Impurities/degradants information

During early phase development there is limited knowledge about the chemistry of the new chemical entity (NCE) with respect to synthetic impurities and degradation pathways and kinetics. It is, therefore, desirable to develop an array of methods that show applicability to a broad range of potential impurities, degradation products, and excipients. The methods are intended to provide the information necessary to guide the improvement of a synthesis route or a new drug formulation. 

Once a database is established, it is made available to other laboratories through the company s secured intranet, so that the information therein can be updated, retrieved and reviewed. The resulting structural library can be referenced throughout the lifetime of the drug for rapid identification of impurities, degradants, and metabolites. 

It is prudent to evaluate impurity peaks observed in a supplier s bulk substance and compare them with those observed in the drug product. The extent that the peaks differ may determine the need to obtain further information, including toxicity. Samples of impurities/degradation products methods should be appropriately validated by the ANDA sponsor for their sensitivities and specificities. It also is recommended that the sponsor of an ANDA set up and maintain a stability program for the bulk drug substance. 

Supporting information for known impurities, degradation pathways, and products... 

Now that we know what some of the tools are, the following will illustrate the utility of MS in the arena of impurity/degradant identification using these tools. Recognize that we have left out a large variety of very valuable and interesting areas and aspects of MS, in order to focus on the analysis of pharmaceutically important compounds. Resources and information on other aspects of MS can be found in the following. 

For non-compendial procedures, the performance parameters that should be determined in validation studies include specificity/selectivity, linearity, accuracy, precision (repeatability and intermediate precision), detection limit (DL), quantitation limit (QL), range, ruggedness, and robustness [6]. Other method validation information, such as the stability of analytical sample preparations, degradation/ stress studies, legible reproductions of representative instrumental output, identification and characterization of possible impurities, should be included [7], The parameters that are required to be validated depend on the type of analyses, so therefore different test methods require different validation schemes. 

As the approach detailed above can result in the generation of numerous samples to be screened, it is frequently possible to combine some solutions into a set of selectivity solutions for some method development activities. However, there is also merit in analyzing the individual solutions separately to obtain information on degradation pathways and DS impurities that can facilitate the understanding of drug chemistry. 

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