USP-1092-溶出度试验的开发和验证(中英文对照版)
溶出度试验的开发和验证
溶出度试验的开发和验证INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation <1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures、It addresses the use of automation throughout the testand provides guidance and criteria for validation、 It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms、溶出实验:开发与验证(1092)指导原则提供了在溶出度方法开发与验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过程,并对方法提供了指导与验证标准。
同时它还涉及对普通制剂与缓释制剂所生成的数据与接受标准进行说明。
Scope范围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms、Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration、General recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in USP general chapters need to be justified、<1092>章节讨论了溶出度实验的开发与验证,重点就是口服固体制剂。
E溶出方法验证
……继续
• 薄膜或类似薄膜的形成，例如透明囊，即 在胶囊周围的橡胶的、膨胀物 • 存在大量悬浮的微粒或大块的剂量单位 • 观察崩解速率（例如，在一定的时间范围 内剂量单位的减少百分比）
• 改进的或包有肠溶衣的产品，包衣的混合 崩解，例如，伴随着气泡和辅料的释放， 部分裸露和裂开（像蛤壳）或壳完全裸露
线性和范围
• • • • • 应该考虑下面最小的指定范围 —药物的含量一般是测定浓度的80 到120% —含量均匀度是70到130% —溶出度试验超过指定范围的+/-20% 例如，控释制剂的规格覆盖的区域是从1h后 20%到24h后90%，验证范围就是标示量的0110% • 典型地， r2>0.98证明线性和截距y应该接近零
吐温
SLS
在低波长下干扰
在低波长下有严重干扰
在高浓度下干扰色谱柱
干扰色谱柱并有时与流动 相不相符
分析方法的验证
• 刻意地验证分析方法—假如这样只有溶出样品 的含量 • 选择性和专一性对溶出方法不重要 • 安慰剂的影响是被允许的（达到2%USP） • 不要求确定杂质和降解产品 • 不需要考虑杂质 —任何>1%的杂质低于溶出试验本身的精密度 —然而，必须证明活性成分本身的稳定性
沉降装置移动 看—不用手
怎样验证自动化？
• 手动溶出被认为是“绝对的”方法，使用 自动化的结果由与手动结果比较来判断 —问题：手动和自动采样获得的结果之间 的耐受力的允许范围是多少？ —回答：与手动和自动采样相关的验证没 有官方的耐受力。这应该以各自案例为基 础来进行评估。
比较过程
同时进行 • 当结果不是高的变量时， 可能的方法是在相同的采 样间隔内并使用各自六个 溶出单位，手动和自动采 样方法同时进行。比较获 得的结果和中间精密度标 准之间的差异 同时采样 • 如果结果是高变量（也就 是，在较早时间点的相对 标准偏差超过20%，在后 面时间点大约10%），在 每个时间点，使用手动和 自动方法同时从溶出杯中 进行采样。 • 注意，同时采样不能获得 探针的流体动力学影响 • 注意体积校正
USP-1092-溶出度试验的开发和验证(中英文对照版)
（1092）溶出度试验的开发和验证【中英文对照版】INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation<1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures. It addresses the use of automation throughout the testand provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。
同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。
Scope范围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration. General recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in USP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。
一致性评价重磅参考资料：(USP1092)溶出度试验的开发和验证(续
圣诞礼物 一致性评价重磅参考资料：（USP1092）溶出度试验的开发和验证（续）20151225刘建华医药信息新药开发3.分析整理溶出步骤也是一个复杂的样品制备过程。
用于测定溶出过程中药物溶出量的处理和分析过程，称为“分析整理”。
虽然本章讨论的分光光度法和高效液相色谱法是最常用的分析方法，其他适宜的分析技术也可以使用。
在第5节，将详细描述方法验证标准。
3.1 样品处理溶出样品在取样后，需要进一步的处理，使能够满足样品释放量的分析方法的测定要求。
例如，过滤可用于除去未溶解的颗粒物样品，或者避光、冷藏贮存样品。
此外，样品可能需要稀释至方法线性范围内的测定浓度。
使用高效液相色谱法时，尽可能采用流动相稀释至样品以减少溶出介质对样品测定的影响。
根据产品特性的要求，其他类型的处理方式也是存在的。
例如加入适当的试剂使产生干扰的物质消除或者失活。
然而，分离可能是不可能的或需要的不是必需的，在一些情况下，在原位测量的方法，如纤维光学或电化学测定方法可能是有用的。
3.2 过滤在上面1.1章节中已经讲述。
3.3 离心离心处理样品是不优选的，具体原因有以下几个方面：在固体颗粒除去之前，药物溶解可以继续发生，是药物的溶出浓度增大，并且离心的动力也可能导致增加溶解的药物颗粒。
然而当所有常见滤膜对药物均有吸附或者所有滤膜均干扰药物的测定时（例如，使用荧光定量），可以选择离心法处理样品。
离心法可以证明是有用的，在方法开发的过滤材料的适用性评价。
3.4 分析方法用于溶出度测定的常用分析方法一般为分光光度法或液相色谱法。
分光光度法较高效液相法更简便快捷，并且分光光度法较HPLC法更容易自动化，并且溶剂量使用较少。
但是分光光度法测定需要专属性良好。
高效液相色谱法是首选的原因有很多，如提供较宽测定范围，减少了需要稀释样品的步骤，提高了低浓度样品的分析灵敏度，并且可用于辅料或者多组分互相干扰的样品的测定。
目前的高效液相色谱系统采用自动进样器，提高了自动化。
USP药典的验证中英文对照
VALIDATION OF COMPENDIAL PROCEDURES 药典方法的验证Test 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 describedin 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.用于评估药品质量的检验方法需要满足不同的要求。
(完整版)USP-1092-溶出度试验的开发和验证(中英文对照版).docx
