培养基灌装是否需要做清洁验证的可行性讨论

发布时间:

2022-12-27

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培养基灌装是否需要做清洁验证的可行性讨论
 
 
首先,我们需要确认的是,什么情况下,需要进行清洁验证。根据GMP正文:“第一百四十三条 清洁方法应当经过验证,证实其清洁的效果,以有效防止污染和交叉污染。清洁验证应当综合考虑设备使用情况、所使用的清洁剂和消毒剂、取样方法和位置以及相应的取样回收率、残留物的性质和限度、残留物检验方法的灵敏度等因素。”
 
附录:《验证和确认》第三十九条  为确认与产品直接接触设备的清洁操作规程的有效性,应当进行清洁验证。应当根据所涉及的物料,合理地确定活性物质残留、清洁剂和微生物污染的限度标准。
 
总结一下两个法规的规定,就是对于有可能产生污染和交叉污染(和产品直接接触设备或区域)的清洁方法,为了证明清洁方法能够有效的清除可能的污染和交叉污染,需要对清洁方法进行清洁验证。
 
培养基灌装中,使用到的设备是会和产品直接接触的,培养基是有可能会对产品产生污染的,所以培养基灌装后的清洁方法是符合以上对于清洁验证的要求,毫无疑问是需要进行验证的,如果没有做,肯定是不符合法规要求。
 
那么该如何去做培养基灌装后的清洁验证呢?因为清洁验证,针对的是清洁程序,所以也分为以下情况来分析:
 
一. 培养基灌装后的清洁方式和产品生产后的清洁方式一致
 
在这种情况下,你需要做的是在你原始的清洁验证方案中,将培养基当成是你的产品来进行分析,分析各类产品的溶解性、毒性指标等,然后再来确定清洁验证的目标物,选择残留限度和检测方法。这个并不需要单独针对培养基灌装的清洁写方案。
 
二.培养基灌装后的清洁方式和产品生产后的清洁方式不一致
 
在这种情况下,你需要单独起草方案,方案的内容和要求和清洁验证的一样,确定残留限度和检验方法。怎么去做,不在这里讨论,因为这是技术活,每个公司的选择都不同,以后有时间再讨论了。
 
有朋友也会问了,我培养基灌装一年才做两次,那么这个清洁验证要怎么做呢,是否可以用清洁确认代替清洁验证?首先,对于新建药厂的朋友,就不用说了,培养基灌装要做三次,你有足够的时间和批次做这个验证。
 
      如果是没有做过,现在需要补充做的朋友呢?首先,清洁验证要求你做三次,没规定你到底需要做多久啊?三次也就一年半时间,你做完一次,写一个阶段性的报告不可以么?做完三次,再出一个报告,不可以么?
 
其次,虽然附录49条说“对于处于研发阶段的药物或不经常生产的产品,可采用每批生产后确认清洁效果的方式替代清洁验证。”但是人家还说“每批后的清洁确认应当根据本附录的相关要求进行。”清洁确认的要求和清洁验证有区别么?
 
你是愿意不写报告,每批培养基灌装完了都去做清洁确认,还是愿意做完三批的清洁验证后,在清洁方法没有变化的前提下,就不需要再做清洁后的效果监测呢?
 
 

Feasibility discussion on whether cleaning validation is required for culture medium filling
 
 
First of all, what we need to confirm is, under what circumstances, clean verification is required. According to the body of GMP: "article 143 cleaning methods shall be verified and verified to be effective in preventing pollution and cross contamination. Cleaning validation should be considered equipment usage, the detergents and disinfectants used, sampling method and location, and the corresponding sampling rate, the nature of the residues and limit, sensitivity factors such as residue method."
 
Appendix: verification and confirmation article 39 in order to confirm the validity of the cleaning operation rules for equipment directly in contact with the product, cleaning verification shall be carried out. The limits for residues of active substances, detergents and microbial contamination shall be reasonably determined based on the materials involved.
 
Summarize two regulations, it is for possible contamination and cross-contamination (direct contact with the equipment and products or regions) cleaning method, in order to prove the cleaning method can effectively eliminate possible contamination and cross-contamination, need cleaning method for cleaning validation.
 
Media fills, the equipment is used and direct contact with the product of the culture medium is may produce pollution to the product, so after media fills the cleaning method is accord with the requirement of the above for cleaning validation, there is no doubt that is the need for validation, if not do, certainly do not conform to the regulations.
 
So how to do the cleaning verification after the filling of culture media? Because the cleaning verification is aimed at the cleaning process, it can be divided into the following situations:
 
1. The cleaning method after culture medium filling is consistent with that after product production
 
In this case, you need to do is in your original cleaning validation scheme, as your products will be medium for analysis, analysis of various kinds of products, such as solubility, toxicity index, and then to determine the target of cleaning validation, choose residue limit and test method. This does not require a separate clean writing scheme for medium filling.
 
2. The cleaning method after filling media is not consistent with that after production
 
In this case, you will need to draft the plan separately. The content and requirements of the plan will be the same as those of the clean verification. How to do this is not discussed here, because this is a technical job, and every company has different choices, which will be discussed later.
 
Some friends will also ask, I only do the culture medium filling twice a year, so how to do the cleaning verification? Can we replace the cleaning verification with the cleaning confirmation? First of all, for those of you who are building a new pharmaceutical factory, you don't have to say that the culture medium is filled three times, and you have enough time and lots to do that.
 
If you haven't, what about the friends you need to add now? First of all, cleaning verification requires you to do it three times, without specifying how long you need to do it. Three times is a year and a half time, you finish once, write a periodic report not ok? Finish three times and give another report, ok?
 
Secondly, although article 49 of the appendix states that "for drugs in the development stage or products not frequently produced, the method of confirming the cleaning effect after each batch of production can be used instead of the clean verification." But it was also stated that "each subsequent cleaning confirmation shall be made in accordance with the relevant requirements of this appendix." Is there any difference between the requirement of cleaning confirmation and the requirement of cleaning verification?
 
You are willing to write a report, every batch of media fills out to do the cleaning validation, or willing to finish three batch of cleaning validation, on the premise of cleaning method does not change, you don't need to do it again after cleaning effect monitoring?