Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms.
OBJECTIVE
To propose and test a new accelerated aging protocol for solid-state, small molecule pharmaceuticals which provides faster predictions for drug substance and drug product shelf-life.


METHODS
The concept of an isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a critical degradant level, is introduced for solid-state pharmaceuticals. Reliable estimates for temperature and relative humidity effects are handled using a humidity-corrected Arrhenius equation, where temperature and relative humidity are assumed to be orthogonal. Imprecision is incorporated into a Monte-Carlo simulation to propagate the variations inherent in the experiment. In early development phases, greater imprecision in predictions is tolerated to allow faster screening with reduced sampling. Early development data are then used to design appropriate test conditions for more reliable later stability estimations.


RESULTS
Examples are reported showing that predicted shelf-life values for lower temperatures and different relative humidities are consistent with the measured shelf-life values at those conditions.


CONCLUSIONS
The new protocols and analyses provide accurate and precise shelf-life estimations in a reduced time from current state of the art.
Waterman
Kenneth C
KC
Pfizer Global Research & Development, Groton, CT 06340, USA. ken.waterman@pfizer.com
Carella
Anthony J
AJ
Gumkowski
Michael J
MJ
Lukulay
Patrick
P
MacDonald
Bruce C
BC
Roy
Michael C
MC
Shamblin
Sheri L
SL
D001205:Ascorbic Acid / Q000737:chemistry; D001241:Aspirin / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D004349:Drug Packaging; D004355:Drug Stability; D004356:Drug Storage; D006813:Humidity; D007700:Kinetics; D008956:Models, Chemical; D009010:Monte Carlo Method; D011237:Predictive Value of Tests; D011810:Quinoxalines / Q000737:chemistry; D012107:Research Design; D013678:Technology, Pharmaceutical / Q000379:methods*; D013696:Temperature
D004304:Dosage Forms; D011810:Quinoxalines; C479133:quinoxaline-2-carboxylic acid (4-carbamoyl-1-(3-fluorobenzyl)-2,7-dihydroxy-7-methyloctyl)amide; D001205:Ascorbic Acid; D001241:Aspirin