新版USP 787和1787章颗粒物质指南评论
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新版USP 787和1787章颗粒物质指南评论
笔记 2014-09-10 ECA 在现行(2010-2015)USP的专家委员会上,剂型委员会新制定并修改了一些通则,提出了关于注射剂产品颗粒物质的指南。对于可见颗粒,在<790> 注射剂可见颗粒中描述的基于目检灵敏度的方法适用于所有无菌注射剂剂型。对于需要使用仪器检测的显微镜下可见的颗粒,发布了新的颗粒物质指南专门用于治疗用生物制品注射剂。 新的通则《<787>治疗用蛋白质注射剂的显微镜下可见颗粒物质指南》在2014年8月1日正式生效,补充了《<788>注射剂颗粒物质指南》,针对更敏感的蛋白制剂提供了新方法。<787>最初是为了将<788>的检测方法改为遮光,以便用于敏感的蛋白质产品。<787>还基于科学和监管考虑,对10µm以下颗粒负载的免疫学影响提供了检验框架。此外,取样量允许更小的体积,减小到0.2mL的整数倍,每个单独容器的取样都要包含温和排气的步骤。虽然颗粒大小的阈值还保持≥10 µm和≥25 µm,与<788>一致,但是建议监测10 µm以下的颗粒总数。对于所有剂型,≥10 µm的颗粒总数不能超过6000,≥25 µm的颗粒总数不能超过600。 为支持<787>,还发布了新的《<1787>治疗用蛋白质注射剂中显微镜下可见颗粒的检测方法》,为所有治疗用蛋白质产品提供了颗粒大小、计数和鉴定的指南。<1787>为推荐的技术提供了重要扩充。这一新的章节会在11月出版的USP38上出现,并在2015年5月1日生效。作为一个信息性章节,该指南并不提供数量限度,而是注重检测内源性蛋白质的数量及其特性 <1787>的目的是帮助所有治疗用蛋白质产品的科学研发过程。这一章对2-µm 到100-µm之间的显微镜下可见颗粒提供了指南。采用这个尺寸范围的原理是, 100µm的可以看做是保守的可见颗粒的阈值限度,2 µm对于推荐的技术是稳健和保险的。这一信息章节包含三个部分:大小和分布,大小和形态,以及特征,每一章节还有对技术的描述,以及每种技术的优势和劣势。这一章还提供了三种颗粒分类的定义与讨论:1. 外来的(完全外来的),2. 内部的(不想要但是由工艺过程或原料产生的),3. 内部的(属于产品的一部分)。还包括了对于硅油含量的讨论;尽管硅油是大部分产品必需的添加剂,它会产生人造颗粒或不想要的颗粒,或由于未控制或过量使用而影响治疗成分的稳定性。 推荐的10-µm以下颗粒总数分成两组来统计:≥2-5 µm和≥5-10 µm。<1787>章是关于在最终产品中出现的所有颗粒种类;然而,首先面向的还是内在治疗成分的情况和可接受性。当然,治疗用蛋白制品的可接受性要依靠研发数据和监管机构的审评。 D.S. Aldrich,USP剂型专家委员会,<787/1787>专家小组主席 Commentary Regarding new USP Chapters <787> and <1787> for Particulate Matter Guidance During the current (2010-2015) USP Expert Committee cycle, the Dosage Forms Expert Committee has developed both new and revised general chapters that provide guidance on particulate matter content of injectable drug products. For visible particles, methods are based upon human detection sensitivity as described in Visible Particulates in Injections <790>, which applies to all sterile injectable dosage forms. For subvisible particle content, which is based upon instrumental determination, new particulate matter guidance has been established specifically for sterile injectable biotherapeutic products. The new general chapter Subvisible Particulate Matter in Therapeutic Protein Injections <787> became official August 1, 2014, and provides an improved version of the approach in the chapter Particulate Matter in Injections <788> for the more-sensitive protein formulations. Chapter <787> was initiated to modify historical <788> testing by light obscuration, in order to address the sensitivities of protein products. Chapter <787> also provides a testing framework for a scientific and regulatory concern regarding the immunological effects of the sub-10-µm particle load. In addition, smaller-volume sampling is allowed, down to 0.2-mL aliquots, and sampling of individual containers as well as gentler de-gassing steps is included. Although particle-size thresholds remain the same at >= 10 µm and >=25 µm, with the same limits as those found in chapter <788>, there is a recommendation to monitor the population below the 10 µm threshold. Total particle content is limited to 6,000 particles >=10 µm and 600 particles >= 25 µm for all dosage forms. The new informational chapter Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections <1787> was developed to support chapter <787> and provides sizing, counting, and characterization guidance for all protein therapeutic products; <1787> provides significant expansion of recommended techniques. The new chapter will appear in USP 38 in November and become official May 1, 2015. As an informational chapter, it provides no count limits but instead is focused on the determination of the inherent protein population and its character. The intent of chapter <1787> is to aid the scientific development process for all therapeutic protein products. The chapter provides guidance on subvisible particles in the 2-µm to 100-µm range. The rationale for using this range is based upon 100 µm as a conservative, lower-limit threshold for visible particles and 2 µm as the lower size domain for which the recommended techniques are considered robust and proven. The informational chapter is presented in three sections: Size and Distribution, Size and Morphology, and Characterization, with descriptions of techniques in each section. Advantages and disadvantages of each technique are presented. The chapter also provides definition and discussion of the three particle categories: a) extrinsic (truly foreign), b) intrinsic (unwanted yet arising from the process or product), and c) inherent (product attribute). A discussion of silicone oil content is included; even though silicone oil is a necessary additive for most products, it may produce artifact counts or unwanted particles, or it may affect the stability of the therapeutic agent if uncontrolled or used in excessive quantity. It is recommended that data on the population below 10-µm is collected in two data bins: >= 2-5 µm and >= 5-10 µm. Chapter <1787> concerns all particle species present in the final product; however, it is primarily oriented toward the inherent therapeutic agent condition and acceptability. Certainly, the acceptability of the therapeutic protein product is dependent upon the innovator data and regulatory review. D.S. Aldrich, USP Dosage Forms Expert Committee, <787/1787> Expert Panel Chair |