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  • Forced Degradation Studies for Drug Substances & Drug Products- Scientific Considerations

    Forced degradation or stress testing is commenced to determine specificity when developing stability-indicating methods, particularly when little information is available about potential degradation products. These studies also provide information about the degradation pathways and degradation products that could form during the storage of drugs substances and drug products. Forced degradation studies may help facilitate pharmaceutical development at various stages as well in areas such as formulation development, manufacturing, and packaging, and stability studies in which knowledge of chemical behavior can be used to improve a drug product.

    The objective of forced degradation –

    1. Development of the degradation pathways of drug substances and drug products.
    2. To identify the chemical characteristics of drug molecules.
    3. Structure elucidation of the structure of degradation products.
    4. To resolve stability-related problems and establishment of the intrinsic stability of a drug substance in the formulation.
    5. To generate the stability-indicating nature of a developed method.
    6. More stable formulations are generated by these studies and the shelf life of drug products

    Experimental approach for forced degradation studies-

    Forced degradation is carried out to produce representative samples for developing stability-indicating methods for drug substances and drug products. The criteria for selecting stress conditions should depend upon the decomposition of the product under normal manufacturing, uses condition, and storage specifications which are specific and different for each drug substance and drug product. Stress factors suggested for forced degradation studies include acid and alkali hydrolysis, thermal degradation, photolysis, and oxidation. All force degradation conditions are mentioned in the below table. There is a number of specification in regulatory guidelines regarding the conditions of pH, temperature, thermal condition, and oxidizing agent used.

    Degradation conditionExperimental conditionsStorageRequirements (Temperature in °C)Sampling time (in days)
    HydrolysisControl API 0.1M HCl 0.1M NaOH Acid control Base control pH 2,4,6,840°C, 60°C1,3,5
    Oxidation1-3% H2O2 Azobisisobutyronitrile (AIBN)25°C, 60°C1,3,5
    PhotolyticOption 1 Option 2D65/ID65  emission light Cool white fluorescent lamp/near UV fluorescent lampLight provides overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200-watt hours/square meter
    ThermalHeat chamber60°C 60°C/75% RH1,3,5

    Characterization by analytical techniques

    Various methods can be used for the identification and characterization of forced degradation products. The most commonly used technique is reverse-phase high-performance liquid chromatography (HPLC). RP-HPLC is chosen because of its compatibility with aqueous and organic solutions, high precision, sensitivity, and ability to detect polar compounds.

    Acidic and basic stressed samples should be neutralized before analysis. Dilution of samples should be carried out depending on the analytical technique used. The calculation should not include a blank. Based on stability results, degradation product identification and characterization shall be performed with ICH requirements. Conventional methods (e.g., column chromatography) or hyphenated techniques (e.g., LC-MS, LCNMR) can be used in the identification and characterization of the degradation products. LCMSMS plays a significant role in the development of the whole degradation pathway of the drug molecule. LCMS help to illustrate the structures of the major degradants. Similar molecular weights compounds may exhibit similar UV profiles, in such cases; attempts must be made to modify the chromatographic parameters to achieve necessary separation.

    Peak purity analysis:

    Peak purity is used as an aid in stability indicating method development. The spectral uniqueness of a compound is used to establish peak purity when co-eluting compounds are present. Peak purity or peak homogeneity of the peaks of interest of unstressed and stressed samples should be established using spectral information from a diode array detector. When instrument software is used for the determination of the spectral purity of a peak, relevant parameters should be set up in accordance with the manufacturer’s guidance. Attention should be given to the peak height requirement for establishing spectral purity.

    Forced degradation studies of the new drug substances and drug products are important to help for developing and determining the specificity of stability indicating methods and also help to determine the degradation pathways and degradation products of active ingredients and structure elucidation of the degradants. They were also useful in the investigation of the chemical and physical stability of crystal forms, the stereochemical stability of the drug substance alone, and mass balance issues in formulations. It is better to start degradation studies earlier in the drug development process to have sufficient time to gain more information about the stability of the molecule. This information will further help in the formulation manufacturing process and determine the storage condition of drug substances and drug products. As there is no specific regulatory guidance for forced degradation, it is recommended to use appropriate conditions to achieve 5-20% degradation.

    References

    1. ICH Harmonized Tripartite Guideline stability testing- https://www.ich.org/page/quality-guidelines
    2. https://www.fda.gov/media/71713/download
    3. https://www.researchgate.net/publication/312134267_Forced_Degradation_Studies
    4. https://www.researchgate.net/publication/260420032_Pharmaceutical_Forced_Degradation_Studies_with_Regulatory_Consideration
    5. USP general chapter <1225> Validation of compendial methods