In 1990 the USA, Japan and Europe collaborated through the “International Conference on Harmonization” (ICH) to set guidelines defining acceptable requirements to enable global regulatory registration of a study in support of marketing approval. Within this framework multiple guidelines have been agreed for the design and interpretation of Stability Studies. While the ICH are particularly focused on pharmaceuticals for human health, the principles and evaluation are relevant to all products Approved for Marketing by the United States Food and Drug Administration (US FDA).
In 1991 the Center for Devices and Radiological Health (CDRH), a Division of the FDA defined Stability as “the extent to which a product retains, within specified limits and throughout its period of storage and use (i.e., its shelf life), the same properties and characteristics that it possessed at the time of manufacture.” According to the FDA Code of Federal Regulations (CFRs), all human pharmaceuticals, biopharmaceuticals, IVD reagents and consumables marketed in the U.S. must undergo testing to determine stability. Thus, a manufacturer wishing to market a product must provide data to support the requested shelf life/ expiration dating under the selected storage conditions.
Our team uses both ICH guidelines and the CFRs when considering stability study design. These documents provide the roadmap for examining stability of products in both accelerated and real-time studies.
Q1A(R2): Stability Testing of New Drug Substances and Products
Q5C: Quality of Biotechnological Products – Stability Testing of Biological Products
FDA CFRs and Guidelines include:
21 CFR 211.166 Stability Testing
Guidance for Industry Q1E Evaluation of Stability Data
Data obtained from stability tests incorporating both accelerated studies and real-time is often used to establish the “shelf life” of therapeutic and diagnostic products.
In accelerated stability testing, a product is stored at high temperatures and/or humidity, often referred to a stress testing. Use of stress conditions to predict future real-time stability at lower temperatures is a generally accepted methodology to rapidly assess stability in diagnostic and therapeutic products. The use is based on the Arrhenius equation which has been shown to support the temperature dependence of chemical reaction rates. The Arrhenius equation relies on the fact that chemical degradation increases with an increase in temperature. While accelerated testing and the use of the Arrhenius equation does have some limitations, degradation at the recommended storage conditions can somewhat predict the product stability using known relationships between the acceleration factor and the degradation rate. In real-time stability testing, a product is stored at recommended storage conditions and monitored until it fails product specifications. While accelerated testing is suitable for early studies, the real-time stability study is the “Gold Standard” for establishing the product shelf life.
The Kemp Proteins “Team” have developed, performed and reported on both real time and accelerated/stress stability studies for clients developing both therapeutic and in vitro diagnostics. Our experienced staff will assure that your stability study is conducted under the appropriate conditions for your biologic or IVD. Working with you, we can design appropriate developmental stability studies for a variety of protein-based products. Products can be stored under the following temperature and humidity control:
-130 oC to -190 oC (LN2)
-20oC ± 3oC
5oC ± 3oC
25oC ± 3oC
30 oC to 80 oC
30oC to 80oC ± 3oC at 50% to 80%RH ± 5%
Our Analytical Team is experienced in working with a range of methodologies (Analytical Services) for determining the stability of various proteins and protein like products. Using these techniques and the modern equipment in Kemp Proteins’ Analytical Group, we can provide data to support the stability of a protein product based on identifying changes in size and conformation, aggregation, chemical and activity profiles as compared to the reference standard.
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