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2014-01-31 识林

罕见之事：FDA向行业问计，如何提高简化新药申请（ANDAs） 质量！

1月23日，FDA在联邦公报（Federal Register）上发表了一篇题为“提高递交FDA的简化新药申请的质量—建立公共卷宗（Public Docket）”的公告。 其目的如下述：
“FDA将建立公共卷宗，接收公众对于提高提交给FDA仿制药办公室（OGD）的简化新药申请（ANDAs）、相关修订及补充申请的质量的意见和建议。具体地讲，FDA有意倾听申请人在起草及编写ANDA申请提交时遇到的任何困难，FDA可以通过诸如向行业提供更多或更好信息的方式帮助解决这些困难。”

这确实是非常难得的机会。通常业内人士只能私下抱怨令其生计艰难的与FDA相关的问题。这是您告诉FDA他们应该如何改善才能使得起草和提交ANDAs变得简单的机会。该公告给出了一份FDA在很多ANDAs中见到的“常见和反复出现的缺陷”的清单。对于申请人而言，这是学习并确保他们的ANDA文件中不会出现这些常见缺陷的非常有价值的一份清单。这份清单包括：

申请提交：未提供完整的FDA 356h表；非活性成分水平不合理；溶出数据不充分；包装量低于推荐阈值，未提供依据；稳定性数据不充分或不足；提交定性和定量（非Q/Q）不一致的处方；电子提交或格式缺陷；申请包含不正确或毫无依据的提交依据。

化学：杂质限度依据较差或不充分；未列出可能杂质及其来源；对原料药的分析方法及成品剂型，未在适当情况下提供充分核实;未明确关键的生产工艺参数或未将中控与研发研究相关联; 对于关键步骤的生产收率，未提供合适的可接受标准，或提供的收率值发生变化，但没有充分理由和解释。

用无菌工艺生产的无菌药品的无菌保证：未说明可能接触无菌药品的设备及包材的灭菌和/或除热源情况；未提供可能接触无菌药品的相关设备及包材的灭菌和/或除热源相关验证数据；在需要的情况下，未提供必要的过滤器级别的验证数据；对于拟采用的无菌灌装工艺/生产线/生产室，未提供工艺模拟数据。

生物等效性：电子表格中包含不准确和/或不完整信息；重复提交药代动力学信息；生物豁免请求不准确和/或不完整（例如，溶解度测定方法不合适，缺乏富有规格的溶出度数据，缺少分析方法标准操作规程）。

致命缺陷：药品设计出现重大缺陷，使得拟议产品不能满足橙皮书收录参照药品的所有使用条件。

药物主文件：申请包含不止一个原料药或者不止一种药品生产工艺；在最初申请提交后大量修订或时间推移之后，未能更新药物主文件；未提供生产工艺和控制的完整说明；未能证明起始物料是适宜的。

这是一份包含常见缺陷的有价值的清单，您可以用来检查你的ANDAs，在提交申请之前确保不出现这些缺陷。

此外，该公告包括4个问题，FDA认为这些问题对于提高ANDA质量工作非常重要，这些问题是：
1. ANDA申请流程令人困惑或没有明确规定的环节有哪些？
2. FDA可以帮助解决那些申请人在准备申请提交时遇到的问题？
3. GDUFA实施之前，在提交之后，ANDA是否通常在某些特定的审评点一直延缓或拖延？如果是，为什么？
4. 除了发布法规指南，FDA如何与行业分享关于提高ANDA申请提交质量的建议？

这些问题有助于帮助申请人思考如何改善ANDA过程。

因此，这是您的绝好机会，告诉FDA应该如何改善，以帮助您起草和提交ANDA。该公告建立的接收意见的公共卷宗一直开放至2014年3月24日。您可以，登陆 http://www.regulations.gov ，根据提示发表意见。正如俗语所说，“现在请讲, 否则就请永远保持沉默！”

北京大学药物信息与工程研究中心 - Garth Boehm 博士 2014-01-25
校译：识林-Kapok 2014-01-31

Well here's something that doesn't happen very often, FDA asking Industry how to improve the Quality of ANDAs!!

