用几个不同的清洁程序相比于选用同一个清洁程序的优缺点。在7.4中对不同策略的效果给出了进一步解释。7.3 Cleaning Procedures 清洁程序For one train, in wh

20、ich several substances are being produced, several cleaning procedures often exist. In order to be able to defend the bracketing into groups, the second criterion is that the same cleaning procedure (method) shall be used for the substances within a group. 对于一条设备链，如果在其中生产几种物质，通常会有几种清洁程序。为了将所涉及的产品进行分

21、组，第二个标准就是对同一组里的产品使用相同的清洁程序（方法）。Cleaning procedures (before change of products) can for example be considered to be the same if: 例如在以下情况下，可以认为清洁程序是相同的：1. Same or equivalent issued cleaning batch records/cleaning SOPs; 相同或等同签署的清洁批记录/清洁SOP2. Same solvent, solubility or similar properties. 相同溶剂、溶解度或相似特性

22、Advantages and disadvantages with several cleaning procedures, compared to one cleaning procedure, are presented in the following table. 下表列出了采用几个清洁程序与采用同一个清洁程序的优缺点。The same cleaning procedure for all substances (chosen to clean out the most difficult substance)所有物质（选取最难清洁的物质做验证）采用同一清洁程序+ Minimum nu

23、mber of cleaning validation studies (perhaps only one)- Not optimal cleaning procedure for each substance longer clean out times on average as well as higher consumption of solvents- Normally a low limit for residues valid for all substances+ 减少清洁验证的次数（可能只需验证一次）- 对所有物质都不是最优的清洁方法平均清洁次数会比较多，同时溶剂消耗量大-

24、一般对所有物质采用同一个较低的残留限度Optimised cleaning procedures for each substance优化每个物质的清洁程序+ Minimum clean out time on average- Maximum number of cleaning validation studies (as many as there are cleaning procedures)+ 降低平均清洁时间- 增加清洁验证的最大次数In the example the Clean Company has evaluated the cleaning procedures. Th

25、e cleaning procedures have been examined and categorised into different classes. Substances in the same class are cleaned in the same way, using the same solvents and usually exhibit some chemical similarity with each other (e. g. salts, chemical structure etc.). In this example, totally, four clean

26、ing procedure classes are included: 在案例中，清洁公司评估了清洁程序，通过检查将其分为不同类别。同一类别中的物质采用相同方法清洁，采用相同的溶剂，通常其所含的化学物质相互类似（例如，盐、化学结构等）。在本例中，共包括四类清洁程序： Class I water soluble substances. 一类：水溶性物质 Class II methanol soluble substances. 二类：甲醇可溶性物质 Class III acetone soluble substances. 三类：丙酮可溶性物质 Class IV separate class f

27、or special substances with defined solubility 四类：根据溶解度制订的特殊物质特定级别7.4 Investigations and Worst Case Rating (WCR)/Risk assessment 调查和最差情况（WCR）风险评估A worst case rating study/Risk assessment, will prioritise existing drug substances, in a cleaning validation program, based on information on applicable cr

28、iteria chosen by the company. Clean company chose the following criteria which are relevant to the molecule preparation in their facility (companies should evaluate individual situations): 进行最差情形分类研究/风险评估时，根据公司选择的可采用标准，对清洁验证程序中已有原料药进行优先顺序排列。清洁公司选择了以下标准，该标准与在该工厂中生产的产品分子相关（公司应对自己的情况进行单独评估）a) Hardest t

29、o clean: experience from production; 最难清洁：生产所得的经验b) Solubility in used solvent; 在所用溶剂中的溶解度c) Lowest Acceptable Daily Exposure( If ADE data are not available, other pharmacological (dose) , OEL or toxicity data ( LD50 ) may be used (see chapter 4); 可接受最低日暴露量（如果不能获得ADE数据，可以使用（参见第4章）其它药学（剂量）数据、OEL或毒性数据

30、（LD50）d) Lowest therapeutic dose (or toxicity data LD50 ); 最低治疗剂量（或毒性数据LD50）In order to present documented evidence supporting the scientific rating for each criterion, investigations (a formalized Risk assessment) should be carried out and formal reports should be written. For each criterion groups

31、 of rating with corresponding descriptive terms should be presented. When available, the descriptive terms can be chosen from the scientific literature on the subject (i. e. for solubility and toxicity). For other cases the rating is based on scientific investigations carried out by the company and

32、collecting experience regarding details on the cleaning processes (i.e. experience from production”). 为了形成书面证据来支持各标准分级的科学性，应进行研究（正式的风险评估）并形成书面的正式报告。每个标准中，要列出分级组所对应的描述性术语。如果可能，应从科学文献中选取相应的术语描述（例如溶解性和毒性）。其它情况下，分类也可以根据公司的科学研究和在清洁工艺方面积累的经验（即“生产经验”）。Clean Company chose to execute the WCR according to a formal protocol, in which the rating system was identified and the rating documented. In a Risk assessment report the results including the WCR were summarised, as well as conclusions. 清