Drug substances synthetic impurities

Modern spectroscopy plays an important role in pharmaceutical analysis. Historically, spectroscopic techniques such as infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) were used primarily for characterization of drug substances and structure elucidation of synthetic impurities and degradation products. Because of the limitation in specificity (spectral and chemical interference) and sensitivity, spectroscopy alone has assumed a much less important role than chromatographic techniques in quantitative analytical applications. However, spectroscopy offers the significant advantages of simple sample preparation and expeditious operation. 

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... 

Understandably, the impurity profiles of the same drug substance produced by different S3mthetic routes will differ qualitatively and quantitatively. This is commonly observed when a drug substance is provided by different suppliers. For example, the HPLC chromatograms from samples of fluoxetine hydrochloride obtained from four different suppliers show the differences in the impurities produced by the presumably different synthetic routes (Figure 1.1) [7]. Supplier A is the innovator company. Supplier B is in Italy, and Suppliers C and D are in India. 

By understanding the manufacturing process and the stability of the drug substance, whether from synthetic, natural, or recombinant sources, the chemist is able to identify, control, and measure the impurities, and so the quahty of the drug substance and reproducibility from production batch to batch are maintained. 

Related substances impurities derived from the drug substance and therefore not including impurities from excipients. Related substances include degradation products, synthetic impurities of drug substance, and manufacturing process impurities from the drug product. 

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]. 

Finally, impurity analysis can also be utilized to demonstrate illegal use of patented reaction routes. The impurity profile of a drug substance is influenced by the synthetic route and the source and quality of the starting materials. Identification of impurities in drug prepared by two different manufacturers may provide valuable insight into the manufacturing route and determine if patent infringement has occurred, because certain impurities may be indicators of a specific synthetic route. 

Level III is applied during clinical phase III and for the submission, as well as for important intermediates, and corresponds to the ICH requirements. At this stage of development, the commercial synthetic process for drug substance is established, and important process and degradation impurities have been identified and synthesized. The final formulations and dosages have also been established. 

In addition to the residual solvents, polymorphic, solvatomorphic, and chiral impurities mentioned previously, impurities in a pharmaceutical compound or a new chemical entity (NCE) can originate during the synthetic process from raw materials, intermediates, and/or by-products. Raw materials are usually produced to lesser purity requirements than a drug substance. Therefore, it is easy to understand why they could include a number of components that in turn could have an impact on the purity of the drug substance. 

The profile of impurities in a new drug substance may change for a variety of reasons, such as process scale-up changes, synthetic route changes, and changes made to key intermediates. ICH decision trees help classify, qualify, and select limits for new molecular entities (NMEs). If an impurity exceeds the qualification threshold listed below in Table 3 (ICFI Q3A(R)), studies are needed to qualify that impurity in drug substances. 

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