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Summary of Limit Test

Purity determinations are applied as part of the quality control of pharmaceuticals, their active pharmaceutical ingredients (and, if applicable, their excipients in case they are not yet obtained in compendial quality). This includes quantitative determinations, resulting in a definite statement of the quantity or concentration, as well as qualitative / semi-quantitative determinations with results allowing only conclusions to be drawn as to whether the impurity is present or not or whether it is below a certain limit value. Such determinations are also known as "limit tests". Some people will think back to a laboratory practical training in drug analysis during their studies with more or less enthusiasm when they hear the word "limit test"...

What are limit tests?
Limit tests are methods of purity testing that are used to detect (± frequently occurring) impurities that can only be tolerated in small quantities. In most cases, the substance to be tested is compared with a reference substance which contains the impurity of interest in a known concentration (comparison test). This enables a semi-quantitative statement to be made about the test substance.

Why are such limit tests important ?
The impurities that can be examined applying limit tests can be very diverse. They range from endotoxins, hepatitis C virus RNA and various (metal) ions to nitrosamines and arsenic, to name just a few examples. Depending on their diversity, different sources are the origin for these substances to become present in the drug, for example by using certain reagents during the (chemical) synthesis in the manufacturing process, by contaminated water, by uptake from the soil (e.g. in case of plant-based active ingredients), by bacterial or viral contamination or by release of unsuitable pipelines or, or, or... Depending on the substance class, such impurities may be harmless per se, but are reducing the therapeutic effect of the drug or, in excessive concentrations, they can cause damage to health or be carcinogenic or toxic. Their content must therefore be limited. This is why limit values are specified in the monographs of the pharmacopoeias or by the ICH Q3 guidelines.

How to perform limit tests in practice ?
If we’d like to examine an active pharmaceutical ingredient that is listed in a compendial monograph, we’ve got to check within the monograph which limit test(s) is / are to be used, prepare the corresponding test solution and then have a look into the general methods of the pharmacopoeia to see how this test is to be carried out. The reference solution containing the impurities’ limit value is also described there. Depending on the complexity (and topicality), spectroscopic or chromatographic (TLC, GC, LC, etc.) methods can then be used for the analysis, but in the simplest case only a visual examination by our eyes is applied. Depending on the chemical reaction, this can lead to cloudiness (such as the precipitation of chloride with silver nitrate) or a color reaction. Both the sample and the reference solution are treated in the same way. The degree of turbidity or the color intensity of the test solution is then compared with that of the reference solution.