首页 > 资讯 > 原料药供应来源的变化能否通过可比性协议向FDA提交

出自识林

2016-10-26 Lachman CONSULTANTS

多年来我一直在努力说服企业，对于已获批ANDA的某些变更必须始终作为之前已获批申请的补充申请（PAS）提交，或者在某些情况下，这些变更可以作为在ANDA中已获批的可比性协议处理。在美国仿制药协会（GPhA）2016秋季技术会议上，FDA药品审评与研究中心（CDER）药品质量办公室（OPQ）检验和研究办公室主任Lucinda (Cindy) Buhse博士在“可用”和“不可用”可比性协议的背景下讨论了这一问题。

Buhsa博士指出，这些协议在ANDA或PAS中对于以下类型的变更很有用：

• 原料药和/或产品的附加生产场地
• 原料药和/或产品的附加检验场地
• 药品的附加包装配置
• 包装组件的附加供应商
• 去除混合均一性检测

她表示，“增加新的原料药来源（即，申请添加新的DMF）不适合使用可比性协议”。原因是由新来源和不同的DMF制造的API可能在质量属性方面有显著差异，包括粒度分布、工艺杂质、降解产物等，这可能对用API制造的成品制剂的质量具有直接影响。（请注意，在这种情况下的“不可用”是使用不同来源的API，而不是在同一DMF下生产场地的变更。）我实在难以统计与客户发生的此类讨论的次数，客户表示他们一直作为CBE-30（待批变更补充申请，在FDA收到补充申请后30天后实施变更）来做。但如果你没有在可比性协议中研究，那么你不能通过CBE-30变更，必须通过PAS完成变更。

Buhse举的另外一个不适合使用可比性协议的例子是，当拟定的变更需要提交新的临床或生物等效性数据时不能使用可比性协议。

我希望这能够理清这个古老的问题，即API供应来源方面的变化应如何提交变更。但在同一DMF下的场地变更可以通过可比性协议或CBE-30提交（只要该场地已经过检查并被FDA所接受）。

Lachman CONSULTANTS - Bob Pollock先生
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Comparability Protocols – One Age-Old Question Answered
By Bob Pollock | October 25, 2016 原文地址

Over the years I have been trying to convince firms that certain changes to approved ANDAs must always be filed as a Prior Approval Supplement (PAS) or, in some cases, these changes may be handled as a Comparability Protocol that is approved in an ANDA. At the GPhA Fall Technical Conference yesterday, Dr. Lucinda (Cindy) Buhse, Director, Office of Testing and Research, in the Office of Pharmaceutical Quality, discussed this issue in the context of dos and don'ts for Comparability protocols.

Dr. Buhsa noted that these protocols are useful in ANDAs or PAS for the following types of changes:

• Additional manufacturing site for drug substance and/or product
• Additional testing site for drug substance and/or product
• Additional packaging configuration(s) for drug product
• Additional supplier for packaging component(s)
• Removal of blend uniformity test

She went on to state that “adding a new drug substance source (i.e., new DMF to the application) is inappropriate for comparability protocols”. The reason for this is that that there could be significant differences in quality attributes of the API manufactured from a new source and a different DMF including particle size distribution, process impurities, degradation products, etc., that may have a direct impact on the quality of the finished dosage form that the API is used to manufacture. (Note that the “don't” in this case is use of a different source of API, and not the change in site of manufacture under the same DMF.) I can't tell you the number of times that this discussion has occurred with clients who said they do this all the time as a CBE-30. Well, if you can't do it in a comparability protocol, you can't do it in a CBE-30, and it must be done in a PAS.

The other example that Dr. Buhse noted was not appropriate for a comparability protocol is when the proposed change requires the submission of new clinical or bioequivalence data.

I hope this clear up this age-old question of how one must submit a change in source of supply of API. But a site change under the same DMF can be the subject of a comparability protocol or a CBE-30 (as long as the site has been inspected and found acceptable to the FDA).