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（1092）溶出度试验的开发和验证【中英文对照版】【第三部分+第四部分】（1） 6 Y1 D# B$ q8 C
原创 2016-01-22 红袖添香 医药信息新药开发 目录 3. ANALYTICAL FINISH 3.完成分析 3.1 Sample Processing 3.1 样品处理 3.2 Filters 3.2 过滤 3.3 Centrifugation 3.3 离心 3.4 Analytical Procedure 3.4 分析方法 3.5 Spectrophotometric Analysis 3.5 光谱分析 3.6 HPLC 3.6HPLC法 4. AUTOMATION 4.自动化 4.1 Medium Preparation 4.1介质的配制 4.2 Sample Introduction and Timing 4.2定时进样 4.3 Sampling and Filtration 4.3取样和过滤 4.4 Cleaning 4.4 清洗 4.5 Operating Software and Computation of Results 4.5操作软件和计算的结果 3. ANALYTICAL FINISH 3. 完成分析 Thedissolution step has been described as an involved sample preparation. Thesample handling and analytical procedure that are used to determine the amountof drug substance dissolved during the dissolution procedure are termed the“analytical finish.” Although spectrophotometric determinations and HPLC areused most commonly and are discussed in this chapter, any suitable analyticaltechnology may be used. Section 5. Validation describes criteria for themethods. 溶出试验已被描述为复杂的样品制备过程。在溶出试验过程中，样品处理和分析程序用于确定药物的溶出量，这在溶出试验中被称为“完成分析”。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节验证中详细描述方法验证标准。 3.1 Sample Processing 3.1 样品处理 After thesamples are withdrawn from the dissolution medium, they may require additionalprocessing to make them suitable for the analytical methodology used todetermine the amount released. For example, filtration may be used to removeundissolved particulate matter, or samples may need to be protected fromexposure to light or may need refrigerated storage.In addition, samples mayhave to be diluted to a level that is within the linear range of the method.With analysis by HPLC, dilution of the sample with mobile phase may benecessary to reduce the effect on the separation of injecting dissolutionmedium. Other types of treatment may be necessary depending on the productformulation, such as the inactivation or elimination of interference caused bycomponents of the formulation by the addition of appropriate reagents. However,separation may not be possible or needed in all cases. In some cases, in situmeasurements obtained with methods such as fiber optics or electrochemicaldetermination may be useful. 溶出样品在取样后，需要进一步的处理，使药物释放量能够满足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，或者样品需要避光，或者需要冷藏贮存样品。此外，样品可能需要稀释至该方法线性浓度范围内进行测定。使用高效液相色谱法时，尽可能采用流动相稀释样品以减少溶出介质对样品测定的影响。根据制剂处方，其他类型的处理方式也是需要的，例如加入适当的试剂消除或者减少处方组分引起的干扰。但是，在上述所有情况下，也存在分离是没必要进行或者不可能做到的。在一些情况下，原位测量方法，比如纤维光学或电化学测定可能是有用的。 3.2 Filters 3.2 过滤 The topic of filtration is discussed in section 1.1 Performing FilterCompatibility. 在上面1.1章节中已经进行描述。 3.3 Centrifugation 3.3 离心 Centrifugation of samples isnot preferred, for several reasons: dissolution can continue to occur until thesolids are removed, a concentration gradient may form in the supernatant, andenergy imparted may lead to increased dissolution of the drug substanceparticles. Possible exceptions, when centrifugation could be preferred, mightinclude the use with compounds that adsorb onto all common filters, orsituations when the potential filter leachables and extractables might interferein the quanti tative step of the dissolution test (e.g., when fluorescenceprocedures are used in quantitation). Centrifugation may prove useful duringmethod development for evaluating the suitability of the filter material. 不优先选择离心来处理样品，具体原因有以下几个方面：离心可以使药物继续溶解，直到固体颗粒被去除，在上清液中可形成浓度梯度。离心产生的热量可增加药物颗粒的溶解。但可能会出现例外情况，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），优选离心进行样品处理。在方法开发过程中评价过滤材料的适用性时，可以选用离心方法进行对比研究。 3.4 Analytical Procedure 3.4 分析方法 The usualassay for a dissolution sample employs either a spectrophotometric procedure ora liquid chromatographic procedure.Spectrophotometric determination may bedirect or may provide the detection for HPLC. Spectrophotometric determinationis used often because results can be obtained faster, the analysis is simpler,it is easier to automate, and fewer solvents are needed. The use of directspectrophotometric determination typically requires confirmation ofspecificity. HPLC is preferred for a number of reasons such as providing a widedynamic range that reduces the need to dilute some samples while also providingsensitivity in the analysis of dilute samples, and greater selectivity whenexcipients or multiple drugs in the formulation present a significantinterference. Modern HPLC systems employ autosamplers that provide speed andsimplicity advantages comparable to spectrophotometric analysis. 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，更容易实现自动化，并且溶剂量使用较少。直接使用分光光度法测定通常需要确定专属性。首选高效液相色谱法的原因有很多，如提供较宽动态测定范围，减少了需要样品稀释的必要性，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，提高了自动化程度。 3.5 Spectrophotometric Analysis 3.5 光谱分析 Directspectrophotometric analysis may be performed on samples that are manuallyintroduced to the cuvette. Alternatively, samples may be automaticallyintroduced into the spectrophotometer using autosippers and flow cells. Routineperformance checks, cleaning, and maintenance, as described in the standardoperating procedures or metrology documents, help to ensure reliable operationof these instruments. Cells with path lengths ranging from 0.02 cm to 1 cm aretypically used, and longer path-length cuvettes can be used to increase therange for quantification of dilute samples. Cell alignment and air bubblescould be sources of error. The shorter path-length cells are used to avoiddiluting the sample; in all cases, however, acceptable linearity and standarderror need to be demonstrated. 直接分光光度法分析采用手动操作。或者也可以采用自动吸样系统或者流通进样池进行自动化取样。按照标准操作规程或者计量文件的要求对仪器进行常规检查、清洁和维护，有助于确保仪器的可靠运行。分光光度计的比色皿的长度一般为0.02cm～1cm，如果测定浓度较小的样品也可以使用长度较大的比色皿来增加稀释样品的定量范围，样品池的校准和气泡可能是误差的主要来源。