20.化学药物质量控制分析方法验证技术指导原则 2005年颁布

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9 指导原则解读系列专题 化学药物质量控制分析方法验证的原则和要求_成海平

9 指导原则解读系列专题 化学药物质量控制分析方法验证的原则和要求_成海平

C h i n e s e J o u r n a l o f N e wD r u g s 2009,18(8)中国新药杂志2009年第18卷第8期[作者简介] 成海平,男,硕士,副主任药师,主要从事化学药品技术审评工作。

联系电话:(010)68585566-470,E -m a i l :c h e n g h p @c d e .o r g .c n 。

·新药申报与审评技术·★指导原则解读系列专题(七)化学药物质量控制分析方法验证的原则和要求成海平(国家食品药品监督管理局药品审评中心,北京100038) [摘要] 质量控制分析方法验证是质量研究的主要内容,也是质量标准各检测项目分析方法制订的基础。

在审评工作中发现分析方法验证方面存在着各类问题,如方法验证设计不科学、验证不充分、实验过程不规范、验证数据不合理等等。

文中以鉴别、杂质检查、定量测定等为例,提出了分析方法验证的原则和要求,并分析了申报资料中常见的问题,以期更好地服务于分析方法验证工作。

[关键词] 化学药物;验证;分析方法[中图分类号]R 95 [文献标识码]C [文章编号]1003-3734(2009)08-0688-03P r i n c i p l e s a n d r e q u i r e m e n t s f o r v a l i d a t i o no f a n a l y t i c a l p r o c e d u r e sC H E N GH a i -p i n g(S F D A C e n t e r f o r D r u g E v a l u a t i o n ,B e i j i n g 100038,C h i n a )[A b s t r a c t ] V a l i d a t i o n o f a n a l y t i c a l p r o c e d u r e s i s t h e f o u n d a t i o n o f d e v e l o p i n g s p e c i f i c a t i o n s ,b u t t h e r e a r e s t i l l a l o t o f p r o b l e m s i n d e s i g n o f t e s t s ,p r o c e s s o f t e s t s a n d e v a l u a t i o n o f r e s u l t s .T h i s a r t i c l e d e s c r i b e d h o wt o v a l i -d a t e a n a l y t i c a l p r o c e d u r e s i n i d e n t i f i c a t i o n a n d a s s a y f o r i m p u r i t i e s .[K e y w o r d s ] c h e m i c a l d r u g s ;v a l i d a t i o n ;a n a l y t i c a l p r o c e d u r e s 质量控制分析方法验证就是基于质量标准中检测项目在质控方面所起的作用,确定检测项目所用分析方法需要验证的内容,并通过设计合理的实验,验证所用分析方法的科学性、准确性和合理性,选择和确立质量标准中各检测项目的分析方法,达到有效控制药品质量的过程。

