Metals, limit tests

VALIDATION STUDY OF JP HEAVY METAL LIMIT TEST... 

In this chapter we describe characteristic validation procedures of the Heavy Metals Limit Test in the Japanese Pharmacopoeia (JP) [1]. Although an equivalent test is commonly listed in both the United States Pharmacopoeia and the European Pharmacopoeia, there are differences in the color reagents and conditions of sample preparation of the JP procedure. Heavy metals are defined in the JP as poisonous metallic impurities such as Pb, Bi, Cu, Cd, Sn, and Hg that form colored colloidal precipitates with sodium sulfide TS in a slightly acidic solution of pH 3 to 4. The level is expressed as the equivalent quantity of lead. 

In JP monographs, the specification value and testing procedure are described as a comparative limit test for the quantity of heavy metals that exist in drug substances as inorganic impurities. The permissible limit on the ppm scale for heavy metals (as Pb) is prescribed as the specification value. From the development stage to the establishment of the limit test method for a monograph, the validation in place has to be done for both the quantitative method for actual measurement and the comparative limit method with the control solution. However, the quantitative procedure has not been stated in the section on the heavy metals limit test in the JP s General Tests and other Japanese official... 

Accuracy. In the quantitative method that is used to measure the heavy metal quantity in the drug substance, the accuracy is usually represented by the recovery rate obtained from a spiked recovery test where lead is added to the samples. Since the heavy metals limit test specified in monograph specifications is a test where the intensity of coloring of the samples with sodium sulfide is compared with that of the control solution, it is necessary to confirm that heavy metal components can be detected fully in the process of test solution preparation. The Heavy Metals Limit Test in JP specifies four preparation methods for the test solutions. An appropriate method will be selected and used for further testing. The test method that gives the best recovery rate is to be adopted. The procedure is as follows ... 

Precision (Repeatability). To evaluate the repeatability as specified in the quantitative method of heavy metals in the drug substance, the drug substance samples are treated according to the test solutions and the control solutions preparation method selected from methods 1 to 4 of Heavy Metals Limit Test in JP. Take five or six aliquot samples collected from a single lot of homogeneous drug substance and determine the quantity of heavy metal in each sample aliquot using the prepared test and control solutions. The data obtained are statistically analyzed. 

The validation of heavy metals limit test method is required to evaluate the specificity and the detection limit of the limit test of impurities. However, since the JP method is capable of detecting Pb, Bi, Cu, Cd, Sn, and Hg, specificity evaluation for these metals is not required. The detection limit of the method should be evaluated visually. 

Detection Limit. The detection limit of heavy metals limit test method is obtained from the test solutions and the control solution. These solutions are prepared using one of methods 1 to 4 of the control solution preparation method. The detection limit is determined by visual inspection of a series of diluted standard lead solutions. 

The following are citations from the section on the preparation of test solutions and control solutions in JP 14, Heavy Metals Limit Test. Unless otherwise specified, test solutions and control solutions are prepared as directed below ... 

How should the criteria for selections from methods 1 to 4 of the test be established, and the solution preparation specified in the heavy metals limit test in JP be controlled ... 

Japanese Pharmacopoeia, JP XIV, General Tests, Processes and Apparatus, 26, Heavy Metals Limit Test, p. 43. See http //jpdb.nihs.go.jp/jpl4e/contents.html. 

Heavy metals limit test (41) Softening point... 

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