较短的比色皿可以使样品不用稀释直接进行测定，然而不管使用什么比色皿，可接受的线性标准以及标准误差有必要进行验证。 The choice of wavelength forthe determination should be based on the spectrum of the drug in solution. Insome cases,where the drug substance can degrade in the dissolution medium(e.g., dosage forms containing aspirin), it is useful to carry out themeasurements at the isosbestic point. Excipients can also have effects, butperforming analysis at multiple wavelengths can minimize their effects. Thecontribution of the absorbance from an excipient at the analytical wavelengthcan sometimes be determined by ratio from its absorbance at a wavelength wherethe absorbance of the drug substance is minimal. 根据药物在溶液中的吸收光谱选择波长必须。在某些情况下，药物在溶出介质中降解（例如，含有阿司匹林的制剂），适合在在等吸收点完成测定。在辅料有干扰的情况下，可以选用多波长进行分析，可以减少干扰。在分析波长处辅料有吸收，有时可通过一定波长下（此波长下药物的吸收最小）辅料的吸光度比确定辅料对吸光度的贡献。 Using a validated analyticalfinish, standard solutions are typically prepared in dissolution media andanalyzed at just one concentration, either at 100% of the dosage strength orthe selected Q value because linearity of the analytical finish has beenestablished. Prior to validation, dissolution profile analysis, or analysis ofproducts of various strengths, requires using multiple standard solutionscovering the expected range of concentration. A typical media blank, standard,and sample may be analyzed in a sequence that brackets the sample withstandards and blanks, especially at the beginning and end of the analysis.Thestandard and sample solutions should both be prepared in the dissolution mediumin the linear concentration range and measured at the same wavelength. However,small amounts of an organic solvent may be used in the preparation of thestandard, provided that the accuracy criteria can be met during validation. 使用经过验证的分析方法，标准溶液通常用溶出介质制备，仅在一个浓度点进行测定，选取溶出量为100%或者溶出度限度值（Q）均可，因为线性范围已经经过验证。但是在方法验证之前，溶出曲线分析或者是分析不同剂量的制剂均需要使用多个覆盖规定限度浓度范围的标准溶液进行测定，典型的空白介质溶液、标准溶液和样品溶液均应在溶出的线性浓度范围内采用相同波长进行测量。但是，少量的有机溶剂也可用于制备的标准溶液，只要在验证过程中满足准确度标准。 The absorptivity is calculated by dividing the mean standard absorbance bythe concentration, in mg/mL, divided by the cell path length in cm. Arearrangement of the Beer-Lambert expression gives the absorptivity, a,as: 吸收率的计算标准吸光度的平均值除以浓度（单位为mg/ml），除以比色皿的长度（cm）,吸收率α的计算公式如下（朗伯比尔定律）： α=A/bc A=吸光度 b=比色皿长度（cm） c=浓度（mg/ml） Typical units for absorptivitythat are used for dissolution testing are in terms of AU · mL/mg, where AU isabsorbance unit.Historical data may be used to provide an acceptableabsorptivity range for the analyte (using the appropriate path-length cell).This value may be useful in troubleshooting aberrant data.Fiber optics as asampling and determinative method, with proper validation, are an option. 用于溶出试验吸光度的单位通常为AU• mL/mg，其中AU是吸收度单位，历史的资料可用来提供分析物的可接受吸光度范围（使用适当光程的样品池）。这个值在故障排除异常数据时非常有用。光导纤维作为取样和测定的方法，经过适当的验证，也可以是一种选择。 3.6 HPLC 3.6 HPLC法 For HPLCanalysis, the effect on the chromatogram of peaks resulting from injection ofdissolution media require enumeration. A large solvent disturbance may affectaccuracy and precision of response if it is poorly resolved from the peak ofinterest. This is even more important if large injector volumes (>100 mL)are needed. System suitability tests may evaluate peak shape; separation of themain peak from solvent disturbance and from closely eluting peaks; andinjection precision. At a minimum,the precision is critical. 对于HPLC分析，需要列出溶出介质对色谱图的影响。如果目标峰响应值解决不好，溶剂的较大干扰可能影响响应值的准确度和精确度。如果进样量较大（>100毫升）这种影响更为重要。系统适用性试验可评估峰形、溶剂干扰、主峰相邻峰的分离和进样精密度。至少，精密度是关键。 Ideally, the standardsolutions should be diluted with the dissolution media at a concentrationwithin the linear range of the method, e.g., 100%, or the selected Q value ofthe dosage strength. However, organic solvent may be used in the preparation ofthe standard, provided that the accuracy criteria can be met during validation.In some cases, the sample may be diluted with mobile phase to improve the peakshape. The standard and sample solutions should both be prepared in the linearconcentration range and measured at the same wavelength. 理想情况下，标准溶液应在线性浓度范围内用溶出介质进行稀释，例如，100％，或者选择制剂剂量Q值。但是，在制备标准溶液时可以使用有机溶剂，在验证过程中要满足准确度标准。在一些情况下，为了改善峰形，样品溶液可以用流动相稀释。应在线性浓度范围内制备标准溶液和样品溶液，并在同一波长处测定。（待续） （1092）溶出度试验的开发和验证【中英文对照版】【第五部分+第六部分】（1） / q; W& r# Z1 f: `
原创 2016-01-29 红袖添香 医药信息新药开发 目录 5. VALIDATION 5.验证 5.1 Specificity/Placebo Interference 5.1专属性/安慰剂（辅料）干扰 5.2 Linearity and Range 5.2线性和范围 5.3 Accuracy/Recovery 5.3准确度/回收率 5.4 Precision 5.4精密度 5.4.1 REPEATABILITY OF ANALYSIS 5.4.1重复性 5.4.2 INTERMEDIATE PRECISION/RUGGEDNESS 5.4.2中间精密度/耐用性 5.4.3 REPRODUCIBILITY 5.4.3重现性 5.5 Robustness 5.5耐用性 5.6 Stability of Standard and Sample Solutions 5.6样品溶液和标准溶液的稳定性 5.7 Considerations for Automation 5.7自动操作注意事项 6. ACCEPTANCE CRITERIA 6.可接受标准 6.1 Immediate-Release Dosage Forms 6.1速释剂型 6.2 Delayed-Release Dosage Forms 6.2延迟释放剂型 6.3 Extended-Release Dosage Forms 6.3延长释放剂型 6.4 Multiple Dissolution Tests 6.4多个溶解度试验 6.5 Interpretation of Dissolution Results 6.5溶出结果说明 6.5.1 IMMEDIATE-RELEASE DOSAGE FORMS 6.5.1即时释放剂型 6.5.2 DELAYED-RELEASE DOSAGE FORMS 6.5.2延迟释放剂型 6.5.3 EXTENDED-RELEASE DOSAGE FORMS 6.5.3延长释放剂型 5. VALIDATION 5.