DEVELOPMENT OF STANDARDS FOR FACTORS VIII AND IX

需要凝血因子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，并允许对其在患者中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，以协调效价定义和生产要求。 一个新的因子IX的美国标准已经建立，并通过了欧洲药典（EP）和世界卫生组织（WHO）。 该标准品选自来自四家美国制造商的四种中间和高纯度因子IX制备物。 选择基于在CBER进行的研究，这些研究确定了标准品和供试品的剂量-响应曲线的平行性;在广泛浓度范围内的剂量-响应线性;试验间和试验内变异性;物理完整性;和短期稳定性。 将选定的因子IX标准品灌装至25，000个玻璃小瓶中，每个小瓶约含11 IU。 然后在涉及36个实验室的多中心国际研究中校准因子IX标准品，并指定值为10.7 IU。 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。 该标准现在可通过这些组织和CBER获得。 CBER最初评价了来自四家美国制造商的六种新的美国凝血因子VIII标准品候选物，包括血浆衍生和重组制剂。 根据上述相同标准以及两种常用效价测定法（一阶段血浆测定法和显色测定法）之间结果的一致性，对每种候选药物进行评估。 在一项涉及18个实验室的多中心国际研究中，选出了两种性能令人满意的候选物，以作进一步评价，这项研究于1997年初完成。 一种候选材料在一期和显色试验中的无偏倚、等效结果方面具有上级优势，但已冻干至不可接受的高含水量。 如果不纠正，这可能会对稳定性产生不利影响。 尚未确定高残留水分的原因，因此目前计划进行额外的中试灌装。 1997年初，负责填充和冻干这一标准品的承包商通知生物评价和评价中心，由于技术人员的变动，该项目无法继续进行。 目前正在寻找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.