Michel Crevoisier is retired senior quality assurance expert, ChemOps, at Novartis Pharmaceuticals
In its 2011 Guidance for Industry on Principles and Practice of Process Validation (1), FDA radically changed its interpretation of process validation. Validation now means “the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.” It will no longer be a formalized activity that is limited in time and, typically, to three validation batches.
For many people, the most challenging consequence of the new approach is that process validation never ends. As long as a process is in use, it is undergoing validation, either in stage 1 (development), stage 2 (qualification) or stage 3 (continued verification), and validation will continue until the process is no longer used.
Once we have fully understood the new concept of the life cycle approach to process validation, we have to recognize that some typical phrases and words that we have been using for decades are now obsolete.（我们以前经常使用的一些典型的用语和用词，在现在看来将是过时的说法）
Here are some examples:
· “The process was validated.”（“工艺已经验证了”将会是过时的说法，应该说“工艺已经被确认了”）
A common statement so far, but it no longer makes sense. Reading or hearing it should make us raise an eyebrow. As validation never ends, to speak of process validation in the past tense has become as much of a fossil as the old validation concept of “three consecutive batches.”
Instead, today, we would say, “The process was qualified.” We should further consider replacing the notion of a “validated process” with the concept of “process validity.” Is the process under control? By FDA‘s definition, the collected process data and their evalation should give us the answer..
（同时“已验证的工艺”也是过时的说法，应该说成是“有效的工艺”，后面一种说法是基于过程控制的说法）
· The beloved “validation runs”（我们喜欢使用的“验证批次”将是过时的说法，run和batch不同的（特别是在连续制造时），但是典型的我们在batch productio的时候说成“验证批次”）
These also belong to history. Under the new definition, every run is a validation run. Depending on the maturity of the process, the validation runs can be called development, qualification, or verification runs.
（在2011 FDA process validation角度看，每一批次都是验证批次，根据工艺的不同成熟阶段，验证批次可以有不同的叫法）
· “Revalidation” now makes no sense.（"再验证”说法也不合适了）
We cannot redo something that never ends. We can imagine situations where a process needs to be requalified or even redeveloped; but not revalidated.
（因为工艺验证是生命周期的，到产品退市才结束，所以我们不能重做一件本身没有结束的事情，我们可以叫其为“工艺再确认”或者甚至“工艺再开发”，而不能叫做“工艺再验证”）
· Retrospective, concurrent, and prospective validation（回顾性验证，同步验证和前验证的说法现在可能也不太合适）
What do they mean today where validation never ends? If process validation is “the collection and evaluation of data,” isn‘t process validation simultaneously concurrent (the collection of data), retrospective (the evaluation of data), and prospective (the application of inferential statistics)? Collecting data prospectively, however, is hard to imagine.
Considering that the new validation concept changes the meaning of many hitherto common terms (think of “qualification” applied to processes, where the term had typically been used for qualifying equipment), one can ask why the FDA decided to still use the term “process validation“ at all. What if they had chosen to use “process control” or “process stability” instead? Wouldn‘t this wording better express what the new guidance is all about?
（为什么不使用“工艺工资”或者“工艺稳定性”代替“工艺验证”呢？？？？一个方面可能是“工艺验证”不仅仅是行业质量保证的工具，监管者仍保持使用“工艺验证”的说法也是基于和产品注册申报中的用语保持一致）
The difficulty may have been that process validation is not only an industrial quality assurance tool (along with keeping process control charts, and evaluations like Six Sigma, for example.)
The term also enters the domain of the application for and the approval of new drugs. To obtain marketing authorization, the applicant has to demonstrate that he is able to reliably produce commercial quantities of the new drug. The proof of the ability to manufacture is typically submitted in the form of a Process Validation package or dossier (2). Regulators must have decided to keep the term “process validation“ to maintain the alignment with the wording governing the application for new drugs.
Still, it would have been interesting to have a process guidance that did not use the word “validation.” It would have allowed for a clean cut away from the old “three validation runs-based” practice and an easy leap to the modern approach to quality assurance the FDA wants us to embrace.
So, do we need brainwashing? Six years after the publication of the new FDA guidance, it seems we do. Perhaps it could begin with our quality assurance vocabulary.
References
1. FDA, “Guidance for Industry; Process Validation: General Principles and Practices,” January 2011.
2. EMA, “Guideline on Process Validation for Finished Products - Information and Data to be Provided in Regulatory Submissions,” Chapter 4, November 2016.
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发表于 2017-10-7 11:13:42
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