Validation of Related-Substances Determination Methods for Detecting Unidentified Substances (A Review)
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Pharmaceutical Chemistry Journal, Vol. 54, No. 9, December, 2020 (Russian Original Vol. 54, No. 9, September, 2020)
STRUCTURE OF CHEMICAL COMPOUNDS, METHODS OF ANALYSIS AND PROCESS CONTROL VALIDATION OF RELATED-SUBSTANCES DETERMINATION METHODS FOR DETECTING UNIDENTIFIED SUBSTANCES (A REVIEW) N. A. Epshtein,1,* V. L. Sevast’yanova,2 and A. I. Koroleva2 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 9, pp. 48 – 56, September, 2020.
Original article submitted March 23, 2020. The review justifies the need to validate the linearity, relative accuracy, and precision of Related Substances methods for detecting unidentified substances. Various approaches and methods for the estimation of linearity, precision, relative accuracy, and other validation characteristics for unidentified impurities are considered. The conditions necessary for the correct application of these approaches are discussed. The term “main unidentified impurities” is proposed and justified for assessing the validation results. Acceptance criteria, examples, and recommendations are provided. Keywords: validation, related substances, unidentified substances, linearity, relative accuracy, precision.
Validation of Related Substances (RSB) procedures is the most complicated problem as compared to validation of other types of procedures used for quality control of active pharmaceutical ingredients (APIs) and medicines. This is especially clear when the necessary reference standards of identified impurities are not commercially available. However, the linearity, accuracy, and precision of procedures for determining impurities must be validated in any case according to instructions of the ICH guideline for Validation of Analytical Procedures [1] and pharmacopoeias [2 – 4]. In such a situation, the only solution may be validation of a procedure for all impurities and for unidentified impurities. It would seem that the need for validation of RSB procedures for unidentified impurities should be obvious. However, validation of procedures only for identified impurities is still often limited in practice. Hundreds of such publications appear on the Internet. Hence, attention is not paid to the fact that one of the main conditions is violated, i.e., analytical procedures must be validated for all regulated (determined) substances. 1 2 *
This condition is always observed in practice for procedures with regulated contents of several drugs in multi-component medicines, several preservatives, and several residual solvents. It should also be fulfilled for procedures in which the contents of unidentified impurities are regulated. It could be argued that the contents of unidentified impurities are unknown and that determination of unidentified impurities is necessary only for quality control of the product. However, such objections are unacceptable. Determinations of unidentified impurities must be precise and as accurate as possible for comparable and reliable product quality control. This is even more important because the total content of unidentified
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