CASE STUDY 8:
Determination of a Comprehensive pH Stability Profile
Business Need
A global biopharmaceutical company is developing a compound entering Phase III clinical trials.
The company wished to conduct a thorough pH rate profile study to support an IND filing and predict the shelf-life as a function of pH and temperature to inform future storage requirements.
Preliminary studies were completed by a different source at five pH values ranging from pH 5.5 to 11.5 at temperatures of 25 and 40 C, and significant degradation was observed with pH 5.5 at 40C. The API appeared to be stable at higher pH values from pH 6.5 to 11.5.
Furthermore, the solubility of the compound was found to be highly pH-dependent, ranging from 100 mg/mL at pH 7.5 to 2 mg/mL at pH 3.5.
Technical Approach
Upon the suggestion of WLI, a feasibility study was conducted to better inform the pH stability profile study regarding sample preparation, testing conditions, and sampling intervals.
An HPLC-UV method was transferred to WLI and the range was extended by WLI to at least three orders of magnitude based on anticipated concentrations as determined by WLI. Known impurities and degradants were characterized for system suitability.
Preliminary assessments including compatability studies were conducted to assess surface adsorption in order to prevent false appearance of loss of API during the stability studies.
Wolfe Laboratories characterized the rate reaction of degradation and analyzed data to derive a rate constant of degradation for prediction of sample stability and estimation of shelf-life projections.
Results
The Feasibility study results proved invaluable in providing estimated API degradation under the testing conditions obtained under the initial feasibility conditions. The observation that sufficient API was not achieved at the lower pH values due to rapid degradation in the order of 1 day allowed for a changes to be made in the stability study resulting in a more informed experiment than was originially requested by the company, saving on resources of time and compound that were then reallocated for use in other more informative assay conditions.
The pH stability profile provided information from which the most stable pH environment for the compound could be established. Calculations and plots produced by WLI yielded observed k values of degradation from which the degradation could be characterized and a predictive evaluations could be made.
Degradation kinetics was evaluated from concentration and temperature data to obtain rates of degradation and approximated predictable shelf-life temperatures were obtained.
