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1、江苏恒瑞医药股份有限公司JIANGSU HENGRUI MEDICINE CO., LTD.管理文件和管理程序Administration Document & Management Procedure质量控制Quality Control 文件名：File Name:药品质量标准分析方法验证 Validation of analytical method adopted in pharmaceutical quality specification 文件号：QC-827BFile Code:页 号：Page 1 of 7 Pages:分发部门：Distribution 质量部 Quality
2、 department 执行日期：Executive date:2005年8月15日变更记载/History文件名称：File Name：文件号：File Code:执行日期:Implement Date变更原因:Rationale:药品质量标准分析方法验证QC-827B2005-08-15版面格式与总公司统一起草/日期Written By/Date审核/日期Reviewed By/Date批准/日期Accepted By/DateQC-827B Page 2 of 71.目的 Purpose 证明采用的方法适合于相应检测要求。To testify the adopted methods me
3、et corresponding detection requirements. 2.范围 Scope 适用于鉴别试验，杂质定量或限度检查，原料或制剂中有效成分含量测定，制剂中其它成分（如降解产物、防腐剂等）的测定。药品溶出度、释放度等功能检查中的溶出量等测试方法，以及微生物限度、细菌内毒素、无菌、清洗验证中的检验方法。It is applicable to identification; quantification or limit test of impurities; content determination of the active ingredient in drug subs
4、tance or preparation and that of other components (degradation products, antiseptics etc. ) in the preparation; dissolution and release test of pharmaceuticals; microbial limit test; tests for bacterial endotoxin, sterility; and test of cleaning validation. 3.程序 Procedures 3.1化学检验方法 Chemical examina
5、tion methods3.1.1准确度 Accuracy 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,一般以回收率(%)表示。The accuracy of an analytical method is the closeness of test results obtained by that method to the true value or the reference value. Accuracy is often expressed as percent recovery value. 1. 含量测定方法的准确度Accuracy of the method for
6、 content determination 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建立准确度的另一方法测定的结果进行比较。The accuracy for drug substance may be determined with a reference substance or sample with known purity, or by comparing the result obtained by this method with the result obtained by another method of which the accuracy has
7、been established. 制剂可用含已知量被测物的各组分混合物进行测定，或向制剂中加入已知量的被测物进行测定，或与另一已建立准确度的方法比较结果。The accuracy for drug preparation may be determined with the mixture of components, to which known amounts of analyte have been added. If it is not possible to obtain all the components, the accuracy may be determined by a
8、dding known amounts of analyte to the preparation, or by comparing the result obtained by this method with the result obtained by another method whose accuracy has been known. 如该法已建立了精密度、线性和专属性，准确度不必再做。When the precision, linearity and specificity of a method have been developed, then it is unnecess
9、ary to determine the accuracy because the accuracy can be calculated. 2. 杂质定量测定的准确度Accuracy of quantitative determination of impurity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。如不能测得杂质或降解产物的相对响应因子，则可用原料药的响应因子。应明确证明单个杂质和杂质总量相当于主成分的重量比（%），或是面积比（%）。The accuracy may be determined by adding kn
10、own amounts of impurity to the drug substance or preparation. When the impurity or degeneration product is unavailable, the accuracy may be determined by comparing the result obtained by this method with the result obtained by another method whose accuracy has been known. When the impurity or degene
11、ration product is unavailable, the accuracy may be determined by comparing the result obtained by this method with the result obtained by another method whose accuracy has been known. When the impurity or degeneration product is unavailable, the accuracy may be determined by comparing the result obt