质量标准——药品质量标准分析方法验证指导原则

质量标准——药品质量标准分析方法验证指导原则

药品质量标准分析⽅法验证的⽬的是证明采⽤的⽅法适合于相应检测要求。

在建⽴药品质量标准时,分析⽅法需经验证;在药品⽣产⼯艺变更、制剂的组分变更、原分析⽅法进⾏修订时,则质量标准分析⽅法也需进⾏验证。

⽅法验证理由、过程和结果均应记载在药品标准起草说明或修订说明中。

需验证的分析项⽬有:鉴别试验,杂质定量检查或限度检查,原料药或制剂中有效成分含量测定,以及制剂中的其他成分(如防腐剂等)的测定。

药品溶出度、释放度等功能检查中,其溶出量等的测试⽅法也应作必要验证。

验证内容有:准确度、精密度(包括重复性、中间精密度和重现性)、专属性、检测限、定量限、线性、范围和耐⽤性。

视具体⽅法拟订验证的内容。

附表中列出的分析项⽬和相应的验证内容可供参考。

⽅法验证内容如下。

⼀、准确度 准确度系指⽤该⽅法测定的结果与真实值或参考值接近的程度,⼀般⽤回收率(%)表⽰。

准确度应在规定的范围内测试。

1.含量测定⽅法的准确度 原料药可⽤已知纯度的对照品或样品进⾏测定,或⽤本法所得结果与已知准确度的另⼀个⽅法测定的结果进⾏⽐较。

制剂可⽤含已知量被测物的各组分混合物进⾏测定。

如不能得到制剂的全部组分,可向制剂中加⼊已知量的被测物进⾏测定,或⽤本法所得结果与已知准确度的另⼀个⽅法测定结果进⾏⽐较。

如该分析⽅法已经测试并求出了精密度、线性和专属性,在准确度也可推算出来的情况下,这⼀项可不必再做。

2.杂质定量测定的准确度 可向原料药或制剂中加⼊已知量杂质进⾏测定。

如不能得到杂质或降解产物,可⽤本法测定结果与另⼀成熟的⽅法进⾏⽐较,如药典标准⽅法或经过验证的⽅法。

在不能测得杂质或降解产物的响应因⼦或对原料药的相对响应因⼦情况下,可⽤原料药的响应因⼦。

应明确表明单个杂质和杂质总量相当于主成分的重量⽐(%)或⾯积⽐(%)。

3.数据要求 在规定范围内,⾄少⽤9个测定结果进⾏评价,例如,设计3个不同浓度,每个浓度各分别制备3份供试品溶液,进⾏测定。

化学药物质量控制分析方法验证技术指导原则

化学药物质量控制分析方法验证技术指导原则

化学药物质量控制分析方法验证技术指导原则化学药物质量控制分析方法验证是确保药物质量稳定可靠的重要环节。

它通过验证分析方法的准确性、精密度、恢复度、线性度、特异性等指标,确保分析方法能够准确地测定药物中的活性成分或者指标物质的含量。

本文将从方法验证的目的、步骤、技术指导原则以及常见问题和挑战等方面进行介绍。

一、方法验证的目的和步骤1.目的:确保分析方法满足药品质量控制的要求,可靠稳定,可用于药物批次的检验。

2.步骤:(1)方法开发:根据药物的特性和质量控制要求,选择适当的分析方法。

(2)方法优化:对选择的分析方法进行优化,包括调整工作条件、选用合适的内标物质等。

(3)方法准确性验证:重复测定样品,评估准确性,并对结果进行统计分析。

(4)方法精密度验证:通过重复测定样品,计算相对标准偏差,评估方法的精密度。

(5)方法线性度验证:通过测定不同浓度的标准品,评估方法的线性关系。

(6)方法特异性验证:通过测定样品的含量,检查方法对其他组分的干扰情况。

(7)方法稳定性验证:评估方法在不同条件下的稳定性,包括反应时间、温度等。

(8)方法恢复度验证:通过添加已知浓度的标准品到药物样品中,评估方法的回收率。

1.确保方法的准确性:方法应具有良好的回归方程和拟合度,并通过统计分析确定测定值的范围。

2.确保方法的精密度:通过反复测定样品确定相对标准偏差,评估方法的精密度,并确保结果的重复性。

3.确保方法的恢复度:通过添加已知浓度的标准品到药物样品中,测定回收率,评估方法的准确性和恢复度。

4.确保方法的线性度:通过测定不同浓度的标准品,构建标准曲线,并通过相关系数确定方法的线性范围。

5.确保方法的特异性:通过测定样品的含量,并检查方法对其他组分的干扰情况,确保方法对药物成分的特异性。

6.确保方法的稳定性:通过评估方法在不同条件下的重复性和稳定性,确定方法的适用范围。

7.验证结果的报告和文档:方法验证应记录在正式的报告和关联文档中,并以书面形式确认。

化学药物质量控制分析方法验证技术指

化学药物质量控制分析方法验证技术指

导原则编号:化学药物质量操纵分析方法验证技术指导原则二○○四年十一月目录一、概述 (1)二、方法验证的一般原则 (2)三、方法验证涉及到的三个要紧方面 (2)(一)需要验证的检测项目 (2)(二)分析方法 (3)(三)验证内容 (3)四、方法验证的具体内容 (3)(一)专属性 (3)1、鉴不反应 (3)2、杂质检查 (4)3、含量测定 (4)(二)线性 (5)(三)范围 (5)1、含量测定 (5)2、制剂含量均匀度 (5)3、溶出度或释放度 (6)4、杂质 (6)(四)准确度 (6)1、含量测定 (6)2、杂质定量试验 (7)(五)周密度 (7)1、重复性 (7)2、中间周密度 (8)3、重现性 (8)(六)检测限 (8)1、直观法 (8)2、信噪比法 (8)(七)定量限 (9)1、直观法 (9)2、信噪比法 (9)(八)耐用性 (10)(九)系统适用性试验 (10)五、方法再验证 (10)六、方法验证的评价 (11)(一)有关方法验证评价的一般考虑 (11)(二)方法验证的整体性和系统性 (12)七、参考文献 (12)八、著者 (12)化学药物质量操纵分析方法验证技术指导原则起草讲明 (13)化学药物质量操纵分析方法验证技术指导原则一、概述保证药品安全、有效、质量可控是药品研发和评价应遵循的差不多原则,其中,对药品进行质量操纵是保证药品安全有效的基础和前提。

为达到操纵质量的目的,需要多角度、多层面来操纵药品质量,也确实是讲要对药物进行多个项目测试,来全面考察药品质量。

一般地,每一测试项目可选用不同的分析方法,为使测试结果准确、可靠,必须对所采纳的分析方法的科学性、准确性和可行性进行验证,以充分表明分析方法符合测试项目的目的和要求,这确实是通常所讲的对方法进行验证。

方法验证的目的是推断采纳的分析方法是否科学、合理,是否能有效操纵药品的内在质量。

从本质上讲,方法验证确实是依照检测项目的要求,预先设置一定的验证内容,并通过设计合理的试验来验证所采纳的分析方法能否符合检测项目的要求。

化学药物药学研究的一般方法和技术要求

化学药物药学研究的一般方法和技术要求

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• 准确度: 也称真实度,是指该方法在规定范围内的 测量值与真实值或参考值接近的程度。含量测定、 杂质定量检测需要进行准确度验证。
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精密度 是指在规定条件下对均质供试品多次取样进行一系列测定结果 之间的接近程度(离散程度),通常用SD或RSD表示。杂质定量检测 和含量测定需要进行精密度验证。
– 重复性:是指在相同条件下,由同一个分析者测定结果的精密
度。 – 中间精密度:是指在同一个实验室,不同日、不同分析者、不 同仪器测定结果的精密度。 – 重现性:是指在不同实验室、不同分析者测定结果的精密度。
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• 检测限:
是指样品中被测物能被检测出的最低量,一般不考
虑准确性。验证方法有非仪器目视法和信噪比法。杂质
– 工艺重现性研究:制备连续3批的样品,进行全检和质量分析,
考察工艺的重现性和稳定性
– 中试放大:取得中试工艺参数,对放大产品全检,进行长期 稳定性试验
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三、质量研究和质量标准制定
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• 研究内容对应的是申报资料
– №7:药学研究资料综述
– №10:质量研究工作的试验资料及文献资料
– №11:药品标准及起草说明,并提供标准品或者对照品 – №12: 样品的检验报告书
第三章 化学药物药学研究 的一般方法和技术要求
药审中心近期受理的新药申请情况
(包括已有国家标准品种) 生物 制品 622 4 385 3
化 药 数目(件) 11752 71 8474 64
中 药 4071 25 4285 33
合 计 16445 100 13144 100
2
2004年
比例(%) 数目(件) 比例(%)
• 结合我国药品研发和生产实际

化学药品主要检测方法应用指导原则

化学药品主要检测方法应用指导原则

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3、溶解度 在溶剂品种的选择上,应尽量采 用与该药品溶解特性密切相关、配制制剂、制 备溶液或精制操作所需用的常用溶剂。溶剂品 种不要罗列太多。对溶解度的描述一定要核 实,千万不要照抄一般参考资料。 我们在药品注册复核检验中多次发现申报单位 申报的溶解度与实际实验不符。

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基本原则
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“实用”是指我国作为发展中国家,有些仪器、 设备、技术尚不普及,在考虑国情及药品生产、 检验队伍的实际情况、确保能准确控制质量的 前提下,应倡导简单实用的原则,即无必要制 定操作繁琐、费用高昂的监测方法去控制那些 用简单方法即可实现的检测项目。 “规范”是药品标准必须坚持的一贯原则。
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三、坚持质量可控性原则 药品标准所载方法控制的质量,是指满足GMP生产 的要求,在正常组织生产的情况下对产品质量所进行 的控制。药品标准的制定,应对于在既定工艺下正常 生产的药品质量力争实现有效的控制。建立准确、专 属的检测方法,以确保公众使用的是优质的药品。 四、坚持标准先进性原则 药品标准所载检测方法,应充分反映现阶段国内和 国际药品质量控制的先进技术和方法,在科学合理的 基础上坚持就高不就低的标准先进性原则。
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药品质量标准分析方法验证指导原则

