Combination products are on the rise for health outcomes and patient adherence, but it’s a challenging field for manufacturers to navigate merging drug development with device development.
Statista reports that in 2018, research and development spending in the pharma industry totaled $179 billion globally. As companies work to develop injectable biologics for patient needs, many turn to partners to overcome development hurdles (Competitive Drugs Demand Innovative Delivery Devices).
Another way suppliers are helping customers in speeding time to market is by offering pre-sterilized, ready-to-use (RTU) primary packaging to streamline pharmaceutical fill/finish operations. These systems are often designed for clinical development phases and small batch commercial manufacturing, and can include components such as vials, seals, stoppers, cartridges and syringes. This eliminates preparation steps for glass containers (washing, depyrogenizing and sterilizing) so that the manufacturer can focus space and resources on filling operations. Global Market Insights estimates that the market for depyrogenated sterile empty vials will surpass $1.4 billion by 2026.
How development services help
Development services can help companies determine factors such as what type of analytical testing is needed, what information goes into the regulatory filing, and what type of information is needed from suppliers so they can enhance their filing with the combination product. It all starts with the molecule—that determines where a manufacturer goes within a regulatory pathway.
West Pharmaceutical Services has put together an Integrated Solutions Program that seeks to simplify the drug development path regardless of what stage a manufacturer is in. For prefilled syringe systems, for example, it’s important to look at drug/package compatibility and device functionality early on. This is also true when a manufacturer wants to take the prefilled syringe and put it into an auto-injector. “With a cartridge system, you’re putting it into a pen or an on-body system. What things to do they need to think about in each phase of development? What do they need to do in phase 1 to properly evaluate not only the primary packaging but that device? In phase 2 and phase 3? We’ve laid out that roadmap to help them move forward in each stage of development,” says Jennifer Riter from West Pharmaceutical Services.
Stevanato Group offers another development service—a product development collaboration with Cambridge Design Partnership (CDP) for pen-injector technology. The agreement combines CDP’s design and development experience in drug delivery devices with Stevanato Group’s experience in glass containers, tooling, injection molding, device assembly, and its global commercial network.
RTU options have emerged from numerous suppliers, including Stevanato’s vials in its EZ-fill configuration and DWK Life Sciences’ WHEATON CompletePAK, a customizable set of commonly used RTU vials, stoppers, and seals delivered with USP certifications for traceability and under a single order number for customers.
Development services may also assistance with the manufacturing/filling side, or determining what training and on-boarding are needed to get the devices into the clinic and to caregivers.
Trends
Riter notes a few trends across the market. Small molecules may be packaged with a higher pH, so manufacturers must choose containment that avoids leachables in the drug product. For large molecules, manufacturers are using a lot of excipients or surfactants to stabilize the drug, which require additional consideration for compatibility with packaging. “And for a more viscous product, they have to consider how to deliver the drug product in a reasonable amount of time into the patient,” Riter says.
Because of product-specific complexity, looking at types of containment and delivery in the preclinical phase or phase 1 can help to minimize risk and avoid returning to the drawing board after considerable development.
Standards
While there are standards such as ISO and compendium studies, manufacturers have to customize and optimize them based on their drug product and delivery system and a partner can help with that development. “With the Office of Combination Products, in terms of the type of information, how it’s put together, and how its ties the drug to the product with the drug, we’ve seen the data expectations have increased.”
Changes to USP 381, and a new chapter in USP 382, focus on the functionality of primary containment systems which now includes prefilled syringe systems and cartridges as well as the vial/stopper/seal. “Also with the ICH Q3D Elemental impurities, customers are trying to understand the elemental impurities that come into their drug product from the primary packaging device over time,” Riter notes.
While Europe does not have an office of combination products, with new expectations for 2020, manufacturers are putting in applications for a medicinal product, combined with a device.
Mitigating risk at different phases
In phase 1, a brand owner may be looking at packaging configurations. If the product has a type of surfactant or excipient that may pull extractables from the stopper, a development firm could help with early compatibility studies with different packaging systems to determine what could be the appropriate type of system.
In phase 2, a brand owner is starting to look at extractables/leachables and at container closure integrity (CCI). With CCI, they may turn to a development firm to determine the right technique to look at their product based on their minimum allowable leak limit. “When you think about things like CCI, per 1207, they want you to validate your system with the drug product. You can’t just run a technique and you’re finished. They want to make sure you are testing through shelf-life or your life cycle management of your product, that you’re actually getting robust results and using an accurate test method.”
Cell and gene therapies are normally stored under cryogenic and frozen conditions. For a standard biologic, helium leak testing may be appropriate at -80° C, where a lot of biologics ship. “But cell and gene therapies are stored over their shelf life at -180° C. We can develop a method for CCI via helium leak under cryogenic conditions to monitor real time over the time product will be in that container.”
