首页 > 资讯 > CMC中“原料药与制剂的杂质列举、表征及其限度依据的汇总表”的新要求

出自识林

2014-01-14 FDA，识林

FDA仿制药办公室（OGD, Office of Generic Drugs）悄无声息地在其“业界信息”页面列上了一套新表格。这些表格题为“原料药与制剂的杂质列举、表征及其限度依据的汇总表”，显然是必须完成并在新ANDA中与其他CMC数据一同提交。这些表格并没有注明日期，但提及表格需要完成并提交的段落注明日期为“2014年1月”。由此推断，从即日起就必须提交这些表格。
表格同时附上。表格相对简单，因为它们已经提供了ANDA要求的涉及杂质的全部数据。表格还要求给出对鉴定限度和质控限限度的计算。另外，申请者还必须罗列所提出的可接受标准，同时对超出ICH的提出限度，证明其合理性。原料药和制剂的该信息应单独列表。
尽管一直要求提供这些信息，但将它们集中于一套表格中，将可以使ANDA验收审评员快速评估是否所有杂质的可接受限度（原料药和制剂）均恰当合理。看来OGD正在继续扩大其验收审评，以保证尽可能所有立卷的ANDA在立卷时实质上就是可批准的。在立卷前消除所有缺陷这一机制，是用于确保NDA符合PDUFA的目标期限。似乎OGD也要效仿这一做法，在接收ANDA前，尽可能多的消除缺陷。如果没有合理的杂质接受标准，将会面临ANDA被拒收同时损失25%申请费的风险。
从实际情况来看，过去许多ANDA申请人都用一个相对宽的杂质接收标准申报ANDA，因为他们的申报批（Exhibit Batches）（通常是大规模生产的第一批）中没有全程稳定性。相应地，他们用较宽的接受限度来申报ANDA，在有更多稳定性数据可用以证明较窄限度时，这些较宽的接受限度可通过CMC审评缺陷收紧。看来这样的日子一去不复返了，申请者将需要接受ICH的限度或对较宽限度有可接受的依据。换句话说，申请人需要足够了解他们的新产品，从而在申报时，能有信心达到那些实质上的最终杂质接受标准。
北京大学药物信息与工程研究中心 - Garth Boehm 博士 2014-01-11
校译：识林-Kapok 2014-01-13

FDAs Office of Generic Drugs (OGD) has very quietly listed a new set of tables on their 'Information for Industry'page. These tables are titled Summary Tables for the Listing and Characterization of Impurities and Justification of Limits in Drug Substance and Drug Products and apparently must be completed and submitted along with the rest of the CMC data in new ANDAs. The tables are not dated but the paragraph referring to the need to complete and submit these tables is dated 'January 2014'. The presumption is that they must be submitted now, that is for now forward. The tables are appended and are relatively simple in that they provide for recording all of the data concerning impurities required in the ANDA. They also require calculation of the identification and qualification thresholds. In addition applicants must list the proposed acceptance criteria and justify any proposed limits over those of ICH. This information is to be separately tabulated for both drug substance and drug product.

While this information has been required, pulling it together in one set of tables will enable ANDA acceptance reviewers to quickly assess whether all impurity acceptance limits (API and Finished Product) are appropriate and justified. It appears that OGD is continuing to expand the acceptance review to assure in as far as possible that all ANDAs filed are essentially approvable when filed. Resolving any significant deficiencies prior to filing is the mechanism used to ensure that NDAs meet the PDUFA goal dates. It seems that OGD is going to follow suit and resolve as many deficiencies as possible prior to receiving an ANDA. If you don't have justified impurity acceptance criteria you run the risk of having your ANDA receival refused and losing 25% of your filing fee.

From a practical perspective, in the past many ANDA applicants have filed ANDAs with relatively wide impurity acceptance criteria based on the fact that they did not have full term stability on the Exhibit Batches which were often the first batches made at a larger scale. Accordingly they got their ANDAs filed by using wide limits which could be tightened via CMC review deficiency when much more stability data was available to justify a tighter limit. It would seem those days are over and applicants will need to either accept ICH limits or have an acceptable justification for a wider limit. In other words they will need to know enough about their new product to be confident that they can meet what will be essentially final impurity acceptance criteria at the time of filing.

Comment by Dr. Garth Boehm 2014/01/13