DEVELOPMENT OF STANDARDS FOR FACTORS VIII AND IX

因素 VIII 和 IX 的标准制定

• 批准号: 6161369
• 负责人: T 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/6161369
• 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 Pharrnacopoeia (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 Il 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.

凝血因子 VIII（抗血友病因子）和的效价标准 需要 IX 来控制这些许可产品的制造并 允许对其在患者中的药代动力学进行临床评估。 CBER 有 历史上为这两种产品提供了工作标准。此外，它 建立国际公认的标准是可取的 为了协调效力定义和制造要求。一个 新的美国因子 Ix 标准已制定并由 欧洲药典 (EP) 和世界卫生组织 (WHO)。这 标准品选自四个中高纯度因子 来自四家美国制造商的 IX 制剂。选择是基于 CBER 进行的研究确立了剂量- 标准材料和测试材料的响应曲线；剂量线性- 在很宽的浓度范围内都有响应；测定间和测定内 可变性；身体健全；和短期稳定性。所选择的 将 Ix 因子标准品装入 25,000 个玻璃瓶中，每个瓶中含有 大约Il IU。然后在 IX 因子标准品中进行校准 涉及 36 个实验室的多中心国际研究，并指定了 值为10.7国际单位。该标准已被欧洲议会和欧盟正式接受 10月世界卫生组织生物标准化专家委员会， 1996 年。该标准现已通过这些组织和 CBER。美国新因子 VIII 标准的六种候选标准，源自 四个美国制造商，包括血浆衍生的和重组的 制剂，最初由 CBER 进行评估。每个候选人都是 评估上述相同标准和一致性 两种常用效价测定之间的结果：一级血浆 测定和显色测定。两名候选人均取得满意成绩 选择属性进行多中心进一步评估， 涉及 18 个实验室的国际研究，于 2017 年完成 1997 年初。一份候选材料在其 在单阶段和显色测定中获得无偏的、相同的结果，但是 已被冻干至不可接受的高水分含量。这会 如果不加以纠正，可能会对稳定性产生不利影响。没有理由 已发现残留水分较高，因此需要额外的飞行员 目前正在计划填充。 1997 年初，承包商 执行该标准的灌装和冻干通知 CBER 由于技术人员的变动，项目无法继续进行。 项目。目前具有所需容量的替代形式是 正在寻求。