（ 1092）溶出度试验的开发和验证【中英文对照版】INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation<1092>provides a comprehensive approach covering items to considerfor developing and validating dissolutionprocedures and the accompanyinganalytical procedures. Itaddresses the use of automation throughout the testandprovides guidance and criteria for validation.It also addresses thetreatment of the data generated and the interpretationof acceptance criteriafor immediate-and modified-releasesolid oral dosage forms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。
同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。
Scope范围Chapter<1092>addresses the development andvalidationof dissolution procedures,with a focus on solid oral dosage forms.Many of the concepts presented, however, may beapplicable to other dosageforms and routes of administration. General recommendations are given with theunderstandingthat modifications of the apparatus and procedures as given in USP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。
溶出度试验的开发和验证
INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation <1092> provides a prehensive approach covering items to considerfor developing and validating dissolution procedures and the acpanyinganalytical procedures. It addresses the use of automation throughout the testand provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms.溶出实验:开发和验证〔1092〕指导原那么提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原那么贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。
同时它还涉及对普通制剂和缓释制剂所生成的数据和承受标准进展说明。
Scope围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented,however, may be applicable to other dosageforms and routes of administration. General remendations are given with theunderstanding that modifications of the apparatus and procedures as given in USP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。
USP溶出度试验开发和验证(中英文对照版)
（1092）溶出度实验的开发和验证【中英文对照版】INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation <1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures. It addresses the use of automation throughout the testand provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。
同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。
Scope范围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration. General recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in USP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。
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（1092）溶出度试验的开发和验证【中英文对照版】INTRODUCTION前言Purpose目的The Dissolution Procedure: Developmentand Validation <1092> provides a comprehensive approach covering items to considerfor developing and validating dissolution procedures and the accompanyinganalytical procedures. It addresses the use of automation throughout the testand provides guidance and criteria for validation. It also addresses thetreatment of the data generated and the interpretation of acceptance criteriafor immediate- and modified-release solid oral dosage forms.溶出实验:开发和验证（1092）指导原则提供了在溶出度方法开发和验证过程中以及采用相应分析方法时需要考虑的因素。
本指导原则贯穿溶出度实验的全部过程，并对方法提供了指导和验证标准。
同时它还涉及对普通制剂和缓释制剂所生成的数据和接受标准进行说明。
Scope范围Chapter <1092> addresses the development andvalidation of dissolution procedures, with a focus on solid oral dosage forms.Many of the concepts presented, however, may be applicable to other dosageforms and routes of administration. General recommendations are given with theunderstanding that modifications of the apparatus and procedures as given in USP general chapters need to be justified.<1092>章节讨论了溶出度实验的开发和验证，重点是口服固体制剂。
所提出的许多概念也可能适用于其他剂型和给药途径。
关于设备和方法的修改部分在USP通则中给出了合理的说明。
