TOOLS OF THE TRADE - TESTING METHODS |
Advances with names like ASAP and RobX are taking evaluations to the next levelTime is money; in the business world, there is little argument with this premise. In the pharmaceutical business, the time between the identification of a lead compound and its regulatory approval for sale represents a great deal of money indeed.
In the interest of saving time, a small army of researchers is dedicated to shortening the time it takes for drug development, as well as extending the marketable shelf life of a product once approved, and the potential to achieve both aims can be enhanced through knowledgeable, innovative stability testing.
One such innovation is ASAP, the accelerated stability assessment program. “Normally, when companies are determining their product’s shelf life, that process takes six to 12 months,” said Ken Waterman, PhD, CEO and founder of FreeThink Technologies in Storrs, Conn. Multiple formulations must be tested, as well as a variety of packaging types. “Obviously, that’s a lot of time, and it may delay the introduction of a product,” he said, “but I’ve figured out how to do it in just two weeks.”
ASAP, a software package recently launched by FreeThink, is a method whereby, with a limited dataset of stability tests under specific conditions, longer time durations under different conditions may be extrapolated.
The theoretical foundation of ASAP is the isoconversional approach, a method that relies on performing a series of experiments at different temperature programs that reveal the values of effective activation energy as a function of molecular conversion.1
ASAP, a software package by FreeThink, is a method whereby, with a limited dataset of stability tests under specific conditions, longer time durations under different conditions may be extrapolated.“Before I did this, people would use different temperatures, certainly, but they didn’t adjust the time so that the amount of conversion to degradation products stayed the same,” explained Dr. Waterman. The results do not usefully inform as to the kinetics of the reaction. Using isoconversion as a basis for extrapolation, Dr. Waterman is able to greatly shorten the time needed for a stability test.
“The other thing I did with ASAP was to consider the importance of water in reactions, and how relative humidity determines reaction rates in the solvents.” This understanding is important, said Dr. Waterman, because even after packaging, the humidity inside the package will change over time.2 “Rates go up exponentially with humidity, so a little change in humidity can result in a large change in the reaction rate.” Reliable estimates for temperature and relative humidity effects are accounted for by using a humidity-corrected Arrhenius equation.
According to Dr. Waterman, the ASAP calculation provides an inside-the-package shelf-life determination that is not only quicker than standard stability testing methods, but is also more accurate—and accounts for humidity. “We can determine the course of the drug degradation, and we know it out to the specification limit. In essence, we know when the drug is going to fail at room temperature because we know when it will fail at higher temperatures.” This knowledge allows for more time to get the formulation just right.
CASE STUDY: State of the Solid-State StabilityThe solid-state chemistry of APIs is of growing importance in the pharmaceutical industry, yet many companies lack the expertise to answer the important questions. “Many are not even looking at this because they don’t realize the impact of the solid-state,” said Robert M. Wenslow Jr., PhD, vice president of business development at Crystal Pharmatech in Suzhou, China.
To illustrate the importance of solid-state awareness, Dr. Wenslow offered a case in point: the HIV drug ritonavir. “This was developed as a liquid formulation, a gelatin, because the compound had very low solubility.”
Initially, all went well. Over 200 batches were manufactured with no stability issues reported. “Then, all of a sudden, they noticed their dissolution profiles slowing down,” said Dr. Wenslow, “and when they broke open the capsules, they saw solid particulates—a new solid-state crystal form—and this form had a much lower bioavailability than the original.”
And the result of this belated observation? The drug was pulled off the market for reformulation. “They lost millions because of solid-state stability issues.”1-2
This loss could have been avoided if more attention had been paid to the solid-state early on in development, Dr. Wenslow said. “Even if you are dealing with a liquid formulation, you need to understand the thermodynamic and kinetic landscape of your solid-state forms,” and if you can’t do it in-house, you can always outsource to the experts.
Chrystal Pharmatech does all types of solid-state research, be it a crystal, a salt, a free-base, free-acid… “We’ll get a complete picture of not just what’s happening to the chemical state, but what’s happening to the physical state as well,” said Dr. Wenslow. “And once you understand the impact of solid-state on your formulation, then you can actually increase shelf life if you chose the appropriate excipients based on solid-state properties.”
For a review of one solid-state detection method, see:
Lin SY, Wang SL. Advances in simultaneous DSC-FTIR microspectroscopy for rapid solid-state chemical stability studies: some dipeptide drugs as examples. Adv Drug Deliv Rev. 2012;64(5):461-478.—NC
- James JS. Ritonavir capsule manufacturing problems will require switch to liquid formulation. AIDS Treat News. 1998;(No 300):1,5.
- Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson O. Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization. Proc Natl Acad Sci U S A. 2003;100(5):2180-2184.
