Pharmaceutical Stability: Scientific and Regulatory Considerations for Global Drug Development and Commercialization - Pharmaceutical Technology

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Pharmaceutical Stability: Scientific and Regulatory Considerations for Global Drug Development and Commercialization
A two-day workshop on the "science behind pharmaceutical stability" was held in conjunction with the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS) on Oct. 21-22, 2011 in Washington, DC.

Artifactual Formylation of the Secondary Amine of Duloxetine Hydrochloride by Acetonitrile in the Presence of Titanium Dioxide: Implications for HPLC Method Development

M. J. Skibic, Ph. D, et al.

This presentation was based on a recent publication in the Journal of Pharmaceutical and Biomedical Analysis (53, 432-439, 2010). The authors showed that duloxetine hydrochloride, a secondary amine containing pharmaceutical, currently marketed as Cymbalta, undergoes N-formylation as an artifact of sample preparation prior to HPLC analysis for impurities. They showed that the reaction is catalyzed by sonication and/or light in the presence of titanium dioxide and is proposed to occur via a hydroxyl radical-initiated mechanism. The proposed mechanism was supported by controlled sample preparation studies with deuterium-labeled acetonitrile, and LC/MS studies showed incorporation of one deuterium into N-formyl duloxetine, proving that the carbon of the formyl group was from the methyl group of acetonitrile. This artifactual reaction can be eliminated or minimized by the replacement of acetonitrile with methanol, or by simply adding at least 10% methanol to the sample diluents. The authors provided rationale for the use of methanol using computational chemistry to show how methanol is able to sufficiently scavenge the hydroxyl radicals to prevent the oxidation of acetonitrile. The authors discussed how this discovery is broadly relevant since sonication is commonly used to aid dissolution of pharmaceuticals in acetonitrile for HPLC analysis, titanium dioxide is a commonly used excipient, the amount of light found in modern analytical laboratories is sufficient to cause the reaction to occur, and secondary amines are present in the structures of many pharmaceuticals.

Strategies for Controlling Genotoxic Degradants in Drug Products: Mitigation Strategy and Case Study

Brian W. Pack,Ph. D. et al.

This presentation focused on genotoxic impurities (GTIs) in drug products, a topic currently receiving significant attention in the pharmaceutical industry. The EMA Guideline on the Limits of Genotoxic Impurities (2006) recommended that potential GTIs should be identified and when there is a structural alert, a bacterial reverse mutation assay should be conducted. In addition, it states potential degradation products of the drug substance and drug product should be considered for genotoxic potential with little guidance to determine those degradation products that may be reasonably likely to form. The authors outlined a strategy implemented at Eli Lilly that hinged upon well-designed stress studies to understand the most probable degradation pathways that a compound may undergo, thus limiting the number of potential degradation products to assess for genotoxic potential. Internal Lilly data was presented that illustrated that degradation products observed on long-term stability were a perfect subset of the major degradation products observed during stress degradation studies (n=15 drugs).

If the potential degradant had an alerting structure and was Ames positive, they recommended the development of an analytical method with an LOQ at 10% of the threshold of toxicological concern (TTC). They proposed that if the degradation pathway was inactive (more than 10% TTC) in the drug product on long-term stability that appropriate due diligence had been demonstrated and there is no risk to patient safety. The proposed strategy is novel in that the assessment of potential degradation products (i.e., those derived from stress degradation studies) is dictated not by subjective judgment of what degradation pathways might likely be active, but rather by well-designed stress studies. A final point made by the authors and supported by a case study was to leverage the information that can be gleaned from using Arrhenius predictions from accelerated stability studies in order to quickly screen multiple formulations in order to predict the GTI levels at the end of the recommended shelf life. They advocated that this approach enables formulation and analytical development to make informed decisions around formulation, package, and storage conditions as they relate to GTI formation.


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