蒲公英 - 制药技术的传播者 GMP理论的实践者
标题: 清洁验证应按品种还是设备做？ [打印本页]
作者: 罗伊鲱 时间: 2016-4-8 14:22
标题: 清洁验证应按品种还是设备做？
本帖最后由 roadman 于 2016-4-8 14:30 编辑
国内做药品注册时，清洁验证大多是按品种做的吧？
清洁验证按品种做根本就是策略性错误。因为清洁验证的对象是设备清洁方法（如果一个设备有多个不同的清洁方法，就应有多个清洁验证），所以应按设备清洁方法来做。原则是：根据多标准分析法选择设备清洁SOP所适用品种中最难清洁（DTC）的产品做为参照物，清洁后取样检测，看是否均小于按毒性、0.1%剂量、10ppm等标准建立的限度。
我们现在的清洁验证国际注册品种是按品种做的，国内的按设备做。国外检查员检查时，注意的是其它品种的残留对检查品种的影响（要看其它品种的清洁验证文件
），而并不在意检查品种的残留。
补充内容 (2016-4-8 16:05):
按品种做清洁验证错误原因：1.只考虑验证品种对其它品种的影响，未考虑其它品种对验证品种的影响。2.需要做每个品种，浪费资源。
补充内容 (2017-7-29 19:33):
新产品清洗验证如何设计？
补充内容 (2017-7-29 20:01):
清洁验证新产品引入的验证问题
作者: 冷血无情 时间: 2016-4-8 14:33
一个设备由不同的清洁方法，究其原因是什么呢？那么我针对产品进行验证又有什么策略上的错误呢？
作者: zysx01234 时间: 2016-4-8 14:34
本帖最后由 zysx01234 于 2016-4-8 15:11 编辑
清洁验证的目的就是验证清洁方法本身对于现有设备的清洁能力，方法好不好要考虑产品的特点和设备的特点，选用何种清洗剂、用量、清洗的方式、方法、程序，因此按品种做或按设备做的说法可以说都行也可以说不行。
在化药的企业通常做法是按品种，在饮片厂的通常做法按设备，在制剂企业尤其是多品种共线通常是设备和品种结合按最差条件（溶解性差的、性状突出的、毒性最大的等）来做，各类型的企业选择自己合适的手段是很重要的
作者: dpzhangxc 时间: 2016-4-8 14:39
如果一个设备有多个不同的清洁方法，就应有多个清洁验证.这个观念需要讨论呀？？
我们是按清洁评估后，最难清洁品种清洁方法，清洁只有一种方法，做清洁验证，我们的理解是最难的都洗干净了，其他的就不存在问题，若验证结果不符这说明清洁方法需要改进，改进后再验证。其他品种只需要做残留就行了，其他项目不必重复。
作者: Sword 时间: 2016-4-8 14:43
这其实是个见仁见智的问题，我觉得无论是按品种还是按设备都没错。
作者: 罗伊鲱 时间: 2016-4-8 15:02
最难清洁品种是某一清洁方法的最难清洁品种。算DTC值时，有一项是清洁难易程度，同一品种使用不同的清洁方法难易程度不一样吧？还有一项是清洁剂中的溶解性，同一品种在不同清洁剂中的溶解性不同吧？所以同一API对于不同的清洁SOP，其DTC值是不同，因此必须按清洁方法进行验证。
作者: zysx01234 时间: 2016-4-8 15:15
谢谢夸奖
。
做清洁验证对一个QA来说，既是交差——法规要求、客户要求，又是企业保证产品质量的工作要求。
怎么样合适，怎么样方便易行，且合规、不给审计员留口舌才是企业的首选
作者: 墨石 时间: 2016-4-8 15:15
这有什么实质性的区别？都是对清洁方法的验证。
作者: 罗伊鲱 时间: 2016-4-8 15:18
本帖最后由 roadman 于 2016-4-8 15:50 编辑
不同品种API溶解性不同，需要用不同的溶剂、方法清洗。
按品种进行验证是浪费资源，真做也无不可，就怕做假的。
另外，如果按品种进行清洁验证，则每做一个新产品，你以前做的其它品种清洁验证都要回顾一遍，考察在将新产品纳入计算后，可接受限度是否降低？检测结果是否仍符合要求？如果回答是否，其它品种清洁验证还需要重做。这个回顾评估报告国内做药品注册时有做过吗？！
选择按品种做，科学上并无不可。但国内企业省略了从科学上来说应做的一些工作，这些工作正好是国内GMP检查员和注册资料审核人员的盲点。
作者: 冷血无情 时间: 2016-4-8 15:25
对啊，所以，设备不同的清洁方法的根源还是产品的API或者API与辅料的相关性质影响的话，那么，根据品种也很正常或者大众，而且，也没有怎么浪费吧？除非前面用水，中间用溶剂，后面又用水，可以考虑通过风险分析判断确认的程度和范围嘛
作者: 冷血无情 时间: 2016-4-8 15:37
增加新产品这件事儿，的确应该做，而且不应该注册的做吧？做质量的做吧？毕竟评估的是原产品会不会影响该产品，该产品会不会影响原产品在进行新产品清洁验证的时候已经进行过了。
如果是分设备做的话，首先，加新产品的时候，验证是必须的，在没有新产品的时候，也没说有10个品种就做10此验证啊，我们可以“风险评估”嘛
作者: syhorchid 时间: 2016-4-8 15:52
按品种做，或按设备做，多可以吧。
作者: 大上海 时间: 2016-4-8 15:55
哥们选第一
作者: 冷血无情 时间: 2016-4-8 16:02
最开始的时候，每个产品都做过，现在，不管是车间转移了，还是到了大量的再验证环节，因为量大，所以进行分析，选择标记产品进行再验证，哪里投机了？新产品进行验证一是对自己负责，二是法规要求，老产品，就连附录都没有明确要求吧，怎么就算偷鸡了呢？不高兴了
作者: 罗伊鲱 时间: 2016-4-8 16:16