For Biologics, Try RobXTo be clear, the utility of ASAP does not extend to proteins. For stability information in that context, you may want to consider the robustness index, or RobX, a new measure being proposed to easily and quickly gauge how to design robustness into biologic formulations across different temperatures over time.3 RobX=B in the equation KT2/KT1 = eBx(T2−T1).
Driving the need for RobX is the intrinsic complexity of macromolecules, a quality that reveals Arrhenius calculations as too simplistic (though some researchers have recently proposed just such an approach).4
“When you have something that is strictly a function of purity, it’s not such a problem,” said Anthony Lonardo, associate vice president of statistics and quantitative sciences for Imclone Systems in Branchburg, N.J. “But when you’re looking at a quality measure like charge heterogeneity, as opposed to simply purity, what does Arrhenius mean in that case?” Lonardo wants a way to look at the multiple critical quality attributes of amino acid-based tertiary structures in a given formulation.
“I’m really interested in being able to define (formulation) robustness as a constant that defines rates of change at different temperatures,” and the objective is to minimize that number to achieve an optimally stable formulation. Put another way, and as simply as only someone who really loves math can do: “For RobX, if you subtract the log of the rates, it turns out really nice—it turns out the RobX index defines a ratio of the rates of change for two temperatures.”
The beauty of this method, as Lonardo described it, is that the calculated RobX is a unitless constant and can therefore be used across a number of quality characteristics. It’s also very easy to understand the meaning of the value once derived: The number represents a ratio, graphically illustrated as a line with an inclination, a slope, which flattens as you approach the value of 1—that being the ratio of no change at all.
One expert is seeing stability protocols with built-in extended time points out to 48, or even 60, months.“Another insight was that I can put all of this in a table,” said Lonardo. “I know what I want—I want the number to near 1 when considering two different temperatures, say 25-48°C, for all the quality characteristics, and then I identify which of those (based on the RobX number) is going to give the most trouble.” For example, if RobX indicates that the acidic peak group has the greatest potential for change, the drug formulators can focus on that issue.
“From our standpoint, we’re relentless in terms of wanting to produce robust and stable formulations,” Lonardo said. “And what RobX does is allow for a single way of thinking about the robustness of a molecule.”
It’s not just theoretical. The accuracy of the approach, as compared to known data points, has already been demonstrated (see Lonardo and colleagues). Lonardo is adamant about the utility of RobX: “Take the data up and see if you can reproduce my results.” (Lonardo is quick to note the vital contributions of his coauthors in the conception of RobX.)
That’s a WrapWhile innovation is wonderful, the CROs doing the large-scale testing will likely wait for the validation. “There’s always been the idea that you can do some extrapolation based on short periods at much higher temperatures and humidities,” said Jeannine Schreiber, manager of stability services at Lancaster Laboratories of Lancaster, Pa. “But so far that hasn’t really flowed through to the regulators.”
With nearly 30 years of tenure at Lancaster, Schreiber does note some recent changes in the focus of regulators when it comes to the stability of drug packaging. This shift may be motivated by the recent publicity surrounding the use of bisphenol A in plastic compounds .5 “Right now we’re doing a lot of studies that are looking at extractables/leachables, so they are using elevated temperatures and humidities to look at how their container closures may be impacting product.”
Schreiber mentioned one example, an IV bag. “Because it’s a plastic product, there are some extractables/leachables in that plastic that may come out of it.” The contaminant itself may pose a problem, or it may even react with the API in solution.6
Schreiber has also witnessed a shift in stability protocols for drug formulations, with clients building in options for time extensions. “Let’s say your approved product currently has a 36-month shelf life,” she recounted. “In most cases, part of the requirements are that [that] company put an annual lot of product on stability, and traditionally that would end at 36 months.” What she is seeing now, though, are protocols with built-in extended time points out to 48, or even 60, months. “They’ve provided enough material so that if they want to push the button and gather the extra data to support an extended expiration period, they have the product and the ability to do that.”
That is if they need the time, and want to save some money.
- Waterman KC. The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability. AAPS PharmSciTech. 2011;12(3):932-937.
- Waterman KC, MacDonald BC. Package selection for moisture protection for solid, oral drug products. J Pharm Sci. 2010;99(11):4437-4452.
- Lonardo AJ, Srivastava A, Singh S, Goldstein J. Robustness index score: a new stability parameter for designing robustness into biologic formulations. J Pharm Sci. 2012;101(2):485-492.
- Martin-Moe S, Lim FJ, Wong RL, Sreedhara A, Sundaram J, Sane SU. A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design. J Pharm Sci. 2011;100(8):3031-3043.
- Geens T, Goeyens L, Covaci A. Are potential sources for human exposure to bisphenol-A overlooked? Int J Hyg Environ Health. 2011;214(5):339-347.
- Chang JY, Xiao NJ, Zhu M, et al. Leachables from saline-containing IV bags can alter therapeutic protein properties. Pharm Res. 2010;27(11):2402-2413.