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方法学验证中关于回收的问题
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请问大家在做方法学验证回收时，怎么配制样品？ 比如我想做低，中，高浓度为80%，100%，120%的回收， 在配制时 1. 是配制低，中，高浓度各3份样品，每份样品各进样1针。 2. 还是低，中，高浓度各配制1份，每个浓度的各进样3针。 大家有什么判断的依据？非CP的，例如USP或ICH上的 |
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jyan1978
金虫 (小有名气)
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8楼2008-10-07 11:27:20
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karl2100(金币+1,VIP+0):3Q
karl2100(金币+1,VIP+0):3Q
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FDA 的 Reviewer Guidance Validation of Chromatographic Methods 在讲准确性那节这么推荐的： Recommendations: Recovery data, at least in triplicate, at each level (80, 100 and 120% of label claim) is recommended. The mean is an estimate of accuracy and the RSD is an estimate of sample analysis precision. 我们平时做的时候是精密度，准确性一起做的，配三份样品，高浓度测三次，低浓度测三次，中浓度测六次。 测高中低回收率，取均值，为准确度。 取中浓度RSD均值，为精密度 |
2楼2008-09-05 09:51:30
3楼2008-09-05 20:10:53
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karl2100(金币+1,VIP+0):多谢提供！
karl2100(金币+1,VIP+0):多谢提供！
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除了楼上的， 我想补充一些内容，因为我们还应该考虑ICH的相关指南（完整的见附件2，From: http://www.emea.europa.eu/pdfs/human/ich/038195en.pdf），因为FDA的指南（稍完整文件的见附件1， 出处http://www.fda.gov/CDER/GUIDANCE/cmc3.pdf）并不详细。 FDA的指南（见附件1）给出了关于RECOVERY的以下内容： F. Recovery Recovery is expressed as the amount/weight of the compound of interest analyzed as a percentage to the theoretical amount present in the medium. Full recovery should be obtained for the compound(s) of interest. During the sample preparation procedure, the compound of interest is recovered from excipients in the formulation matrix ranging from a simple aqueous solution to complex cream formulation, and from potential adhesion to container/closure components, e.g., glass vial, metered valve. In general, a simpler sample preparation procedure will result in a lower variation of recovery. Data collection for recovery are discussed in section IV.A under Accuracy. IV. PARAMETERS FOR VALIDATION OF HPL CHROMATOGRAPHIC METHODS FOR DRUG SUBSTANCE AND DRUG PRODUCT Though many types of HPL chromatographic techniques are available, the most commonly submitted method, the reversed-phase HPLC with UV detection, is selected to illustrate the parameters for validation. The criteria for the validation of this technique can be extrapolated to other detection methods and chromatographic techniques. For acceptance, release or stability testing, accuracy should be optimized since the need to show deviation from the actual or true value is of the greatest concern. A. Accuracy Accuracy is the measure of how close the experimental value is to the true value. Accuracy studies for drug substance and drug product are recommended to be performed at the 80, 100 and 120% levels of label claim as stated in the Guideline for Submitting Samples and Analytical Data for Methods Validation. For the drug product, this is performed frequently by the addition of known amounts of drug by weight or volume (dissolved in diluent) to the placebo formulation working in the linear range of detection of the analyte. This would be a true recovery for liquid formulations. For formulations such as tablet, suppository, transdermal patch, this could mean evaluating potential interaction of the active drug with the excipients in the diluent. From a practical standpoint, it is difficult to manufacture a single unit with known amount of active drug to evaluate recovery. This test evaluates the specificity of the method in the presence of the excipients under the chromatographic conditions used for the analysis of the drug product. It will pick up recovery problems that could be encountered during the sample preparation and the chromatographic procedures. However, it does not count the effect of the manufacturing process. At each recommended level studied, replicate samples are evaluated. The RSD of the replicates will provide the analysis variation or how precise the test method is. The mean of the replicates, expressed as % label claim, indicates how accurate the test method is. Recommendations: Recovery data, at least in triplicate, at each level (80, 100 and 120% of label claim) is recommended. The mean is an estimate of accuracy and the RSD is an estimate of sample analysis precision. 但是ICH的相关指南（完整的文件见附件2）给出了更为详细的指导原则， 请注意测定CU时， 应该考虑70％， 100％，130％范围；测定溶出度或杂质时的规定又不一样了。 3. RANGE The specified range is normally derived from linearity studies and depends on the intended application of the procedure. It is established by confirming that the analytical procedure provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical procedure. The following minimum specified ranges should be considered: • for the assay of an active substance or a finished product: normally from 80 to 120 percent of the test concentration; • for content uniformity, covering a minimum of 70 to 130 percent of the test concentration, unless a wider more appropriate range, based on the nature of the dosage form (e.g., metered dose inhalers), is justified; • for dissolution testing: +/-20 % over the specified range; e.g., if the specifications for a controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24 hours, the validated range would be 0-110% of the label claim. • for the determination of an impurity: from the reporting level of an impurity （Please refer: chapters Reporting Impurity Content of Batches of the corresponding ICH-Guidelines: Impurities in New Drug Substances and Impurities in New Drug Products） to 120% of the specification; for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the detection/ quantitation limit should be commensurate with the level at which the impurities must be controlled. Note: for validation of impurity test procedures carried out during development, it may be necessary to consider the range around a suggested (probable) limit; 1 • if assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities to 120% of the assay specification. |
4楼2008-09-13 12:37:49