所以我问你们有没有清洁验证策略。大多数公司（不是说你）都是不写入文件，采用新产品按品种做，老产品就风险评估的偷鸡策略。
作者: 于磊 时间: 2016-4-8 16:21
按品种和设备都可以，关键你的确认对象是你的清洁SOP不要搞错就行！！
作者: 罗伊鲱 时间: 2016-4-8 16:29
本帖最后由 roadman 于 2016-4-8 16:31 编辑
既然确认对象是清洁SOP，当然应该按SOP做了。怎么又说按品种和设备都可以呢？如果一台设备有多个清洁SOP，你在一个方案中验证多个SOP？
大多数方案都没有说明清洁验证的对象是什么。强调的是某产品或某设备的清洁验证，对真正的验证对象（清洁SOP）却一笔带过。也没有对清洁SOP的关键性评估文件。
补充内容 (2016-4-15 14:51):
做工艺验证大家都知道要有工艺关键性评估，怎么清洁工艺就可以没有呢？
补充内容 (2016-4-27 14:07):
http://www.dxy.cn/bbs/thread/24683176
补充内容 (2019-1-31 16:04):
https://www.ouryao.com/thread-468542-1-1.html
补充内容 (2021-7-18 10:01):
https://www.sterislifesciences.c ... ess-parameters.ashx
作者: 晚上吃什么 时间: 2016-4-8 16:34
感觉楼主是对的，应该以品种去做清洁验证。
这样确实有出现同一个设备不同清洁方案。但是如果考虑所有的共线品种做最严格的设置设备清洁方案也是允许的。
因为每个产品的规格和洗涤（去除）方法是不一样的，所以感觉以品种做清洁更加合适节省，同时也符合法规要求。
作者: 于磊 时间: 2016-4-8 16:35
清洁验证有按品种做的，例如一个生产线多个品种生产，采用同样的清洁方法和设备，那么可以以品种为主线将多个设备的清洁验证串联到一起来执行。也有按设备做的，例如某生产线有多个品种生产，但是只有部分设备是全部共用的，这个时候你以品种为主线很难执行。那么也可以按设备去做。按品种和按设备做只是你的方案起草的模式和范围的不同而已对于清洁验证的本质是没什么影响的。而你清洁验证的对象永远是你的SOP，在SOP的操作下设备的清洁是符合产品生产的要求的。
作者: 于磊 时间: 2016-4-8 16:36
至于确定公司清洁验证的范围，建议按照公司的清洁SOP来进行确定
作者: 乔丹2号 时间: 2016-4-8 20:35
如果共线的话当然先按产品来。
作者: 北重楼 时间: 2016-4-9 08:42
按设备结合品种进行的
作者: kiddlyx 时间: 2016-4-9 12:19
应该是要做最难品种吧。。。
作者: hy1943 时间: 2016-4-13 13:40
应付注册基本都是按品种做，所以说来也很可笑，明明此品种非最难清洁，确仍然需要做清洁验证，写方案的时候基本也忽略目标物质选择的过程了，直接选定注册品种，做完交差。
作者: dpzhangxc 时间: 2016-4-14 14:11
所以只能选定一种清洁方法。一个设备选定一个清洁方法，不建议有多个清洁方法。
作者: beyondfaya 时间: 2016-4-14 15:35
设备不共用按品种做 设备共用按设备做
作者: dpzhangxc 时间: 2016-4-14 16:45
建议选定一种方法，方法太多那验证就要做N多，实际你们真实做会
作者: dpzhangxc 时间: 2016-4-14 16:46
建议选定一种方法，方法太多那验证就要做N多，实际你们真实做会
作者: 罗伊鲱 时间: 2016-4-14 16:52
本帖最后由 roadman 于 2016-4-14 17:09 编辑
GMP2010版第一百四十三条 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。
在北京市局的《药品生产质量管理规范（2010 年修订）检查指南》第72页有：
2.清洁操作规程的验证应当反映设备实际使用情况。如果多个原料药或中间产品共用同一设备生产，且采用同一操作规程进行清洁的，则可选择有代表性中间产品或原料药作为清洁验证的参照物。应当根据溶解度、难以清洁的程度以及残留物的限度来选择清洁参照物，而残留的限度则需根据活性、毒性和稳定性确定。
3.清洁验证方案应当详细描述需清洁的对象、清洁操作规程、选用的清洁剂、可接受限度、需监控的参数以及检验方法。……
在河北省局的《药品生产质量管理规范（2010 年修订）检查指南》第70页有：
1. 典型缺陷：某企业在同一条生产线上共三种原料药，选择了其中一种原料药为代表执行清洁验证，但该原料药生产后的清洗工艺与另外两种不同。
缺陷分析：同一条生产线生产不同品种的原料药，企业可以选择有代表性的产品执行清洗验证，但前提是这些品种的清洗工艺需要是相同的。对于不同清洗工艺的原料药品种，只能分别执行相应的清洁验证。
作者: dpzhangxc 时间: 2016-4-14 16:55
在制剂企业尤其是多品种共线通常是设备和品种结合按最差条件（溶解性差的、性状突出的、毒性最大的等）来做，统一用一种方法做验证，减少工作量，这是策略，否则老外检查你们你们
作者: 云来云去 时间: 2016-4-14 20:59
楼主，有一本书，专门讲清洁验证，是国外出版的，论坛里有，600多页，你看过吗？
我猜你应该是没有看过的。
作者: 郦无悔 时间: 2016-4-15 09:58
着实没想到roadman大侠会抛出这个问题, 也着实没想到原来对这种验证最源头的东西还存在这么多理解上的差异!
