Modeling Streamlines Package Stability Testing

Stability tests determine if specific packaging choices will protect a pharmaceutical drug product for its required shelf-life-typically two to three years. Traditional time-based studies can take years and often involve testing many package variations. Data-based modeling, however, can streamline the package selection process, determining such factors as the lowest-cost options for package material, number of doses, and amount of desiccant. Modeling identifies the optimum configuration for the required shelf-life, assuring a high probability of passing the stability test, thereby eliminating the need to put more than one or two packaging options through the traditional test process. The modeling also prevents over-packaging and offers the potential for cutting costs since higher barrier materials tend to carry higher price tags.  

Such modeling can be used for any product-solid doses, gels, ointments, small molecules, peptides, and biologics, according to Ken Waterman, president of FreeThink Technologies, a specialist in stability studies and supplier of the ASAPprime accelerated stability assessment program software. Results generated by the software have been proven to correlate well with traditional stability tests and have been accepted by FDA as proof that a post-approval packaging change will meet shelf-life requirements (1). Blister packaging provider Aptar CSP Technologies uses the program to help determine shelf-life as part of its Xcelerate Development Services (2). Klöckner Pentaplast’s BlisterPro XCEL package design and prototyping services also rely on ASAPprime software (3).  

In a webinar on June 9, 2020, “Selecting Primary Packaging for Stability for Solid Dosage Forms,” Waterman explained that the accelerated stability assessment program takes less than one month to complete. It exposes the product to temperature, relative humidity (RH), and oxygen to the failure point; models stability performance via an isoconversion method; determines packaging impact based on the calculated environment inside the package; and calculates the probability of passing the stability test. Ideally, he said, “you want a >95% confidence level in the shelf-life [projection].” The software also can account for conditions the package will experience in different climate zones, for example, when shipping to the tropics. Other parameters can be calculated, such as whether a desiccant is necessary and what size it should be (1). 

The physical testing involves ovens to control temperature and saturated salts to control RH. With exposure to different temperatures and RH levels, a drug product is examined for changes that indicate its stability has been affected, such as degradant formation, assay (potency) loss, dissolution changes, crystal growth, and appearance change (1). 

Humidity can cause a sudden failure, including a phase transition, such as deliquescence or hydrate formation. In deliquescence, as soon as a product exceeds its critical RH, it begins taking water from the air to make a solution. “This is a sharp transition that depends on temperature,” said Waterman. But RH is more likely to work in a continuous fashion to shorten shelf-life. “This is because humidity impacts the mobility of the molecules and increases reactivity,” he explained (1). 

Humidity sensitivity is, thus, a critical factor in determining shelf-life and optimizing the package structure. A calculation based on a modified Arrhenius Equation determines how humidity sensitivity affects shelf-life. In one example, a product with a high humidity sensitivity had a projected shelf-life of 3.0 years at 60% RH but only 9.3 months at 75% RH. Such a product would require packaging with high barrier properties (1). 

With the humidity sensitivity and product degradation rate known, the RH inside the package must be determined with the knowledge that this level changes over time. Waterman said, “Headspace is not important,” but surface-to-volume ratio and moisture sorption by the dosages are. This means that larger bottles will provide a longer shelf-life with the same percentage fill. Several other factors impact the package RH level over time including water vapor transmission at temperature; the RH outside and inside the pack; moisture sorption vs. RH of the dosage, mass, and initial water content of dosages; and moisture sorption vs. the RH of any desiccants. Desiccants can absorb a lot of water vapor. In fact, under certain circumstances, a high-density polyethylene bottle with a desiccant can outperform a foil/foil blister (1). 

Drug degradation is influenced by oxygen as well as RH. As with RH, oxygen’s impact is time-sensitive and temperature-dependent. Oxidation of the product consumes oxygen. As the oxygen in the package decreases, its transmission rate increases until oxygen consumption slows and a steady-state is reached. An equation similar to the one used for the RH calculation predicts oxygen consumption, sensitivity, and permeability as a function of initial conditions and sensitivity to moisture and temperature (1). 

With the capability of modeling the impact of moisture, oxygen, and temperature on the product, optimum packaging options can be identified, with a high level of confidence that product quality will be protected for the required shelf-life (1). 

References

1. K. Waterman, “Selecting Primary Packaging for Stability for Solid Dosage Forms,” Webinar (June 9, 2020).

2. Aptar CSP Technologies, “Thank You For Joining the Rethinking Oral Solid Dose Packaging Live Webinar Last Week,” Email (April 2, 2019).  

3. Klöckner Pentaplast Group, “Pentapharm BlisterPro XCEL Services,” www.kpfilms.com, accessed July 1, 2020.