Limit tests for metallic impurities

Describe the theory, apparatus and procedure involved in the limit tests for metallic impurities e. g., Pb2+, As3+ and Fe3+. 

AAS is used in a number of limit tests for metallic impurities, e.g. magnesium and strontium in calcium acetate palladium in carbenicillin sodium and lead in bismuth subgallate. It is also used to assay metals in a number of other preparations zinc in zinc insulin suspension and tetracosactrin zinc injection copper and iron in ascorbic acid zinc in acetylcysteine lead in bismuthsubcarbonate silver in cisplatinum lead in oxyprenolol aluminium in albumin solution and calcium, magnesium, mercury and zinc in water used for diluting haemodialysis solutions. 

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... 

Numerous specifications and control measures are employed to determine final product quality, the first of which is ensuring adequate quality of excipients and active ingredients. Excipient testing ensures compliance with compendial specifications, as well as specifications determined during development of the fill material and/ or shell formulation. Among these are limiting values for trace impurities, especially peroxides, aldehydes, some metals, and ionic salts. 

Elaborate the various limit tests recommended for the Non-metallic Impurities in official compendia e.g.,... 

Fluorescence measurements are useful in limit tests where the trace impurity is fluorescent or can be rendered fluorescent by chemical modification. An example is the determination of aluminium in water for use in haemodialysis solutions by formation of its salt with 8-hydroxyquinolone (Fig. 7.5) followed by quantifieation of the complex using fluorescenee speetrophotometry. The excitation wavelength is set at 392 nm and the emission is measured at 518 nm. This type of fluorescent complex can be used to determine low levels of a number of metal ions. 

In this chapter, validation studies for developing the quantitative and JP limit test methods for heavy metals described in Specifications and Testing Methods of the drug substance section are described. Procedures to evaluate validation characteristics concerning the validation items of each test method are described. Table 7.1 summarizes the validation characteristics required by JP for testing of impurities. 

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. 

Metallic picrates and oxalates should be absent, and other nitrocompounds should be present only in traces, The melting point or setting point carried out on a well-dried sample should be at least 20. The moisture content is generally limited to o i-o 3S per cent., and the ash to o-oS-o t per cent. this should not be of a gritty nature. Impurities insoluble in water should not exceed the uh content by more than 0 05 per cent. The picric acid should be almost completely soluble in benzene. Sulphates are restricted to 0 05 0 i per cent, as SO,). Chlorides and nitrates are sometimes tested for. Absence of lead in any form which might give rise to the formation of lead picrate is of special importance. Lead sulphate is, however, comparatively harmless. 

The comprehensive German development and testing of metallic high temperature-resistant materials for the application in helium systems and helium turbines at design temperatures up to 950 C (max. 1050 °C) have shown the need for a careful control of the helium atmosphere at a narrow limited band for the permissible impurities. 

Another approach is needed for procedures for the determination of impurities in active substances and excipients or degradation products in finished pharmaceutical products. These procedures may include quantitative assays as well as limit tests. Impurities of interest are various, including metals such as lead and other inorganic substances, catalysts, genotoxic impurities, residual solvents etc. Details can be found in the scientific guidelines on e.g. quality from EMA [22], see also Sect. 22.4.2. 

United States Pharmacopeia (USP) A federal agency who is responsible for all standards, limits, methods, and guidelines for aU pharmaceutical products made in the United States. After a 4-year review and approval process, it has just published Chapters <232>, <233>, and <2232> for the determination of elemental impurities in pharmaceutical products and dietary supplements, as a replacement for Chapter <231>, a 100-year-old colorimetric test for heavy metals. 

---