我一直就是认为清洁验证是对清洁工艺的验证, 跟产品工艺验证, 灭菌工艺验证一样, 都是一种"工艺"的验证
但是其表现形式, 必须要通过设备和品种来体现, 还是这一次验证的范围是怎么定义的
清洁工艺验证不像产品工艺验证, 一长串全加在一起, 是一个"产品工艺", 清洁工艺, 大多是每台设备每台设备的去定义, 设备与设备之间, 关联性不强, 主要指单型设备哈, 压片机包衣机这种, 连动线的就另外论了.
因而, 可以是只针对其中一台设备做清洁验证,这台设备做10个品种, 1-5用到了A清洁工艺, 6-10用到了B清洁工艺, 就需要针对A工艺, 从1-5中选择最难清洁的作为代表品种执行验证, 再从6-10中选择最难清洁的作为代表品种再执行验证, 那这个清洁验证方案的内容, 就包括了该设备的两个清洁工艺的验证. 当然, 也可以把这台设备的两种清洁工艺验证分成两个方案. 没有对与错, 只有是否最适合.
作者: 莎瓦娜 时间: 2016-4-15 10:47
一般来说如果是不同品种，设备应该是单独的，针对每个设备所涉及的品种的最难清洗的标准物残留做验证；如果是公用设备则需要每个品种都要做。
作者: 情之殇 时间: 2016-4-15 11:38
清洗验证到底如何选择，每个公司都可能不一样，只要达到目的就行。按品种做清洁验证真的就是错误的吗？新进品种只考虑对其他品种的影响那算不算是你们的评估就有问题而不是这种验证手段有问题呢？至于说浪费资源也不能一概而论吧。有时候这样做了是拿数据说话，避免解释不清带来的风险吧。
作者: window 时间: 2016-4-15 11:54
师兄，确实一语道破
每每看到固体制剂清洁验证方案或报告，无论是自家还是他家的，我都用了保持沉默。（API和注射剂的企业情况似乎好些）
清洁验证本应是对清洁方法的验证，不同的产品可能采用了不同的清洁方法。指示性产品的选择应是在同一清洁方法下进行评估后选择的。但貌似大家都走到了纯粹看产品溶解性，毒性，剂量的评价方法上却忽略了清洁方法本身
曾审核过一外企的固体制剂清洁验证，采用的就是品种清洁的方法。其共线的品种约10多个，其中有采用水清洁的，也有采用水清洁后酒精最终清洁的。再问其为何不是按方法验证时，其回答，我们就是已经考虑了最难清洁中溶解性最差的情况，也是因此在清洁方法中增加了用酒精清洁的处理，这已经是最差状况了。
作者: PharmaGMP 时间: 2016-4-15 13:24
GMP里规定很明确啊，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。至于你的清洁操作规程是针对不同的设备还是不同的品种，应该基于实际的产品情况来确定。
作者: 罗伊鲱 时间: 2016-4-15 13:56
从投票结果来看，大多数选择3按清洁SOP做清洁验证。但何以解释各论坛内大多数方案是按品种或设备来做的呢？难道投票的蒲友大多数是外资或合资的？
作者: 于磊 时间: 2016-4-15 14:11
清洁SOP都在乱写，你清洁验证也就是个形式而已！
作者: 罗伊鲱 时间: 2016-4-15 15:39
你有没有见过在某个设备上生产的每个品种都有一个清洁SOP？然后在一个方案中引用几十个甚至上百个清洁SOP
作者: 于磊 时间: 2016-4-18 13:22
这个问题没有错与对的，按品种、按设备去做目前各个企业多有实施，只是形式不同而已，谁和你讲的一个清洁验证方案只能针对一个清洁SOP的内容呢，思考问题不要走极端！楼主是高手其实没必要发帖子的！你心中已有定论！
作者: 于磊 时间: 2016-4-18 13:28
如果一个SOP同时适用于2台不同车间的设备呢，原料和制剂？你难道还是按照SOP去写方案？你还是要分开写原料和制剂的清洁验证方案。楼主太纠结形式了，本质不变就好！
作者: 罗伊鲱 时间: 2016-4-18 13:55
如郦无悔说，清洁验证是对清洁SOP的验证，但通过设备和品种来体现。但验证主计划中应明确清洁验证策略（按清洁方法进行）。
按品种进行的坏处已说过了。按设备进行，可能混淆不同的清洁方法。
作者: xiazhenhua8 时间: 2016-4-18 14:22
应该按照设备来进行，先按照清洗规程进行清洗，测定本品的残留量，如更换品种，根据批量进行清洗的评估。
作者: 幽林深水 时间: 2016-4-19 09:07
过来学习一下
作者: 591975258 时间: 2016-5-18 16:52
谢谢分享
作者: jinxing0561 时间: 2016-5-31 10:04
是否考虑一个最具代表性的清洁方案（针对最难清洁品种），监测清洁后共线的其他品种残留情况，以合规为通过！
作者: hejubian_2009 时间: 2016-6-2 12:07
按方法做。
作者: 良轩 时间: 2016-6-3 07:51
其实我觉得清洁验证应该是对于同一设备的共线的每个品种都应有清洁验证。只不过大家都会根据清洁方法、清洁剂、产品特性来进行评估。对于完全不同清洁剂、特性的产品而言，当然是需要两次清洁验证啦
作者: 制药者的先锋 时间: 2016-6-7 19:47
正确的应该是结合设备与产品做，比如共用设备，应该选择最难清洁的产品做。如不共用，就选设备用于的产品生产的品种做。
作者: beiwei5du 时间: 2016-6-7 19:54
本帖最后由 beiwei5du 于 2016-6-7 20:02 编辑
清洗验证是在设备确定的情况下验证方法的，产品作用仅仅是确定验证目标产物(solubility and hard to clean)和相应的限度(ADE and therapeutical dose)问题。@windy
作者: windy 时间: 2016-6-7 21:31
以清洁SOP作为验证基础，其本质还是以设备来分类的。
作者: 一天一天 时间: 2016-6-13 10:53
同一设备不同产品 清洗方法还是不同的
作者: 白企心飞 时间: 2016-6-13 11:01
清洁验证的最终目的是确认清洁方法的有效性，按设备啊、按品种啊，我觉得出发点不对。
作者: lindaqueen 时间: 2016-6-13 14:14
非常赞同：清洁验证有按品种做的，例如一个生产线多个品种生产，采用同样的清洁方法和设备，那么可以以品种为主线将多个设备的清洁验证串联到一起来执行。也有按设备做的，例如某生产线有多个品种生产，但是只有部分设备是全部共用的，这个时候你以品种为主线很难执行。那么也可以按设备去做。按品种和按设备做只是你的方案起草的模式和范围的不同而已对于清洁验证的本质是没什么影响的。而你清洁验证的对象永远是你的SOP，在SOP的操作下设备的清洁是符合产品生产的要求的。
其实采取什么样的形式，主要依赖于你清洁sop的主线是依据设备为主线，还是以产品为主线，具体的就是“XX产品+FM101（设备：单个设备）的清洁SOP，一个产品使用多个设备，每个设备均有一个清洁sop”这是设备为主线，那么清洁验证的时候，可以以设备为主线（包括设备有多个SOP（产品不一样）），验证方案列出sop，进行比较，如果方法不一样，每个方法都进行验证，如果方法一样，比较产品的溶解性等参数选择难清洁的，当然弊端就是，部分产品不生产的情况（且计划性不强），会导致验证报告拖得时间很久。