12、ained by this method with the result obtained by another method whose accuracy has been known. The response factor of the drug substance may be used if the response factor or the relative response factor of the impurity or degeneration product to the drug substance can not be determined. The percent
13、 ratio of weight or area of a single impurity and total impurities to that of the active ingredient should be testified definitely. 3. 数据要求Requirement for the data 在方法范围内，至少用9次测定结果进行评价，如制备3个不同浓度级别的样品，各测定3次。计算9个测定结果的回收率及相对标准偏差，均应在规定限度之内。In specified range, the accuracy should be evaluated using at le
14、ast 9 testing results of the sample, 3 testing solutions of each concentration level (3 different concentration levels in all) are prepared and measured. The recovery value and RSD of testing results shall be calculated and within specified ranges. 起草/日期Written By/Date审核/日期Reviewed By/Date批准/日期Accep
15、ted By/Date3.1.2精密度 Precision QC-827B Page 3 of 7精密度系指在规定的测试条件下,同一个均匀样品,经多次取样测定所得结果之间的接近程度,用偏差、标准偏差或相对标准偏差表示。含量测定和杂质定量测定应考查方法的精密度。The precision of an analytical method is the degree of agreement among individual test result when the procedure is applied repeatedly to multiple samplings of a homogeno
16、us sample. It is usually expressed as deviation, standard deviation (SD) or relative standard deviation (RSD). Precision measurement is required to content determination and quantification of impurity. 1.重复性：在相同条件下，由一个分析人员测定所得结果的精密度称为重复性。在方法起草/日期Written By/Date审核/日期Reviewed By/Date批准/日期Accepted By/D
17、ate范围内，至少用9次测定结果进行评价，如制备3个不同浓度级别的样品，每个浓度级别测3次；或取100%的被测物浓度，用至少测定6次的结果进行评价。应自样品制备开始制备6份样品溶液，所得结果的相对标准偏差即为方法重复性。自动进样器重复性的测试，一般取同一样品溶液至少重复进样10次，其相对标准偏差不应大于1%。Repeatability: it is the precision obtained by the same analyst within a laboratory over a short period of time with the same equipment. In speci
18、fied range, repeatability should be evaluated with at least 9 measurement results, for example, 3 different concentration levels are selected, and 3 testing solutions of each level are prepared and measured. Repeatability can also be evaluated with at least 6 measurement results when the concentrati
19、on level of the analyte at 100%, the RSD of measurement results is the repeatability value. During automatic sampler repeatability test, a homogenous solution shall be at least sampled and injected for 10 times, and the RSD of results shall not be greater than 1%.2. 中间精密度：在同一实验室，不同时间由不同分析人员用不同设备测定结果
20、的精密度称为中间精密度。色谱分析方法由于受外界因素的影响较大，需考查中间精密度，至少应在两种不同条件下进行考察。Intermediate precision: it is the precision obtained by different analyst within the same laboratory on different day with different equipment. Chromatographic analysis is susceptible to influences of external factors; therefore, intermediate p
21、recision should be assessed at least under two different conditions. 4. 数据要求Requirement for data 均应报告标准偏差、相对标准偏差和可信限。Standard deviation, RSD and confidential limit should be reported. 3.1.3专属性 Specificity 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，采用的方法能准确测定出被测物的特性。The specificity of an analytical method is abil
22、ity to measure accurately and specifically the analyte in the presence of components that may be expected to be present in the same matrix, such as impurity, degradation products and excipients. 1. 鉴别反应 Identification 应能与可能共存的物质或结构相似化合物区分。不含被测成分的样品，以及结构相似或组分中的有关化合物，均应呈负反应。The compounds that may coex
23、ist or have close related structures should be distinguished from the active ingredient. The sample without compounds being examined or having close related structures and related chemical compositions should offer negative response. 2. 含量测定和杂质测定 Assay and test for impurity 色谱法和其他分离方法，应附代表性图谱，以说明专属性