On January 23rd FDA published a Notice in the Federal Register entitled:“Improving the Quality of Abbreviated New Drug Application Submissions to the Food and Drug Administration; Establishment of a Public Docket” The purpose is stated as:
“The Food and Drug Administration (FDA) is establishing a public docket toi receive input and suggestions from the public on ways to improve the quality of abbreviated new drug applications (ANDAs) and associated amendments and supplements to FDA’s Office of Generic Drugs (OGD). Specifically, FDA is interested in hearing about any difficulties sponsors are having developing and preparing their ANDA submissions that FDA could help address, for example by providing more or better information to industry.”

This is a rare opportunity indeed. Most often people working in Industry can only complain among themselves about FDA related issues that make their lives difficult. This is your opportunity to tell FDA what they should do to improve the ease of developing and submitting ANDAs. The Notice gives a list of “common recurring deficiencies” that they see in many ANDAs. This is a valuable list for any sponsor to study and to make sure that these common deficiencies do not occur in their ANDA filings. The list includes:

Filing: Failure to provide a completed Form FDA 356h; unjustified inactive ingredient levels; inadequate dissolution data; packaging less than the recommended threshold amount without justification; inadequate or insufficient stability data; submissions of non-qualitative and non-quantitative (not Q/Q) same formulations; electronic submission and formatting deficiencies; applications containing an incorrect or unfounded basis of submission.

Chemistry: Poor or inadequate justification of impurities limits; failure to provide a list of potential impurities and their origins; failure to provide adequate verification of analytical procedures for active pharmaceutical ingredient and finished dosage forms, where appropriate; failure to identify the critical manufacturing process parameters or to link in-process controls to development studies; failure to provide appropriate acceptance criteria of manufacturing yields for the critical steps, or providing yield values varying without adequate rationale or explanation.

Sterility assurance for sterile drug product applications manufactured by aseptic processing: Failure to describe sterilization and/or depyrogenation of relevant equipment and components that may come in contact with the sterile drug; failure to provide relevant validation data for sterilization and/or depyrogenation of relevant equipment and components that may come in contact with the sterile drug; failure to provide validation data for sterilizing grade filters, if needed; failure to provide process simulation data for the proposed aseptic filling process/line/room.

Bioequivalence: Inaccurate and/or incomplete information contained in electronic tables; submission of pharmacokinetic repeats; inaccurate and/or incomplete biowaiver requests (e.g., inappropriate method of solubility determination, lack of dissolution data for all strengths, missing standard operating procedures for analytical methods).

Fatal flaws: Significant flaws in the design of a drug product such that the proposed product will not be able to meet all conditions of use of the reference listed drug.

Drug master files: Submission contains more than a single drug substance or more than a single drug manufacturing process; failure to update the drug master file following a large number of amendments or time lapse since the original submission; failure to provide a complete description of manufacturing process and controls; failure to justify appropriate starting materials.

This is a valuable checklist of common deficiencies that can be used to check that your ANDAs do not have these deficiencies before you file them.

In addition the Notice contains 4 questions that FDA thinks are important to the task of improving ANDA quality. These questions are:

1. What aspects of the ANDA application process are confusing or not well defined?
2. What problems do ANDA applicants encounter when developing a submission that FDA could help address?
3. Prior to GDUFA, were ANDA submissions consistently slowed or stalled at certain recurring review points post-filing? If so, why?
4. How should FDA share suggestions for improving ANDA submissions with industry, beyond issuing regulatory guidance?

These questions should help in focusing sponsor thinking about how to improve the ANDA process.

So this is your opportunity to tell FDA what they should improve to help you in developing and filing ANDAs. The docket established by this notice to receive comments will remain open until March 24, 2014. Comments can be sent electronically by going to http://www.regulations.gov and following the instructions. As the saying goes “speak now or forever hold your silence!”

相关链接 Improving the Quality of ANDA Submissions 2014-01-27
识林资讯 仿制药办公室征询关于如何改善简化新药申请的意见 2014-01-28