作者: lindaqueen 时间: 2016-6-13 14:17
目前大多数公司没有验证执行的具体策略，如同步验证时，产品不生产，或者验证三批，由于市场需求，三批要生产三年，这种特殊情况是缺少sop规定的
作者: lindaqueen 时间: 2016-6-13 14:24
我们的就是这种方法，缺点是若果共用单个产品，其中一个产品不常生产，就会导致验证结束不了
作者: lindaqueen 时间: 2016-6-13 14:26
其实在进行验证方案起草是应该进行验证范围的评估，特别是增加产品时，根据前面验证的情况进行评估，评估是否需要重新做
作者: 诺叶知秋 时间: 2016-6-13 16:53
一台设备有多个清洁SOP，操作者不会弄混吗，风险太大了
作者: 诺叶知秋 时间: 2016-6-13 17:05
清洁验证的初衷我认为应该是要验证清洁SOP中的清洁方法是否能对设备进行有效的清洁，降低污染的风险，如果一个SOP中有两种清洁方法，就应该分别对每种方法进行验证，所以按品种还是按设备做都可以。但是国内的情况通常都是一条生产线有好多品种共线，如果按品种做就得有好多种清洁方法，这样操作者可能存在用错清洗方法的风险，有什么好方法来降低这个风险？
作者: 情之殇 时间: 2016-6-14 08:56
是的，增加新品种后可能会影响限度，这样新旧限度对比，限度和以前结果对比都要有的
作者: 情之殇 时间: 2016-6-14 08:59
我们是FENMA和鱼骨图
作者: 77月亮 时间: 2016-6-14 09:06
你确定话没有说反了？
作者: 77月亮 时间: 2016-6-14 09:07
这是真理
作者: 欣然一笑 时间: 2016-6-14 09:28
我们公司API车间是按品种做的，确实如楼主所说，检察官更关心的是其他品种对本产品的清洁影响，所以我在方案里加了一页附录，列举其他品种的清洁验证限度及报告编号想关联，但是也比较麻烦。。。
还有个问题请教下楼主，如果按设备来做，在计算残留限度时，我们是设备表面积是按单个设备面积算，还是按你整个工艺设备面积的总和算~~~
作者: 给力宏 时间: 2016-6-20 20:59
共用设备的话，就做几次
作者: 三国杀大神 时间: 2016-6-23 09:12
到处是你这位大神的回复，感觉很牛逼
作者: zysx01234 时间: 2016-6-23 09:23
吹吹牛啊
作者: zyl20030605 时间: 2016-6-25 06:41
如果是不同品种共线生产，考虑到各品种主药的溶解性质不同而致清洁方法不同，我觉得还是按品种做清洁验证方案。
作者: ceq518 时间: 2016-6-25 07:50
共线一般进行风险评估后按设备进行验证清洁SOP的有效性吧，要不那是很麻烦的
作者: wangjin1023 时间: 2016-6-25 08:09
应该是按照产品和设备两个组来确定
作者: 三国杀大神 时间: 2016-6-28 08:54
热循环烘箱可以写持续性清洁验证吗？
我只写过清洁验证。
作者: zysx01234 时间: 2016-6-28 09:02
本帖最后由 zysx01234 于 2016-6-28 09:04 编辑
啥个持续性清洁验证，没有听过。
清洁验证主要包括以下几种情况：
1、随着3批验证批做生产后的清洁SOP规定的清洗方法验证；
2、连续生产N批次后再按清洁SOP规定的清洗方法验证；
3、就是对规定的存放有效期进行验证（无菌药品必须的）。
4、多品种共用设备使用同一清洁方法的（选择最差产品生产三批进行清洗方法验证）。
5、清洗方法经过验证后，对于更换品种生产、过清洗有效期等的生产前进行清洗确认（这个只做一次检测，合格即可）6、就是定期（每2年或3年）对清洁方法进行再验证；
7、当清洁方法改变或工艺、设备发生变更时评估需要时对清洁方法进行再验证。
作者: 三国杀大神 时间: 2016-6-28 10:11
我是新人，我们主管带我，最近没什么事情要做，他就随便交代一下要我写的。说之前没有模板的。
你说的我基本看的懂，那我要和他说这个我写不了吗？
我真的无从下手。
作者: zysx01234 时间: 2016-6-28 10:17
没有模板可以上网上搜索啊。
你这个应该属于再验证了吧，把之前的清洁验证方案/报告和清洁SOP拿出来看看，再结合搜索到的方案，一定要试着做才能有进步
作者: swylove1987 时间: 2016-6-28 15:23
依照不同清洁方法、设备、选取代表品种
作者: fanzhenj 时间: 2016-7-1 17:08
我们是选择含量最大的产品做的（清洁方式都一样）
作者: kbf2009 时间: 2016-10-16 13:50
单设备不用专门做的
作者: liangliangliu12 时间: 2016-11-7 20:18
对于多产品共线的生产设备，进行风险评估，确定最难清洗产品进行清洁验证较为可行，个人意见
作者: wyyalih 时间: 2016-11-25 19:31
清洁验证验证的是清洗方法，有几种清洗方法，需要做几个验证
作者: 淋雨琴 时间: 2017-2-7 14:23
学习了，谢谢各位老师
作者: lw0219 时间: 2017-2-9 10:26
分析的很透彻，学习下！
作者: 山外青山 时间: 2017-2-15 15:39
都可以，看文件怎么要求了。公司应该有清洁验证SOP吧。
作者: jaysun 时间: 2017-2-22 09:52
基于清洁流程，按物料最差情况VS设备最差情况作为最差条件来确认，否则就全部都确认，累死
作者: hk17675408 时间: 2017-3-16 09:50
我们一律按品种
作者: fx_boy299 时间: 2017-7-7 22:47
个人觉得应该按设备做，设备验证也是如此。
作者: jcm813 时间: 2017-7-24 13:33
我觉得应该按设备清洁SOP去验证，因为这是通用方法，如果新加入品种验证不能通过，那就制定新的方法（一般是变更清洁溶剂），然后制定特殊的清洁SOP。
作者: jcm813 时间: 2017-7-24 13:34
其实一般情况下一个设备最多两套清洁SOP就能满足要求了，难清洁的需用特殊溶剂，规定相应的品种，易清洁的用一套
作者: 韶光换 时间: 2017-9-4 10:20
对于我们本企业来说，只能评估出需要验证的参考品种（根据溶解性、毒性、可检测性等），然后按照设备去做。如果按品种去进行，共线生产几十样那还生产什么了，天天验证玩吧。
作者: 罗伊鲱 时间: 2017-12-8 13:58
标题: CLEANING VALIDATION - ORIGIN
本帖最后由 roadman 于 2017-12-8 14:14 编辑
Cleaning validation is a program which demonstrates that the used cleaning procedures are adequate to eliminate/ control potential cross contamination.