验证 Thevalidation topics described in this section are typical but not all-inclusiveand can be viewed in the context of Validation of Compendial Procedures <1225>,as well as the International Conference on Harmonization (ICH) document, Validationof Analytical Procedures (18). Validation for both parts of the dissolutionprocedure, the analytical finish and the dissolution step, will bediscussed in this section. The dissolution step is the release of the drug inthe dissolution medium and sampling. The analytical finish is defined insection 3. Analytical Finish. Validation of the analytical finish willevaluate the attributes, linearity and range, precision, specificity,accuracy/recovery, robustness, and stability of the sample and standardsolutions. Validation of the dissolution step will include evaluation ofprecision and robustness of the dissolution sample preparation. Validation ofthe analytical finish is performed either using a standard solution orspiked placebo or by the method of standard addition (spiked drugproduct as described in Accuracy in <1225>), as specified in thesections below. Validation of the dissolution step requires the use of awell-characterized dosage form (e.g., having tight content uniformity anduniform performance). Depending on the parameter of interest, validationof the sample handling and analytical procedure can be performed in situ, e.g.,within the dissolution vessel. The validation parameters addressed andthe extent of the validation may vary, depending on the phase of developmentor the intended use for the data. 本章节所涉及的验证是一些典型的验证，但不包括所有的验证，这些验证在药典分析方法验证<1225>的上下文中和ICH指导原则分析方法验证。本章节讨论的溶出实验的验证包括溶出和分析两部分验证。溶出步骤是指药物在溶出介质中的释放和取样，分析方法的定义详见第3章节分析方法。分析方法的验证包括专属性、线性和范围、精密度、准确定/回收率、耐用性、对照品溶液和供试品溶液的稳定性。而溶出步骤的验证主要是对溶出样品制备的精密度和耐用性评估。分析方法验证一般使用标准溶液或者空白辅料溶液或通过下面章节中指定的标准加入法（按照<1225>准确度试验中描述的加入标准的药品）。溶出步骤的验证需要使用具有良好特性的产品（例如：具有良好的含量均匀度和溶出均一性）。根据关注的参数，在原来位置，比如在溶出仪里进行分析方法和样品处理的验证。验证参数处理和验证程度会有所不同，这取决于开发阶段或数据的使用目的。 The acceptance criteria are presented as guidelinesonly, and may differ for some products. Manufacturers should document theappropriate acceptance criteria for their products in pertinent StandardOperating Procedures (SOPs) or in validation protocols.Other considerations maybe important for special dosage forms. Validation studies should be performedacross the range of profile time points. For products containing more than asingle active ingredient, the dissolution procedure needs to be validatedfor each active ingredient. It is expected that investigations into filtersuitability and the potential for glass adsorption will have been undertakenalready (see 1.1 Performing Filter Compatibility). Validation of theseassessments may occur during spiked recovery experiments. 本章节的验证标准仅作为指导，对有些产品可能有所不同。生产厂家应该在相关的标准操作规程（SOP）中或在验证方案中对制剂产品提供合适的可接受标准。对特殊剂型的其他考虑也是重要的。所进行的验证研究应横跨溶出曲线时间点范围。对于复方或者多组分制剂，每一种活性成分的溶出方法均需要进行验证。过滤器的相容性以及玻璃器的潜在吸收已经进行研究（见1.1滤膜的选择和相容性），在加标回收率试验中将对这些评估进行验证。 5.1 Specificity/PlaceboInterference 5.1专属性/安慰剂（辅料）干扰 It isnecessary to demonstrate that the results are not unduly affected by placeboconstituents, other active drugs, or degradants. The placebo consists of allthe excipients and coatings, with inks and capsule shells included ifappropriate, without the active ingredient. Placebo interference can beevaluated by using a spiked placebo that is prepared by weighing samples of theplacebo blend, dissolving or dispersing them in dissolution medium atconcentrations that would be encountered during testing, and adding a knownamount of the drug in solution. It may be preferable to perform this experimentat 37°, comparing the solution to a standard solution at the concentrationexpected to be encountered during testing, by using the formula: Result = (AP/AS) × CS × (V/L) × 100 AP =absorbance of the placebo AS =absorbance of the standard CS =concentration of the standard (mg/mL) V =volume of the medium (mL) L =label claim (mg) 证明安慰剂（空白辅料）成分、其他活性药物或降解产物并非影响试验结果是很有必要的。安慰剂是指除了活性成分以外的所有辅料和包衣材料，在适当的时候还包括油墨和胶囊壳。安慰剂的干扰可以使用加入标准的安慰剂进行评价，通过称取安慰剂的混合样品，将该混合样品溶解或分散在溶出介质中，制备的浓度为测试过程中使用的浓度，然后向溶液中加入一定量药物，优选在37℃试验条件进行这个试验，使用如下公式比较样品溶液和标准溶液在测试过程中预计浓度点的吸光度： 结果= (AP/AS)×Cs×(V/L) ×100 AP为安慰剂的吸光度 AS为标准溶液的吸光度 Cs为标准溶液的浓度（mg/ml） V为溶出介质的体积（ml） L为标示量（mg） Theinterference should not exceed 2%. Note that for extended-release products, aplacebo version of the finished dosage form may be more appropriate than blendsbecause this placebo formulation will release the various excipients in amanner more nearly reflecting the product than will a simple blend of theexcipients. In this case, it may be appropriate to evaluate potentialinterference at multiple sampling points in the release profile, withworst-case interference expected at the later sampling points. 干扰不能超过2%。值得注意的是：缓释制剂，空白剂型可能比混合物更合适，因为空白剂型比各种辅料简单的混合物更能反映出不同辅料制剂的释放方式。在这种情况下，在多个取样点的释放曲线更适合评估潜在干扰，尤其是后面的取样点预计出现的最坏干扰。 The blank is the dissolution medium withoutdissolved sample, and it is treated in the same manner as the sample. Theeffect of the absorbance of the blank at the analytical wavelength should beevaluated. In most cases, the absorbance of the dissolution medium blank maynot exceed 1% of the standard solution at the concentration used for analysis.Values >1% should be evaluated on a case-by-case basis. 空白是指不含溶解样品的溶出介质，按照供试品溶液的处理方法处理空白介质，在分析检测波长评估空白介质对吸光度的影响。在大多数情况下，空白溶出介质的吸光度不得超过用于分析的标准溶液浓度吸光度的1%。如果超过1%，应根据情况进行评估。 If the placebo interference exceeds 2%, modificationof the method may be necessary. Possible modifications include choosing anotherwavelength, subtracting baseline using a longer wavelength, transformingabsorbance values (e.g., first derivative),and using an alternative analyticaltechnique such as HPLC. Other means for minimizing the placebo interferencewould be acceptable with appropriate justification. When other active drugsubstances or significant levels of degradants are present,it is necessary toshow that these do not significantly affect the results. One procedure fordoing this is to measure the matrix in the presence and absence of the otheractive drug substance or degradant: any interference should not exceed 2%.Similar approaches may be used if other techniques are used for the analyticalfinish. 如果安慰剂干扰超过2%，有必要对该方法进行改进，可能的改进方法包括选择另一个检测波长、通过使用较大波长以减少空白吸收、转化吸光度值（例如：一阶导数）或者使用高选择性的方法如HPLC法。