143 use different safety factors for different dosage forms based on physi-ological response (this method is essential for potent materials).
根据不同的生理反应，针对不同的剂型使用不同安全因子（尤其是针对活性成分）。
11.6 Limits may be expressed as a concentration in a subsequent product (ppm), limit per surface area (mcg/cm), or in rinse water as ppm.
产品中，前次生产的残留限度以浓度（ppm）和每单位表面积的限度（mcg/cm）表示；对淋洗水样品，可用ppm表示。
11.7 The sensitivity of the analytical methods should be de?ned to enable reasonable limits to be set.
为便于设置合理的残留限度，应说明分析方法的灵敏度。
11.8 The rationale for selecting limits for carry-over of product residues should meet de? ned criteria.
产品残留限度的选择原理应符合既定标准的要求。 11.9 The three most commonly used criteria are: 常用的三种标准有：
144 visually clean. (No residue should be visible on equipment after clean-ing.) Spiking studies should determine the concentration at which most active ingredients are visible. This criterion may not be suitable for high-potency, low-dosage drugs; 不得有肉眼可见的残留物。（清洁后，设备上不得有肉眼可见的残留物）
145 no more than 10 ppm of one product will appear in another product (basis for heavy metals in starting materials); and
先加工产品在后续加工产品中的残留限度不得超过10ppm（根据起始物料的重金属限度）；
146 no more than 0.1% of the normal therapeutic dose of one product will appear in the maximum daily dose of a subsequent product.
服用最大日剂量的后续加工产品而带入体内的先加工产品的量不得超过后者正常治疗剂量的0.1% 。
11.10 The most stringent of three options should be used. 应选择这三种标准中最严格的标准。 11.11 Certain allergenic ingredients (e.g. penicillins and cephalosporins) and highly potent material (e.g. anovulent steroids, potent steroids and cytotoxics) should be undetectable by the best available analytical methods. (In practice this may mean that dedicated manufacturing facilities should be used for the manufacturing and processing of such products.)
选用的最佳分析方法应能检测出特定的致敏物质（如青霉素和头孢菌素）和高效物质（如可抑制排卵的甾体类物质、效价很强的类固醇和细菌毒素等）。（在生产实践中，指应有生产和加工这类产品的专用生产设施。）
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Appendix 4 附录 4
Analytical method validation 分析方法验证
147 Principle 基本原理 148 General 概述
149 Pharmacopoeial methods 药典方法
150 Non-pharmacopoeial methods 非药典方法
151 Method validation 方法验证
152 Characteristics of analytical procedures 分析程序的特点
1. Principle 基本原理
1.1 This appendix presents some information on the characteristics that should be considered during validation of analytical methods. Approaches other than those speci?ed in this appendix may be followed and may be acceptable. Manufacturers should choose the validation protocol and procedures most suitable for testing of their product.
这则附录给出了在分析方法验证过程中需要注意的关于方法特性的一些资料，但并不保证这些资料并能完全代表需要注意的所有内容，该附录未提及的其它方法也可能是验证过程中需要遵循且可行的。生产商应当根据他们的产品的需要，选择最适合自己要求的验证方案和验证程序。
1.2 The manufacturer should demonstrate (through validation) that the analytical procedure is suitable for its intended purpose.
供应商应当证明（以验证的方式）所选用的分析方法能满足预期期望。
1.3 Analytical methods, whether or not they indicate stability, should be validated. 所有的分析方法，不论是否属于稳定性指示方法，都应经过验证。
1.4 The analytical method should be validated by research and development before being transferred to the quality control unit when appropriate.
将分析方法技术转移到质量控制部门之前，应适当以研发的方式对分析方法进行验证。 2. General 概述
2.1 There should be speci?cations for both, materials and products. The tests to be
performed should be described in the documentation on standard test methods. 针对物料和产品，都应当制订有相应的合格标准；针对需要执行的试验，应
以文件形式说明标准的试验方法。
2.2 Speci?cations and standard test methods in pharmacopoeias (―pharmacopoeial methods‖), or suitably developed speci?cations or test methods (―non-pharmacopoeial methods‖) as approved by the national drug regulatory authority may be used.
可使用的合格标准和检验方法有：1.药典中列出的各项标准和标准检验方法（即―药典方法‖）；2.自主研发的标准和检验方法，且已经通过国家药政机构证实可行的。
2.3 Well-characterized reference materials, with documented purity, should be used in the validation study.
验证研究中使用的参照标准物料应当是特性已清晰明了的，且纯度已经得到证明的。
2.4 The most common analytical procedures include identi?cation tests, assay of drug substances and pharmaceutical products, quantitative tests for content of impurities and limit tests for impurities. Other analytical procedures include dissolution testing and determination of particle size.
常见的分析方法有：鉴别试验，药物成分和诊疗用品的含量分析方法，杂质的定量试验和限度试验。此外还有溶出度试验和粒径分析试验。
2.5 The results of analytical procedures should be reliable, accurate and reproducible. The characteristics that should be considered during valida-tion of analytical methods are discussed in paragraph 6.