24、。图中应标明诸成分的位置，色谱法中的分离度应符合要求。The representative graphs should be recorded for verifying specificity when chromatography or other separation methods are used. The position of each component should be marked in the graph. The resolution of the chromatographic method meets the requirements. 对于杂质的测定，一般取含一
25、定杂质量的样品进行分析，证明此杂质测定其具有适宜的准确度和精密度。As to test for impurity: a certain amount of the impurity may be added to the sample to testify the accuracy and precision of the method.对于含量分析，可通过加入一定量的杂质或赋形剂至样品，通过分析证明结果不受影响。As to content determination: if available, the impurities or excipients may be added to the
26、 sample for assay to inspect whether the result is interfered. 若杂质或降解产物为未知物，可将样品用强光照射、高温、高湿、酸QC-827B Page 4 of 7碱水解或氧化的方法进行加速破坏，而后将此样品进行分析，将分析结果与另一经验证的方法或法定方法所得结果进行比较。含量测定应比较两方法的分析结果，杂质测定若有色谱图，则应对比杂质峰的形状。If the impurities or degradation products are not known (not available), accelerating decomposit
27、ion may be done for studying degradation products, such as irradiation with strong light, high temperature, high humidity, acidic or alkaline hydrolysis, oxidation etc. the results shall be compared with that obtained by the pharmacopoeial method or other validated method. As for assay: analysis res
28、ults shall be compared, as for test for impurity: if chromatographic graphs are available, peaks of impurities shall be compared. 3.1.4检测限 Limit of detection (LOD)检测限指样品中被测物能被检测出的最低量。LOD is the lowest concentration of the analyte in a sample that can be detected. The methods in common use are as fol
29、lows: 1 非仪器分析目视法：通过用已知浓度的样品分析来确定可检出的最低水平作为检测限。Noninstrumental method: the LOD 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. 2 仪器分析方法：可以非仪器分析所用的目视法来确定检测限，也可用已知浓度的样品与空白试验对照，以信
30、噪比为2：1或3：1来确定检测限的最低水平。需制备相应检测限浓度的样品，反复测试来确定。Instrumental method (signal-to-noise ratio method): limit of detection can be determined with noninstrumental method, like visual method; LOD can also be determined by the comparing the test results from samples with known concentration of analyte with tho
31、se of blank samples. The lowest concentration of LOD can be established with the signal-to-noise ratio of 2：1or 3：1. Prepare samples with corresponding concentration for repeat LOD test. 3.1.5定量限 Limit of quantification (LOQ)定量限系指样品中被测物能被定量测定的最低量，其测定结果应具有一定准确度和精密度。杂质和降解产物用定量测定方法研究时，应确定定量限。Limit of q
32、uantification (LOQ) is the lowest concentration of the analyte in a sample that can be determined with acceptable precision and accuracy under the stated experimental conditions. LOQ should be determined when the quantitative determination for impurities and degradation products are developed. 1 非仪器
33、分析方法：与检测限的非仪器分析方法所用方法相同，只是所得结果需符合一定的准确度和精密度要求。Noninstrumental method: like the noninstrumental method used for LOD determination, the results shall meet the requirements for precision and accuracy. 2 仪器分析方法：一般以信噪比为10：1时相应的浓度作为定量限的估计值，然后配制相应定量限浓度的样品，反复测试来确定。Instrumental method: the estimate value of
34、LOQ is the concentration when the signal-to-noise ratio is 10：1. 3.1.6线性 Linearity 线性指在设计的范围内，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。可用一贮备液精密稀释或分别精密称样，制备一系列的供试品（至少5份不同浓度的供试品）进行测定。以测得的响应信号作为被测物浓度的函数，进行线性回归，求出回归方程及相关系数。The linearity of an analytical method is its ability to elicit test results that ar
35、e directly proportional to the concentration of analyte in samples within a given range. Linearity relationship should be determined over the claimed range of the method. The samples with varying concentrations of analyte for linearity determination are prepared by diluting accurately a stock soluti