The organization of <1092> follows the sequence of actions often performed inthe development and validation of a dissolution test. The sections appear inthe following sequence.在进行溶解度实验的开发和验证时，常遵循指导原则<1092>，具体内容如下：1. PRELIMINARY ASSESSMENT (FOR EARLY STAGES OF PRODUCTDEVELOPMENT/DISSOLUTION METHOD DEVELOPMENT)1.前期评估（对产品开发以及溶出度方法开发的前期研究评估）1.1 Performing Filter Compatibility1.1滤膜相容性研究1.2 Determining Solubility and Stability of DrugSubstance in Various Media1.2原料药在不同溶出介质中溶解度测定和稳定性研究1.3 Choosing a Medium and Volume1.3溶出介质和体积选择1.4 Choosing an Apparatus1.4溶出设备选择（桨法和篮法以及其他方法）2. METHOD DEVELOPMENT2.方法开发2.1 Deaeration2.1脱气2.2 Sinkers2.3 Agitation2.3转速2.4 Study Design2.4研究设计2.4.1 TimePoints2.4.1取样时间点2.4.2 Observations2.4.2观察2.4.3 Sampling2.4.3取样2.4.4 Cleaning2.4.4清洗2.5 Data Handling2.5数据处理2.6 Dissolution Procedure Assessment2.6溶出方法评估3. ANALYTICAL FINISH3.完成分析3.1 Sample Processing3.1 样品处理3.2 Filters3.3 Centrifugation3.3 离心3.4 Analytical Procedure3.4 分析方法3.5 Spectrophotometric Analysis3.5 光谱分析3.6 HPLC3.6HPLC法4. AUTOMATION4.自动化4.1 Medium Preparation4.1介质的配制4.2 Sample Introduction and Timing4.2定时进样4.3 Sampling and Filtration4.3取样和过滤4.4 Cleaning4.4 清洗4.5 Operating Software and Computation of Results4.5操作软件和计算的结果5. VALIDATION5.1 Specificity/Placebo Interference5.1专属性/安慰剂（辅料）干扰5.2 Linearity and Range5.2线性和范围5.3 Accuracy/Recovery5.3准确度/回收率5.4 Precision5.4精密度5.4.1 REPEATABILITY OF ANALYSIS5.4.1重复性5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS 5.4.2中间精密度/耐用性5.4.3 REPRODUCIBILITY5.4.3重现性5.5 Robustness5.5耐用性5.6 Stability of Standard and Sample Solutions5.6样品溶液和标准溶液的稳定性5.7 Considerations for Automation5.7自动操作注意事项6. ACCEPTANCE CRITERIA6.可接受标准6.1 Immediate-Release Dosage Forms6.1速释剂型6.2 Delayed-Release Dosage Forms6.2延迟释放剂型6.3 Extended-Release Dosage Forms6.3延长释放剂型6.4 Multiple Dissolution Tests6.4多个溶解度试验6.5 Interpretation of Dissolution Results6.5溶出结果说明6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS6.5.1即时释放剂型6.5.2 DELAYED-RELEASE DOSAGE FORMS6.5.2延迟释放剂型6.5.3 EXTENDED-RELEASE DOSAGE FORMS6.5.3延长释放剂型1. PRELIMINARYASSESSMENT (FOR EARLY STAGES OF PRODUCT DEVELOPMENT/DISSOLUTION METHODDEVELOPMENT)1. 前期评估（产品开发/溶出度方法开发的初期阶段）Beforemethod development can begin, it is important to characterize the molecule sothat the filter, medium, volume of medium, and apparatus can be chosen properlyin order to evaluate the performance of the dosage form.在开始溶出方法开发之前，我们对用以评价制剂溶出行为的滤膜、溶出介质、溶出介质体积和溶出设备进行适当的筛选是非常重要的。
1.1 Performing Filter Compatibility1.1滤膜相容性研究Filtrationis a key sample-preparation step in achieving accurate test results. Thepurpose of filtration is to remove undissolved drug and excipients from thewithdrawn solution. If not removed from the sample solution, particles of thedrug will continue to dissolve and can bias the results. Therefore, filteringthe dissolution samples is usually necessary and should be done immediately ifthe filter is not positioned on the cannula.为获得准确试验结果，过滤是样品制备的一个关键步骤。
过滤的目的是为了除去溶出液中未溶解的药物和辅料。
如果不把未溶解的药物和辅料从样品溶液中除去，那么未溶解的药物颗粒将会继续溶解使试验结果出现偏差，因此，如果取样管中没有过滤器，应立即对溶出度样品进行过滤。
Filtration also removes insolubleexcipients that may otherwise interfere with the analytical finish. Selectionof the proper filter material is important and should be accomplished, andexperimentally justified, early in the development of the dissolutionprocedure. Important characteristics to consider when choosing a filtermaterial are type, filter size, and pore size. The filter that is selectedbased on evaluation during the early stages of dissolution procedure developmentmay need to be reconsidered at a later time point. Requalification has to beconsidered after achange in composition of the drug product or changes in thequality of the ingredients (e.g. particle size of microcrystalline cellulose).过滤也可除去可能会干扰分析测定的不溶性辅料。