Accelerated stability and forced degradation studies

Accelerated stability and forced degradation studies are critical to the development and regulatory approval of new biologics.

These studies are helpful for early-stage molecule design and candidate selection, manufacturability evaluation, and formulation development. Furthermore, they can facilitate degradation monitoring, device compatibility tests, and manufacturing comparability assessments before and after market approval. Changes to the formulation, packaging, or product use may also require additional stability testing of a previously described drug substance.

Supplementing the accelerated stability and forced degradation experiments with LC-MS analysis is particularly useful for evaluating product performance and the impact of drug substance and process parameters on product quality. Most of our clients use forced degradation studies multiple times during the product lifecycle to determine degradation pathways of candidate molecules during the clinical phases from IND to Phase III.

Protein-based medicines and vaccines are particularly susceptible to chemical degradation and physical instability, potentially resulting in aggregation or loss of potency. Drug product stability depends on environmental factors (ambient temperature, humidity, and light) and product-related factors (the biochemical and biophysical properties of the active pharmaceutical ingredients and excipients).

The ICH guidelines recommend stress-testing biologics to identify and characterize likely degradation products and to establish degradation pathways and the intrinsic stability of the molecule. Accelerated stability and forced degradation studies supported by LC-MS comply with regulatory requirements and may speed up getting a biologic on the market while ensuring the quality, safety, and efficacy of the drug product.

You can use stability and degradation studies to determine the proposed shelf life and expiration date of new drug substances and/or drug products. Furthermore, the studies highlight the influence of environmental factors, which you can use to determine the optimal transportation and storage conditions. Finally, you can use the results to validate which specific test parameters are best for monitoring product stability to ensure overall quality.

Stability-indicating methods (SIMs) are quantitative analytical procedures used to measure concentration decreases of a drug substance over time due to degradation. According to regulatory authority guidelines, SIMs must be validated for linearity, accuracy, precision, specificity, quantitation limit, detection limit, ruggedness, and robustness.

Various HPLC-UV methods are the most used SIM for impurity quantification. However, compounds with similar molecular weights often exhibit similar UV profiles, which means the drug peak in the HPLC readout may hide peaks from impurities or degradants that co-elute with the drug.

To determine the suitability of the SIM, you can use LC-MS peak purity analysis to demonstrate the spectral peak's homogeneity. If the analysis shows that the peak is heterogeneous, we can help you optimize the HPLC array for separating closely eluting peaks to reveal impurities or degradants of concern.