DEVELOPMENT OF STANDARDS FOR FACTORS VIII AND IX

因素 VIII 和 IX 的标准制定

• 批准号: 6293803
• 负责人: Thomas J Lynch
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6293803
• 关键词: coagulation factor IX; coagulation factor VIII; drug quality /standard; immunoaffinity chromatography; recombinant proteins; western blottings

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.

需要凝血因子 VIII（抗血友病因子）和 IX 的效力标准来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了工作标准。 此外，希望建立国际认可的标准，以协调功效定义和制造要求。 欧洲药典 (EP) 和世界卫生组织 (WHO) 已制定并采用了新的美国因子 IX 标准。 该标准品选自四家美国制造商的四种中纯度和高纯度因子 IX 制剂。 该选择基于 CBER 进行的研究，该研究建立了标准材料和测试材料的剂量反应曲线的平行性；在很宽的浓度范围内剂量反应呈线性；测定间和测定内变异性；身体健全；和短期稳定性。 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 11 IU。 随后，因子 IX 标准品在一项涉及 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 EP 和 WHO 生物标准化专家委员会正式接受。该标准现已通过这些组织和 CBER 提供。 美国新的因子 VIII 标准的六种候选药物来自四家美国制造商，包括血浆衍生制剂和重组制剂，最初由 CBER 进行了评估。 每个候选者均按照上述相同标准进行评估，并评估两种常用效价测定（一阶段血浆测定和显色测定）之间结果的一致性。 在一项涉及 18 个实验室的多中心国际研究中，选择了两种具有令人满意特性的候选材料进行进一步评估，该研究于 1997 年初完成。一种候选材料在单阶段和显色测定中的公正、等效结果方面表现出色，但已被冻干至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。 目前尚未确定残留水分高的原因，因此目前计划进行额外的试点填充。 1997 年初，负责该标准灌装和冻干的承包商通知 CBER，其技术人员的变动导致该项目无法继续进行。 目前正在寻找具有所需能力的替代形式。