Category: Formulation and Quality
Purpose: The ability of an HPLC method to detect and control impurities as well as potential degradation products is an essential requirement of any well-designed quality control strategy for a new Active Pharmaceutical Ingredient (API). The term stability indicating is often used to describe an HPLC method’s ability to detect and resolve impurities and potential degradation products. The resolution criteria for potential degradation products is typically achieved through laborious and time-consuming forced degradation studies.
In support of the method validation specificity criteria, a fully automated tool that can perform sample preparation for forced degradation studies and linearity was developed. The system prepares a series of forced degradation samples and a linearity concentration series. The developed system is compliant with current worldwide regulatory expectations and has met all validation requirements.
Methods: Forced degradation experimental conditions were established to be consistent with all current regulations (e.g. ICH, RDC-58). Additionally, the level of degradation observed in past internal development programs was evaluated against current requirements. These observations of degradation from development program, the relevant regulations, along with considerations of relative reaction rates (e.g. Arrhenius equation, temperature, time, concentration) lead to the following final set of forced degradation experiments: (Table)
Automation platform requirements were evaluated against the operation of assorted liquid handlers. The RTC PAL3 platform was selected and custom configured with 3 agitators, 3 independently temperature-controlled sample drawers, two bulk diluent containers and related needle wash stations. HPLC vial tray locations for the stress condition samples, the API stock solutions and the reagent solutions were selected. Two syringe tools (1000uL and 100uL) were included for the accurate pipetting required to prepare the stress samples.
Results: Completion of the IQ/OQ and extensive system testing was followed by UAT execution. Evaluation and comparison of the chromatograms and the related data for the manually and automatically produced samples met all pre-established criteria. Namely, the chromatograms and results for the twelve non-blank PAL 3 platform forced degradation samples compared to the corresponding manually produced samples. Also, all established internal criteria for the linearity samples were met.
Conclusion: The developed and validated custom configured system is now routinely used in an "open access" format in the MRL Research Laboratories. The solution-based stress conditions completed include acid and base, typical radical reaction conditions (AIBN), nucleophilic oxidation (H2O2), and a metal catalyst stress condition. The system completes a collection of solution stress conditions spanning 3 to 48 hours and from room temperature to 60 °C. These conditions were selected based on regulations, theoretical reaction rates and the historical internal degradation patterns of typical compounds. Solid thermal stress at 100 ℃ is also completed as part of the series. The system met all GMP requirements and in addition to forced degradation sample preparation also prepares a concentration series (LOD to 120%) suitable for method linearity testing. This automated forced degradation approach significantly reduces the amount of manual labor used to perform these experiments and seeks to harmonize forced degradation approaches across the pharmaceutical industry.
Lina Liu– Senior Scientist, Merck & Co, Inc, Rahway, New Jersey
Robert Hartman– Rahway, New Jersey
Timothy Rhodes– Rahway, New Jersey
Leonardo Allain– Senior Principal Scientist, Merck & Co., Inc., West Point, Pennsylvania
Ryan Peters– Rahway, New Jersey