The role of degradant profiling in active pharmaceutical ingredients and drug products

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Abstract

Forced degradation studies are used to facilitate the development of analytical methodology, to gain a better understanding of active pharmaceutical ingredient (API) and drug product (DP) stability, and to provide information about degradation pathways and degradation products. In order to fulfill development and regulatory needs, this publication provides a roadmap for when and how to perform studies, helpful tools in designing rugged scientific studies, and guidance on how to record and communicate results.

Section snippets

Regulatory requirements

From a regulatory perspective, forced degradation studies provide data to support the following:

  • identification of possible degradants

  • degradation pathways and intrinsic stability of the drug molecule

  • validation of stability indicating analytical procedures.

Issues addressed in regulatory guidances include:

  • Forced degradation studies are typically carried out using one batch of material.

  • Forced degradation conditions are more severe than accelerated stability testing such as > 50 °C; ≥ 75% relative

Forced degradation timing and strategy

The requirements for forced degradation testing depend on project needs and the stage of development of the compound. For example, pre-clinical through phase 2 project needs dictate intense method development, and the rate of compound attrition is high. Therefore, when developing a rational study design, forced degradation deliverables should be focused on method development activities, and not isolation and identification of degradants. As a compound progresses into later phase 2 through

CAMEO

CAMEO [5] is a computer program that predicts the products of organic reactions given starting materials, reagents and conditions (see Fig. 1, Step 1: Predict degradants). The analyses cover the following key degradation conditions: basic/nucleophilic, acidic/electrophilic, radical, oxidative/reductive and photochemical as well as mechanistic interpretations of these reactions. In general, the CAMEO algorithms have been designed to give product mixtures that err on predicting more degradation

Experimental approach tools

Forced degradation studies of API and DP include appropriate solid state and solution state stress conditions (e.g. acid/base hydrolysis, heat, oxidation, and light exposure) in accordance with ICH guidelines (Fig. 1, Steps 2 and 3: Design protocol and perform experiments) [1], [6]. Forced degradation studies should be conducted whenever a stability indicating method is required. Studies may need to be repeated as methods, processes, or formulations change. The tables in Appendix A General

Stability-indicating method development

A stability-indicating method is defined as an analytical method that accurately quantitates the active ingredients without interference from degradation products, process impurities, excipients, or other potential impurities. A method that accurately quantitates significant degradants may also be considered stability-indicating. A proactive approach to developing a stability indicating HPLC method should involve forced degradation at the early stages of development with the key degradation

Degradation database

A structure-searchable degradation profile database has been created to compile API/DP degradation data and share degradation knowledge globally at Pfizer (Fig. 1, Step 8: Document degradants and mechanisms) [14]. The database is a web-based system. It was developed to address certain key goals including: improve communication, minimize duplication of effort, and establish a proactive approach to drug stability, predict problems and identify trends in data. With the degradation profile

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This review is part of the Advanced Drug Delivery Reviews theme issue on “Pharmaceutical Impurities: Analytical, Toxicological and Regulatory Perspectives".

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