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2014-07-18 识林

摘要：7月14日FDA发布新的QbR化学问题草案[pdf] ，用于征询企业意见。草案中的一些问题影响广泛而深远。识林对草案全文翻译并请业内专家撰写评论。详细内容请见下文。如希望针对该草案反馈问题或意见，请发送邮件到support@shilinx.com，邮件标题请注明“QbR化学问题草案”，识林将汇总所有评议反馈到OGD。

OGD发布新的QbR化学问题草案

7月14日FDA仿制药办公室（OGD）发布了一份化学问题草案修订清单。这些问题并不用于实施，仅专门发布用来收集行业对于拟议问题的相关意见。这些问题覆盖了活性成分DMF和成品制剂申请（ANDA）。前24个问题与DMF相关，剩下的38个问题与制剂相关。

草案的具体目的是为了征求来自于API企业和FDF企业的意见。现在FDA竭尽全力获得企业的意见，这通常意味着寻求的一些问题或信息可能是“有争议的”，换而言之，可能是很难回答（或不清楚）的问题，或寻求企业可能不认为是合适的信息。作为一般原则，FDA向企业征求意见的次数越多，对于企业来说越是需要认真地阅读这些问题并确保理解了到底什么是被要求的，并且在每种情况下都能回答所有问题。如果你现在或将来打算提交DMF和/或ANDA，那么这是你的责任现在就发表评论，或如俗话说，永远保持你的沉默。

一些问题的影响相当广泛而深远，例如：
　"关键工艺参数（CPPs）是什么？它们如何与原料药质量相联系？"

这一问题没有一个简单的答案。试想你在一件API的DMF中到底应该如何回答这一问题。如果不是很清楚，那么请在评议中提出。如果你有信心可以回答上面的问题，那么来看看这个：
　“商业化规模的原料药拟定控制策略是什么？在商业化规模实施控制策略的剩余风险是什么？”

类似的拟议问题对于ANDA申请人同样存在。例如：
　“成品药的质量属性是什么？哪些质量属性被认为是关键质量属性（CQAs）？对于每个CQA，目标是什么？如何确立的？”

如果你发现这些问题是容易回答的，那么你应该相信你确切地知道这一问题需要什么：
　“满足CQA与临床表现相关的方法是什么？如适用，在药物开发过程中使用什么体外生物表现评估（如，溶出方法、通量测定等）来保证临床表现？”

尽管这些征求意见的草案问题看起来是发布用于寻求仿制药公司的看法，很明显，这些问题可以应用于所有的制剂申请、NDA和ANDA。

如果你准备给出评论，有人可以帮助我来问问原料药的“机械”性质是什么吗？显然，它们与原料药的物理、化学、生物性质不同。

北京大学药物信息与工程研究中心 - Garth Boehm博士 2014-07-18
校译：识林-椒 2014-07-18

The Office of Generic Drugs issues new DRAFT Question based Review (QbR) Chemistry Questions
Written by Garth Boehm • July 18, 2014

On July 14 OGD issued a revised list of DRAFT Chemistry Questions. These questions are not intended to be implemented but have been issued specifically to get comments from Industry about the proposed questions. They cover BOTH Active Ingredient DMFs and Finished Dose Form Applications (ANDAs). The first 24 questions relate to DMFs and the following 38 questions relate to dosage form.

The specific purpose is to solicit comments from Industry which in this case is both the API industry and the FDF industry. Now when FDA goes to great lengths to get input from industry, it usually means the some of the questions or information sought might be “controversial”, in other words questions might difficult to answer (or unclear) or seeking information that industry may not believe is appropriate. As a general rule, the more times FDA asks for industry comment, the more important it is for industry to CAREFULLY read the questions and to be sure that you understand EXACTLY what is being asked and that you can answer all questions in every circumstance. If you now, or in the future propose to, file DMFs and/or ANDAs it is your responsibility to comment NOW, or as the saying goes, to forever hold your silence.

Some of the questions are quite broad and far reaching, for example:
　“What are the critical process parameters (CPPs) and how are they linked to drug substance quality?”

This question does not have a short answer. Imagine exactly how you are going to answer this question for an API DMF. If it is not clear, then say so in a comment. If you feel confident that you can answer that question, then how about this one:
　“What is the proposed control strategy for the drug substance manufactured at commercial scale? What are the residual risks upon implementation of the control strategy at commercial scale?”

Similar proposed questions exist for ANDA filers. For example:
　“What are the Quality Attributes of the finished product? Which quality attributes are considered Critical Quality Attributes (CQAs)? For each CQA, what is the target and how is it justified?”

If you find that easy to answer, then you should be confident you know exactly what is required for this question:
　“What is the approach for meeting the CQAs related to clinical performance? If applicable, what in vitro bioperformance evaluations (i.e., dissolution method, flux assay, etc.) were used during pharmaceutical development to ensure clinical performance?”

Although these draft questions for comment seem to be issued seeking generic drug company input, it is apparent that they can apply to all FDF applications, NDAs and ANDAs.

If you do comment, can somebody do me a favor and ask what are the "mechanical" properties of a drug substance? Apparently they differ from the physical, chemical, and biological properties of the drug substance.

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