Analytical Chemistry in Pharmaceutical Development

This area can cover a lot of ground. What I am referring to here is the work that is done after the characterization of an Active Pharmaceutical Ingredient (API) to determine and demonstrate chemical structure. However, the structural proof is essential in the Investigational New Drug (IND) application and New Drug Application (NDA) for a New Chemical Entity (NCE).

I will be covering the essentials of analytical chemistry and how it is used in pharmaceutical development in this blog. This first entry will discuss the testing of API.

In early development and for each synthetic process for a given API, the purity profile must be determined. The purity profile is critical in determining the safety profile of the API as it goes into animal studies. These animal studies qualify the impurities and a no-effect level is determined from these studies. Typically, very little is known at this early stage regarding the impurity profile. High Performance Liquid Chromatography (HPLC) is usually the method of choice in the analytical lab for pharmaceuticals. Most molecules have a UV absorbing moiety wihch provides sufficient sensitivity to quantitate the parent molecule as well as most impurities and degradation products. A long slow (shallow) gradient is recommended to fully separate impurities from the parent molecule. It is usually assumed that the impurities have a response factor of 1. That is to say that the molar extinction coefficient of these compounds in the mobile phase matrix is the same as that of the parent compound. Therefore, quantitation of these impurities can be determined initially using an area percent method.

Area percent quantitation is typically used prior to certification of a reference standard. Once a reference standard is qualified, quantitation of the parent compound and impurities can be performed using the external standard calibraion method. A reference standard is usually selected based upon it's extraordinary purity. The route of synthesis of the reference standard need not be the same as that of the API. There also may be additional purification steps taken on the reference standard lot such as recrystallization or chromatographic purification.

See Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients,
http://www.fda.gov/cder/guidance/4286fnl.pdf

For guidance on impurities in API, see ICH Q3A, Impurities in New Drug Substances, http://www.fda.gov/cder/guidance/4164fnl.pdf

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