Synthetic drug substances performance

Eollowing finalization of drug substance synthetic routes and drug product formulation, the focus shifts to the development of robust and transferable methods for post-approval support at quality control units. It is important to remember during the final stage of method development that achievement of separation conditions is only one of the necessary parameters for successful method implementation. Extensive studies to measure robustness and quantitative method performance are conducted to assure that the method performs as intended in quality control laboratories. It should be emphasized that successful method development requires extensive cooperation between the development laboratory and the receiving quality control laboratories. 

Chiral separations can be considered as a special subset of HPLC. The FDA suggests that for drugs developed as a single enantiomer, the stereoisomeric composition should be evaluated in terms of identity and purity [6]. The undesired enantiomer should be treated as a structurally related impurity, and its level should be assessed by an enantioselective means. The interpretation is that methods should be in place that resolve the drug substance from its enantiomer and should have the ability to quantitate the enantiomer at the 0.1% level. Chiral separations can be performed in reversed phase, normal phase, and polar organic phase modes. Chiral stationary phases (CSP) range from small bonded synthetic selectors to large biopolymers. The classes of CSP that are most commonly utilized in the pharmaceutical industry include Pirkle type, crown ether, protein, polysaccharide, and antibiotic phases [7]. 

It is absolutely essential that the accuracy be validated with the same quantitation method that is used in the control test procedure. Recovery deviations from the theoretical values while performing a calibration with a drug substance alone may indicate interferences between the analyte and placebo components. In such a case, the calibration should be done with a synthetic mixture of placebo and drug substance standard. Such interferences may also be detected by the separate determination of linearity for dilutions of the drug substance and for a spiked placebo. 

The second portion of this chapter describes the process development of nevirapine, a novel nonnucleoside reverse transcriptase (NNRT) inhibitor used in the treatment of AIDS. This case study details the evolution of the nevirapine process from conception in medicinal chemistry through process development, pilot plant scale-up, and commercial launch of the bulk active drug substance. Restricting the case study to nevirapine allows the process and rationale to be described in more detail. The authors are aware of the vast amount of excellent process development that has been performed in the commercialization of other drug products. The processes described herein are not necessarily a unique solution to this particular synthesis. To some extent, they reflect the culture, philosophy, raw materials, equipment, and synthetic tools available during this period of time (1990-1996) as well as the initiatives of the process chemists. 

In addition to support of the drug substance, analyses are performed on starting materials and any raw materials used in the last step of the synthesis. Small batches of the drug substance which will be used in animal toxicology and pharmacokinetic studies must also be analysed. Once a synthetic process and final form have been selected, an investigational new drug (IND) application is filed with the FDA. 

Solid-phase methodology was established in 1963 in pioneering work conducted by Merrifield in the area of peptide synthesis [19]. Interest in this synthetic strategy continues unabated to this day, particularly in connection with the production of new active components for drugs, since the repetitive amide bond formation performed in automated synthesisers lends itself ideally to the construction of extensive substance libraries by combinatorial chemistry [20]. 

Early methods of rational lead optimization sought to find a set of potential leads from a database of small molecules chemically similar to a known lead. The earliest of these techniques was performed by the synthetic chemist in the process of producing the next substance to test and was performed without the aid of a computer. The chemist would make a set of small changes to the structure and determine if those changes had a beneficial or detrimental effect on the efficacy. This process, called analog synthesis, is quite effective. Analog synthesis is the basis for medicinal chemistry and remains an important part of drug discovery today. 

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