粒度节制不大白的看过AG娱乐网址来,FDA专家把要点给你归

Naiqi Ya is a Team Leader in the Divison of Chemistry II, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA. In his current capacity, he is responsible for reviewing chemistry and manufacturing control sections of new drug applications (ANDA/IND/NDA). Prior to joining FDA in 1996, he held a position at Biocraft Laboratories, Inc.,where his responsibilities included developing and validating analytical methods for drug substances and drug products. He received his Ph.D. in Bioanalytical and Biophysical Chemistry from New York University in 1994.

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RichardC. Adams

Richard C. Adams is the Deputy Director in theDivision of Chemistry II, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA. He joined FDA’s Office of Generic Drugs in 1990 as a review chemist and later became Branch Supervisor, and Deputy Division Director. He has served on numerous office and center technical committees and ad hoc working groups and has chaired the Center Stability Technical Committee. Prior to joining CDER, he worked with Pfizer, Inc. at their Central Research Facility in Groton, CT, having responsibilities as a Senior Research Scientist and Project Leader in Process Research and Development. Richard holds a B.S. in Chemistry from the University of Maine and an M.B.A. from the University of New Haven.

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Florence Fang

Florence Fang is the Director in the Division of Chemistry II, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA. She has been involved with the chemistry review function for abbreviated new drug applications for twenty years. Prior to the regulatory work at the Food and drug Administration, she was with Alza in the development of biodegradable polymers and drug delivery systems. She also worked at Gillette Research Institute in keratin chemistry. She holds a B.S. in Chemistry from Purdue University and a M.S. in Biochemistry from the University of Wisconsin at Madison.

The views and opinions expressed in this article are only of the authors and do not necessarily reflect the views or policies of the FDA.

本文仅代表作者概念,不代表FDA概念和政策!

1

前 言

在制药行业中,粉体的颗粒特征已成为口服固体制剂产物开拓和质量节制中至关重要的身分之一。质料药的粒度漫衍(Particle Size Distribution,PSD),也许会对终产物的机能发生明显的影响(如:消融度、生物操作度、含量匀称度、不变性等)。另外,质料药和辅料的粒度漫衍也会影响药物的可出产性(如:活动性、总混匀称度、可压性等),最终也许影响药物的安详性、有用性和质量。许多出书物中都提到,粉体的粒度漫衍对口服固体制剂出产进程中的每一步都有很大影响,包罗预殽杂/殽杂、制粒、干燥、整粒、包衣、包装和压片[1-3]。因此,在每个特定药物申报的差异开拓阶段,应评估药物出产进程中粉体的粒度影响[4]。一旦在最终开拓阶段确定了粒度的影响,就可以选择粉体的粒度漫衍,并确定吻合的质量尺度,到达节制产物质量的目标,担保出产的同等性。

本文将从禁锢的角度,对口服固体制剂粒度尺度拟定的几个重要方面举办接头。接头将包罗粒度作为处方构成和中间产物要害物料属性的一部门,在成立粒度尺度方面的要害思量。

2

何时必要拟定粒度尺度?

对付质料药,ICHQ6A指导原则中提出了何时必要拟定粒度尺度的提议(决定树#3)[5]。总之,假如质料药的粒度对药品的机能(如:溶出度、消融度、生物操作度、含量匀称度、不变性或产物外面)或产物的可出产性(即工艺可行性)至关重要,那么就必要成立一个粒度尺度。然而,在很多新药申请(NDAs)和仿制药申请(ANDAs)中,对粒度的节制凡是被以为是对药品机能的节制,而对产物的可出产性(如:活动性、殽杂匀称度、可压性等)的影响凡是未被思量。譬喻,在粒度尺度成立时,只存眷了低消融性质料药(对生物操作度有影响)或低剂量药物(对含量匀称度的存眷)。假如药品不是低剂量药物,同时质料药是高消融性的,那么粒度尺度就也许不消成立或制按时不消思量那么多或基础不消思量其科学性。

对付口服固体制剂,粒度对产物的可出产性的影响长短常明显的,由于其出产进程中险些每一个工序与粒度相干。譬喻,制粒和包衣会与粒度增大有关,而毁坏和研磨(milling and grinding)与粒度减小有关。过筛和筛分(screening and sieving)会与差异粒度的颗粒疏散有关。殽杂和混匀(mixing and blending)与差异组分的粒子殽杂有关,这些组分间的粒度差别对殽杂匀称性都有很大影响。因此,在每个药物的申请中,领略粉体粒度对出产工艺的影响至关重要。对付质料或进程中的物料(in-process material),假如它们的粒度对出产工艺(如:殽杂、制粒、整粒、总混、包衣等)影响较大,那么有须要对这些粉体举办粒度节制,以确保出产的同等性。因此,每种物料都必要拟定粒度尺度,不只包罗质料药、辅料也包罗进程中的物料。接下来将接头几个出产工艺,以证明何时必要成立口服固体制剂的粒度尺度。

2.1 片剂出产:直接压片法

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