Maintaining critical quality attributes through sorbents

Pharmaceutical manufacturers are delving deeper into understanding the sensitivities of their drug products, with many finding that they require more than just an off-the-shelf solution.

Thanks to ICH Q8 on Pharmaceutical Development, considerations such as Quality by Design, Critical Quality Attributes, and Design Space have crept into day-to-day drug development and production, influencing several packaging decisions. In essence, these concepts have encouraged drug manufacturers to better understand drug stability, resulting in a closer examination of risks using science.

For instance, understanding a product’s critical quality attributes and how they all interact can reveal a threshold area, or a design space, that can meet the necessary combination of parameters. Developing container-closure solutions that sit within that design space and monitoring all processes can yield designs based on quality considerations. In other words, quality by design (QbD).

Drug manufacturers are increasingly taking a QbD approach when determining the type and amount of sorbents needed to maintain drug stability, notes Adrian Possumato, global director, healthcare packaging, Multisorb Technologies (www.multisorb.com).

“Rather than using an off-the-shelf desiccant, drug companies are looking to find just the type and right amount of sorbent needed to address relative humidity and/or oxygen concentration in package headspace,” he says.

As a result, Possumato says Multisorb has been doing about 75 to 100 simulations per month using its 
pseudo-empirical modeling tools SimulSorb and SimulOx. “These programs can calculate exact sorbent formulations with respect to sorbent chemistry and quantity needed.”

CUSTOMIZATION
Possumato says that simulation can eliminate the need for sorbent ranging studies. “We plug a drug’s isotherms into the software and begin calculating what is needed based on the packaging presentation selected. This can cut out about six to 12 months of time and cost, which for some pharmaceutical companies could mean being early or even first to market,” he reports.

Basing sorbent selection on science not only prevents excessive use of unneeded sorbent, but also allows for package optimization. “In an effort to improve our customers’ sustainability programs, we can consider reduced bottle thickness and balance package barrier with the amount of sorbent needed to obtain a desired stability outcome. We can look at a variety of formats, including Drop-In, Fit-In, Built-In solutions. Desiccant is cheaper than plastic.” Reductions in weight and shipping cost as well as in carbon footprint are possible, he adds.

For instance, Multisorb’s drop-in sorbents utilizing sachets or packets are meant to use less plastic than canisters, such as the MiniPax/StripPax, which use 85% less plastic than the leading canister, Possumato reports. In addition, its fit-in sorbents such as the Multiform CSF compressed sorbents are made up of only 15 to 18% plastic. Built-in sorbents incorporate the sorbent in the thermoplastic, reducing the overall amount of plastic used. All formats can employ Multisorb’s IntelliSorb formulation, which is designed to “intelligently manage multiple environmental conditions within package headspace,” says Possumato.

Süd-Chemie Performance Packaging (www.s-cpp.com) is seeing increased interest for its customizable EQ-Pak packet and EQ-Can canister sorbents, reports Mark Florez, global marketing manager. “Instead of just a desiccant, these products also function as humectants and can be calibrated to achieve a certain relative humidity in a given package. Humidity is often a primary degradant for pharmaceuticals, but package environments that are too dry can also be problematic.

Florez says Süd-Chemie can run simulations for package modeling using its own analytical tools to determine optimum protective packaging options, especially in the protection against moisture and oxygen.

“Some products, like gelatin capsules or dry-powder inhalers, require some humidity, often around 20%,” Florez says.

COMBINED APPROACH
Süd-Chemie approaches product protection by looking at both passive and active solutions. “We work with companies to determine the right polymer, closure, and container to use for the package itself and couple that with the sorbent,” Florez explains. “We can draw from a spectrum of offerings to build a system offering both passive and active protection, rather than just dropping in a desiccant.”

For products that need significant protection, Süd-Chemie suggests its Oxy-Guard bottles utilizing EVOH in a six-layer configuration.

About a year ago, Süd-Chemie launched its Integrated Desiccant Closure (IDC). “We designed the closure and bottle together so that the two create a tight seal limiting ingress according to USP requirements and eliminating the need for an induction seal,” Florez explains. “With the desiccant integrated into the closure, there are no separate parts to insert or desiccants to drop into the bottle.”

Tamper evidence is provided via a breakaway ring, and there are two options for child resistance: push and turn or squeeze and turn. A snap-hinge closure is also available.

The IDC “builds in a lot of efficiencies,” he adds. “It eliminates the need to procure a separate desiccant, and it eliminates both the drop-in process as well as the induction seal.

“It is a disruptive change,” continues Florez. “The idea started with our washer insert for caps for Europe. Two pieces then evolved into one, which eliminates the need for assembly.”

APPLICATION
In order to add desiccants to a blister package, CSP Technologies (www.csptechnologies.com) worked with Rohrer AG (www.rohrerag.ch) to develop a new system for heat-staking its desiccant film to blister package foil.

Rohrer AG has developed a module to be added to a blister packaging line that can affix CSP’s desiccant film elements to foil prior to blister sealing. The material can be supplied on a reel and slit to custom widths. The two companies will demonstrate the approach for the first time in May at Interpack in Germany.

The idea evolved through CSP’s progression from providing active polymer technology for flip-top vials to thin films for heat-stakable applications, explains Dan L’Ecuyer, vice president of sales and marketing for CSP.

“We then brought the approach to molded active components and more recently to blisters,” he says.

Silica gel, molecular sieve, or other material types can be used to scavenge moisture, oxygen, odors, or other volatiles. A 0.33-mm-thick element utilizing molecule sieve features a moisture capacity of 2.1 mg/cm² and oxygen capacity of 0.04 cm³/cm², while a 0.6-mm-thick element utilizing silica gel has a moisture capacity of 7.3 mg/cm².

The films use CSP’s polymer blend technology allowing them to absorb and release targeted molecules as needed. CSP can tap its technology to custom develop child-resistant packaging, vials, active molded components, and a range of films.
Rohrer’s solution welds the desiccant film tightly to either push-through or peel-away foil. The two companies are demonstrating the solution at Interpack 2011, showcasing Rohrer’s A1150 AFA for applying the absorption film on Rohrer’s R550 blister machine for development and stability samples.

According to Toni Lang of Rohrer, the lid foil and the applicator staking properties (attachment force, peel off force) need to be verified, optimized, and selected.

“Various combinations of materials are feasible, but it must appropriate for the API and other packaging requirements. We currently design the staking system to be integrated (like a lid foil printer) on an intermittent or continuously running production machine,” Lang explains.

In Rohrer’s system, the lidding film passes through the applicator system, where the absorber is cut from the absorber film reel and attached to the lid film. A camera system controls positioning along x and z axes.

OPERATION
Pharmaceutical companies also “are looking for efficient solutions that can streamline their operations,” observes Possumato of Multisorb Technologies. To that end, Multisorb can offer companies both sorbents and dispensing machinery.

The company uses the same seal detection technology on its packet manufacturing equipment and on its dispensers, which means that packets are prequalified to run reliably on dispensers, Possumato says.

Dry-air and inert-gas purges are included in the dispensers, protecting sorbent capacity during packaging operations to avoid waste, Possumato adds.