首页 > 资讯 > 缺乏杂质限度依据可能导致ANDA拒收

出自识林

2016-08-25 Lachman CONSULTANTS

8月24日，FDA重新发布《ANDA提交 — 缺乏杂质限度依据的拒绝接收》行业指南，替代了之前于2014年9月发布的《ANDA提交 — 缺乏杂质限度适当依据的拒绝接收》行业指南草案，标题中删除了“适当”一词。FDA在联邦公告通报中解释指出，“在审查了对指南草案提交的评议之后，FDA将‘适当’一词从标题中删除，以强调该指南不适用于对ANDA中提交的杂质限度依据的技术审评。”

但指南文件本身基本上是相同的，FDA指出，ANDA申请中提交杂质限度依据的审评是ANDA技术审评。但 FDA 强调“杂质限度依据”必须与 ICH 杂质指南一致，并且包含在 ANDA 申报资料中，否则将引发 ANDA 的拒绝接收（RTR）。RTR的决定说明FDA已确定该ANDA是不完整的，不能进入实质性技术审评。FDA继续表示：
“具体来说，引发 ANDA RTR 的缺陷包括：(1)未能对在原料药和制剂中特定已知杂质（specified identified impurities）超出界定阈值的拟定限度提供依据；(2)未能对超出鉴定阈值的特定未知杂质（specified unidentified impurities）提供依据；(3)非特定杂质（unspecified impurities）（例如，任何未知杂质）的拟定限度超出鉴定阈值。”

如果一个仿制药包含超出界定阈值的特定已知杂质或超出鉴定阈值的特定未知杂质，FDA表示，ANDA中应提出杂质限度并包括支持数据以证明：
(1) 观察到的杂质水平和拟定杂质限度不超过在参照药品（RLD）中观察到的水平；
(2) 杂质是原料药的重要代谢产物；
(3) 观察到的杂质水平和拟定杂质限度通过科学文献已充分论证；或
(4) 观察到的杂质水平和拟定杂质限度不超过已在毒性研究中得到充分评估的水平。

杂质问题包括设定适当限度，是申请人持续面对的问题，并且在许多情况下，还引发在ANDA中的审评问题导致多轮ANDA审评周期。在这种情况下，FDA正在提醒申请人注意在递交ANDA或产品新规格的补充申请时提供与拟定限度相适应的依据的要求，以避免申请收到RTR函。

Lachman CONSULTANTS - Bob Pollock先生
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“Proper” Was Not Proper in Guidance
By Bob Pollock | August 24, 2016 原文地址

Today, FDA reissued the Guidance for Industry: Abbreviated New Drug Application Submissions-Refuse to Receive for Lack of Justification of Impurity Limits, but the word “Proper” was removed from its title. The title of the previous version read Abbreviated New Drug Application Submissions- -Refuse to Receive for Lack of Proper Justification of Impurity Limits (emphasis added).

While the Guidance document (here) itself is essentially the same, FDA notes that the review of the justification submitted in the application is a matter for the technical review of the ANDA. But FDA emphasizes there must be a justification that is consistent with the ICH guidance on impurities and that appears in the ANDA, otherwise the deficiencies may be serious enough to cause the FDA to Refuse-to-Receive (RTR) the ANDA. FDA goes on to say:

“Specifically, these deficiencies include: (1) Failing to provide justification for proposed limits for specified identified impurities in drug substances and drug products that are above qualification thresholds; (2) failing to provide justification for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification thresholds.”

The justification is required to address any of these issues and the FDA has expectations as to what information may be necessary to justify exceeding any limits, including, but not limited to:
(1) the observed impurity levels and proposed impurity limits do not exceed the level observed in the reference listed drug (RLD) product;
(2) the impurity is a significant metabolite of the drug substance;
(3) the observed impurity levels and proposed impurity limits are adequately justified by the scientific literature;
or
(4) the observed impurity levels and proposed impurity limits do not exceed the level that has been adequately evaluated in toxicity studies.

Impurity issues, including setting appropriate limits, have been an ongoing problem for applicants and in many instances, still cause review problems in the ANDA that result in multiple ANDA review cycles. In this instance, FDA is reminding applicants of the requirement to provide a justification commensurate with the limits they propose at time of filing an ANDA or a supplement for a new strength of a product to avoid the application receiving an RTR letter.