Towards global stability protocols: a decade of lost opportunities
This year marks the 10th anniversary of the introduction of the International Conference on Harmonisation (ICH) guidance on stability testing of new drug substances and products (ICH Q1A(R2)) and the ancillary guidance on storage conditions (ICH Q1F). In 2003, the pharmaceutical industry thought that it had achieved its goal of globally acceptable stability requirements, but unfortunately, that early optimism rapidly dissipated. Less than two years later, the ASEAN (Association of South East Asian Countries) group had broken ranks with ICH guidance and introduced their own guideline on stability requirements. In particular, they mandated the use of 30°C/75%RH for the long term storage conditions for climatic zone IV (hot and wet).
This left WHO (the World Health Organisation) in an extremely difficult position. WHO had been an active collaborator in the ICH discussions and to facilitate harmonisation, they had agreed to change their recommended long-term storage conditions for zone IV to align with the ICH proposals. However, in October 2005, the WHO secretariat reached an agreement that WHO stability guidelines should be modified for zone IV and introduced a sub-division into zones IVa (hot and humid) and zones IVb (hot and very humid). In addition, they recommended that each zone would have different storage conditions; i.e. 30°C/65%RH (zone IVa) and 30°C/75%RH (zone IVb). Due to this divergence in global stability testing requirements, the ICH Steering Committee decided to withdraw ICH Q1F in mid-2006. ICH agreed to leave definition of storage conditions in climatic zones III and IV to the respective regions and WHO. The BRIC collective (Brazil, Russia, India, China) which accounts for more than one quarter of global GDP and constitutes more than 40 per cent of the world’s population (2.9 billion people) could find no consensus either. India adopted 30°C/70%RH, Brazil approved zone IVb storage conditions; whereas, Russia and China accepted zone IVa storage conditions. In 2009, WHO published a full listing of globally acceptable long term storage conditions for 183 different countries. There were eight different long term storage conditions reported: 25°C/60%RH (18.6 percent); 25°C/65%RH (0.5 per cent); 30°C/35%RH (0.5 per cent); 30°C/50%RH (0.5 per cent); 30°C/60%RH (0.5 per cent); 30°C/65%RH (65.0 percent); 30°C/70%RH (0.5 per cent) and 30°C/75%RH (13.7 percent). This graphically outlines the level of disharmony and the challenges facing companies trying to prepare global stability protocols.
Hence, after a decade of controversy and missed opportunities, is there any light at the end of this long, dark tunnel? The answer is yes! Whilst no major regulatory harmonisation initiatives are currently anticipated, there has been significant increase in the underlying science behind stability prediction; particularly the synergistic effects that humidity has on temperature. As a general guidance, the higher the relative humidity then the greater the anticipated level of both physical and chemical degradation. Thus acceptable stability performance at 30°C/75%RH can be typically used to predict acceptable stability of the same product (in the same pack) at lower temperatures and humidities; i.e. 30°C/65%RH or 25°C/60%RH, with the caveats that polymorphic modifications, hydrate formation, improved crystallinity (annealing, conditioning, etc.) can all affect chemical stability. A humidity correction of the well established Arrhenius equation can be used to provide dependable estimates of the combined effect of temperature and humidity on degradation rates. The temperature dependence of degradation can be modelled based on different activation energies. Similarly, the humidity dependence of degradation can be modelled based on limited effect to high effect (where the degradation rate doubles for every 10 per cent increase in relative humidity). Finally, the protective effect of the pack on the amount of available moisture experienced by the product within the pack can be assessed (using the MVTR (moisture vapour transmission rate) across the pack and moisture sorption isotherms of the naked product).
These methodologies produce reliable predictions of the degradation rate and can be used to ultimately predict shelf life. Thus, once a predictive model for product in the designated pack has been developed, it can be used to predict the effect of any proposed formulation change, pack change or any potential storage condition in any country in the world. Thus rationale risk based decisions can be made about which packs are set down in which storage conditions for how long, thus leading to more efficient, cost effective and time sensitive decision making, aligned with Quality by Design (QbD) approaches to product development.