Stability testing is required to demonstrate the pharmaceutical product meets its acceptance criteria throughout its lifetime and to gain regulatory approval to extend a previously approved shelf life. The birth of ICH Q1A in 1993 began the harmonization of worldwide stability requirements, and initiated the development of a series of further ICH stability guidelines. The resources required to conduct stability tests of mature products in line with these current ICH standards can be very large, and companies struggle to balance efficiency with diverse worldwide regulatory requirements. This symposium discussed several current stability issues, including shortfalls in existing compendial monographs, using stability data to set specifications, special stability challenges for filings in non-ICH regions, and the path to further harmonization of worldwide regulatory requirements
Tim Wozniak, Eli Lilly, opened the symposium, presenting “Stability Issues and Initiatives From a Compendial Perspective.” Compendial monographs and General Chapters play an important role with respect to assessing the stability of drug products. Monographs can be used to support the innovators marketed products, generic drug products, and for clinical trial comparators. Specific monographs are intended to ensure the quality and performance of the drug product throughout its expiry dating. A key component of a monograph is the ability of the sum total of the tests to demonstrate that the drug product is compliant with the defined acceptance criteria, including stability-indicating tests where appropriate. The applicability of General Chapters as either guidances or as legal requirements was discussed, and the concept of verification and validation of the compendial monographs was introduced. Looking forward, much work remains to be done to update the monographs of legacy products and ensure the quality of future monographs.
Abbie Gentry, McNeil Pharmaceuticals, continued the session with “Establishing Impurities Specifications for New Drug Products.” New drug products such as pediatric dosage forms, modified release dosage forms or combinations of active ingredients are often developed as part of lifecycle management of pharmaceutical compounds. The new drug products may demonstrate different rates of degradation formation, as well as the formation of new degradants relative to the original drug product. In addition, assessments of the stability of the new products may be made with limited data at the long-term storage condition. Discussion centered on strategies for predicting and assessing drug product stability of these complex formulations. Specific topics included: limitations of preformulation studies, and kinetic and equilibrium
Justina Molzon, CDER/FDA, presented “Current International Harmonization Efforts: Opportunities and challenges—Regulator’s Perspective.” Efforts towards international cooperation or harmonization can occur at varying levels. They could be at the level of technical and scientific requirements, the level of format and content of dossiers or the level of assessment and review practices. The contrasting models for regional cooperation in drug regulation were described and compared. Regional cooperative efforts currently underway, the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) and the Pan American Network for Drug Regulatory Harmonization (PANDRH), a harmonization initiative under the aegis of the Pan American Health Organization, were explained in terms of these models. The challenges presented by both ICH and PANDRH were discussed and solutions for a way forward will be presented.
Manuel Zahn, Astra Zeneca, explained the scientific rationale behind the assertions of regulators in many Southeast Asian and South American countries that the ICH stability guidances do not sufficiently represent the range of temperature and humidity conditions that may be expected in these markets. He presented actual climatic data from each region to demonstrate the worstcase temperatures and partial water vapor pressures, and used this to classify hot and humid countries into either Climatic Zone IVA or IVB. His presentation titled “Trying to Cover It All—From Brazil via Jordan to ASEAN: A Risk Based Approach to a Global Stability Testing Protocol,” explained the scientific rationale behind more extreme long-term stability testing conditions which have been established for the following countries with tropical and subtropical moist climates: Southeast Asian countries (ASEAN), Brazil and other countries in South America, China (Mainland), Hong Kong, and Macau, South Africa and most of the other countries in southern Africa (SADC), some Caribbean Islands, Northern and Eastern Africa, the Arabian Peninsula, the Middle East and Southern Asia. The temperatures and partial water vapor pressure values found have been compared to different stability testing conditions, establishing a method to calculate safety margins and the probability of failure of a product in a particular market. As a result of this risk assessment, an appropriate long-term stability testing condition is proposed for each selected country. In addition to the long-term testing condition 25°C/60% RH for markets in Climatic Zone II, the hot and humid countries are categorized as either belonging to category Climatic Zone IVA, for which testing at 30°C/65% RH would be sufficient, or to Climatic Zone IVB, with suggested testing at 30°C/75% RH.
A panel discussion was gathered at the end of the symposium with much interest regarding the above issues. Much effort will be needed in the industry to harmonizing the storage requirements for a cost-effective stability program as well as optimizing stability operations to balance efficiency with the requirements to ensure patient safety and meet regulatory requirements worldwide.
From left to right, Capt. Justina Molzon (CDER/FDA), Dr. Abbie Gentry (McNeil), Dr. Tim Wozniak (Eli Lilly) and Dr. Manuel Zahn (AstraZeneca).