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
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
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 50°C 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.