如果有合适的理由，其他降低安慰剂干扰的方法也可以使用。当存在其他活性成分或者降解显著时，证明这些不会对结果产生显著影响是有必要的。另外解决的方法是不管其他活性成分或者存在存在的降解产物，对主要成分的干扰均不得超过2%。如果其他的方法用于分析，也可使用类似的方法。 5.2 Linearity and Range 5.2线性和范围 Linearity istypically established by preparing solutions of the drug substance, ranging in concentrationfrom less than the lowest expected concentration to more than the highestconcentration during release. The solutions may be prepared either using eithera standard solution or spiked solution or by the method of standard addition. Aminimum of five concentrations is normally used (see <1225>). Typically,solutions are made from a common stock if possible. The concentration range maynot exceed the linearity limits of the method, including the instrumentation.Organic solvents may be used to enhance drug solubility for the preparation ofthe linearity standard solutions. However, no more than 5% (v/v) of organicsolvent should be present in the final solution unless validated. Linearity istypically calculated by using an appropriate least-squares regression program.Typically, a square of the correlation coefficient (r2 ³0.98) demonstrates linearity. In addition, the y-intercept must not beimportantly different from zero. 线性通常制备一系列原料药溶液，浓度范围为低于药物释放过程中的最低点浓度至高于药物释放过程中最高点的浓度。可以使用标准溶液或加标溶液，或者通过标准加入法制备的溶液。通常至少使用5个浓度点（参见<1225>）。通常情况下，如果可能，溶液有一个共同的线性贮备溶液稀释制得。浓度范围不得超过线性方法范围包括仪器的测量范围。线性贮备溶液制备过程中为了增加药物的溶解度，可能会用到有机溶剂，除非经过验证外，有机溶剂的量均不得超过总体积的5%（v/v）。线性方程一般通过最小二乘法计算，相关系数（r2≥0.98）证明线性较好,此外，y轴截距应接近于0。 The range ofthe procedure is the interval between the upper and lower concentrations of thedrug substance (including these levels) that has been demonstrated to have asuitable level of precision, accuracy, and linearity using the procedure aswritten. 线性范围内包括原料药的最低点和最高点在内的所有浓度，均应证明精密度和准确度水平，并且在报告中记录。 5.3 Accuracy/Recovery 5.3准确度/回收率 Accuracy/recoveryis typically established by preparing multiple samples containing the drugsubstance and any other constituents present in the dosage form (e.g.,excipients, coating materials, capsule shell) ranging in concentration fromless than the lowest expected concentration to more than the highestconcentration during release. Accuracy/recovery may be done in conjunction withlinearity determination. The method of standard addition can also be used.Before this activity, it is expected that filter assessment will already havebeen performed, and adsorption of drug onto the glass has also beeninvestigated and ruled out. 准确度/回收率通常是由含有原料药和制剂中存在的其他成分（如辅料、包衣材料、胶囊壳）制备的多个样品，浓度范围的下限为药物释放时低于最低预计浓度值，上限高于释放的最高浓度值。准确度/回收率由线性决定。也可以使用标准加入法。在进行试验之前，过滤器预计对药物的吸附要进行评估，同时要考虑并设法排除由于仪器的玻璃材质部分对样品的吸附而对测试结果造成的影响。 Individual solutions may be directly prepared inthe dissolution medium. Alternatively, to enhance drug solubility it may beappropriate to prepare a stock solution by dissolving the drug substance in asmall amount of organic solvent (typically not exceeding 5% organic solvent inthe final dissolution media) and diluting to the final concentration withdissolution medium.An amount of stock solution equivalent to the targeted labelclaim may be used instead of the drug substance powder. Similarly,for very lowstrengths, it may be more appropriate to prepare a stock solution than toattempt to weigh very small amounts. 直接用溶出介质制备每一个溶液。或者，如果药物溶解性较差，可以将药物溶解在少量有机溶剂（一般不超过5%）中制备储备液，并用溶出介质稀释到最终浓度。储备液的量与标示量量相当，可用于代替药物粉末。同样地，对于剂量非常小的药物，制备储备液比尝试着称量非常少量的药物进行配制更合适。 The measured recovery is typically 95%–105% of theamount added. Bracketing or matrixing of multiple strengths may be useful. Aspecial case for validation is the Acid Stage procedure described in <711>,Delayed-Release Dosage Forms. The limit of NMT 10% needs to be validated.Recovery experiments for drugs that have low solubility in acidic media may bechallenging or impossible to perform and may need to be addressed on a case-by-casebasis. If the compound degrades in acid, the validation experiment must addressthis fact. 回收率测得值通常为加入量的95%~105%。多规格制剂括号法或矩阵化是常用方法。在<711>缓释剂型中描述了酸性阶段的分析验证的例子。需要对NMT不超过10%这个限度进行验证。在酸性介质中低溶解度药物的回收率试验有挑战性或者不可能进行，需要根据具体情况进行说明，如果药物在酸性条件下降解，验证实验中须对这一事实进行说明。 5.4 Precision 5.4精密度 5.4.1 REPEATABILITY OFANALYSIS 5.4.1重复性 Forthe analytical finish, repeatability is evaluated by obtaining replicatemeasurements of standard and/or spiked placebo/standard addition solutions. Itcan be determined by calculating the RSD of the multiple injections orspectrophotometric readings for each standard solution, or by using theaccuracy or linearity data. ICH guidance, Validation of AnalyticalProcedures: Methodology, recommends that repeatability should beassessed using a minimum of nine determinations covering the specified rangefor the procedure (i.e., three concentrations and three replicates of eachconcentration) or using a minimum of six determinations at 100% of the testconcentration. A typical acceptance criterion is an RSD of <2%. Thedemonstration of the repeatability for the dissolution step is conducted byperforming the dissolution step on separate units of a well-characterized dosageform or equivalent composite. 对于分析方法，通过获得标准和/或加入安慰剂/标准加入溶液的重复测定结果对重复性进行评估，通过多次进样或者每个标准溶液分光光度计读数或者使用精密度或者线性数据来计算RSD值， ICH指导原则，分析方法的验证：方法，推荐重复性测定用覆盖特定分析范围的九个确定浓度点（三个浓度点，每个浓度点重复制备三份样品）或在100%测试浓度点至少制备6份样品溶液进行测试，通常可接受的标准：RSD<2%。通过采用质量好的制剂或与制剂相等组成（原料+辅料）进行溶出步骤的独立单元的重复性证明。 