Abstract：
In 2010, the reporting of thrombotic adverse events for one subcutaneous and certain intravenous immunoglobulins (IGs) raised some concerns. In Europe, regulatory bodies rapidly revised compendial specifications for therapeutic IGs to ensure they do not exhibit thrombogenic (procoagulant) activity (PCA). At the global level, a working group (GWG) was launched with the aim of assessing PCA measurement methods and limits, considering results obtained by human IG manufacturers during in-process controls. The GWG created three dedicated subgroups to investigate the FXIa chromogenic assay, the non-activated partial thromboplastin time (NAPTT) test and the thrombin generation assay (TGA). The European Directorate for the Quality of Medicines & HealthCare (EDQM) was responsible for co-ordinating the subgroup in charge of evaluating the FXIa chromogenic assay in a study that assessed the sensitivity and robustness of two commercial chromogenic FXIa test kits. The impact of IG product formulation on FXIa recovery and the suitability of PCA-containing IG products as potential reference standards/controls were also assessed. IG materials representative of marketed products were provided to four laboratories for a study that was carried out in two steps: 1) two chromogenic FXIa test kit manufacturers assessed the performance and determined optimal test conditions by their respective methods, 2) two OMCLs studied both kits using an optimised study design. Regarding sensitivity, the study results identified suitable dose-response intervals and limits with both chromogenic FXIa test kits. This allowed the establishment of dilution ranges for optimal detection of FXIa/PCA in 5 % and 10 % IG products in the range of 1-6 mIU/mL. However, careful optimisation of the sample dilutions was required (notably to avoid potential matrix effects) and the choice of the mode of data acquisition (kinetic or end-point method) contributed to sensitivity in routine use. Importantly, the composition of IG products was of minor concern for FXIa determination with both test kits. Potential reference materials evaluated in the study behaved as expected and could be useful should a separate reference standard to the FXIa WHO IS be deemed necessary in future.
摘要：
2010年，一种皮下和某些静脉免疫球蛋白（IG）的血栓不良事件的报告引起了一些关注。在欧洲,监管机构迅速修订了治疗性IG的药典规范，以确保它们不表现出血栓形成（促凝血）活性（PCA）。在全球范围内,成立了一个工作组(GWG)，旨在评估PCA测量方法和限值，考虑到人工IG制造商在过程控制期间获得的结果。GWG创建了三个专门的亚组来研究FXIa显色测定，非活化部分凝血活酶时间（NAPTT）测试和凝血酶生成测定（TGA）。欧洲药品和医疗保健质量局（EDQM）负责协调负责评估FXIa显色测定的亚组，该研究评估了两种商业显色FXIa测试试剂盒的灵敏度和稳健性。还评估了IG产品配方对FXIa回收率的影响以及含PCA的IG产品作为潜在参考标准/对照的适用性。向四个实验室提供了代表上市产品的IG材料，以进行分两步进行的研究：1）两个显色FXIa测试试剂盒制造商通过各自的方法评估了性能并确定了最佳测试条件，2)两个OMCL使用优化的研究设计研究了两种试剂盒。关于敏感性，研究结果确定了两种显色FXIa检测试剂盒的合适剂量-反应间隔和限度.这允许建立用于在1-6mIU/mL范围内的5%和10%IG产物中最佳检测FXIa/PCA的稀释范围。然而,需要仔细优化样品稀释度(特别是为了避免潜在的基体效应),并且数据采集模式(动力学或终点方法)的选择有助于常规使用的敏感性.重要的是,对于两种检测试剂盒的FXIa测定,IG产品的成分是次要问题.研究中评估的潜在参考材料的行为符合预期，如果将来认为有必要为FXIaWHOIS提供单独的参考标准，则可能有用。