使用分析方法得到的结果应当可靠、准确、可再现。第６段就验证分析方法时应考虑的方法的特征参数展开了讨论。
2.6 Veri?cation or revalidation should be performed when relevant, for example, when there are changes in the process for synthesis of the drug sub-stance; changes in the composition of the ?nished product; changes in the analytical procedure; when analytical methods are transferred from one labo-ratory to another; or when major pieces of equipment instruments change.
出现原料药的合成工艺变更、成品的配方变更、分析方法变更、主要设备变更时，应执行确认或再确认；将分析方法从一个实验室移交到另一个实验室时，也需要执行确认或再确认。
2.7 The veri?cation or degree of revalidation depend on the nature of the change(s).
根据变更的性质，确定确认或再验证的程度。
2.8 There should be evidence that the analysts, who are responsible for certain tests, are appropriately quali?ed to perform those analyses (―analyst pro?ciency‖). 负责某项实验的检验员应当有执行这些分析的资格证明（―检验员资格证‖）。 3. Pharmacopoeial methods 药典方法
3.1 When pharmacopoeial methods are used, evidence should be avail-able to prove that such methods are suitable for routine use in the laboratory (veri? cation).
如使用了药典中记载的分析方法，应证明该方法适合实验室日常使用，且该证明过程应有据可查。
3.2 Pharmacopoeial methods used for determination of content or impurities in pharmaceutical products should also have been demonstrated to be speci?c with respect to the substance under consideration (no placebo interference).
应证明所使用的药品含量或杂质的药典测定方法对待测物具专一性（对照实验对实验无干扰）。
4. Non-pharmacopoeial methods 非药典方法
4.1 Non-pharmacopoeial methods should be appropriately validated. 如使用了药典未记载的方法，应验证。 5. Method validation 方法验证
5.1 Validation should be performed in accordance with the validation pro-tocol.
The protocol should include procedures and acceptance criteria for all characteristics. The results should be documented in the validation report.
应严格按照验证方案实施验证。方案中，应阐明验证程序和所有方法的特征参数的合格标准。验证结果应记录在验证报告中。
5.2 Justi?cation should be provided when non-pharmacopoeial methods are used
if pharmacopoeial methods are available. Justi?cation should in-clude data such as comparisons with the pharmacopoeial or other methods.
在有药典方法可用的情况下，如使用了非药典的方法，应就此给出采用后者的合理证明；在证明文件中，应给出药典方法和非药典方法的比较。
5.3 Standard test methods should be described in detail and should provide
suf?cient information to allow properly trained analysts to perform the analysis in a reliable manner. As a minimum, the description should include the chromatographic conditions (in the case of chromatographic tests), reagents needed, reference standards, the formulae for the calculation of results and system suitability tests.
应详细说明标准实验方法，同时给出实验资料，以保证培训后的检验员能可靠地完成分析实验。对实验进行说明时，至少应阐明色谱条件（如采用了色谱分析方法）、实验试剂、对照标准品、结果计算公式和系统适应性实验。 6 Characteristics of analytical procedures 分析方法的特征
6.1 Characteristics that should be considered during validation of analytical methods include:
验证分析方法时，应考虑的方法的特征参数有： 153 — speci? city 专属性 154 — linearity 线性 155 — range 范围
156 — accuracy 准确度 157 — precision
精确度
158 — detection limit 检测限
159 — quantitation limit 定量限 160 — robustness. 耐用性。
6.1.1 Accuracy is the degree of agreement of test results with the true value, or the closeness of the results obtained by the procedure to the true value. It is normally established on samples of the material to be examined that have been prepared to quantitative accuracy. Accuracy should be estab-lished across the speci?ed range of the analytical procedure. 准确度系指测量值与真实值的偏离程度，或指根据分析方法获得的结果与真实值之间的接近程度。确定准确度时，通常需要特地针对该目的制备待测物样品，然后测量样品，从而确定该方法的特征参数。对于指定的分析方法的所有范围，最终确定的准确度应都适用。
Note: it is acceptable to use a ―spiked‖ placebo where a known quantity or concentration of a reference material is used.
注：分析时，可向对照品中添加已知量或已知浓度的对照品。
6.1.2 Precision is the degree of agreement among individual results. The complete procedure should be applied repeatedly to separate, identical samples drawn from the same homogeneous batch of material. It should be measured by the scatter of individual results from the mean (good group-ing) and expressed as the relative standard deviation (RSD).
精确度系指测量值之间的偏离程度。确定精确度时，应先对同一个均匀的产品批取样，然后再对同一样品重复、完整地实施整个分析程序，最后比较单个测量值与平均值（要精确分类）。一般用相对标准偏差（RSD）表示精确度。
6.1.2.1 Repeatability should be assessed using a minimum of nine determi-nations covering the speci?ed range for the procedure e.g. three concentra-tions/three replicates each, or a minimum of six determinations at 100% of the test concentration.
确定重复性时，至少要评估代表了规定的分析范围的9个测量值，如三种浓度/每种浓度三个样品；或在不稀释供试品的情况下取同一浓度的6个样品，而后分析测试。
6.1.2.2 Intermediate precision expresses within-laboratory variations (usually on different days, different analysts and different equipment). If reproducibility is assessed, a measure of intermediate precision is not required.
中间精密度指的是实验室内的偏差（往往指在不同测试时间、不同的检验员和使用不同的仪器时出现的偏差）。如已评估了方法的再现性，可不必再测量中间精密度。