USP1092溶出度试验的开发和验证中英文对照版文档格式.docx

1、 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

2、apparatus and procedures as given in USPgeneral chapters need to be justified.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 follows the sequence of actions often performed inthe development and validation of a dissolution test. The sections appear

3、 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，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 M

4、edia1.2 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 Sinkers2.2 沉降篮2.3 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

5、.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 Filters3.2 过滤3.3 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

6、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.验证5.1 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/

7、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/RUGGEDNESS5.4.2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 CR

8、ITERIA6.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 DOSA

9、GE 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

10、 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。Filtrationis a key sample-preparation step in achieving accurate test results. Thepurpose of filtration is to remove undissolved drug and

11、 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

12、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 accomplishe

13、d, 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 development

14、may need to be reconsidered at a later time point. Requalification has to beconsidered after a change 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。选择适当的过滤材料是非常重要，应该在早期溶出方法开发的过程中通过实验确定和完成。在选择滤膜时

15、有必要重点考虑滤膜的材料、型号和孔径大小。通常对早期阶段溶出方法开发过程的评价选择过滤器，但在后期试验中如果制剂成分改变或组成成分质量变化可能需要重新考虑过滤器，（例如：微晶纤维素粒径的改变）。Examples of filters used in dissolutiontesting can be cannula filters, filter disks or frits, filter tips, or syringefilters. The filter material has to be compatible with the media and the drug.Common p

16、ore sizes range from 0.20 to 70 mm, however, filters of other poresizes can be used as needed. If the drug substance particle size is very small（e.g., micronized or nanoparticles）, it can be challenging to find a filterpore size that excludes these small particles.用于溶出试验的过滤器有管路过滤器、过滤盘或玻璃过滤器、滤头或针头式过滤

17、器。过滤材料必须与介质和药物相适合。常见孔径大小范围：0.2070m，如果需要也可使用其他孔径大小的过滤器。如果原料药的粒度很小（例如，微分化颗粒或纳米颗粒），找到一个合适的过滤器过滤这些小颗粒至今仍具有挑战性。Adsorption of the drug（s） by the filtermay occur and needs to be evaluated. Filter materials will interact withdissolution media to affect the recovery of the individual solutes and must beconsi

18、dered on a case-by-case basis. Different filter materials exhibitdifferent drug-binding properties. Percentage of drug loss from the filtratedue to binding may be dependent on the drug concentration. Therefore theadsorptive interference should be evaluated on sample solutions at differentconcentrati

19、ons bracketing the expected concentration range. Where the drugadsorption is saturable, discarding an initial volume of filtrate may allow thecollection of a subsequent solution that approaches the original solutionconcentration. Alternative filter materials that minimize adsorptiveinterference can

20、usually be found. Prewetting of the filter with the medium maybe necessary. In addition, it is important that leachables from the filter donot interfere with the analytical procedure. This can be evaluated by analyzingthe filtered dissolution medium and comparing it with the unfiltered medium.过滤时可能会

21、发生药物的吸附，需要进行评估。过滤材料将与溶出介质相互作用，影响每个溶质的回收率应该根据具体问题进行考虑。不同的过滤材料表现出与药物结合的不同特性。由于药物与滤膜结合引起药物从滤液中损失的比例，可能依赖于药物浓度。因此，应采用预期浓度范围内不同浓度的样品溶液来评估滤膜吸附干扰。由于药物吸附是可饱和的，弃去一定体积的初滤液，收集续滤液，以达到接近原来的溶液浓度的样品也是可取的。通常选择适合的过滤材料，最大限度地减少滤膜吸附干扰，润湿滤膜对减少吸附也是必要的。此外，过滤后的溶出物不干扰分析检测也是非常重要的，这可以通过过滤后的溶出介质过滤与未过滤的溶出介质进行比较，评估滤膜是否干扰分析测定。The

22、 filter size should be based on thevolume to be withdrawn and the amount of particles to be separated. Use of thecorrect filter dimensions will improve throughput and recovery, and also reduceclogging. Use of a large filter for small-volume filtration can lead to loss ofsample through hold-up volume

23、, whereas filtration through small filter sizesneeds higher pressures and longer times, and the filters can clog quickly.根据要过滤样品溶液的体积以及样品溶液中颗粒的量选择滤膜孔径。使用正确的滤膜孔径将提高溶液的通过率和回收率，并减少滤膜堵塞。使用大孔径滤膜过滤小体积溶液，能够导致样品溶液损失量过大而收集不到所用样品量；使用小孔径滤膜过滤，需要更高的压力和较长的时间，并且溶液迅速堵塞滤膜。Filters used for USP Apparatus 4 needspecial

24、 attention because they are integrated in the flow-through process.Undissolved particles may deposit on the filters, creating resistance to theflow.USP仪器4中使用的过滤器需要特别注意，因为它们在流动过程中使用。不溶颗粒会沉积在过滤器，产生流动阻力。In the case of automated systems,selection of the filter with regard to material and pore size can b

25、e done in asimilar manner to manual filtration. Flow rate through the filter and cloggingmay be critical for filters used in automated systems. Experimentalverification that a filter isappropriate may be accomplished by comparing the responses for filtered andunfiltered standard and sample solutions

26、. This is done by first preparing asuitable standard solution and a sample solution. For example, prepare atypical dissolution sample in a beaker and stir vigorously with a magneticstirrer to dissolve the drug load completely.For standard solutions, comparethe results for filtered solutions （after d

27、iscarding the appropriate volume） tothose for the unfiltered solutions. For sample solutions, compare the resultsfor filtered solutions （after discarding the appropriate volume） to those forcentrifuged, unfiltered solutions.在自动化系统的情况下，关于过滤器滤膜材料和孔径大小可以用类似的方式通过手动过滤进行选择。在自动化系统中通过过滤器的流量和过滤器的堵塞可能是至关重要的。通

28、过试验比较过滤和未过滤的标准溶液和样品溶液的含量差别，验证该过滤器是合适的。首先制备一个合适的标准溶液和样品溶液。例如，在烧杯中制备一个标准溶解样品，用磁力搅拌器搅拌使药物完全溶解。对于标准溶液，比较过滤溶液（弃去的适当体积后）和未过滤溶液的含量测定结果；对于样品溶液，比较过滤（弃去适当体积后）、离心、未过滤样品溶液的含量测定结果。1.2 原料药在不同溶出介质中的溶解度测定和稳定性研究Physical and chemical characteristics of the drug substance need to be determinedas part of the process of

29、 selecting the proper dissolution medium. Whendeciding the composition of the medium for dissolution testing, it is importantto evaluate the influence of buffers, pH, and if needed, different surfactantson the solubility and stability of the drug substance. Solubility of the drugsubstance is usually evaluated by determining the saturation concentration ofthe drug in different media at 37 using the shake-flask solubility method（equilibrium solubility）. To level out potential ion effects bet