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.