药品质量标准分析方法验证指导原则

药品质量标准分析方法验证指导原则药品质量标准分析方法验证的目的是证明采用的方法适合于相应检测要求。

在建立药品质量标准时,分析方法需经验证;在药品生产工艺变更、制剂的组分变更、原分析方法晶型修订时,则质量标准分析方法也需进行证明。

方法检验理由、过程和结果均应记载在药品质量起草标准说明或修订说明中。

需验证的分析目的有:鉴别试验、杂质定量检测或限度检查、原料药或制剂中有效成分含量测定,以及制剂中其他成分的测定。

药品溶出度、稀放度等检测中,其溶出度等的检测方法也应作必要验证。

验证内容有:准确度、精密度、准属性、检测限、定量限、线性、范围和耐用性。

视具体方法拟定验证的内容。

附表中流出的分析项目和相应的验证内容可共参考。

一、检测限检测限系指试样中被测物能被检测出的最低量。

药品的鉴别试验和杂志检查方法,均应通过测试确定方法的检测限。

常用的方法有:1、非仪器分析目视法用已知浓度的被测物,试验出能被可靠的检测出的最低浓度或量。

2、信噪比法用于能显示基线噪声的分析方法,即把已经低浓度试样测出的信号与空白样品测出的最低浓度或量。

一般以信噪比为3:1或2:1时相应浓度或注入仪器的量确定检测限。

3.数据要求应附测试图谱,说明测试过程和检测限结果。

二、定量限定量限系指试样中被检测无能被定量测定的最低量,其策定结果应具一定准确度和精密度。

杂志和降解产物用定量测定方法研究时,应确定方法的定量限。

常用信噪比确定定量限。

一般以信噪比为10:1时相应浓度或注入仪器的量确定定量限。

三、线性线性系指在设计范围内,测试结果与试样中被测物浓度直接呈正比关系的程度。

应在规定的范围内测定线性关系。

可用一贮备液经精密稀释,或分别精密称样,制备一系列供试样品的方法进行测定,至少制备5份供试样品。

以测得的响应信号作为被测物浓度的函数作图,观察是否呈线性,再用最小二乘法进行线性回归。

必要时,响应信号可以数学转换,再进行线性回归计算。

数据要求:应列出回归方程、相关系数和线性图。

国家标准化学药品研究技术指导原则

国家标准化学药品研究技术指导原则

已有国家标准化学药品研究技术指导原则(第二稿草稿)二OO 五年三月1目录一、前言 (2)二、已有国家标准药品研究的基本原则 (2)(一)安全、有效和质量可控原则 (2)(二)等同性原则 (3)(三)仿品种而不是仿标准原则 (5)三、质量控制研究 (7)(一)制备工艺研究 (8)(二)结构确证研究 (9)(三)制剂处方筛选及工艺研究 (10)(四)质量研究与质量标准 (13)(五)稳定性研究 (18)四、安全性、有效性研究 (20)(一)口服给药制剂 (22)(二)注射给药制剂 (25)(三)局部给药制剂 (27)五、参考文献 (29)六、已有国家标准化学药品研究技术指导原则起草说明 (30)七、著者 (35)2一、前言根据《药品注册管理办法》(试行),已有国家标准药品的申请是指境内注册申请人提出的生产国家食品药品监督管理局已经颁布正式标准的药品的注册申请。

我国已经颁布的化学药物研究技术指导原则,涵盖了已有国家标准药品研究的一般性技术要求。

本指导原则在此基础上,结合我国已有国家标准药品研制的现状,针对其不同于新药的特点,较为系统地提出了已有国家标准药品研究过程中有关安全性、有效性和质量控制研究的一般性原则,并重点阐述了在已有国家标准药品研制中相关技术要求之间的内在联系及其科学内涵,旨在指导注册申请人在研制已有国家标准药品时,能够科学、合理地运用已有的化学药物研究技术指导原则,达到研究的系统性、科学性要求。

本指导原则适用于已有国家标准药品申请中的化学药品。

在已有国家标准药品研发和评价中,需要在本原则指导下,以科学性为根本,对具体问题作具体分析。

二、已有国家标准药品研究的基本原则在已有国家标准药品的研究中应注意遵循如下原则,以保证研究的科学性。

(一)安全、有效和质量可控原则无论创新药还是已有国家标准药品,对其安全性、有效性和质量可3控性的要求是一致的,研发的根本原则都是要围绕安全、有效和质量可控进行充分的研究。

分析方法验证指导原则

分析方法验证指导原则

分析方法验证指导原则验证的分析项目有:鉴别试验、杂质测定(限度或定量分析)、含量测定(包括特性参数和含量/效价测定,其中特性参数如:药物溶出度、释放度等)。

验证的指标有:专属性、准确度、精密度(包括重复性、中间精密度和重现性)、检测限、定量限、线性、范围和耐用性。

在分析方法验证中,须用标准物质进行试验。

由于分析方法具有各自的特点,并随分析对象而变化,因此需要视具体情况拟订验证的指标。

表1中列出的分析项目和相应的验证指标可供参考。

方法验证内容如下。

专属性专属性系指在其他成分(如杂质、降解产物、辅料等)可能存在下,采用的分析方法能正确测定出被测物的能力。

鉴别反应、杂质检查和含量测定方法,均应考察其专属性。

如方法专属性不强,应采用一种或多种不同原理的方法予以补充。

二、准确度准确度系指用所建立方法测定的结果与真实值或参比值接近的程度,一般用回收率(%)表示。

准确度应在规定的线性范围内试验。

准确度也可由所测定的精密度、线性和专属性推算出来。

在规定范围内,取同一浓度(相当于100%浓度水平)的供试品,用至少6份样品的测定结果进行评价;或设计至少3种不同浓度,每种浓度分别制备至少3份供试品溶液进行测定,用至少9份样品的测定结果进行评价,且浓度的设定应考虑样品的浓度范围。

两种方法的选定应考虑分析的目的和样品的浓度范围。

三、精密度精密度系指在规定的测定条件下,同一份均匀供试品,经多次取样测定所得结果之间的接近程度。

精密度一般用偏差、标准偏差或相对标准偏差表示。

在相同条件下,由同一个分析人员测定所得结果的精密度称为重复性;在同一实验室内的条件改变,如不同时间、不同分析人员、不同设备等测定结果之间的精密度,称为中间精密度;不同实验室测定结果之间的精密度,称为重现性。

含量测定和杂质的定量测定应考察方法的精密度。

1.重复性在规定范围内,取同一浓度(分析方法拟定的样品测定浓度,相当于100%浓度水平)的供试品,用至少6份的测定结果进行评价;或设计至少3种不同浓度,每种浓度分别制备至少3份供试品溶液进行测定,用至少9份样品的测定结果进行评价。

16.化学药物原料药制备和结构确证研究技术指导原则 2005年颁布

16.化学药物原料药制备和结构确证研究技术指导原则 2005年颁布

【H】G P H 2-1指导原则编号:化学药物原料药制备和结构确证研究的技术指导原则二○○五年三月目 录一、化学药物原料药制备研究的技术指导原则 (1)(一)概述 (1)(二)原料药制备研究的一般过程 (2)(三)原料药制备研究的基本内容 (3)1、工艺的选择 (3)2、起始原料和试剂的要求 (4)3、工艺数据的积累 (5)4、中间体的研究及质量控制 (6)5、工艺的优化与中试 (8)6、杂质的分析 (9)7、“三废”的处理 (9)8、工艺的综合分析 (10)(四)名词解释 (10)(五)参考文献 (10)(六)附件 (12)二、化学药物原料药结构确证研究的技术指导原则 (12)(一)概述 (12)(二)原料药结构确证研究的一般过程 (13)(三)原料药结构确研究的基本内容 (14)1、研究方案的制订 (14)2、测试样品的要求 (18)3、结构确证研究的一般内容 (18)4、参考文献和结构确证用对照品对结构确证的意义与要求 (25)5、综合解析 (26)6、药物的名称、结构式及理化常数 (26)(四)名词解释 (28)(五)参考文献 (28)三、著者 (29)一、化学药物原料药制备研究的技术指导原则(一)概述原料药的制备是药物研究和开发的基础,是药物研发的起始阶段,其主要目的是为药物研发过程中药理毒理、制剂、临床等研究提供合格的原料药,为质量研究提供信息,通过对工艺全过程的控制保证生产工艺的稳定、可行,为上市药品的生产提供符合要求的原料药。

本指导原则旨在反映原料药制备研究的基本规律,并遵循该规律进行原料药的研发,确定符合相关法规的、科学的基本技术要求,为药物研发者在原料药制备研究中提供基本的技术指导,同时使药物研发者对在药品评价过程中所需要关注的问题有一个清楚的认识。

