首页 > 资讯 > FDA低分子量肝素表征和免疫原性考量指南定稿

出自识林

2016-02-19

2月18日，FDA发布题为《低分子量肝素（LMWH）免疫原性相关考量》的最终更新指南。指南对（ANDA中）活性成分一致性的正确表征以及此类产品的免疫原性检测考量提供了建议。该指南为NDA持有人（新产品或已有产品的变更）和ANDA申请人提供指导。关于变更的建议适用于原始申请，以及原材料或其它组分存在不同或需要改变生产工艺的补充申请。FDA还指出DMF持有人必须注意本指南，因为如果API原材料或生产发生变化，可能严重地影响成品制剂。因此，DMF持有人应向授权申请人通知任何变更。

FDA指出，免疫原性经常在临床试验中被研究；然而，FDA提供了可用于评估免疫原性风险的替代方法，通过与参照药品（RLD）（对ANDA而言）或原始NDA产品（对NDA的补充变更而言）相比较。FDA列出以下3种对于免疫原性的评估标准：

(1) 原料药（API）的一致性(仅针对ANDA)；

(2) 产品中可能影响LMWH产品与趋化因子血小板因子4（PF4）的关联的杂质，以及与PF4形成的复合物的大小和电荷（针对NDA/ANDA）；

(3) 产品中可能改变产品（或与PF4形成的复合物）对免疫系统的检测、吸收、加工或呈现的杂质（针对NDA/ANDA）。

FDA还指出，生物分析表征可能不够，因此推荐各种体外或体内研究用以检测仿制药（或变更后的NDA产品）与原始RLD的不同。

该指南还列出关于ANDA一致性表征的5种标准，有一节专门详细描述对于NDA、ANDA和各种申请的补充申请的杂质和免疫风险的鉴别。为便于比较，FDA建议使用多批新生产的、效期中间的、临近效期的LMWH产品批次，和类似阶段的相应参照产品批次。

指南是全面的，并且提供了解决与研发和批准LMWH产品相关的重要和潜在危及生命问题的良好路线图。

Lachman CONSULTANTS - Bob Pollock先生
编译：识林-椒
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FDA Finalizes Guidance on Low Molecular Weight Heparin Characterization and Immunogenicity Considerations
By Bob Pollock | February 18, 2016

Today, the FDA published its final updated Guidance entitled, Immunogenicity – Related Considerations for Low Molecular Weight Heparin (LMWH). The document provides advice on the proper characterization of active ingredient sameness (for ANDAs), as well as considerations for immunogenicity testing for such products. The document provides guidance for NDA holders (for new products or changes to existing products) and for ANDA applicants. The advice on changes applies to original filings, as well as supplemental filings, where the source material or other component differs or there is a need to alter the manufacturing process. FDA also notes that DMF holders must be mindful of this Guidance because, if changes occur in the API source or manufacture, it could critically impact the finished dose form product. DMF holders, thus, should notify authorized applicants of any changes.

FDA notes that immunogenicity is often studied in clinical trials; however, they provide alternate methods that can be used to assess the risk of immunogenicity, by comparison to the reference listed drug (RLD) that is subject to the ANDA or the original NDA product if a supplemental change is made to the NDA product. FDA lists the following 3 assessment criteria for immunogenicity:

(1) the sameness of the active pharmaceutical ingredient (API) (ANDAs only);

(2) the impurities in the product that may impact on the association of the LMWH product with the chemokine PF4, as well as the size and charge of the complexes formed with PF4 (NDAs/ANDAs); and

(3) the impurities in the product that could modify the detection, uptake, processing or presentation of the product (or the complexes it forms with PF4) to the immune system (NDAs/ANDAs).

FDA also notes that bioanalytical characterization might not be sufficient, so they also recommend various in vitro or in vivo studies to detect differences between the generic (or changed NDA product) and the original RLD.

The Guidance goes on to list the 5 criteria for sameness characterization for ANDAs and has a section devoted to describing, in detail, identification of the impurities and immunogenicity risk for NDAs, ANDAs, and supplements to each type of application. For comparative purposes, FDA suggests the use of multiple freshly manufactured, mid-expiry-cycle, and close-to-expiry product lots for the LMWH, and similar-stage lots of the relevant reference product.

The Guidance is comprehensive and provides a good roadmap for addressing important and potentially life threatening issues associated with development and approval of LMWH products.