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  • Forced Degradation Studies for Drug Substances and Drug Products – A Regulatory Considerations

    Various regulatory guidance is available which provides useful definitions and general comments about degradation studies. However, guidance concerning the scope, timing, degradation condition, and best practices for degradation studies is very general. Various issues related to stress testing are addressed in numerous guidance documents but not always in the context of stress testing. Therefore, stress-testing conditions should be realistic and not excessive.

    Forced degradation studies are also expected

    1. Structure elucidation of possible degradation pathways.
    2. Identification of degradation products that may be spontaneously generated during drug storage and during use.
    3. To facilitate improvements in the manufacturing process and formulations in parallel with accelerated pharmaceutical stability studies.

    Overview of regulatory authorities

    ICH Q1A – Testing of stability for new drug molecules and their products

    The intrinsic stability of drugs is determined using these guidelines. These guidelines are helpful in designing methods for determining the stability of drugs. According to Q1A, degradation depends on the respective drug molecules and the nature of drug products. To conduct these forced decomposition analyses on drug substances and their products several accelerated conditions were mentioned. Those conditions include the effects of temperature (>40°C), humidity (≥75% relative humidity), oxidation, photolysis, and a diverse range of pH (solution/suspension).

    ICH Q1B – Photostability testing of new drug substances and drug products

    These methods are used to estimate the photostability nature of drug molecules normally in the development stage. These guidelines provide knowledge about how to assess the photostability of molecules that are under study for stability studies. 

    ICH Q2B – Validation of analytical procedures: Methodology

    The ICH Q2B guidelines provide information about the protocols to be followed for the validation of different analytical protocols. This explains about usage of samples for forced degradation studies. It emphasizes that the samples should be subjected to stress under different accelerating conditions such as humidity and heat and further used for the determination of specificity.

    ICH Q3A Impurities in new drug substances

    ICH Q3A guidelines provide information about the determination of contaminants present in new drug molecules. This section provides insights about different aspects such as the identification, types, and specification of impurities, analytical protocols, and generation of reports.

    ICH Q3B Impurities in new products

    ICH Q3B provides information about analytical procedures. It is important for an analytical procedure to validate specific or non-specific degradation products under various stress conditions.

    EMA Guidelines

    This guideline covers the data for the type of studies performed, procedures used, and outcomes thus obtained from the analysis. It explains the stability testing for API and dosage forms. The development of the analytical method, validation of the method, degradation pathways, and intrinsic stability are also determined.

    FDA Guidelines

    FDA is providing guidelines for photostability analysis of newer drug molecules and their products. According to the FDA, degradation studies should be conducted using normal development conditions. It covers the degradation pathway of samples when they exposed are to light. These guidelines help to develop a stability-indicating method and also summarize the data of validation which are in turn helpful for confirmatory studies. Stress conditions used for forced degradation studies are pH, temperature, and oxygen.

    USP Pharmacopoeia: Validation of Compendia Procedures

    According to these guidelines, if degradation standards or contaminants are not available, the specificity can be estimated in comparison of the data with the results obtained from the analytes (containing the contaminants or degradation products) using an alternative procedure under the same accelerated conditions.

    National Health Surveillance Agency (ANVISA)

    It mentions the requirements regarding stability and forced degradation.  ANVISA was developed to promote public health and protect from risks caused by the production and use of various drug products. ANVISA coordinates states, districts, and municipalities, according to the Brazilian Unified Health System principles, so as to enhance the quality of life of the people.

    Japanese Pharmacopoeia

    It states that the proposed method should be specific, and be able to identify and estimate the amount of analyte present in the sample.  For comparative studies, if reference standard impurities are not available, samples will be exposed to stress conditions and degradation products may be used for further studies

    Forced degradation studies of new drug substances and drug products are essential to aid development and establish the specificity of stability-indicating methods and determine the degradation pathways. Knowledge acquired from these studies can be used to monitor formulation development and improvement in manufacturing and packaging processes.

    For marketing applications, current FDA and ICH guidance recommend the inclusion of the results, including chromatograms of stressed samples, demonstration of the stability-indicating nature of the analytical procedures, and the degradation pathways of the drug substance in solution, solid-state, and drug product. The structures of significant degradation products and the associated procedures for their isolation and/or characterization also are expected to be included in the filing. The experimental protocol for degradation studies will depend on the active ingredients and formulation involved because the chemistry of each compound is different. A target of not more than 10% of degradation of the active ingredient or exposure to energy in slight excess of accelerated storage is recommended.

    A compound may not necessarily degrade under a given stress condition.No further stressing is advised in these cases.

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    1. ICH Harmonized Tripartite Guideline stability testing-
    5. USP general chapter <1225> Validation of compendial methods