DEVELOPMENT OF STANDARDS FOR FACTORS VIII AND IX

因素 VIII 和 IX 的标准制定

• 批准号: 6101311
• 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/6101311
• 关键词: coagulation factor IX; coagulation factor VIII; drug quality /standard; immunoaffinity chromatography; recombinant proteins; western blottings

SUMMARY OF WORK: 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.

工作摘要：凝结因子VIII的效力标准 （抗亲密因素）和IX需要控制的制造 这些有执照的产品，并允许对其 患者的药代动力学。 CBER历史上提供了工作 两种产品的标准。 此外，希望建立 在国际上被认可以和谐的标准 效力定义和制造要求。 美国新标准 对于第IX因子已被欧洲建立和采用 药典（EP）和世界卫生组织（WHO）。 标准是 从四个中间和高纯度因子IX中选择 来自四个美国制造商的准备工作。 选择是基于 在CBER进行的研究建立了 标准材料和测试材料的剂量反应曲线；线性的 剂量反应在广泛的浓度范围内；互际和 测定内变异性；身体完整性；和短期稳定性。 所选因子IX标准被填充为25,000个玻璃小瓶，每个玻璃小瓶 包含大约11 IU。 那时的因子IX标准是 在涉及36的多中心，国际研究中校准 实验室，并分配了10.7 IU的值。 该标准被接受 EP和生物标准化专家委员会正式正式 1996年10月的世卫组织。现在可以通过这些标准获得 组织和来自CBER。 六个候选人是新的美国因素VIII 标准，来自四个美国制造商，包括 首先评估了血浆衍生和重组制剂的 CBER。 评估了每个候选人的相同标准 以及在两个常用的效力分析之间的结果一致性： 单阶段的血浆测定法和成色测定。 两个候选人 选择令人满意的属性以进一步评估 一项涉及18个实验室的多中心，国际研究， 于1997年初完成。一种候选材料优越 尊重其公正，等效的结果，在一个阶段和 成色测定，但已被冻干到不可接受的高度 水分含量。 这可能会对稳定产生不利影响 如果未校正。 没有理由是高残留水分 确定的，因此目前计划了额外的飞行员填充。 在早期 1997年，要执行填充和冻干的承包商 在这一标准的通知CBER中，其技术人员的变化 不可能继续该项目。 一种替代形式 目前正在寻求必要的能力。