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（抗亲密因子）和IX的效力标准，以控制这些许可产品的生产，并允许对患者的药代动力学进行临床评估。 CBER历史上为这两种产品提供了工作标准。 此外，希望建立在国际上认可的标准，以协调效力定义和制造要求。 欧洲药典（EP）和世界卫生组织（WHO）已建立和采用了新的美国第IX因子标准。 该标准是从四个美国制造商的四个中间和高纯度因子IX制剂中选择的。 该选择是基于在CBER进行的研究，该研究确定了标准材料和测试材料的剂量反应曲线的平行性；剂量反应的线性在广泛的浓度范围内；测定和测定内变异性；身体完整性；和短期稳定性。 所选因子IX标准被填充到25,000个玻璃小瓶中，每个玻璃瓶含有大约11 IU。 然后在涉及36个实验室的多中心研究中对IX标准进行了校准，并分配了10.7 IU的值。 该标准被EP和WHO生物标准化专家委员会正式接受，1996年10月。现在可以通过这些组织和CBER获得该标准。 CBER最初评估了六名新的美国第VIII标准标准，这些候选者源自四家美国制造商，包括等离子体衍生和重组制剂。 评估了上述相同标准的每个候选者，并在两个常用的效力分析之间的结果一致性：一阶段的血浆测定法和成色测定。 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，选择了两名具有令人满意的特性的候选者，以进一步评估。在其公正的单阶段和成色性测定中，一种候选材料在其公正的，等效的结果方面表现出色，但已被乳液溶解至不可接受的水分含量高。 如果未校正，这可能会对稳定性产生不利影响。 没有发现剩余水分高的理由，因此目前计划了额外的试点填充物。 1997年初，将对CBER进行填充和冻干的承包商，其技术人员的变化使得无法继续该项目。 目前正在寻求具有必要能力的另一种形式。