The Resin story:
The awareness on cross contamination was came in light in 1988 due to recall of a finished drug product Cholestyramine Resin USP due to inadequate cleaning procedures.
Reason for recall:
The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agriculture pesticides.
The main reason for cross contamination is Solvent recovery storage drums were used twice without proper cleaning. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process.
The firm did not have adequate controls over these solvent drums and did not have validated cleaning procedures for the drums.
This event which increased the FDA awareness over cleaning validation and potential cross contamination due to inadequate procedures.
FDA Expectation:
1.FDA expects firms to have written procedures detailing the cleaning processes used for various piece of equipment.
If firm have one cleaning process for cleaning between different batches of same product and use a different process for cleaning between product changes, we expect the written procedures to address these different scenario.
2.FDA expects firm to have written general procedures on how cleaning processes will be validated.
3.FDA expects the general validation procedures to address who is responsible for performing and approving the validation study , the acceptance criteria and when re-validation will be required.
4.FDA expects firm to prepare specific written validation protocols in advance for studies to be performed on each manufacturing system or piece of equipment which should address such issue as sampling procedures, and analytical methods to be used including the sensitivity of those methods.
5.FDA expects firm to conduct the validation studies in accordance with the protocols and to document the result of studies.
6.FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should supports a conclusion that residues have been reduced to an acceptable level.
So as part of cleaning validation firm should focus on following.
Acceptance criteria
Levels of cleaning
Control of the cleaning process
Bracketing and worst case rating
Determination of Amount of residue
作者: 罗伊鲱 时间: 2017-12-8 14:33
标题: CLEANING VALIDATION ACCEPTANCE LIMITS
本帖最后由 roadman 于 2017-12-8 14:36 编辑
1984 - Samuel Harder Article: ‘Validation of Cleaning procedures’
Concerning the setting of acceptable limits Harder wrote that “Must be practical and achievable by reasonable cleaning procedure… …must be verifiable by analytical methodology existing in the company…. … must be safe and acceptable”
1989 – Doug mendenhall Article: “Cleaning validation”
Mendenhall expanded upon the ideas presented by Harder adding ideas, Such as using matrix approach, testing for cleaning agents, placebo batches, and most interestingly pointed out the potential use of visual inspection.And also mendenhall proposed that limits for surface residue levels be calculated based on smallest batch size / Maximum dose combination.