5.4.2 INTERMEDIATEPRECISION/RUGGEDNESS 5.4.2中间精密度/耐用性 Assuming thatthe major contributor to the variance is from the dissolution step,intermediate precision may be evaluated to determine the effects of randomevents on the precision of the dissolution procedure. This evaluation istypically done later in the development of the drug product and is required forfull method validation. For many analytical procedures intermediate precisionis typically assessed by determination of contributions to variance and,possibly, by a comparison of means. The use of an experimental matrix design isencouraged for evaluation of intermediate precision because interaction effectsmay be observed more clearly relative to a single variable experiment. Indissolution testing, a ruggedness approach that compares means alone is oftentaken to investigate the factors that contribute to intermediate precision. Theruggedness can be evaluated across the range of product strengths. Typicalvariations to be studied include different days, analysts, and equipment. If possible,ruggedness can be evaluated using a drug product lot if well characterized, forexample, by having tight content uniformity and uniform performance, but ifthis type of lot is not available, a premeasured placebo with activeingredients may be used to investigate the intermediate precision. The use ofsuch a spiked placebo would additionally support the assessment of thecontribution of the analytical finish to the observed variability of results. 假设溶出步骤是产生偏差的主要因素，可以用中间精密度评估，以确定随机事件对溶出精密度的影响。这种评估通常在制剂开发后完成，需要对方法学进行充分验证。对于很多分析方法，中间精密度通常通过确定偏差来源进行评估，通过比较分析的方式。鼓励使用实验室矩阵设计对中间精密度进行评估，因为与单因素试验相关的相互作用会更清楚地观察到。在溶出度测定时，耐用性试验方法可以采取单独比较的方法来研究中间精密度的影响因素。这些影响因素可能是由中间精密度引起的。耐用性试验可以评估制剂的浓度范围。研究过程中的典型的变化，包括不同天、不同操作人员和设备。如果可能，耐用性试验可以用较好质量特征的制剂批次进行评估，例如：较好的含量均匀度。但如果这种批次的不可获得测，可用活性成分加安慰剂进行中间精密度研究。使用加入标准的安慰剂（空白辅料）将支持观察到的变化结果对分析方法误差的影响。 Thedissolution procedure on the same lot of well-characterized dosage form may berun by at least two different analysts from the same laboratory, with eachanalyst preparing the standard solutions and the medium and following thedefined extraction/quantification procedure. Typically, the analysts usedifferent dissolution baths, spectrophotometers or HPLC equipment (includingcolumns), and autosamplers, and they perform the test on different days. Fullprofiles are assessed where relevant to the product. This procedure may not benecessary at each strength; instead, bracketing with high and low strengths maybe acceptable. 同一批次质量特征较好的制剂的溶出试验可以由同一实验室至少两个不同的分析人员进行，每个分析人员制备标准溶液和溶出介质和依据明确的提取和定量步骤进行。通常情况下，分析人员用不同的溶出液、分光光度计或HPLC（包括色谱柱）和自动进样器，在不同天进行试验。与制剂相关的曲线进行全面的评估，这个分析操作对每个浓度可能不是必须的，而是使用高浓度和低浓度进行分析是可以接受的。 Acceptancecriteria for intermediate precision or for ruggedness are predetermined. Atypical acceptance criterion for ruggedness is that the difference in the meanvalue for dissolution results between any two conditions, using the samestrength,does not exceed an absolute 10% at time points with <85% dissolvedand does not exceed 5% for time points >85%. Acceptance criteria may beproduct specific, and other statistical tests and limits may be used. 中间精密度的可接受标准或耐用性是预先确定的。通常耐用性的可接受标准是使用相同浓度，在任何两个条件之间溶出结果平均值的差，在溶出度小于85%的时间点，绝对误差不能超过10%；大于85%的时间点，绝对差值不能超过5%，可接受标准可以用于特定产品、也可以使用其他统计方法和范围。 5.4.3 REPRODUCIBILITY 5.4.3重现性 Reproducibilityfollows the general concepts of intermediate precision, but is performed by twodifferent analysts at different labs. 重现性遵照中间精密度的一般概念，但在不同实验室由两位不同的分析人员进行试验。 5.5 Robustness 5.5耐用性 Evaluation ofrobustness, which assesses the effect of making small, deliberate changes tothe dissolution conditions, typically is done later in development of the drugproduct and is a requirement for full method validation. It is performed usinga well-characterized lot of drug product, for example having tight contentuniformity and uniform performance. The number of replicates(typically 3 or 6) is dependent on the intermediate precision. All profilepoints should be evaluated. 评估溶出条件做一下小的、故意改变溶出条件对耐用性的影响，通常是在制剂开发出来以后进行，需要进行充分的方法学验证。用具有良好表征的制剂批次进行，例如，具有较好的含量均匀度。重复性数量（通常3或6）取决于中间精密度，所有的曲线点都应进行评估. Selection ofparameters to be varied depends on the dissolution procedure and analysis type.The parameters may include medium composition (e.g., buffer or surfactantconcentration, pH, deaeration), volume, agitation rate, sampling time, and temperature.Statistical analysis of the data generated will help determine the extent towhich the parameters must be controlled in the method. The robustnessassessment is well suited to Design of Experiments (DoE) methodologies toefficiently investigate the impact of the individual parameters and/or theirinteraction 参数选择是多种多样的取决于溶出过程和分析类型，参数包括溶出介质组合物（例如，缓冲液、表面活性剂浓度、pH、脱气），体积、转速、取样时间和温度。得到的数据进行统计分析将有助于确定参数在方法中控制的程度，试验设计方法（DOE）非常适合耐用性评估,以有效研究各个参数和他们相互作用的影响。 Robustness of analytical finish is referenced in <1225>.HPLC analysis parameters may include mobile phase composition (percentageorganic, buffer concentration, pH), flow rate, wavelength, column temperature,and multiple columns (of the same type). For spectrophotometric analysis, thewavelength may be varied. 分析方法的耐用性参考<1225>，HPLC分析参数包括流动相成分（有机相的百分比、缓冲液浓度、pH）、流速、波长、柱温、同一类型的多根色谱柱、对于分光光度计方法，波长可能不同。 5.6 Stability of Standard andSample Solutions 5.6样品溶液和标准溶液的稳定性 The standardsolution is stored under conditions that ensure stability. The stability of thestandard solution is analyzed over a specified period of time (for at least thetime of the entire dissolution procedure), using a freshly prepared standardsolution at each time interval for comparison. The acceptable range forstandard solution stability is influenced by the concentration and is typicallybetween 98% and 102% at the expected final concentration. 标准溶液贮藏在能保证其稳定性的条件下，应在指定的时间内（完全溶出的最少时间）分析标准溶液的稳定性，在每个时间间隔使用新配制的标准溶液进行比较，标准溶液稳定性可接受的范围受浓度的影响，通常是预期最终浓度的98%-102%。 The sample solution is typically stored at roomtemperature. The sample is analyzed over a specified period of time, using theoriginal sample solution response for comparison. The typical acceptable rangefor sample solution stability may be between 98% and 102%, compared with theinitial analysis of the sample solutions. If the solution is not stable,aspects to consider include temperature (refrigeration may be needed), lightprotection, and container material (plastic or glass). 样品溶液一般在室温下贮存，样品应在指定时间段进行分析，与最初分析的样品溶液进行比较，样品溶液稳定性通常的可接受范围98%-102%，，如果溶液不稳定，需要考虑温度（需要冷藏）、避光、以及容器材料（塑料或玻璃）。 The proceduremay state that the standards and samples need to be analyzed within a timeperiod demonstrating acceptable standard and sample solution stability. 该过程表明，需要分析对照品和样品在一段时间内的可接受标准和样品溶液稳定性。 （1092）溶出度试验的开发和验证【中英文对照版】【第五部分+第六部分】（2） 4 M& j D4 W# j' l. J1 x% D