本指导原则主要内容为概述、研究的一般过程、研究的基本内容、名词解释、参考文献等。

概述就本指导原则起草的目的意义、适用范围等方面进行介绍。

最新化学药物质量控制分析方法验证技术指导原则汇编

最新化学药物质量控制分析方法验证技术指导原则汇编

化学药物质量控制分析方法验证技术指导原则一、概述⏹保证药品安全、有效、质量可控是药品研发和评价应遵循的基本原则,其中,对药品进行质量控制是保证药品安全有效的基础和前提。

为达到控制质量的目的,需要多角度、多层面来控制药品质量,也就是说要对药物进行多个项目测试,来全面考察药品质量。

一般地,每一测试项目可选用不同的分析方法,为使测试结果准确、可靠,必须对所采用的分析方法的科学性、准确性和可行性进行验证,以充分表明分析方法符合测试项目的要求,这就是通常所说的对方法进行验证。

方法验证的目的是判断采用的分析方法是否科学、合理,是否能有效控制药品的内在质量。

⏹从本质上讲,方法验证就是根据检测项目的要求,预先设置一定的验证内容,并通过设计合理的试验来验证所采用的分析方法能否符合检测项目的要求。

⏹方法验证在分析方法建立过程中具有重要的作用,并成为质量研究和质量控制的组成部分。

⏹只有经过验证的分析方法才能用于控制药品质量,因此方法验证是制订质量标准的基础。

方法验证是药物研究过程中的重要内容。

二、方法验证的一般原则⏹原则上每个检测项目采用的分析方法,均需要进行方法验证。

⏹方法验证的内容应根据检测项目的要求,结合所采用分析方法的特点确定。

⏹同一分析方法用于不同的检测项目会有不同的验证要求。

例如,采用高效液相色谱法用于制剂的鉴别和杂质定量试验应进行不同要求的方法验证,前者重点要求验证专属性,而后者重点要求验证专属性、准确度、定量限。

三、方法验证涉及的三个主要方面⏹(一)需要验证的检测项目⏹鉴别、⏹杂质检查⏹定量测定(含量测定、溶出度、释放度等)、⏹其他特定检测项目(分子量及分子量分布、生物活性等)⏹鉴别的目的在于判定被分析物是目标化合物,而非其它物质,用于鉴别的分析方法要求具有较强的专属性。