Surprisingly these two industry articles laid the foundation from which most cleaning validation acceptance criteria were derived and are origin of many cleaning validation activities.Shortly after these publications a major event began to unfold that shaped the direction of cleaning validation and industry practices.
1989-1992 – The US-FDA Vs Barr Laboratories and the Wolin decision
From 1989 to 1992 US-FDA inspected several Barr Laboratories facilities and issued multiple FDA form 483’s with increasing number of observations. The FDA finally sued a Barr Laboratories with district judge Alfred M. Wolin presiding over trail court. The trial ended in Feb 1993 with the decision by judge Wolin injunction against Barr Laboratories.The action on Barr Laboratories case was closely followed by Pharmaceutical Industry and PMA (Pharmaceutical Manufacturer Association) conducted a survey asking many questions on what they were doing in regarding cleaning validation and how companies were setting acceptance limits. In the survey results, PMA listed 44 unique acceptance criteria from the responses which were inconsistent from company to company and in many cases arbitrarily (randomly) selected.Concurrent with Barr Laboratories trial and PMA survey, Foundation or acceptance Limits were further expanded by another publication known in the industry The Fourmen and Mullen Article.
1993 – Fourman and Mullen Article:
At the time of Barr Laboratories trial, another company Ely Lilly, was also involved in a number of issues with FDA over cleaning validation specifically on setting of acceptable limits. In 1993 Gary Fourman and Dr. Mike Mullen published an article where they suggested carryover of product residue meet the following criteria.
1. Not more than 0.001 dose of any product will appear in the maximum daily dose of another product.
2. Not more than 10 ppm of a product will appear in another product.
3. No quantity of residue will be visible on the equipment after cleaning procedure are performed.
The author even though provided explanation for 0.001 & 10 ppm that is not scientific and no regulatory reference provided.
However at that time, this article was land mark in the world of cleaning validation as it was first publication to lay out specific criteria for determining cleaning validation acceptance limits.
After effects of Barr Laboratories Decision:
During course of trial Judge Wolin observed that GMP regulations were vague and not very detailed- Certainly not detailed enough to expect companies to easily understand what the FDA interpretation and expectations were. Judge Wolin criticized the GMPs for their lack of detail and clarity.
The FDA inspectors in the Mid-Atlantic region put together a guide clarifying that what their expectation for cleaning validation. This guide is very detailed and specific. One year later the guide developed by Mid-Atlantic region inspectors was adopted by national centre for use by all FDA inspectors.
The guide states that
1.The firm rationale for the residue limits established should be logical based on the manufacturer knowledge of the material involved and be practical, achievable and verifiable.
2.It is important to define the sensitivity of analytical methods in order to set reasonable limits.
3.Clearly stated companies will put thought and analysis in to the selection of their cleaning validation acceptance limits. Simple adoption of the three Fourman and Mullin criteria is not satisfactory without a scientific justification for using these limits.
In this guide there is short section with concerns about detergents used in the cleaning process.
“If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which make it difficult to user to evaluate residues, As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of cleaning process for the removal of residues”.
Moreover FDA make it clear that they expected companies to test for detergent residues not just API residues.
Current Cleaning Validation Approach:
After Barr Laboratory decision, the concept of cleaning validation was changed year to year in a very drastic way and the number of regulatory agencies guided pharma industries on cleaning validation with detailed guidelines.
Current Cleaning Validation Approach: Acceptance Criteria.
After Barr Laboratory decision, the concept of cleaning validation was changed year to year in a very drastic way and the number of regulatory agencies guided pharma industries on cleaning validation with detailed guidelines.
The subject of cleaning validation has continued to receive a large amount of attention from regulators, companies and customers alike. The integration of cleaning validation with in an effective quality system supported by Quality risk management process enlightens the significance of cleaning validation.
Companies must demonstrate during cleaning validation that cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational.
Cleaning validation should give assurance that the manufacturing operations are performed in such a way that risk to patients related to cleaning validation are understood, assessed for impact are mitigated as necessary.
The acceptance criteria for equipment cleaning should be based on visually clean in dry condition and an analytical Limit.
Methods for calculating Acceptance criteria:
Based on Health based Data
MACO should be based on health based data when this data is available.
MACO = (PDE/ADE previous X MBS Next) / TDD Next
MACO – Maximum Allowable carryover (mg)
ADE – Acceptable Daily exposure of previous product (mg/day)
PDE - Permitted daily exposure of previous product (mg/day)
MBS – Minimum batch size of next product.
TDD – Therapeutic Daily dose for the next product (mg/day)
ADE = (NOAEL X BW) / (F1 X F2 X F3 X F4 X F5)
NOAEL – No observed adverse effect level
BW – Weight of Average adult (ex. 70 Kg)
F1 – A factor (Value between 2 and 12) to account extrapolation between species.
F1=5 for extrapolation from rats to humans
F1=12 for extrapolation from rats to humans
F1=2 for extrapolation from rats to humans
F1=2.5 for extrapolation from rabbits to humans
F1=3 for extrapolation from monkeys to humans
F1=10 for extrapolation from other animals to humans
F2 – A factor of 10 to account for variability between species
F3 – A factor of 10 to account for repeat dose toxicity studies of short term exposure
F3 = 1 for studies that last at least one half lifetime
(1 year for rodent/rabbits, 7 years for cats, dog and monkeys)
F3 = 1 for reproductive studies in which the whole period of organogenesis is covered.
