Drugs impurity testing

Further, [2.2]paracyclophane-4-acetic acid, a potential drug candidate tested for its anti-inflammatory activity (NSAID could be resolved on the 0-9-(tert-butylcarbamoyl)quinine-based CSP with a = 1.12 Rs = 2.6) and elution order (R)-(-)- before (5)-(- -)-enantiomer [125]. Samples that were assessed to be enan-tiomerically pure by an enantioselective H-NMR spectroscopic method contained 6% and 8% enantiomeric impurity in S- and/ -enantiomers, respectively. This clearly reveals that enantioselective HPLC is a more powerful technique than NMR-methods to assess stereoisomeric purity, in particular, if the enantiomeric impurity amounts to less than 10%. 

Impurity testing is pivotal in pharmaceutical development for establishing drug safety and quality. In this chapter, an overview of impnrity evaluations of drug substances and products by HPLC is presented from both the laboratory and regulatory standpoints. Concepts from the development of impurity profiles to the final establishment of public specifications are described. Useful strategies in the identification and quantification of impurities and degradation products are summarized with practical examples to illustrate impurity method development. 

This chapter provides the novice and the experienced analyst with an overview of sample preparation techniques focusing on solid dosage forms. It describes the best practices in the dilute and shoot approach, and the tricks of the trade in grinding, mixing, sonication, dilution and filtration of drug products. Selected case studies of sample preparations for assays and impurity testing are used to illustrate the strategies, trade-offs... 

During the course of chemical development, impurity profiles in drug substances may change due to changes in synthetic route and changes in the size of the batch. ICH guidelines for Impurities in New Drug Substances (ICH Q3A), require that impurity test results for... 

Q6A Specifications Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Chemical Substances (including Decision Trees) Specification setting/ impurity testing... 

For the impurity test, the determination should be established by spiking drug substance or drug product with the appropriate levels of impurities and demonstrating the separation of these impurities individually and/or from other components in the sample matrix. Representative chromatograms should be used. 

Which performance criteria have to be evaluated depends also on the purpose of the method. Different ICFI/USP guidelines are set up for (1) identification tests, (2) impurity tests, and (3) assay tests. An identification test ensures the identity of an analyte in a sample by comparison to a known reference material. An impurity test is intended to confirm the identity of (limit impurity test) or to accurately quantify (quantitative impurity test) an impurity, defined as an entity which may normally not be present. An assay test finally implies the major component or active ingredient in a sample and quantifies the drug substance as such as a whole or the drug substance in a drug product. 

Q3 Impurity testing Q3A(R) Impurities in new drug substances (revised guideline)... 

FDA-483 issued for drug product. An impurity tested for and limited to X % in Y tablets is quantified by comparing its response directly to that of a standard Z. There is no response factor included in the method to correct for the differences in absorptivities between these two compounds or data to demonstrate that the response factors are similar or that the amount of this impurity will be overestimated if no response factor is included. 

---