The Application of the Accelerated Stability Assessment Program (ASAP) to Quality by Design (QbD) for Drug Product Stability

Abstract

An isoconversion paradigm, where times in different temperature and humidity-controlled stability chambers are set to provide a fixed degradant level, is shown to compensate for the complex, non-single order kinetics of solid drug products. A humidity-corrected Arrhenius equation provides reliable estimates for temperature and relative humidity effects on degradation rates. A statistical protocol is employed to determine best fits for chemical stability data, which in turn allows for accurate estimations of shelf life (with appropriate confidence intervals) at any storage condition including inside packaging (based on the moisture vapor transmission rate of the packaging and moisture sorption isotherms of the internal components). These methodologies provide both faster results and far better predictions of chemical stability limited shelf life (expiry) than previously possible. Precise shelf-life estimations are generally determined using a 2-week, product-specific protocol. Once the model for a product is developed, it can play a critical role in providing the product understanding necessary for a quality by design (QbD) filing for product approval and enable rational control strategies to assure product stability. Moreover, this Accelerated Stability Assessment Program (ASAP) enables the coupling of product attributes (e.g., moisture content, packaging options) to allow for flexibility in how control strategies are implemented to provide a balance of cost, speed, and other factors while maintaining adequate stability.

Prediction of the changes in drug dissolution from an immediate-release tablet containing two active pharmaceutical ingredients using an accelerated stability assessment program (ASAPprime®)

“…The computer software (ASAPprime®) uses the isoconversion method (Waterman (2011)), rather than regression analysis to calculate the values of A, E a , B, where the isoconversion time, IC is the time to reach the predetermined value for the acceptance criteria (not less 80 % dissolved after 20 min). Replacement of the rate constant, k with the reciprocal of IC gives:…”

“…1) in more complex, heterogenous systems, make the prediction of stability in solid dosage forms (SDF) more difficult. However, Waterman and co-workers (Waterman & Swanson 2014;MacDonald 2010;Colgan & Hofer 2015;Stella 2000;Timmerman 2003;Waterman 2011) have shown that the predominant factor that determines the rate of degradation in solid dosage forms, in addition to temperature, is the presence of water. That group has shown the rate of degradation of active pharmaceutical ingredients in tablets and other SDFs may be predicted using a modified Arrhenius equation (Eq.…”

“…Having demonstrated the applicability of various statistical approaches for the evaluation of data (Eq. 2) to predict the shelf life of SDFs, Waterman and co-workers (Waterman & Swanson 2014;MacDonald 2010;Colgan & Hofer 2015;Stella 2000;Timmerman 2003;Waterman 2011) contains two independent variables (T and RH); therefore, at least three combinations (a 3-point protocol) of T and RH are necessary to obtain values of A, E a and B by regression analysis or other curve fitting techniques. The greater the number of points in the protocol the greater the reliability of the estimates of the regression coefficients, and the predicted shelf life.…”

“…Accordingly, the objective of this study was to test the hypothesis that ASAPprime® software can be used to predict the dissolution rate of change of the active ingredients in tablets at the intended storage condition, based on data obtained at elevated temperature and relative humidity. This approach is reasonable because the majority of changes in dissolution rate of SDFs can be attributed to changes in water content (Waterman & Swanson 2014;MacDonald 2010;Colgan & Hofer 2015;Stella 2000;Timmerman 2003;Waterman 2011). The SDF used to test the hypothesis was an investigational immediate release tablet containing two active pharmaceutical ingredients (API 1 and API 2) that had previously shown slowed dissolution at 40°C/75 % RH in an open dish study and enabled better understanding of the risk to dissolution changes at room-temperature storage.…”

Non-isothermal stability by linear heating: a fast method for preformulation stability screening of drugs at the discovery and development interface

“…For chemical stability assessment of drugs in the solid state, an Accelerated Stability Assessment Program or ASAP can be used, which is discussed in detail elsewhere in the literature (Waterman 2011). The ASAP method is based on an isoconversion concept that compensates for the complexity of solid-state degradation reaction kinetics and applies a moisture-corrected Arrhenius equation that explicitly takes into account the effect of relative humidity (RH) on the degradation rates in solid state (Waterman 2011).…”