AMRI’s Global Analytical Services Introduces Comprehensive Forced Degradation Services

AMRI’s Global Analytical Services is pleased to launch a new comprehensive forced degradation service to meet the industry demand for supporting drug substance, product including medical devices, and associated packaging system development and commercialization.

“We are excited to introduce this service to help our customers navigate the lack of specific regulatory recommendations in available guidance documents on how to conduct forced degradation studies,” said Pamela A. Smith, PhD, Vice President, Global Analytical Services at AMRI. “This service is made possible by the union of industry-leading analytical capabilities from AMRI, SSCI, and Whitehouse Laboratories with the aim to provide essential knowledge to overcome one of the most often cited deficiencies in the chemistry, manufacturing, and controls (CMC) section of new drug and abbreviated new drug applications.”

Stability chambers 25°C/60%RH, 2°C to 8°C, 30°C/65% RH, 40°C /75% RH, low (-20°C to -10°C) and ultra-low freezer conditions (-70°C) and photostability are available at AMRI to achieve commonly used accelerated conditions prescribed by the International Conference of Harmonization (ICH). However, in a purposeful forced degradation strategy more severe conditions than these are often needed to establish the impurity profile for the product, provide knowledge about the possible chemical and physical degradation pathways, and guide the selection of excipients for drug product formulations and the design suitable packaging configurations.

For drug substance and drug product, stress is applied to test samples in solution and/or in the solid-state to evaluate acid and base hydrolysis, extreme temperatures, photolytic and oxidation conditions, and may also include freeze-thaw cycles. Stability-indicating methods are developed and validated to accurately measure the changes in active ingredients’ concentration with time, without interference from other degradation products, impurities, and excipients. AMRI’s Global Analytical Services offers a variety of advanced chromatographic techniques with various detectors to provide the sensitivity necessary to detect impurities at or below the ICH threshold limits. Preparative chromatography capabilities allow impurities at small to medium scale to be isolated. Identification and characterization of degradation product are performed based on formal stability results in accordance with ICH requirements. When required, nuclear magnetic resonance (NMR) spectroscopy is used along with high-resolution mass spectrometry (MS) techniques to elucidate the structures of unidentified impurities.

While forced degradation studies are often focused solely on chemical degradation, stress testing of the drug substance must also evaluate the potential physiochemical changes of the targeted polymorphic form to avoid unintended changes in properties outlined in ICH Q6A that can impact drug product performance.

For containers and medical devices, test samples are exposed to extreme conditions, as well as dynamic extractions (such as sonication) to meet the needs of ISO 10993 -13, 14, and 15. Stressed samples can be evaluated using a variety of chromatographic capabilities, such as HPLC, UHPLC, GC, with various detectors available. LC or UHPLC-high-resolution MS, MS/MS, or HRAM are available to provide either tentative or definitive structural identification of major degradants. A comprehensive extractable/leachable impurity database is also available to identify potential leachates – and their degradants – that may migrate from container/closure system or drug delivery device. The resulting impurity profile can then be further evaluated by structural activity relationship assessments (knowledge based and/or statistical based) as well as through traditional toxicological risk assessments, to identify and mitigate the risk associated with potentially genotoxic degradants, as required by ICH M7 and/or ISO 10993-17. If warranted, a leachable method also can be developed and validated. In the end, a stability-indicating method may be developed to separate all degradants, appropriately validated based on the need, and carried out for risk control over the concerning shelf-life of the article in question.

For packaging systems, in addition to the stress conditions cited above, physical forced degradation techniques, such as vibration and shock testing, are available. These techniques are used to evaluate the reaction of drug product and/or combination devices and packaging to temperature excursions and mechanical forces that might be encountered during the shelf-life of the product. Global Analytical Services at AMRI maintains a series of qualified test chambers to assist clients in evaluating and defining shelf life claims: high performance cycling chambers (-70°C to +140°C), -70°C through -90°C Cryogenic Storage, and various bench top and reach-in environmental chambers with capabilities from -70°C to +190°C for developmental studies. AMRI’s Whitehouse Laboratories is an ISTA- and ISO 17025-certified testing laboratory and provides distribution simulation services (shock and vibration) in accordance with ISO 11608 and the most current test methods from ASTM and ISTA (International Safe Transit Association).