FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions - Pharmaceutical Technology

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FDA Perspectives: Scientific Considerations of Forced Degradation Studies in ANDA Submissions
The author outlines the scientific aspects of forced degradation studies that should be considered in relation to ANDA submissions.


Pharmaceutical Technology
Volume 36, Issue 5, pp. 73-80

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. A generic approach for stress testing has been proposed to achieve purposeful degradation that is predictive of long-term and accelerated storage conditions (7). The generally recommended degradation varies between 5-20% degradation (710). 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. Although there are references in the literature that mention a wider recommended range (e.g., 10-30%), the more extreme stress conditions often provide data that are confounded with secondary degradation products.

Photostability. Photostability testing should be an integral part of stress testing, especially for photo-labile compounds. Some recommended conditions for photostability testing are described in ICH Q1B Photostability Testing of New Drug Substances and Products (2). 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. It is also important to note that the labeling for generic drug products should be concordant with that of the reference listed drug (RLD) and with United States Pharmacopeia (USP) monograph recommendations, as applicable.

Heat. Thermal stress testing (e.g., dry heat and wet heat) should be more strenuous than recommended ICH Q1A accelerated testing conditions. 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 (1). Studies may be conducted at higher temperatures for a shorter period (10). 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 hydrolysis. 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, 1012) at room temperature for two weeks or up to a maximum of 15% degradation (7). 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 are suggested as suitable reagents for hydrolysis (10). 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. Prior knowledge of a compound can be useful in selecting the stress conditions. For instance, if a compound contains ester functionality and is very labile to base hydrolysis, low concentrations of a base can be used. Analysis of samples at various intervals can provide information on the progress of degradation and help to distinguish primary degradants from secondary degradants.

Oxidation. Oxidative degradation can be complex. Although 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 (e.g., azobisisobutyronitrile, AIBN) 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 (10). Samples can be analyzed at different time intervals to determine the desired level of degradation.

Different stress conditions may generate the same or different degradants. The type and extent of degradation depend on the functional groups of the drug molecule and the stress conditions.


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