36、on, or by measuring accurately an amount of analyte separately. Five portions of samples should be prepared at least. The treatment is normally a calculation of a regression line by the method of least squares of test results versus analyte concentrations. Regression equation and correlation coeffic
37、ient should be calculated. 3.1.7范围 Range 范围指能达到一定精密度、准确度和线性，测试方法适用的高低限浓度或量的区间。分析方法的范围应根据具体分析方法以及对线性、准确度、精密度的结果和要求确定。可采用以下标准：The range of an analytical method is the concentration or quantity interval between the upper and lower levels of analyte (including these levels) that have been demonstrated t
38、o be determined with precision, accuracy, and linearity using the method as written. The range should be determined according to practical application and the results and requirement of linearity, accuracy and precision. 1 对于原料药和制剂的含量测定，范围应为测试浓度的80%120%；The range should be 80%120% of the test concen
39、tration for content determination of drug substance and preparation. 2 杂质测定，范围应为测试浓度的50%120%；起草/日期Written By/Date审核/日期Reviewed By/Date批准/日期Accepted By/DateQC-827B Page 5 of 7The range should be 50%120% of the test concentration for impurity test. 3 含量均匀度，范围应为测试浓度的70%130%，根据某些剂型的特点，此范围起草/日期Written By
40、/Date审核/日期Reviewed By/Date批准/日期Accepted By/Date可适当放宽；The range should be 70%130% of the test concentration for content uniformity of preparation, and may be widened appropriately according to the dosage forms. 4 溶出度范围应为标准规定范围的20%；For the test of dissolution or release, the range should be 20% of the
41、 limit. 5 若含量测定与杂质检查同时测定，用百分归一化法，则线性范围应为杂质规定限度的-20%至含量限度的20%。If the content determination and impurities test are to be done with normalization method simultaneously, the linear range should be -20% of the provided limit of impurity to +20% of the provided limit of content. 3.1.8粗放性 Extensiveness 指在
42、不同实验条件下（如不同实验室、不同实验员、不同仪器、不同批的试剂、不同的分析温度、不同时间等）对同一样品进行分析所得结果的重现性。此实验条件应仍在方法规定的限度内。Extensiveness is the result reproducibility of test to the same sample under different experimental conditions (different laboratories, analysts, instruments, temperature and time for analysis, and different batches of
43、 reagent to be used), but these experimental conditions are within given ranges of this method. 将在不同实验条件下所得结果的重现性与方法和重复性进行比较，来衡量分析方法的粗放性。Compare the reproducibility obtained under different experimental conditions with repeatability, so as to determine the extensiveness of an analytical method. 3.1.
44、9耐用性Ruggedness 耐用性指测定条件有小的变动时，测定结果不受影响的承受程度。典型的变动因素有：被测溶液的稳定性，样品提取次数、时间等。液相色谱法中典型的变动因素有：流动相的组成和pH、不同厂牌或不同批号的同类型色谱柱、固定相、柱温、进样器和检测器温度等。如果测试条件要求比较苛刻，则应在方法中写明。Ruggedness of an analytical method is the degree of tolerance that the determinating result is not affected when there is small change in the ope
45、rational condition. The typical variable factors are stability of the test solution, times and duration of sample extraction, and so on. The variable factors of liquid chromatography are composition and PH value of the mobile phase, same type of chromatographic column but from different manufacturer
46、s or different batches, column temperature, sampler and detector temperature, etc. If the requirement for test condition is hard, it should be recorded clearly in the method. 对于已有国家标准的药品，可只检测系统适用性试验。As for national standard drugs, system suitability shall be tested only. 3.2生物检测 Biological detection 3.2.1无菌检查法 Test for sterility 方法验证试验：Validation test: 薄膜过滤法：将规定量的供试品按薄膜过滤法过滤，冲洗，在最后一次的冲洗液中加入小于100cfu的试验菌，过滤。取出滤膜接种至硫乙醇酸盐流体培养基或改良马丁培养基中，或将培养基加至滤筒内。另取一装有同体积培养基的容器，加入等量试验菌，作为对照。按规定温度培养35天。各试验菌同法操作。Membrane filtr