F3 = 2 for a 6 month study in rodents or 3-5 study in non-rodents
F3 = 5 for 3 month study in rodents or a 2 year study in non-rodents
F3 = 10 for studies shorter duration
F4 – A factor (1-10) that may be applied in case of sever toxicity
F4 = 1 for fetal toxicity associated with maternal toxicity
F4 = 5 for fetal toxicity without maternal toxicity
F4 = 5 for a teratogenic effect with maternal toxicity
F4 = 10 for a teratogenic effect without maternal toxicity
F5 – A variable factor that may be applied if no –effect level was established, when LOEL is available.
A factor 10 could be used based on severity and toxicity.
PDE = (NOAEL X BW) / (UFc X MFX PK)
UFc –Composite Uncertainty Factor: combination of factors which reflects the interindividual variability, interspecies differences, sub-chronic-to-chronic extrapolation, LOEL-to-NOEL extrapolation, database completeness.
MF –Modifying Factor: a factor to address uncertainties not covered by the other factors
PK –Pharmacokinetic adjustment
Based on Therapeutic daily dose
When limited toxicity data is available and the TDD is known MACO should be calculated by following formulae. It is used for final product change over API process A to API process B.
MACO = (TDD previous X MBS Next) / (SF X TDD Next)
SF – Safety Factor (Generally 1000 used for calculations)
Based on LD50
In case where no other data available and only LD50 data is available. Use following formulae.
NOEL = (LD50 x BW) /2000
MACO = (NOEL previous X MBS Next) / (SF Next X TDD Next)
LD50 – Lethal dose 50 mg/kg animal. The identification of the animal (mouse, rat…etc.) and the way of entry is important.
(LD50 is the amount of toxic agent that is sufficient to kill 50% of a population of animals usually with in certain time.)
BW – Weight of average adult (ex.70 Kg)
SF Next – Safety Factor (For Topical 10-100, for oral products 100 – 1000, for parental 1000 - 10000)
General Limit as Acceptance criteria:
If MACO values are unacceptably high or irrelevant carry over figures or toxicological data for intermediates is not known the approach of general limit may be suitable.
MACO PPM = MAXCONC X MBS Next
MAXCONC = Maximum allowed concentration (kg / kg or ppm) of previous substance in the next batch
A general upper limit for maximum concentration of contaminating substance in a subsequent batch is often set to 5 – 500 ppm (100 ppm in APIs is very frequent) of the previous product in to next product depending on the nature of the products produced from the individual company.
作者: 罗伊鲱 时间: 2017-12-8 15:22
标题: CLEANING VALIDATION – BRACKETING – WORST CASE RATING
本帖最后由 roadman 于 2017-12-8 16:14 编辑
BRACKETING APPROACH
- The cleaning process of multi product use equipment are subjected to requirements of cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach of for the validation can be used.
- Cleaning procedures for products or process which are very similar do not need to be individually validated. A single validation study under consideration of worst case can then be carried out which takes account of relevant criteria used for worst case selection.
- The bracketing approach may be considered acceptable for similar products and/or equipment’s provided appropriate justification based on sound and scientific rationale is given.
- Company should demonstrate the objective of bracketing and its scientific rationale for its worst case rating of the substances in the cleaning validation programme.
Approach:
- By means of bracketing procedure the substances/ products/ equipment’s are grouped and then sub grouped as applicable.
- A worst case rating procedure is used to select the worst case in each group/sub group as applicable.
- Validation of worst case situation takes place. However it is of utmost important that a documented scientific rational for chosen worst case exist.
Grouping by Equipment Train:
For example if a multipurpose site has manufacturing number of organic substances by using number of equipment trains as given below.
Train A – 9 Substances can be produced which have same cleaning procedure
Train B – 9 Substances can be produced which have same cleaning procedure
Train C – 8 Substances can be produced with two different cleaning procedures. Out of 8 substances 4 substances have cleaning procedure-A, and other 4 have different cleaning procedure-B
Train D – 8 Substances can be produced which have same cleaning procedure
Train E – 10 Substances can be produced which have same cleaning procedure.
Train F –11 Substances can be produced Out of 11 substances 6 substances have cleaning procedure-C, and other 5 have different cleaning procedure-D.
With no bracketing and worst case rating cleaning validation studies required for each of 55 substances.
The substances to be grouped first based on equipment train. Hence 6 groups will be formed as per above data. Then the groups to be sub grouped based on cleaning procedure. Hence 2 sub-groups will be formed in each Train C & Train F groups.
Finally the company would have 8 groups for cleaning validation purpose as follows
Train A – 1 Group
Train B – 1 Group
Train C – 2 Group
Train D – 1 Group
Train E – 1 Group
Train F – 2 Groups
Once the product groups have been established the next step is determined the so-called ‘worst case’ representative of each group and cleaning validation of the same.
By using bracketing approach we validated only 8 products out of 55 products.
Grouping by Substances:
Substances can be grouped as follows
- Produce in the same train substances with the same cleaning procedure.
- Produce in the same train substances with very low therapeutic dose and/or low batch sizes. (Then sub groups to be formed based on cleaning process)
- Produce in the same train substances with very high therapeutic dose and/or large batch sizes. (Then sub groups to be formed based on cleaning process).
- Produce in the same train substances with very low ADE. (Then sub groups to be formed based on cleaning process).
- Produce in the same train substances with very High ADE. (Then sub groups to be formed based on cleaning process).
Once the product groups have been established the next step is determined the so-called ‘worst case’ representative of each group and cleaning validation of the same.
Grouping by Product:
1. The common basis for grouping is by product. The grouping is usually based on the formulations or dosage form of the product. When this approach is used products are divided in to groups according to the dosage form and then according to formulation.
