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发表于 2015-11-27 20:02:11
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本帖最后由 beiwei5du 于 2015-11-27 20:07 编辑
其实今天我有看到CPG Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval这篇文章，对于前验证和同步验证又有了不同的理解，其实针对前验证的批次是否能够放行的问题，不是一个关键点，本来前验证批次是完全的GMP compliance，基于逻辑和推理，如果该前验证的批次产品完全合格，为什么不能放行？？？？FDA也不会像CFDA那样不讲道理（一刀切），特别是现在基于科学和风险的面向21世纪的GMP的观念下。大家将prospective validation和current validation两个区别偏重于是否销售的问题，有点本末倒置了。其实个人认为的两种的区别在于前验证是基于验证做完后才能进行相关批次放行，比如AAAAA(验证批）A(验证批）A(验证批）AAAAAAAA(所有的A都是按照GMP compliance生产，并且工艺和批量一致，验证批前面的A的生产可以定义为demonstration/exhibition batches），就是说当第三批A(验证批做完了）才能进行相关的放行（不论是验证批次以前的，验证批次还是验证批次以后的）。而对于同步验证就不同的，因为他是Concurrent Validation. Validation carried out in exceptional circumstances, justified on the basis of significant patient benefit, where the validation protocol is executed concurrently with commercialisation of the validation batches.其中对于commercialisation的关注点不是否可以销售的问题，而是怎么销售的方式。同步验证是可以验证一批就放行一批的（这个是关注点，即下文说的the distribution of individual batches prior to completion of the initial conformance batches）.这个风险是很大的。所以一般企业也不会这样干的，同时regulatory agent也不会容易批准这样做的，所以才会有在你定义为concurrent validation需要监管机构进行介入评估，但是对于某些情况下确实是考虑到benefit-risk ratio for the patient，是必须这样开展的，所以在现在的相关法规上为什么没有删除concurrent validation的一个原因（必须是in exceptional circumstances的条件下）。
下面一段选自CPG Sec. 490.100的话可参阅：
4. Completion of initial conformance batch manufacture prior to commercial distribution:
For some products, the completion of the initial conformance batch phase of process validation（这个我理解的是基于生命周期的工艺验证的stage 2中的process qualification） before the distribution of any one batch would require the manufacture of unneeded batches（这个我理解的是不能distributed的，而不是“完全没有”的） (e.g., certain orphan drug products), which would not be in the interest of public health. In addition, the completion of multiple batches before first distribution may also be impractical for a product with a very short shelf-life or that is intended for limited use (e.g., some radiopharmaceuticals). Therefore, the need to manufacture multiple conformance batches in advance of initial product distribution may not be needed under these circumstances. In such cases, product distribution may have occurred concurrently with the release (or approval for release) of each conformance batch.
The agency's evaluation of a firm's decision to release batches concurrent with the manufacture of the initial conformance batches should include review and/or audit and assessment of:
a. the firm's basis for justifying the distribution of individual batches prior to completion of the initial conformance batches (to include review of the product/process development effort);（要有证明实施同步验证基础，比如包括对开发阶段的工作的评价）
b. the firm's protocol/plan and available data to verify that there are adequate batch controls and testing prior to release for distribution of each batch, and provides for adequate and timely assessment of the validity of the process once all initial conformance batches have been manufactured; and,（方案计划和相关的数据可证明验证批次在放行前有足够的控制和检测，并且能在完成验证批次后能充分及时的对工艺有效性进行评估）
c. the firm's program for monitoring distributed batches and provisions for a rapid response to information suggesting the process is not under control (e.g., subsequent batch failures, production problems related to process design or equipment performance, complaints).（公司应该要有相关的程序对该放行的验证批进行监控，并且在当知道验证失败的情况后能迅速的对放行的批次做出反应，比如迅速的recall）@hongwei2000 @意林枫
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我觉得我们的观点没有什么太大的不同。工艺验证批并非不能放行，而是必须要等工艺验证的结论出来后，工艺是稳定可行的，也就是工艺验证报告的结论是合格的，才可以放行产品。工艺验证通常需要进行三批，所以对于一些品种，一年可能都生产不了三批，或者说需要立马投入市场使用的，也不可能等待三批后，再进行放行，所以可以在工艺验证报告的结论没有出来之前，就进行放行。综上，区别前验证和同步验证，最关键的就是是否需要等待验证报告的结论，才予以放行，而放行，就对应的是商业批。