⏹杂质检查主要用于控制主成分以外的杂质,如有机杂质、无机杂质等。

杂质检查可分为限度试验和定量试验两种情况。

用于限度试验的分析方法验证侧重专属性和检测限。

USP-化学药物质量控制分析方法验证技术指导原则

USP-化学药物质量控制分析方法验证技术指导原则

1225VALIDATION OF COMPENDIAL PROCEDURESTest procedures for assessment of the quality levels of pharmaceutical articles are subject to various requirements. According to Section 501 of the Federal Food, Drug, and Cosmetic Act, assays and specifications in monographs of the United States Pharmacopeia and the National Formulary constitute legal standards. The Current Good Manufacturing Practice regulations [21 CFR 211.194(a)] require that test methods, which are used for assessing compliance of pharmaceutical articles with established specifications, must meet proper standards of accuracy and reliability. Also, according to these regulations [21 CFR 211.194(a)(2)], users of analytical methods described in USP–NF are not required to validate the accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use. Recognizing the legal status of USP and NF standards, it is essential, therefore, that proposals for adoption of new or revised compendial analytical procedures be supported by sufficient laboratory data to document their validity.The text of this information chapter harmonizes, to the extent possible, with the Tripartite International Conference on Harmonization (ICH) documents Validation of Analytical Procedures and the Methodology extension text, which are concerned with analytical procedures included as part of registration applications submitted within the EC, Japan, and the USA.SUBMISSIONS TO THE COMPENDIASubmissions to the compendia for new or revised analytical procedures should contain sufficient information to enable members of the USP Council of Experts and its Expert Committees to evaluate the relative merit of proposed procedures. In most cases, evaluations involve assessment of the clarity and completeness of the description of the analytical procedures, determination of the need for the procedures, and documentation that they have been appropriately validated. Information may vary depending upon the type ofmethod involved. However, in most cases a submission will consist of the following sections.Rationale— This section should identify the need for the procedure and describe the capability of the specific procedure proposed and why it is preferred over other types of determinations. For revised procedures, a comparison should be provided of limitations of the current compendial procedure and advantages offered by the proposed procedure.Proposed Analytical Procedure— This section should contain a complete description of the analytical procedure sufficiently detailed to enable persons “skilled in the art” to replicate it. The write-up should include all important operational parameters and specific instructions such as preparation of reagents, performance of system suitability tests, description of blanks used, precautions, and explicit formulas for calculation of test results.Data Elements— This section should provide thorough and complete documentation of the validation of the analytical procedure. It should include summaries of experimental data and calculations substantiating each of the applicable analytical performance characteristics. These characteristics are described in the following section.VALIDATIONValidation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteristics of the procedure meet the requirements for the intended analytical applications. Typical analytical performance characteristics that should be considered in the validation of the types of procedures described in this document are listed in Table 1. Because opinions may differ with respect to terminology and use, each of the performance characteristics is defined in the next section of this chapter, along with a delineation of a typical method or methods by which it may be measured. The definitions refer to “test results.” The description of the analytical procedure should define what the test results for the procedure are. As notedin ISO 5725-1 and 3534-1, a test result is “the value of a characteristic obtained by carrying out a specified test method. The test method should specify that one or a number of individual measurements be made, and their average, or another appropriate function (such as the median or the standard deviation), be reported as the test result. It may also require standard corrections to be applied, such as correction of gas volumes to standard temperature and pressure. Thus, a test result can be a result calculated from several observed values. In the simple case, the test result is the observed value itself.” A test result also can be, but need not be, the final, reportable value that would be compared to the acceptance criteria of a specification. Validation of physical property methods may involve the assessment of chemometric models. However, the typical analytical characteristics used in method validation can be applied to the methods derived from the use of the chemometric models.The effects of processing conditions and potential for segregation of materials should be considered when obtaining a representative sample to be used for validation of procedures.Table 1. Typical Analytical CharacteristicsUsed in Method ValidationAccuracyPrecisionSpecificityDetection LimitQuantitation LimitLinearityRangeRobustnessIn the case of compendial procedures, revalidation may be necessary in the following cases: a submission to the USP of a revised analytical procedure; or the use of an established general procedure with a new product or raw material (see below in Data Elements Required for Validation).The ICH documents give guidance on the necessity for revalidation in the following circumstances: changes in the synthesis of the drug substance; changes in the composition of the drug product; and changes in the analytical procedure.Chapter 1225is intended to provide information that is appropriate to validate a wide range of compendial analytical procedures. The validation of compendial procedures may use some or all of the suggested typical analytical characteristics used in method validation as outlined in Table 1 and categorized by type of analytical method in Table 2. For some compendial procedures the fundamental principles of validation may extend beyond characteristics suggested in Chapter 1225. For these procedures the user is referred to the individual compendial chapter for those specific analytical validation characteristics and any specific validation requirements.Analytical Performance CharacteristicsaccuracyDefinition— The accuracy of an analytical procedure is the closeness of test results obtained by that procedure to the true value. The accuracy of an analytical procedure should be established across its range. [A note on terminology: The definition of accuracy in 1225and ICH Q2 corresponds to unbiasedness only. In the International Vocabulary of Metrology (VIM) and documents of the International Organization for Standardization (ISO), “accuracy” has a di fferent meaning. In ISO, accuracy combines the concepts of unbiasedness (termed “trueness”) and precision.]Determination— In the case of the assay of a drug substance, accuracy may be determined by application of the analytical procedure to an analyte of known purity (e.g., a Reference Standard) or by comparison of the results of the procedure with those of a second, well-characterized procedure, the accuracy of which has been stated or defined.In the case of the assay of a drug in a formulated product, accuracy may be determined by application of the analytical procedure to synthetic mixtures of the drug product components to which known amounts of analyte have been added within the range of the procedure. If it is not possible to obtain samples of all drug product components, it may be acceptable either to add known quantities of the analyte to the drug product (i.e., “to spike”) or to compare results with those of a second, well-characterized procedure, the accuracy of which has been stated or defined.In the case of quantitative analysis of impurities, accuracy should be assessed on samples (of drug substance or drug product) spiked with known amounts of impurities. Where it is not possible to obtain samples of certain impurities or degradation products, results should be compared with those obtained by an independent procedure. In the absence of other information, it may be necessary to calculate the amount of an impurity based on comparison of its response to that of the drug substance; the ratio of the responses of equal amounts of the impurity and the drug substance (relative response factor) should be used if known.Accuracy is calculated as the percentage of recovery by the assay of the known added amount of analyte in the sample, or as the difference between the mean and the accepted true value, together with confidence intervals.The ICH documents recommend that accuracy should be assessed using a minimum of nine determinations over a minimum of three concentration levels, covering the specified range (i.e., three concentrations and three replicates of each concentration).Assessment of accuracy can be accomplished in a variety of ways, including evaluating the recovery of the analyte (percent recovery) across the range of the assay, or evaluating the linearity of the relationship between estimated and actual concentrations. The statistically preferred criterion is that the confidence interval for the slope be contained in an interval around 1.0, or alternatively, that the slope be close to 1.0. In either case, the interval or the definition ofcloseness should be specified in the validation protocol. The acceptance criterion will depend on the assay and its variability and on the product. Setting an acceptance criterion based on the lack of statistical significance of the test of the null hypothesis that the slope is 1.0 is not an acceptable approach. Accuracy of physical property methods may be assessed through the analysis of standard reference materials, or alternatively, the suitability of the above approaches may be considered on a case-by-case basis.precisionDefinition— The precision of an analytical procedure is the degree of agreement among individual test results when the procedure is applied repeatedly to multiple samplings of a homogeneous sample. The precision of an analytical procedure is usually expressed as the standard deviation or relative standard deviation (coefficient of variation) of a series of measurements. Precision may be a measure of either the degree of reproducibility or of repeatability of the analytical procedure under normal operating conditions. In this context, reproducibility refers to the use of the analytical procedure in different laboratories, as in a collaborative study. Intermediate precision (also known as ruggedness) expresseswithin-laboratory variation, as on different days, or with different analysts or equipment within the same laboratory. Repeatability refers to the use of the analytical procedure within a laboratory over a short period of time using the same analyst with the same equipment.Determination— The precision of an analytical procedure is determined by assaying a sufficient number of aliquots of a homogeneous sample to be able to calculate statistically valid estimates of standard deviation or relative standard deviation (coefficient of variation). Assays in this context are independent analyses of samples that have been carried through the complete analytical procedure from sample preparation to final test result.The ICH documents recommend that repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure(i.e., three concentrations and three replicates of each concentration) or using a minimum of six determinations at 100% of the test concentration.specificityDefinition— The ICH documents define specificity as the ability to assess unequivocally the analyte in the presence of components that may be expected to be present, such as impurities, degradation products, and matrix components. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedures. [Note—Other reputable international authorities (IUPAC, AOAC-I) have preferred the term “selectivity,” reserving “specificity” for tho se procedures that are completely selective. ] For the tests discussed below, the above definition has the following implications:Identification Tests: ensure the identity of the analyte.Purity Tests: ensure that all the analytical procedures performed allow an accurate statement of the content of impurities of an analyte (e.g., related substances test, heavy metals limit, organic volatile impurities).Assays: provide an exact result, which allows an accurate statement on the content or potency of the analyte in a sample.Determination— In the case of qualitative analyses (identification tests), the ability to select between compounds of closely related structure that are likely to be present should be demonstrated. This should be confirmed by obtaining positive results (perhaps by comparison to a known reference material) from samples containing the analyte, coupled with negative results from samples that do not contain the analyte and by confirming that a positive response is not obtained from materials structurally similar to or closely related to the analyte.In the case of analytical procedures for impurities, specificity may be established by spiking the drug substance or product with appropriate levels of impurities and demonstrating that these impurities are determined with appropriate accuracy and precision.In the case of the assay, demonstration of specificity requires that it can be shown that the procedure is unaffected by the presence of impurities or excipients. In practice, this can be done by spiking the drug substance or product with appropriate levels of impurities or excipients and demonstrating that the assay result is unaffected by the presence of these extraneous materials.If impurity or degradation product standards are unavailable, specificity may be demonstrated by comparing the test results of samples containing impurities or degradation products to a second well-characterized procedure (e.g., a Pharmacopeial or other validated procedure). These comparisons should include samples stored under relevant stress conditions (e.g., light, heat, humidity, acid/base hydrolysis, and oxidation). In the case of the assay, the results should be compared; in the case of chromatographic impurity tests, the impurity profiles should be compared.The ICH documents state that when chromatographic procedures are used, representative chromatograms should be presented to demonstrate the degree of selectivity, and peaks should be appropriately labeled. Peak purity tests (e.g., using diode array or mass spectrometry) may be useful to show that the analyte chromatographic peak is not attributable to more than one component.For validation of specificity for qualitative and quantitative determinations by spectroscopic methods, chapters related to topics such as near-infrared spectrophotometry, raman spectroscopy, and X-ray powder diffraction should be consulted.detection limitDefinition— The detection limit is a characteristic of limit tests. It is the lowest amount of analyte in a sample that can be detected, but not necessarily quantitated, under the stated experimental conditions. Thus, limit tests merely substantiate that the amount of analyte is above or below a certain level. Thedetection limit is usually expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample.Determination— For noninstrumental procedures, the detection limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be reliably detected.For instrumental procedures, the same approach may be used as for noninstrumental procedures. In the case of procedures submitted for consideration as official compendial procedures, it is almost never necessary to determine the actual detection limit. Rather, the detection limit is shown to be sufficiently low by the analysis of samples with known concentrations of analyte above and below the required detection level. For example, if it is required to detect an impurity at the level of 0.1%, it should be demonstrated that the procedure will reliably detect the impurity at that level.In the case of instrumental analytical procedures that exhibit background noise, the ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank samples. The minimum concentration at which the analyte can reliably be detected is established. Typically acceptable signal-to-noise ratios are 2:1 or 3:1. Other approaches depend on the determination of the slope of the calibration curve and the standard deviation of responses. Whatever method is used, the detection limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared at, the detection limit.quantitation limitDefinition— The quantitation limit is a characteristic of quantitative assays for low levels of compounds in sample matrices, such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions. Thequantitation limit is expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample.Determination— For noninstrumental procedures, the quantitation limit is generally determined by the analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be determined with acceptable accuracy and precision.For instrumental procedures, the same approach may be used as for noninstrumental procedures. In the case of procedures submitted for consideration as official compendial procedures, it is almost never necessary to determine the actual quantitation limit. Rather, the quantitation limit is shown to be sufficiently low by the analysis of samples with known concentrations of analyte above and below the quantitation level. For example, if it is required that an analyte be assayed at the level of 0.1 mg per tablet, it should be demonstrated that the procedure will reliably quantitate the analyte at that level.In the case of instrumental analytical procedures that exhibit background noise, the ICH documents describe a common approach, which is to compare measured signals from samples with known low concentrations of analyte with those of blank samples. The minimum concentration at which the analyte can reliably be quantified is established. A typically acceptable signal-to-noise ratio is 10:1. Other approaches depend on the determination of the slope of the calibration curve and the standard deviation of responses. Whatever approach is used, the quantitation limit should be subsequently validated by the analysis of a suitable number of samples known to be near, or prepared at, the quantitation limit.linearity and rangeDefinition of Linearity— The linearity of an analytical procedure is its ability to elicit test results that are directly, or by a well-defined mathematical transformation, proportional to the concentration of analyte in samples within a given range. Thus, in this section, “linearity” refers to the linearity of therelationship of concentration and assay measurement. In some cases, to attain linearity, the concentration and/or the measurement may be transformed. (Note that the weighting factors used in the regression analysis may change when a transformation is applied.) Possible transformations may include log, square root, or reciprocal, although other transformations are acceptable. If linearity is not attainable, a nonlinear model may be used. The goal is to have a model, whether linear or nonlinear, that describes closely the concentration-response relationship.Definition of Range— The range of an analytical procedure is the interval between the upper and lower levels of analyte (including these levels) that have been demonstrated to be determined with a suitable level of precision, accuracy, and linearity using the procedure as written. The range is normally expressed in the same units as test results (e.g., percent, parts per million) obtained by the analytical procedure.Determination of Linearity and Range— Linearity should be established across the range of the analytical procedure. It should be established initially by visual examination of a plot of signals as a function of analyte concentration of content. If there appears to be a linear relationship, test results should be established by appropriate statistical methods (e.g., by calculation of a regression line by the method of least squares). Data from the regression line itself may be helpful to provide mathematical estimates of the degree of linearity. The correlation coefficient, y-intercept, slope of the regression line, and residual sum of squares should be submitted.The range of the procedure is validated by verifying that the analytical procedure provides acceptable precision, accuracy, and linearity when applied to samples containing analyte at the extremes of the range as well as within the range.ICH recommends that, for the establishment of linearity, a minimum of five concentrations normally be used. It is also recommended that the following minimum specified ranges should be considered:Assay of a Drug Substance (or a finished product): from 80% to 120% of the test concentration.Determination of an Impurity: from 50% to 120% of the acceptance criterion. For Content Uniformity: a minimum of 70% to 130% of the test concentration, unless a wider or more appropriate range based on the nature of the dosage form (e.g., metered-dose inhalers) is justified.For Dissolution Testing: ±20% over the specified range (e.g., if the acceptance criteria for a controlled-release product cover a region from 30%, after 1 hour, and up to 90%, after 24 hours, the validated range would be 10% to 110% of the label claim).The traditional definition of linearity, i.e., the establishment of a linear or mathematical relationship between sample concentration and response, is not applicable to particle size analysis. For particle size analysis, a concentration range is defined (instrument- and particle size-dependent) such that the measured particle size distribution is not affected by changes in concentration within the defined concentration range. Concentrations below the defined concentration range may introduce an error due to poor signal-to-noise ratio, and concentrations exceeding the defined concentration range may introduce an error due to multiple scattering.robustnessDefinition— The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in procedural parameters listed in the procedure documentation and provides an indication of its suitability during normal usage. Robustness may be determined during development of the analytical procedure.system suitabilityIf measurements are susceptible to variations in analytical conditions, these should be suitably controlled, or a precautionary statement should be included in the procedure. One consequence of the evaluation of robustness and ruggedness should be that a series of system suitability parameters isestablished to ensure that the validity of the analytical procedure is maintained whenever used. Typical variations are the stability of analytical solutions, different equipment, and different analysts. In the case of liquid chromatography, typical variations are the pH of the mobile phase, the mobile phase composition, different lots or suppliers of columns, the temperature, and the flow rate. In the case of gas chromatography, typical variations are different lots or suppliers of columns, the temperature, and the flow rate. System suitability tests are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being evaluated. They are especially important in the case of chromatographic procedures. Submissions to the USP should make note of the requirements under the System Suitability section in the general test chapter Chromatography 621.Data Elements Required for ValidationCompendial test requirements vary from highly exacting analytical determinations to subjective evaluation of attributes. Considering this broad variety, it is only logical that different test procedures require different validation schemes. This chapter covers only the most common categories of tests for which validation data should be required. These categories are as follows:Category I— Analytical procedures for quantitation of major components of bulk drug substances or active ingredients (including preservatives) in finished pharmaceutical products.Category II— Analytical procedures for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These procedures include quantitative assays and limit tests.Category III — Analytical procedures for determination of performance characteristics (e.g., dissolution, drug release, etc.).Category IV — Identification tests.For each category, different analytical information is needed. Listed in Table 2 are data elements that are normally required for each of these categories.Table 2. Data Elements Required for ValidationAnalytical Performance Characteristics Category I Category IICategory IIICategory IV Quantitative Limit Tests AccuracyYes Yes **No PrecisionYes Yes No Yes No SpecificityYes Yes Yes *Yes Detection LimitNo No Yes *No Quantitation LimitNo Yes No *No LinearityYes Yes No *No Range Yes Yes **No * May be required, depending on the nature of the specific test. Already established general procedures (e.g., titrimetric determination of water, bacterial endotoxins) should be verified to establish their suitability for use, such as their accuracy (and absence of possible interference) when used for a new product or raw material.When validating physical property methods, consider the same performance characteristics required for any analytical procedure. Evaluate use of the performance characteristics on a case-by-case basis, with the goal ofdetermining that the procedure is suitable for its intended use. The specific acceptance criteria for each validation parameter should be consistent with the intended use of the method.Physical methods may also be classified into the four validation categories. For example, validation of a quantitative spectroscopic method may involveevaluation of Category I or Category II Analytical Performance Characteristics, depending on the method requirements. Qualitative physical propertymeasurements, such as particle size, surface area, bulk and tapped density,which could impact performance characteristics, often best fit in Category III. Category IV Analytical Performance Characteristics usually applies to validation of qualitative identification spectroscopic methods. However, the various techniques may be used for different purposes, and the specific use of the method and characteristics of the material being analyzed should be considered when definitively applying a category to a particular type of method.The validity of an analytical procedure can be verified only by laboratory studies. Therefore, documentation of the successful completion of such studies is a basic requirement for determining whether a procedure is suitable for its intended application(s). Current compendial procedures are also subject to regulations that require demonstration of suitability under actual conditions of use (see Verification of Compendial Procedures 1226for principles relative to the verification of compendial procedures). Appropriate documentation should accompany any proposal for new or revised compendial analytical procedures.contacting USP.Topic/Question Contact Expert CommitteeGeneral Chapter Horacio N. Pappa, Ph.D.Principal ScientificLiaison1-301-816-8319 (GCPA2010) General Chapters - Physical AnalysisUSP34–NF29 Page 778Pharmacopeial Forum: Volume No. 35(2) Page 444。

