Forced degradation studies for Drug Substances and Drug Products

Forced Degradation

Forced degradation is an important part of the drug development process as it provides knowledge about the degradation chemistry of drug substances and drug products. This knowledge is used primarily to develop stability-indicating analytical methods but is also useful for other purposes such as formulation development, packaging development and the design of the official stability studies. As there is no formal regulatory guidance for forced degradation, it is recommended to use appropriate conditions to achieve 5-20% degradation[1].

Degradation in QbD approach

A systematic process of manufacturing quality drug products that meet the predefined targets for the critical quality attributes (CQA) necessitates the use of knowledge obtained in forced degradation studies. A well-designed, forced degradation study is indispensable for analytical method development in a QbD approach. It helps to establish the specificity of a stability indicating method and to predict potential degradation products that could form during formal stability studies. Incorporating all potential impurities in the analytical method and establishing the peak purity of the peaks of interest helps to avoid unnecessary method re-development and revalidation.

Knowledge of chemical behaviour of drug substances under various stress conditions can also provide useful information regarding the selection of the excipients for formulation development. Excipients compatibility is an integral part of understanding potential formulation interactions during product development and is

a key part of product understanding. Degradation products due to drug-excipient interaction or drug-drug interaction in combination products can be examined by stressing samples of drug substance, drug product, and placebo separately and comparing the impurity profiles.

Information obtained regarding drug-related peaks and non-drug related peaks can be used in the selection and development of more stable formulations. For instance, if a drug substance is labile to oxidation, addition of an antioxidant may be considered for the formulation.

Knowledge gained in forced degradation studies can facilitate improvements in the manufacturing process. If a photostability study shows a drug substance to be photolabile, caution should be taken during the manufacturing process of the drug product. Useful information regarding process development (e.g., wet versus dry processing, temperature selection) can be obtained from thermal stress testing of drug substance and drug product[2].

In addition to develop stability indicating methods, studies of this nature provide information for degradation pathways and degradation products that could form during storage and transportation. Forced degradation studies may help facilitate pharmaceutical development as well in areas such as formulation development, manufacturing, and packaging, in which knowledge of chemical behaviour can be used to improve a drug product.

Table 1. Conditions generally used for forced degradation studies

[1] Trivikram Rawat et al /J. Pharm. Sci. & Res. Vol. 7(5), 2015, 238-241

[2] Ragine Maheswaran. FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions. Pharmaceutical

Technology 2012; 36:73-80