原创 2016-01-29 红袖添香 医药信息新药开发 5.7 Considerations forAutomation 5.7自动操作注意事项 Automated methods offer opportunitiesfor increased precision and reproducibility; however, bias may be introduced.In particular, the sampling probe and the sample lines warrant attention asplaces where inaccuracies may occur. Deviations from the procedure described in<711>, such as resident sampling probes, sampling through the stirringelement shaft (hollow-shaft sampling), or fiber-optic probes, should bevalidated. Other aspects of automation validation may include carryover ofresidual drug, effect of an in-residence probe, adsorption of drug, andcleaning and/or rinse cycles. Validation is performed using the automateddissolution system including materials. Therefore, any change in materials willrequire demonstration of suitability based on the validation attributes thatare impacted by the change. 自动化的方法可以增加精密度和重复性，但可能会引入偏差，特别是取样探针和样品序列可能发生错误的地方值得注意，在（711）中描述了分析方法偏差，比如，保留取样针、通过搅拌元件轴（空心轴采样）、或者光纤维进样，都应该进行验证，自动进样其他方面的验证包括夹带的残留药物、探针内的残留药物影响、药物吸附、清洗和/或清洗周期。使用自动溶解解系统，材料也需要进行验证。根据验证属性受变化的影响，因此材料的任何变化都需要证明适用性。 Manual andautomated procedures should be compared to evaluate the interchangeability ofthe procedures. This is done by performing two automated runs at each dosageconcentration, using all sampling points, compared to manually sampled runs ofthe same samples. The effect of the in-resident probe cannot be determined bysampling both ways from the same vessel. Results should be consistent with therequirements for intermediate precision if the procedures are to be considered interchangeable.The difference in the mean value for dissolution results between any twoconditions using the same strength should not exceed an absolute 10% at timepoints with <85% dissolved nor exceed 5% for time points >85%. Acceptancecriteria may be product specific, and other statistical tests and limits may beused. 手动和自动程序应该进行对比研究，评估程序的可互换性。这是通过在每一剂量浓度两个自动运行程序，使用所有采样点比较同一样品的手动采样运行。通过同一容器中两种采样方式，不能确定内置探针的作用。如果程序认为是可以交换的，试验结果应与中间精密度的要求相一致。同一浓度在任一两个条件之间的溶出结果平均值在溶出<85%的点绝对误差不应超过10%，>85%的点绝对误差不得超过5%。可接受标准可以用于特定产品、也可以使用其他统计方法和范围。 Revalidationmay be necessary when the automated system is used with different formulationsbecause of the interaction with excipients. Dissolution media containingsurfactants or lipids may require additional validation efforts. 自动化系统用于不同的剂型时需要进行再验证，因为赋形剂之间可能会相互作用。包含表面活性剂和脂质的溶出介质也需要另外进行验证。 6. ACCEPTANCE CRITERIA 6.可接受标准 The acceptance criteria should be consistent withhistorical release or stability data. There is an expectation that acceptable batcheswill have results that fall within the acceptance criteria and that allmanufactured batches should have similar dissolution behavior, thushighlighting the importance of having a method that is not highly variable. Theacceptance criteria and time point(s), therefore, should discriminate betweenan acceptable and an unacceptable batch. In addition, the dissolution testresults are viewed as a link to the pivotal clinical trial batches. Whenchanges in dissolution rate have been shown to affect bioavailabilitysignificantly, the dissolution test and acceptance criterion should distinguishbatches with unacceptable bioavailability (19). Likewise, when changesin the formulation and manufacturing process significantly affect dissolutionand such changes are not controlled by another aspect of the specification, thedissolution test and criteria should distinguish these changes. 验收标准应与历史释放或稳定性数据相一致。我们期望可接受的批次的预期试验结果在验收标准范围内，所有的出厂批次具有类似的溶出行为，因此方法的耐用性是需要重点考虑的。因此，验收标准和取样时间点应该能够区分可接受与不可接受批次。此外，溶出的试验结果与临床试验关键批次链接。当改变溶出速率显著影响生物利用度时，溶出试验和可接受标准应该能够区分生物利用度不可接受的批次（19）。否则，当处方和工艺过程改变显著影响溶出时，这些变量不受质量标准的控制，溶出试验和溶出标准应该能够区分这些改变。 6.1 Immediate-Release DosageForms 6.1速释剂型 Although release and stability data are collectedduring dosage form development, it is common to record the entire dissolution profileor the amount of drug dissolved at specified intervals, such as 10, 20, 30, 40,50, and 60 min or 15, 30, 45, and 60 min. At registration, dissolution for animmediate-release tablet usually becomes a single-point test. The acceptancecriterion and test time are established by evaluating the dissolution profiledata. The acceptance criterion for a dissolution test is a function of Q,which is expressed as a percentage of label claim of drug dissolved at aspecified time. Typical Q values are in the range of 75%–80% dissolved. Qvalues in excess of 80% are not generally used because allowance needs tobe made for assay and content uniformity ranges. 虽然在剂型开发过程中收集到的释放和稳定性数据，通常绘制整个溶出曲线图或者计算出在指定时间间隔药物的溶出量，比如在10、20、30、40、50和60分钟，或在15、30、45和60分钟。在注册时，速释片的溶出经常采用单点测试，通过对溶出曲线数据进行评估确定可接受标准和测试时间。溶出试验的可接受标准用函数Q表示，Q表示为在指定时间药物溶出占标示量的百分比。Q值通常在75%-80%的溶出范围内，Q值超过80%通常不能使用，因为需要考虑分析和含量均匀度的范围。 