DEVELOPMENT OF STANDARDS FOR FACTORS VIII AND IX

需要制定凝血因子VIII（抗血友病因子）和IX的效价标准，以控制这些许可产品的生产，并允许对其在患者体内的药代动力学进行临床评估。CBER历来为这两种产品提供工作标准。此外，最好建立国际公认的标准，以协调效力定义和生产要求。欧洲药典（EP）和世界卫生组织（WHO）已经建立并采用了一项新的美国因子IX标准。该标准品是从四家美国制造商的四种中纯度和高纯度因子IX制剂中选择的。选择的依据是在CBER进行的研究，建立了标准材料和测试材料的剂量响应曲线的平行性；在很宽的浓度范围内，剂量反应呈线性；测定间和测定内的变异性；物理完整性;短期稳定。将选定的因子IX标准品装入25,000个玻璃瓶中，每个玻璃瓶约含有11iu。因子IX标准随后在一项涉及36个实验室的多中心国际研究中进行了校准，并指定了10.7 IU的值。该标准于1996年10月被欧洲议会和世界卫生组织生物标准化专家委员会正式接受。该标准现在可以通过这些组织和CBER获得。CBER初步评估了来自四家美国制造商的六种新的美国因子VIII标准候选产品，包括血浆衍生和重组制剂。根据上述标准和两种常用效价测定法（一期血浆测定法和显色测定法）结果的一致性，对每个候选药物进行评估。在1997年初完成的一项涉及18个实验室的多中心国际研究中，选择了两种具有满意性质的候选物质进行进一步评估。一种候选材料在单阶段和显色分析中具有无偏性，等效的结果，但已被冻干到不可接受的高水分含量。如果不加以纠正，这可能会对稳定性产生不利影响。目前还没有确定高残余水分的原因，因此目前计划进行额外的先导充填。1997年初，负责该标准的灌装和冻干的承包商通知CBER，其技术人员的变动使该项目无法继续进行。目前正在寻求一种具有必要能力的替代形式。

Potency standards for coagulation factors VIII (Antihemophilic Factor) and IX are needed to control the manufacture of these licensed products and to permit clinical assessment of their pharmacokinetics in patients. CBER has historically provided working standards for both products. In addition, it is desirable to establish standards that are recognized internationally in order to harmonize potency definitions and manufacturing requirements. A new U.S. standard for Factor IX has been established and adopted by the European Pharmacopoeia (EP) and World Health Organization (WHO). The standard was selected from among four intermediate- and high-purity factor IX preparations from four U.S. manufacturers. The selection was based on studies conducted at CBER that established the parallelism of dose-response curves for the standard and test materials; linearity of dose-response over a wide range of concentrations; inter-assay and intra-assay variability; physical integrity; and short-term stability. The selected factor IX standard was filled into 25,000 glass vials, each containing approximately 11 IU. The factor IX standard was then calibrated in a multicenter, international study involving 36 laboratories and assigned a value of 10.7 IU. The standard was accepted formally by the EP and the Expert Committee on Biological Standardization of the WHO in October, 1996. The standard is now available through these organizations and from CBER. Six candidates for a new U.S. factor VIII standard, derived from four U.S. manufacturers and including both plasma-derived and recombinant preparations, were initially evaluated by CBER. Each candidate was assessed for the same criteria indicated above and for consistency of results between two commonly used potency assays: the one-stage plasma assay and the chromogenic assay. Two candidates having satisfactory properties were selected for further evaluation in a multicenter, international study involving 18 laboratories, which was completed in early 1997. One candidate material was superior with respect to its unbiased, equivalent results in the one-stage and chromogenic assays, but had been lyophilized to an unacceptably high moisture content. This would likely have an adverse effect on stability if uncorrected. No reason for the high residual moisture has been identified, so an additional pilot fill is currently planned. In early 1997, the contractor who was to perform the filling and lyophilization of this standard informed CBER that changes in its technical staff made it impossible to continue with the project. An alternative form with the requisite capacity is currently being sought.