In pharmaceutical industry, the forced degradation studies or stress studies demonstrate the degradation pathway of new drug substance and drug product at conditions more severe than accelerated conditions. It’s help to establish the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used.


Objectives of forced degradation studies

  • To identify the degradation pathways of a drug substance or a drug product.
  • To elucidate the structure of degradation products.
  • To understand the chemical properties of a drug substance.
  • To determine the intrinsic stability of a drug substance in formulation.
  • To develop a more stable formulation.
  • To select the right packaging material.


As per ICH guideline, examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. Where the stress studies include the effect of temperatures, humidity, hydrolysis across a wide range of pH values, oxidation, photo-stability etc. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved.


As per FDA recommendation, stress testing (forced degradation) is necessary only for identifying the routes of degradation and the suitability of the analytical procedures and need to submit during the third phase of the regulatory submission of the drug substance or drug product.


Usually the forced degradation studies are carried out in a drug substance or drug product by considering the related substances and assay during development stage and the studies should be performed through an approved protocol containing different stress factors. 


Types of degradation for a typical forced degradation studies considering related substances:

  • Alkali degradation
  • Acid degradation
  • Solution heating at 60°C
  • Thermal degradation
  • Peroxide degradation


Types of degradation for a typical forced degradation studies considering assay:

  • Acid Hydrolysis
  • Base Hydrolysis
  • Oxidation
  • Solution heating at 60°C
  • Thermal degradation
  • White fluorescent light exposure
  • UV light exposure


Degradation conditions

  • Thermal degradation: should be carried out at more extreme conditions than ICH Q1A recommended accelerated testing conditions.
  • Hydrolysis: is one of the most common degradation pathway over a wide range of pH.
  • Oxidation: hydrogen peroxide is widely used for oxidation of drug substances in forced degradation studies.
  • Photolysis: photo-stability should be conducted with white fluorescent light exposure and UV light exposure.


A systematic approach to photo-stability testing is recommended covering, as appropriate, studies such as:

  • Tests on the drug substance;
  • Tests on the exposed drug product outside of the immediate pack; and if necessary;
  • Tests on the drug product in the immediate pack; and if necessary;
  • Tests on the drug product in the marketing pack.


Reference:

  • ICH Q1A
  • ICH Q1B


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