6.2 Delayed-Release DosageForms 6.2延迟释放剂型 The discussion about dissolution of delayed-releasedosage forms in <711> focuses on enteric-coated dosage forms, which is themost common delayed-release dosage form. A dissolution test for adelayed-release tablet or capsule is a two-part test, and each part hasacceptance criteria. First, the dosage forms are exposed to an acid medium,followed by exposure to a buffer medium. To ensure that the enteric coatingperforms properly, a “NMT” acceptance criterion is indicated in <711> forthe acid stage. The medium used for an acid stage is usually 0.1 N HCl, and theduration of this stage is typically 2 h. The dosage forms are then exposed to abuffer medium, usually 0.05 M phosphate buffer at pH 6.8, but other buffers andpH targets may be used if justified. The duration of the buffer stage isusually 45 min for compendial tests, but this duration may vary, depending onthe drug product. As with immediate-release dosage forms, a Q value andtime point are determined by evaluating the entire dissolution profile. 在<711>部分，主要对肠溶缓释剂型的溶出度进行讨论，也是最常见的缓释剂型。缓释片或胶囊的溶出度试验分为两部分，每部分都有可接受标准。第一部分，剂型在酸性介质中的释放，随后暴露在缓冲介质中，为了确保肠溶包衣正常进行，在<711>部分对在酸性介质中“不小于”接受标准的情况进行了说明，酸性介质通常是0.1N盐酸，通常持续释放2小时，然后放在缓冲盐介质中，通常是0.05M磷酸盐缓冲液（pH=6.8）。如果有正当理由可使用其他缓冲剂和pH范围，根据药典试验，缓冲阶段的释放时间通常为45分钟。但这个持续时间是可以变化的，取决于制剂。正如即时释放剂型，通过评估整个溶出曲线图来决定Q值和取样时间点。 6.3 Extended-Release DosageForms 6.3延长释放剂型 A dissolution test for an extended-release dosageform is generally similar to that used for an immediate- or delayed-release drugproduct, except that the duration of the test is longer, and at least threetime points are specified for pharmacopeial purposes (20). Additionalsampling times may be required for drug approval purposes. An early time point,usually 1–2 h, is chosen to show that dose dumping is not probable. Anintermediate time point is chosen to define the in vitro release profile of thedosage form, and a final time point is chosen to show essentially completerelease of the drug (20). The time points for the test should bedetermined by evaluating the dissolution profile across the desired testduration. Often, additional time points are obtained during dosage formdevelopment to aid with selecting the appropriate time points for thespecification or monograph. 延长释放的溶出度试验通常和即时释放和延迟释放相似，所不同的是测试的持续时间较长，药典规定至少三个时间点（20）。考虑到药物的审评目的，需要增加取样点。在时间点的早期，通常1-2小时，不可能产生剂量倾卸，选择中间时间点作为剂型的体外释放曲线，选择的最后时间要能表明药物基本完全释放（20）。评估跨过所需的测试时间的溶出曲线来确定测试时间点。通常情况下，质量标准或药典正文中合适时间点的选择有助于在制剂开发过程中增加取样时间点。 As with an immediate- or delayed-release drugproduct, the acceptance criteria and time points for an extended-release drugproduct should discriminate between an acceptable and an unacceptable batch.The acceptance criteria for the first stage of testing (L1) should beestablished on the basis of available batch data (19,20). If humanbioavailability data are available for formulations exhibiting differentrelease rates, then an in vitro/in vivo relationship may be used to establishacceptance criteria (19,20). Acceptance criteria for the second (L2) andthird (L3) stages are derived from the L1 criteria using Acceptance Table2 in <711>. 正如立即或延迟释放的药物产品，延长释放的药物产品的可接受标准和时间点应该能够区分可接受和不可接受的批次。在试验的第一阶段，根据可用的批次数据建立可接受标准（19,20）。如果人体的生物利用度数据表现出制剂的不同释放速率，那么体外/体内关系可用于建立可接受标准（19,20）。第二（L2）和第三（L3）阶段的可接受标准来源于L1标准（在<711>中使用表2可接受标准）。 6.4 Multiple Dissolution Tests 6.4多个溶解度试验 Typically, monographs for extended-release dosageforms contain multiple dissolution tests representing specific products.Inaccordance with General Notices and Requirements 4.10.10, theappropriate test, if not Test 1, is indicated on the product labeling.For example, the USP monograph for Oxycodone HydrochlorideExtended-Release Tablets (21) lists two dissolution tests, each of whichhas either three or four time points. If the Tablets are analyzed using Test2 and the dissolution results comply with the criteria provided in themonograph, the labeling for Tablets can indicate that the Tablets meet USP DissolutionTest 2.Multiple dissolution tests also can be found in monographs forimmediate- and delayed-release dosage forms. For example,the USP monographsfor Levothyroxine Sodium Tablets and Pantoprazole SodiumDelayed-Release Tablets provide four dissolution tests (22,23). 通常情况下，正文中的延长释放剂型代表的特定产品包含多个溶出试验。符合4.10.10凡例和要求，如果不是测试1，在产品标签上注明所进行的适用试验，说明。例如，美国药典正文中列出了盐酸羟考酮缓释片剂（21）的两个溶出试验，每个试验各取三个或四个时间点。如果使用试验2对片剂进行分析，溶出结果与正文中提供的标准相符合，片剂标签可以标明片剂符合美国药典溶出试验2。在即时和延迟释放的药典正文中发现多个溶出试验，例如，美国药典正文中提供了左甲状腺素钠片和泮托拉唑钠缓释片四种溶出试验（22,23）。 6.5 Interpretation ofDissolution Results 6.5溶出结果说明 The Interpretationsection of <711> discusses immediate-, delayed-, and extended-releasedosage forms. The discussion for each of these release patterns is expandedhere with examples to assist with applying the criteria during the variousstages of testing. Understanding how these criteria are applied will assist insetting appropriate acceptance criteria. 在<711>说明部分讨论了即时释放、延迟和延长剂型。在不同测试阶段，在不同测试阶段，运用标准有助于用实例对这些释放模式的讨论进一步扩展。理解了这些标准适用范围有助于制定相应的可接受标准。 6.5.1 IMMEDIATE-RELEASE DOSAGEFORMS 6.5.1即时释放剂型 Once the Qvalue is established, the dissolution test is a staged test of threelevels. In the first level of testing called S1, six dosage forms are tested.Each dosage form must be Q + 5% (absolute percentage points) dissolvedat a specified time. For example, the time and tolerances in a monograph wouldbe: Time: 30 min Tolerances:NLT 80% (Q) of the labeled amount of “drug substance” is dissolved. 一旦Q值确定，溶出试验在测试阶段需要三个浓度水平。在测试的第一个浓度水平被称为S1，用6片进行测试。每种剂型在指定时间点溶出度必须是Q +5％（绝对百分点）。例如，在正文中提到的时间和允许偏差分别为： 时间：30分钟 允许偏差：Q值不小于80%为“药物活性物质”标示量的80%被溶出。 If the Q valuefor a 200-mg label claim (LC) immediate-release tablet is specified as 80% andthe time point is 30 min, then NLT 85% LC (170 mg) of the drug substance ineach tablet must be dissolved at 30 min. 如果200mg标示量（LC）的即时释放片的Q值指定为80%，时间点是30分钟，那么在每个片子中在30分钟溶出必须不小于标示量（170mg）的85%。 