Impurities/degradants strategy

For compounds with one or more stereocenters, it is prudent to screen the key samples (10-20% degradation timepoint) with the current chiral purity method to determine if the degradation pathway is stereospecific. From the achiral method development perspective, stereospecific degradation pathways will not affect the outcome of the method development process, but this information can affect the impurity control strategy for the compound. 

Chapter 14 provides practical guidance with case studies on isolating and characterizing process-related impurities and degradation products for pharmaceutical drug candidates. The case studies utilize isolation or synthesis in conjunction with mass spectral and NMR characterizations. A collaborative multiple disciplinary strategy has been found to be the most efficient way to solve impurity/degradation product problems. 

For the analytical use of MS/MS, other scan modes can be useful as well as the product-ion scan mode. The various modes are explained and summarized in Table 1. The precursor-ion and neutral-loss scan modes are particularly useful in screening. They are part of a powerful analytical strategy applicable in impurity, degradation product and/or metabolite profiling, as well as other applications where searching for structurally related compounds is important. After an appropriate ionization mode is found, a product-ion mass spectrum is obtained for the parent compound. In this spectrum, possible common precursor ions and/or common neutral losses have to be identified. 

From a regulatory standpoint, the FDA s concern regarding safety involves the toxicity, degradants, and impurities of excipients, as discussed in other chapters in this book. In addition, other chapters of this book address types of toxicity concerns, toxicity testing strategies, and exposure and risk assessment of excipients. 

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. 

Olsen BA, Baertschi SW. Strategies for investigation and control of process-related and degradation-related impurities in Pharmaceuticals. In Ahuja S, Alsante KM, eds. Handbook of Isolation and Characterization of Impurities in Pharmaceuticals, Volume 5 of Separation Science and Technology. San Diego, CA Academic Press, 2003. 

Obviously, the best way to develop a good method is to use all of the information that is available and not to rely solely on available impurities or partially degraded samples. For example, perhaps one or two impurities are available or are present in the drug substance. In this case the best strategy to develop a stability-indicating method is to use these impurities and to also generate partially degraded samples. 

The MS/MS identification strategy is based on the premise that much of the parent drug structure will be retained in the metabolites, impurities, or degradants (Perchalski et al., 1982 Lee et al.,... 

Preventive Strategy. The firm should have an SOP for the validation of analytical methods that contains specificity requirements. If so, the firm would have shown in the specificity portion of the validation that X and Y indeed form the critical resolution pair. If this were proven in the specificity section with confirmation of the resolution of unknown impurities during a purposeful degradation study, this FDA-483 citation would have been avoided. 

The strategy for impurity and degradant identification described by Rourick et al. subjects lead candidates to various development conditions followed by LC/MS and LC/MS/MS analysis protocols. A structure database is constructed from the corresponding results and is used to reveal unstable regions within the drug structure as well as to ascertain which candidate or homologous series of drug candidates may be the most favorable for further development. 

STRATEGIES FOR INVESTIGATION AND CONTROL OF PROCESS- AND DEGRADATION-RELATED IMPURITIES... 

The overall strategy for investigation and control of degradation-related impurities can be illustrated as shown in Figure 12. Stress testing studies provide the foundation for the overall strategy. Various parts of the strategy are explored in more detail below. 

FIGURE 12 Illustration of the overall strategy for investigating and controlling degradation-related impurities. 

The selection of the set of samples that best covers the impurity and degradation profiles of the API is critical to successful method development. For a given API there are several ways to design the method development sample set some of which are more advantageous, but incur more risk in terms of the ability to track peaks from column to column and condition to condition. This section will address method development sample set design strategies, experimental concerns, and trade-offs. 

Actual case studies using these isolation and syntheses as well as mass spectral and NMR approaches are outlined in the remainder of this chapter. This collaborative multidisciplinary strategy is applied to the structure elucidation of all the impurity and degradant case studies presented. The successful elucidation of these structures was essential to predict potential toxicity, set threshold limits, and identify ways to prevent or greatly reduce their formation. The case studies have been organized into degradation and process-related impurities examples. 

The aim in paper I was to develop a method capable of separating the product and the substrate from each other and from degradation products and impurities from the fermentation medium to enable rapid product identification. The aim in paper II was to develop a method for accurate quantitative analysis of both products and substrate with high precision. It was also desired that the strategies used in paper I and guidelines given in paper II should be useful for ordinary fermentation laboratories. 

As part of its operations between 1955 and 1977, a Finnish sawmill had been impregnating timber with a preservative to inhibit microbial degradation. This product, called Ky-5, contained a mixture of chlorophenols, namely, 2,4,6-trichlorophenol (7-15%), 2,3,4,6-tetrachlorophenol ( 80%) and pentachlorophenol (6-10%). Ky-5 also contained traces of polychlorinated phenoxyphenols and dibenzo-p-dioxins as impurities. Over the years this product had contaminated the soils around the sawmill. A cost-effective bioremediation strategy was needed that could be used at this site but also throughout Finland where 800 other sites of this type existed. 

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