FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions. (Part-02).
Stress conditions
Typical stress tests include four main degradation mechanisms: heat, hydrolytic, oxidative, and photolytic degradation. Selecting suitable reagents such as the concentration of acid, base, or oxidizing agent and varying the conditions (e.g., temperature) and length of exposure can achieve the preferred level of degradation.
Over-stressing a sample may lead to the formation of secondary degradants that would not be seen in formal shelf-life stability studies and under-stressing may not serve the purpose of stress testing. Therefore, it is necessary to control the degradation to a desired level.
The generally recommended degradation varies between 5-20% degradation. This range covers the generally permissible 10% degradation for small molecule pharmaceutical drug products, for which the stability limit is 90%-110% of the label claim.
In an attempt to minimize deficiencies in the ANDA submissions, some general recommendations to conduct forced degradation studies, to report relevant information in the submission, and to utilize the knowledge of forced degradation in developing stability indicating analytical methods, manufacturing process, product handling, and storage are provided in this article.
| Photostability testing should be an integral part of stress testing, especially for photo-labile compounds. Samples of drug substance, and solid/liquid drug product, should be exposed to a minimum of 1.2 million lux hours and 200 watt hours per square meter light. The same samples should be exposed to both white and UV light. To minimize the effect of temperature changes during exposure, temperature control may be necessary. The light-exposed samples should be analyzed for any changes in physical properties such as appearance, clarity, color of solution, and for assay and degradants. The decision tree outlined in the ICH Q1B can be used to determine the photo stability testing conditions for drug products. The product labeling should reflect the appropriate storage conditions. Thermal stress testing samples of solid-state drug substances and drug products should be exposed to dry and wet heat, whereas liquid drug products can be exposed to dry heat. It is recommended that the effect of temperature be studied in 10 °C increments above that for routine accelerated testing, and humidity at 75% relative humidity or greater. Testing at multiple time points could provide information on the rate of degradation and primary and secondary degradation products. In the event that the stress conditions produce little or no degradation due to the stability of a drug molecule, one should ensure that the stress applied is in excess of the energy applied by accelerated conditions (40 °C for 6 months) before terminating the stress study. Acid and base hydrolytic stress testing can be carried out for drug substances and drug products in solution at ambient temperature or at elevated temperatures. The selection of the type and concentrations of an acid or a base depends on the stability of the drug substance. A strategy for generating relevant stressed samples for hydrolysis is stated as subjecting the drug substance solution to various pHs (e.g., 2, 7, 10–12) at room temperature for two weeks or up to a maximum of 15% degradation. Hydrochloric acid or sulfuric acid (0.1 M to 1 M) for acid hydrolysis and sodium hydroxide or potassium hydroxide (0.1 M to 1 M) for base hydrolysis is suggested as suitable reagents for hydrolysis. For lipophilic drugs, inert co-solvents may be used to solubilize the drug substance. Attention should be given to the functional groups present in the drug molecule when selecting a co-solvent. Analysis of samples at various intervals can provide information on the progress of degradation and help to distinguish primary degradants from secondary degradants. Oxidative degradation Hydrogen peroxide is used predominantly because it mimics possible presence of peroxides in excipients, other oxidizing agents such as metal ions, oxygen, and radical initiators can also be used. Selection of an oxidizing agent, its concentration, and conditions depends on the drug substance. Solutions of drug substances and solid/liquid drug products can be subjected to oxidative degradation. It is reported that subjecting the solutions to 0.1%-3% hydrogen peroxide at neutral pH and room temperature for seven days or up to a maximum 20% degradation could potentially generate relevant degradation products. |