If thiscriterion is not met, then 6 additional tablets are tested at level 2 (S2).To pass the S2 acceptance criteria, the average of all 12 tabletsmust be equal to or greater than Q (80% LC; 160 mg in the aboveexample), and no tablet has less than Q –15% (65% LC; 130 mg in theabove example). 如果不能满足这个标准，那么在浓度2（S2）用另外6片进行测试。12片的平均值必须等于或大于Q值（标示量的80%，在上面的例子中160mg），没有片子少于Q-15%（标示量的 80%，在上面的例子中130mg），表明通过S2的可接受标准。 If thesecriteria are not met, then level 3 or S3 testing must be performed by testing12 additional tablets. To pass S3, the average of all 24 tablets must be equalto or greater than Q (80% LC; 160 mg in the above example). Twoadditional criteria must be met as well: 1) no more than 2 tablets are lessthan Q – 15% (65% LC; 130 mg in the above example), and 2) no tablet isless than Q – 25% dissolved (55% LC; 110 mg in the above example.) 如果都不能满足这些标准，那么在浓度3或（S3）用另外12片进行测试。24片的平均值必须等于或大于Q值（标示量的80%，在上面的例子中160mg），表明通过S3的可接受标准。两个增加的标准必须满足：1)不超过两片是（标示量的65%，在上面的例子中130mg）,2）.没有片子小于Q-25%（标示量的55%，在上面的例子中110mg）。 6.5.2 DELAYED-RELEASE DOSAGEFORMS 6.5.2延迟释放剂型 An aliquot of the acid medium from each vessel isanalyzed at the end of the acid stage. For the acid stage, the acceptance criteriahave three levels. Level 1 (A1) testing is passed if no individual valueexceeds 10% dissolved. If the A1 criteria are not met, then the dissolutiontest is performed on 6 additional dosage forms for level 2 (A2) testing. LevelA2 criteria are passed if the average of all 12 dosage forms in the acid stageis NMT 10% dissolved and if no individual dosage form is more than 25% dissolved.Level 3 testing is performed if the A2 criteria are not met. The A3 criteriaare passed if the average of all 24 dosage forms in the acid stage is NMT 10%dissolved and if no individual tablet is more than 25% dissolved. For thespecial case in which the solubility of the drug in an acidic medium because ofconversion to the free acid is too low to support an acceptance criterion ofnot more than 10% the drug product should be exposed to the acid stage for thedefined duration and then exposed to the buffered medium. Alternate acceptancecriteria for the acid stage based on drug solubility may be justified. 在酸性阶段结束时分析每个溶出杯中的酸性介质。酸阶段，可接受标准有三个浓度。如果溶出度单个值没超过10% ，浓度1（A1）测试通过。如果不能满足A1标准，则在溶出试验用另外6个片剂型在浓度别2（A2）中进行测试。如果通过A2标准，所有12个剂型在酸性阶段的溶出度平均值不超过10％，如果每片溶出度不超过25％。在特殊情况下，该药物在酸性介质中因转化为游离酸，溶解度太低，不符合质量标准中不超过10%的制剂应该暴露在酸性阶段持续释放然后暴漏在缓冲介质中。在酸性阶段根据药物溶解度制定的可选择标准是合理的。 For delayed-releasedosage forms, the total percentage dissolved is determined by adding themeasured amounts in the acid and buffer phases for each individual dosage form.These calculated values are then compared to staged acceptance criteria (B1,B2, and B3) that are based on a Q value. The B1, B2, and B3 criteria areidentical to those for the immediate release S1, S2,and S3 criteria. 对于延迟释放剂型，溶解度的总百分比是通过每片在酸性和缓冲阶段测得的量来确定的。 比较这些计算值，然后，根据Q值分阶段比较验收标准（B1，B2，和B3）。B1，B2、B3标准和即时释放S1，S2、S3标准相同 6.5.3 EXTENDED-RELEASE DOSAGEFORMS 6.5.3延长释放剂型 In the following hypothetical example, which isused to describe the criteria for a extended-release dosage form, the time pointsare 1, 4, and 8 h. The acceptance range for each time point is as follows: • Between 24%and 44% LC drug substance dissolved at 1 h • Between 56%and 76% LC drug substance dissolved at 4 h • NLT 85% LCdrug substance dissolved at 8 h. Acceptanceranges are often expressed in tabular form in the USP–NF (see Table 3): 在下面假设的例子中，用于描述延长释放剂型在时间点为1、4和8小时的释放标准，每个时间点的可接受范围如下： · 在1小时间主药溶出度介于标示量的24％和44％ · 在4小时主药溶出度介于标示量的56％和76％ · 在8小时主药溶出度不小于85％。 在USP-NF（见表3）列出了通常可接受范围。 表3.L1标准 Six tablets are analyzed at Level 1 (L1);acceptance criteria are met if no individual value lies outside each of thestated ranges,and no individual value is less than the percentage specified forthe final time point. If the L1 criteria are not met, then 6 additional tabletsare analyzed at level 2 (L2). The L2 criteria are met if these three conditionsare met: 1. Theaverage value of the 12 tablets lies within each of the stated ranges and isNLT the stated range of the final time point. 2. None ofthe 12 tablets is >10% of the labeled content outside each of the statedranges. 3. None ofthe 12 tablets is >10% of the labeled content below the stated amount at thefinal test time. For the above example, the L2 acceptance criteriafor the 12 tablets (see Table 4) are as follows: 在浓度1（L1）分析了6片，如果每片都在规定的范围之内，并且没有一个值小于最终时间点指定的百分比，满足可接受标准。 如果不能满足L1条件，则用另外6片在2级（L2）进行分析。如果下面这三个条件都满足，那么满足L2标准： 1.12片的平均值均在所规定述范围内且不小于最后时间点规定范围。 2.12片中没有一片大于标示含量10％，且每片在规定范围之外。 3. 12片中没有一片大于标示含量10％，且低于最终测试时间点规定值。( i% q$ Y9 m/ @
上述例子中12片L2验收标准列于表4： 表4.L2标准 If the L2criteria are not met, then 12 additional tablets are tested at level 3 (L3).The L3 criteria are met if these five conditions are met: 1. Theaverage value of the 24 tablets lies within each of the stated ranges and isNLT the stated range of the final time point. 2. NMT 2 ofthe 24 tablets are >10% of labeled content outside each of the statedranges. 3. NMT 2 ofthe 24 tablets are >10% of the labeled content below the stated amount atthe final test time. 4. None ofthe 24 tablets is >20% of the labeled content outside each of the statedranges. 5. None ofthe 24 tablets is >20% of the labeled content below the stated amount at thefinal test time. The L3acceptance criteria for the 24 tablets in the above example are summarized in Table5: 如果没有满足二级标准，那么另外12片在3级（L3）进行测试。如果满足这五个条件符合L3标准： 1、24片的平均值均在上述的每个范围内，且不低于最后时间点的范围 2、24片中不超过2片>标示含量的10％，且每片在规定范围之外。 3、24片中不超过2片>标示含量的10％，且低于最终时间点规定值。 4、24片中没有1片标示含量>20％，且每片都在规定范围之外， 5、24片中没有1片标示含量> 20％，且低于最终测试时间点规定值。 上述例子中24片L3可接受标准列于表5 表 5.L3标准 | 1h | | | | 在14％-54％范围之外不超过2片，任何一片都在4％-64％的范围之内 | 在46％-86％的范围之外不超过2片，任一片都在：36％-96％的范围之内 | 释放度<75％不超过2片，每一片的释放度都不超过65％ |
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