AAPS Workshop Summary - Pharmaceutical Technology

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AAPS Workshop Summary
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. This article summarizes some of the topics presented at the AAPS workshop on various scientific aspects affecting pharmaceutical stability. A full summary can be read online at www.PharmTech.com/AAPSstability. A follow-up AAPS workshop on pharmaceutical stability is being planned for 2013.


Pharmaceutical Technology
Volume 36, Issue 11, pp. 66-68

ICH Q1B photostability guideline —time for a revision?
Steven W. Baertschi

The presentation, based on a recent publication (1), highlighted the deficiencies with the International Conference on Harmonization (ICH) Q1B photostability guideline implemented in the US, EU, and Japan. The presenters noted that since publication in November 1996, the guideline has provided a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution; however, the guideline does not cover the photostability of drugs under conditions of patient use. Areas that would benefit from revision include specifications of the option 2 UVA and visible lamp choices as well as the current recommendation of quinine as an actinometer, which should be specified only for a specific option 2 UVA lamp. These assertions were supported with examples and literature references.

Designing stability studies for global development programs
Bekki Komas

A global approach to stability beyond ICH requirements was discussed. Case studies on post-approval changes and emerging market draft guidelines were shared. A decision tree with consideration of product stability and the countries where the drug is marketed provided a clear recommendation for long-term and accelerated stability conditions. Current emerging market draft guidelines including the draft ASEAN stability and variations guidelines and challenges associated were outlined for group discussion. Key messages from the presentation were that regional stability guidance exists for emerging markets and may be different from the WHO stability guideline. Science- and risk-based approaches are not always accepted. Some new guidelines indicate an acceptance of stability commitments instead of upfront data for process changes. The ICH Global Cooperation Group, which includes six regional harmonization initiatives APEC, ASEAN, Global Cooperation Council, PANDRH, SADC East Africa Community, are making improvements towards harmonization.

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

This presentation was based on a recent publication (2) that showed that duloxetine hydrochloride, a secondary amine containing pharmaceutical, undergoes N-formylation as an artifact of sample preparation prior to HPLC analysis for impurities. 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. This reaction can be eliminated or minimized by replacing acetonitrile with methanol, or by simply adding at least 10% methanol to the sample diluents. The authors provided a rationale for the use of methanol considering that 1) sonication is commonly used to aid dissolution of pharmaceuticals in acetonitrile for HPLC analysis, 2) titanium dioxide is a commonly used excipient, 3) the amount of light found in modern analytical laboratories is sufficient to trigger this reaction, and 4) secondary amines are present in the structures of many pharmaceuticals.

Strategies for controlling genotoxic degradants in drug products: mitigation strategy and a case study
Brian W. Pack, Evan M. Hetrick, Linda Dow, Steve Baertschi, and Marvin Hansen

This presentation outlined a novel strategy implemented at Eli Lilly that hinged upon stress studies which have been well designed to understand the most probable degradation pathways a compound may undergo, thus limiting the number of potential degradation products to assess for genotoxic potential. The development of an analytical method with a limit of quantification (LOQ) at 10% of the threshold of toxicological concern (TTC) was recommended if the potential degradant had an alerting structure and was Ames positive. It was proposed that an inactive degradation pathway of <10% TTC in the drug product long-term stability profile indicated that appropriate due diligence had been demonstrated, and hence would pose no risk to patient safety. The speaker used a case study to demonstrate that genotoxic impurities (GTI) levels at the end of the recommended shelf life can be predicted with the information based on Arrhenius predictions from accelerated stability studies used to quickly screen multiple formulations. This approach enables informed decisions to be made around formulation, package, and storage conditions relating to GTI formation.

Dissolution failure and failure mode analysis of a hot-melt extrusion product—a case study
Saji Thomas

The step-by-step investigation of a dissolution failure of a melt extrusion product, which failed at six months under accelerated stability conditions, was discussed as case study. Because the initial investigation did not result in identifying the root cause, a five-factorial/eight-experiment design was used to evaluate the robustness of the method based on a normal probability plot of the data generated from the DOE. Products cured at 50C were analyzed using solid-state nuclear magnetic resonance (SSNMR), environmental electron scanning microscope, and time of flight-secondary ion mass spectroscopy (TOF–SIMS). The dissolution failure was found to be caused by the stearyl alcohol migrating to the surface of the product when exposed to heat.


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