For example
A company might have 10 tableted products, 6 ointment products and 4 liquid products. In this case the first evaluation would be that the products fall naturally in to 3 broad groups.
However if 6 of the tableted products were manufactured by wet granulation process, whereas 4 of the products were manufactured by a dry, direct compression method this would be a basis for subdividing the tablet in to 2 sub-groups. Likewise if 2 of liquid products were suspensions and other 2 liquid product were true solutions. This will also create 2 subgroups for this group.
The company would have 5 groups of products for cleaning validation purpose.
Tableted products – 2 groups
Ointment products – 1 group
Liquid products – 2 groups.
Once the product groups have been established the next step is determined the so-called ‘worst case’ representative of each group.
2. Another example is would be a group composed of several products of similar potency. In this case the worst case selection might be based on the basis of solubility.
3. Third example might be group composed of several products having same API and differing only in concentration of API. In this it would be reasonable to select product having highest concentration as worst case.
It is unlikely that single worst case product could apply to entire line of products having significantly different formulation and dosage forms.
The substance / Product which does not fall within bracketing approach must be validated individually.
WORST CASE RATING
Worst case rating will generally depend on following points.
a) Hardest to clean, Experience from production
b) Solubility in used solvent
c) Lowest acceptable daily exposure
d) Lowest therapeutic dose
Hardest to clean, Experience from production:
One criterion which can be used is, experience from production with regard to how difficult a substance is to clean out. This study is recommended to be in the form of interviews with operators and supervisors.
Difficulty of cleaning could be rated according to the three categories suggested below.
Category: 1 = Easy
2 = Medium
3 = Difficult
Solubility in used solvent:
Solubility rating should be carried out as follows.
Acceptable daily exposure (ADE):
The acceptable daily exposure (ADE) defines a limit at which patient may be exposed every day for a life time with acceptable risk related to adverse health effects.
ADE rating should be carried out as follows.
If ADE data are not available, other pharmacological (dose), OEL or toxicity data LD50 may be used.
Therapeutic dose:
Rating based on therapeutic dose can be given as follows.
If dose data are not available, other pharmacological (dose), OEL or toxicity data LD50 may be used.
Rating Procedure:
The worst case rating can be executed according to an issued protocol in which the methods and procedures for rating will be identified. And a formal rating matrix has been filled as follows.
For example if a group has formed from 9 substances (Esubstance, Fsubstance, Csubstance, Lsubstance, Osubstance, Msubstance, Psubstance, Rsubstance and Tsubstance) which can produce from same equipment train. Out 9 substances 6 substances have one cleaning procedure where as other 3 have different cleaning procedure.
All categories are introduced as column in matrix to identify worst case based on rating.
v For the products in this train two cleaning procedures (Class 1 & Class III) are used.
Therefore two groups have to be validated.
- The worst case product (for the validation study) for class III is Osubstance (Solubility 2 and hardest to clean is 2.8).
- The worst case product (for the validation study) for class I is Rsubstance (Solubility 2 and hardest to clean is 2.6)
- In both cases the limit should be calculated with the most active substance (ADE4) if ADE data not available the limit should be calculated with the most active substance (Therapeutic substance 4).
- If limit calculated with ADE4 or therapeutic dose 4 is achievable for all products this limit can be chosen for both the groups. If limit is two low and not achievable Esubstance & Fsubstance should be considered as a separate group or produced in dedicated equipment’s.
The limit for the remaining group should be calculated with the next most active substance (i.e ADE 3 or Therape
作者: honker 时间: 2017-12-11 12:08
认同
作者: Rickzhen 时间: 2018-12-12 10:54
首先，清洁验证的对象是清洁方法，清洁方法是针对设备上的残留物（产品）。
清洁验证并非单纯地针对产品或者针对设备进行。而是首先要找出关键的产品，通过分析所涉及到所有产品的溶解度、药理活性、制剂含量、是否含有难以清洁的辅料等因素来确定关键的或者说“高风险”的产品。
在确定了关键产品后，可以选择的两种验证方式，
1. 针对产品的模式；
2. 针对设备的模式；
针对产品的模式的确会有工作重复等问题，但并非如果楼主所言是“错误”的。
最佳的验证方式是首先分析出关键出产品，然后再结合生产设备，分析出每个设备各种可能的生产模式，从而确定验证对象（目标残留），最后制定验证方案。
但是目前国内的检查官，通常接受的做法还是按照产品进行清洁验证，从现实角度出发，企业也只能按照单个产品模式进行清洁验证。
作者: qiyue 时间: 2019-1-16 10:25
很多公司的清洁规程是按品种来的，一个品种一种清洁方法，按方法来做清洁验证和按品种有什么区别
作者: hjhw888 时间: 2019-1-31 08:32
清洁SOP来进行确定
作者: S尘梦S 时间: 2019-1-31 11:55
很好奇，一个设备可以有很多种清洁方法，难道你文件会把每一个清洁方法都写上去吗？以设备进行清洁验证选择目标品种又不是说说那么简单的，我理解的清洁验证应该考虑到品种和设备的特性对清洁方法进行验证。
作者: zhangya5834 时间: 2019-9-26 10:39
我有点不明白，一个设备有多种清洁方法是出于什么目的？难道不是因为品种不一样，清洁难度不一样？你同一个品种针对同一台设备难道把所有清洁方法都列上？那才是真的浪费资源
作者: cheng9gong 时间: 2019-11-21 09:18
按品种做是覆盖按设备和SOP的
作者: GMP20130222 时间: 2019-11-26 11:54
说那些都没用，看你们公司谁有话语权让谁拍板，反正检查去了又不会有啥大问题
作者: circle123 时间: 2020-1-9 15:57
学习了
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