药品质量标准分析方法验证指导原则

药品质量标准分析方法验证指导原则

附录二药品质量标准分析方法验证指导原则药品质量标准分析方法验证的目的是证明采用的方法适合于相应检测要求。

在建立药品质量标准时,分析方法需经验证;在药品生产工艺变更、制剂的组分变更、原分析方法进行修订时,则质量标准分析方法也需进行验证。

方法验证理由、过程和结果均应记载在药品标准起草说明或修订说明中。

需验证的分析项目有:鉴别试验,杂质定量检查或限度检查,原料药或制剂中有效成分含量测定,以及制剂中的其他成分(如防腐剂等)的测定。

药品溶出度、释放度等功能检查中,其溶出量等的测试方法也应作必要验证。

验证内容有:准确度、精密度(包括重复性、中间精密度和重现性)、专属性、检测限、定量限、线性、范围和耐用性。

视具体方法拟订验证的内容。

附表中列出的分析项目和相应的验证内容可供参考。

方法验证内容如下。

一、准确度准确度系指用该方法测定的结果与真实值或参考值接近的程度,一般用回收率(%)表示。

准确度应在规定的范围内测试。

1.含量测定方法的准确度原料药可用已知纯度的对照品或样品进行测定,或用本法所得结果与已知准确度的另一个方法测定的结果进行比较。

制剂可用含已知量被测物的各组分混合物进行测定。

如不能得到制剂的全部组分,可向制剂中加入已知量的被测物进行测定,或用本法所得结果与已知准确度的另一个方法测定结果进行比较。

如该分析方法已经测试并求出了精密度、线性和专属性,在准确度也可推算出来的情况下,这一项可不必再做。

2.杂质定量测定的准确度可向原料药或制剂中加入已知量杂质进行测定。

如不能得到杂质或降解产物,可用本法测定结果与另一成熟的方法进行比较,如药典标准方法或经过验证的方法。

在不能测得杂质或降解产物的响应因子或对原料药的相对响应因子情况下,可用原料药的响应因子。

应明确表明单个杂质和杂质总量相当于主成分的重量比(%)或面积比(%)。

3.数据要求在规定范围内,至少用9个测定结果进行评价,例如,设计3个不同浓度,每个浓度各分别制备3份供试品溶液,进行测定。

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指导原则编号:【H】G P H 5-1化学药物质量控制分析方法验证技术指导原则二○○五年三月目 录一、概述 (1)二、方法验证的一般原则 (2)三、方法验证涉及到的三个主要方面 (2)(一)需要验证的检测项目 (2)(二)分析方法 (3)(三)验证内容 (3)四、方法验证的具体内容 (3)(一)专属性 (3)1、鉴别反应 (4)2、杂质检查 (4)3、含量测定 (4)(二)线性 (5)(三)范围 (5)1、含量测定 (6)2、制剂含量均匀度 (6)3、溶出度或释放度 (6)4、杂质 (6)(四)准确度 (6)1、含量测定 (7)2、杂质定量试验 (7)(五)精密度 (7)1、重复性 (8)2、中间精密度 (8)3、重现性 (8)(六)检测限 (8)1、直观法 (8)2、信噪比法 (9)(七)定量限 (9)1、直观法 (9)2、信噪比法 (9)(八)耐用性 (10)(九)系统适用性试验 (10)五、方法再验证 (11)六、方法验证的评价 (12)(一)有关方法验证评价的一般考虑 (12)(二)方法验证的整体性和系统性 (12)七、参考文献 (13)八、著者 (13)化学药物质量控制分析方法验证技术指导原则一、概述保证药品安全、有效、质量可控是药品研发和评价应遵循的基本原则,其中,对药品进行质量控制是保证药品安全有效的基础和前提。

为达到控制质量的目的,需要多角度、多层面来控制药品质量,也就是说要对药物进行多个项目测试,来全面考察药品质量。

一般地,每一测试项目可选用不同的分析方法,为使测试结果准确、可靠,必须对所采用的分析方法的科学性、准确性和可行性进行验证,以充分表明分析方法符合测试项目的目的和要求,这就是通常所说的对方法进行验证。

方法验证的目的是判断采用的分析方法是否科学、合理,是否能有效控制药品的内在质量。

从本质上讲,方法验证就是根据检测项目的要求,预先设置一定的验证内容,并通过设计合理的试验来验证所采用的分析方法能否符合检测项目的要求。

方法验证在分析方法建立过程中具有重要的作用,并成为质量研究和质量控制的组成部分。

只有经过验证的分析方法才能用于控制药品质量,因此方法验证是制订质量标准的基础。

方法验证是药物研究过程中的重要内容。

本指导原则重点探讨方法验证的本质,将分析方法验证的要求与所要达到的目的结合起来进行系统和规律性的阐述,重点阐述如何科学合理地进行论证方案的设计。

本指导原则主要包括方法验证的一般原则、方法验证涉及的三个主要方面、方法验证的具体内容、对方法验证的评价等内容。

本原则与其他相关技术指导原则一起构成较完整的质量控制指导原则。

随着我国新药研发水平的不断提高,对方法验证的认识也会不断深入,本指导原则将会逐步完善和修订。

由于生物制品和中药的特殊性,本原则主要适用于化学药品。

二、方法验证的一般原则原则上每个检测项目采用的分析方法,均需要进行方法验证。

方法验证的内容应根据检测项目的要求,结合所采用分析方法的特点确定。

同一分析方法用于不同的检测项目会有不同的验证要求。

例如,采用高效液相色谱法用于制剂的鉴别和杂质定量试验应进行不同要求的方法验证,前者重点要求验证专属性,而后者重点要求验证专属性、准确度、定量限。

三、方法验证涉及的三个主要方面(一)需要验证的检测项目检测项目是为控制药品质量,保证安全有效而设定的测试项目。

根据检测项目的设定目的和验证内容的不同要求,本指导原则将需验证的检测项目分为鉴别、杂质检查(限度试验、定量试验)、定量测定(含量测定、溶出度、释放度等)、其他特定检测项目等四类。

鉴别的目的在于判定被分析物是目标化合物,而非其它物质,用于鉴别的分析方法要求具有较强的专属性。

杂质检查主要用于控制主成分以外的杂质,如有机杂质、无机杂质等。

杂质检查可分为限度试验和定量试验两种情况。

用于限度试验的分析方法验证侧重专属性和检测限。

用于定量试验的分析方法验证强调专属性、准确度和定量限。

定量测定包括含量测定、制剂的溶出度测定等,由于此类项目对准确性要求较高,故所采用的分析方法要求具有一定的专属性、准确度和线性。

其他特定检测项目包括粒径分布、旋光度、分子量分布等,由于这些检测项目的要求与鉴别、杂质检查、定量测定等有所不同,对于这些项目的分析方法验证应有不同的要求。

(二)分析方法本指导原则所指分析方法是为完成上述各检测项目而设定和建立的测试方法,一般包括分析方法原理、仪器及仪器参数、试剂、系统适用性试验、供试品溶液制备、对照品溶液制备、测定、计算及测试结果的报告等。

测试方法可采用化学分析方法和仪器分析方法。

这些方法各有特点,同一测试方法可用于不同的检测项目,但验证内容可不相同。

(三)验证内容验证内容包括方法的专属性、线性、范围、准确度、精密度、检测限、定量限、耐用性和系统适用性等。

四、方法验证的具体内容(一)专属性专属性系指在其他成分(如杂质、降解物、辅料等)可能存在下,采用的分析方法能够正确鉴定、检出被分析物质的特性。

通常,鉴别、杂质检查、含量测定方法中均应考察其专属性。

如采用的方法不够专属,应采用多个方法予以补充。

1、鉴别反应鉴别试验应确证被分析物符合其特征。

专属性试验要求证明能与可能共存的物质或结构相似化合物区分,需确证含被分析物的供试品呈正反应,而不含被测成分的阴性对照呈负反应,结构相似或组分中的有关化合物也应呈负反应。

2、杂质检查作为纯度检查,所采用的分析方法应确保可检出被分析物中杂质的含量,如有关物质、重金属、有机溶剂等。

因此杂质检查要求分析方法有一定的专属性。

在杂质可获得的情况下,可向供试品中加入一定量的杂质,证明杂质与共存物质能得到分离和检出,并具适当的准确度与精密度。

在杂质或降解产物不能获得的情况下,专属性可通过与另一种已证明合理但分离或检测原理不同、或具较强分辨能力的方法进行结果比较来确定。

或将供试品用强光照射,高温,高湿,酸、碱水解及氧化的方法进行破坏(制剂应考虑辅料的影响),比较破坏前后检出的杂质个数和量。

必要时可采用二极管阵列检测和质谱检测,进行色谱峰纯度检查。

3、含量测定含量测定目的是得到供试品中被分析物的含量或效价的准确结果。

在杂质可获得的情况下,对于主成分含量测定可在供试品中加入杂质或辅料,考察测定结果是否受干扰,并与未加杂质和辅料的供试品比较测定结果。

在杂质或降解产物不能获得的情况下,可采用另一个经验证了的或药典方法进行比较,对比两种方法测定的结果。

也可采用破坏性试验(强光照射,高温,高湿,酸、碱水解及氧化),得到含有杂质或降解产物的试样,用两种方法进行含量测定,比较测定结果。

必要时进行色谱峰纯度检查,证明含量测定成分的色谱峰中不包含其他成分。

(二)线性线性系指在设计的测定范围内,检测结果与供试品中被分析物的浓度(量)直接呈线性关系的程度。

线性是定量测定的基础,涉及定量测定的项目,如杂质定量试验和含量测定均需要验证线性。

应在设计的测定范围内测定线性关系。

可用一贮备液经精密稀释,或分别精密称样,制备一系列被测物质浓度系列进行测定,至少制备5个浓度。

以测得的响应信号作为被测物浓度的函数作图,观察是否呈线性,用最小二乘法进行线性回归。

必要时,响应信号可经数学转换,再进行线性回归计算,并说明依据。

(三)范围范围系指能够达到一定的准确度、精密度和线性,测试方法适用的试样中被分析物高低限浓度或量的区间。

范围是规定值,在试验研究开始前应确定验证的范围和试验方法。

可以采用符合要求的原料药配制成不同的浓度,按照相应的测定方法进行试验。

范围通常用与分析方法的测试结果相同的单位(如百分浓度)表达。

涉及到定量测定的检测项目均需要对范围进行验证,如含量测定、含量均匀度、溶出度或释放度、杂质定量试验等。

范围应根据剂型和(或)检测项目的要求确定。

1、含量测定范围应为测试浓度的80%~100%或更宽。

2、制剂含量均匀度范围应为测试浓度的70%~130%。

根据剂型特点,如气雾剂、喷雾剂,必要时,范围可适当放宽。

3、溶出度或释放度对于溶出度,范围应为限度的±20%;如规定限度范围,则应为下限的-20%至上限的+20%。

对于释放度,如规定限度范围为,从1小时后为20%至24小时后为90%,则验证范围应为0~110%。

4、杂质杂质测定时,范围应根据初步实测结果,拟订出规定限度的±20%。

如果含量测定与杂质检查同时测定,用面积归一化法,则线性范围应为杂质规定限度的-20%至含量限度(或上限)的+20%。

(四)准确度准确度系指用该方法测定的结果与真实值或认可的参考值之间接近的程度。

有时也称真实度。

一定的准确度为定量测定的必要条件,因此涉及到定量测定的检测项目均需要验证准确度,如含量测定、杂质定量试验等。

准确度应在规定的范围内建立,对于制剂一般以回收率试验来进行验证。

试验设计需考虑在规定范围内,制备3个不同浓度的试样,各测定3次,即测定9次,报告已知加入量的回收率(%)或测定结果平均值与真实值之差及其可信限。

1、含量测定原料药可用已知纯度的对照品或符合要求的原料药进行测定,或用本法所得结果与已建立准确度的另一方法测定的结果进行比较。

制剂可用含已知量被测物的各组分混合物进行测定。

如不能得到制剂的全部组分,可向制剂中加入已知量的被测物进行测定,必要时,与另一个已建立准确度的方法比较结果。

2、杂质定量试验杂质的定量试验可向原料药或制剂中加入已知量杂质进行测定。

如果不能得到杂质,可用本法测定结果与另一成熟的方法进行比较,如药典方法或经过验证的方法。

如不能测得杂质的相对响应因子,可在线测定杂质的相关数据,如采用二极管阵列检测器测定紫外光谱,当杂质的光谱与主成分的光谱相似,则可采用原料药的响应因子近似计算杂质含量(自身对照法)。

并应明确单个杂质和杂质总量相当于主成分的重量比(%)或面积比(%)。

(五)精密度精密度系指在规定的测试条件下,同一均质供试品,经多次取样进行一系列检测所得结果之间的接近程度(离散程度)。

精密度一般用偏差、标准偏差或相对标准偏差表示。

用标准偏差或相对标准偏差表示时,取样测定次数应至少6次。

精密度可以从三个层次考察:重复性、中间精密度、重现性。

1、重复性重复性系指在同样的操作条件下,在较短时间间隔内,由同一分析人员测定所得结果的精密度。

重复性测定可在规定范围内,至少用9次测定结果进行评价,如制备3个不同浓度的试样,各测定3次,或100%的浓度水平,用至少测定6次的结果进行评价。

2、中间精密度中间精密度系指在同一实验室,由于实验室内部条件改变,如时间、分析人员、仪器设备、测定结果的精密度。

验证设计方案中的变动因素一般为日期、分析人员、设备。

3、重现性指不同实验室之间不同分析人员测定结果的精密度。

当分析方法将被法定标准采用时,应进行重现性试验。

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