By Jerry Martin
A metered-dose inhaler filled with asthma medicine and an auto-injector loaded with epinephrine don't appear to have much in common at first glance. However, both share one major identifier: they fall within the pharmaceutical category of a "combination product." Although sometimes mistakenly referred to as combination drugs, which mix two or more active ingredients in single-dose form, the FDA defines combination products as "therapeutic and diagnostic products that combine drugs, devices, and/or biological products." Regardless of the format or the application, combination products pair a set drug dose with a tool that delivers that medicine to the patient — all in one consolidated item.
Blending formula and function into one neatly packaged item may seem to simplify the drug delivery process for end users, be they healthcare professionals or patients, but a product that pulls double duty comes with its own set of challenges. Combination products require their own precautions and packaging measures that help to ensure quality, safety, and reliability. Luckily, as the industry witnesses the emergence of more mixed products, manufacturers can leverage innovative packaging solutions and industry expertise to ensure their products avoid potential pitfalls and make it to market in the most efficient way possible.
Uncovering Unknowns With Combination Products
Traditionally, packaging a drug requires a vastly different approach from packaging a device. Ergo, marrying a drug with a device yields some challenges. Manufacturers must take into account how those two parts are going to interact both individually and together as a unit. They must also protect the stability and often the sterility of the drug up to the point at which the patient is using it — and beyond for some multiple dose products, such as inhalers.
Depending on the application, the drug will take a different form, and the device may use a different method for delivery. With a metered-dose inhaler, for example, the medicine is provided as a gas, liquid aerosol, or dry powder and inhaled, whereas an auto-injector employs a syringe to drive sterile liquid directly to the bloodstream. Throughout the supply chain, these products will face individual threats. A drug for inhalation could be easily contaminated or lose potency if not packaged with airtight materials, while an auto-injector dosage could pose a hazard if deployed accidentally. Both may be susceptible to leaks, wasting valuable product and shaving profit off the bottom line. With any combination products that feature premixed or prefilled solutions, it is imperative to find a container that can both safeguard medicine but also easily deploy it when the time comes for activation. These needs underscore the importance of reliable packaging components that provide closure integrity and maintain the stability of the product during its shelf life.
In addition, once in the hands of the end user administering the treatment, combination products are not immune to human error. As these products feature a device designed around one specific medicine, it is possible the user may not understand how to operate the tool. Without clear instructions, this lack of understanding can lead to improper or ineffective deployment of the drug.
Another major roadblock facing manufacturers involves meeting government regulations. After a pharmaceutical company has taken steps to address potential issues with faulty packaging or product use, it must be able to demonstrate those steps before the FDA, which will assess whether a design is suitable for use. A challenge for product developers is that the FDA has not issued specific regulations for many combination products, nor has it offered a designated channel to review combination products.
Historically, drugs and devices would enter separate review processes at distinct regulatory centers and be judged against a set of practices specific to that product category. For example, before the arrival of the prefilled syringe auto-injector with a drug like epinephrine, these two items were marketed separately, with the liquid drug and syringe not interacting until the point of use. As a result, each product moved through its respective review process, with epinephrine considered a drug and the syringe/auto-injector considered a device.
With the drug and the device paired in one simple preloaded product, the approval process becomes more complicated because the current FDA structure does not include a specific center for combination products. In an attempt to bridge this gap, the FDA issued guidance for defining combination products and, in 2002, created the Office of Combination Products. The purpose of this new group was to field new product submissions and assign them to an existing center dedicated to drugs or devices. Once assigned, the manufacturer would work with a representative from that center to understand the requirements and establish the appropriate post-market regulation of the combination product. This step provided critical guidance for companies intending to launch combination products, as they could determine relatively early on which FDA center they would answer to and could use that knowledge to dictate design.
In 2016, the FDA created the Combination Products Policy Council (CPPC) to modernize the review process and further improve communications between the individual centers. The CPPC makes regulatory and production guidelines more seamless, allowing manufacturers to potentially get their products to market faster. Still, this group does not go so far as to offer a standardized set of guidelines. As a result, manufacturers should recognize that the FDA does not yet provide a unified voice, making it difficult to anticipate exactly how a product will be judged or the hurdles it may face throughout production. For example, a common route in developing combination products is to take an established drug previously sold alone and pair it with a device. In many cases, the drug manufacturer did not originally anticipate its product being regulated partly as a device and must subsequently determine how a particular formulation is going to behave in conjunction with a specific delivery tool.
Solving The Combination Product Puzzle
With these challenges in mind, how can manufacturers launching a combination product learn to adapt? While there is no way to anticipate every potential curveball thrown during regulatory review, proactive planning is an absolute must in mitigating risk.
Typically, the drug company is the entity pursuing production of a combination product — not the device manufacturer. For drug companies considering creating a new device themselves, it’s critical to understand they might be entering new territory and may need to start from scratch. The device will require validation on its own, facing testing for precision and accuracy. If sourcing a device from another supplier, drug companies must establish complete transparency with their partners in terms of the reliability and lifespan of the tool. In the event that something goes wrong with the device, the parent company (again, often the drug company) will be liable for that failure as an element of the combination product. In addition, if the device manufacturer halts production or fails to communicate any manufacturing changes to the drug company using the device for combination products, that company can be left in the lurch, with a device that no longer interacts properly with the medicine. This brings the drug company right back to square one and requires sourcing a new device and even potentially restarting clinical trials and the entire regulatory approval process.
With an awareness of these risks, pharmaceutical companies can take the following precautions:
- Change control: It is important to incorporate a process that will monitor degrees of change, enable proper documentation of any tweaks, and ensure they do not interfere with the performance of the final product. Along with this, the parent company should establish quality agreements and production standards with any partners. These steps are critical for navigating production issues and maintaining ownership of the combination product even when sourcing from outside suppliers.
- Protective packaging: Implementing the right packaging components can help prepare a combination product for its path throughout shipping and storage, as well as prepare it for scrutiny by regulatory bodies. Manufacturers should consider the features required for primary packaging, such as tamper-resistant and tamper-evident closures that will properly seal the device, prevent contamination, and show signs of interference. They should also ensure their secondary packaging helps meet standards of compliance by utilizing printing technologies that can display information crisply and clearly and use detailed imagery to demonstrate proper administration of the drug.
- Expert guidance: Pharmaceutical companies can be susceptible to the “until it happens to you” mind-set, meaning that possible pitfalls in production are often unaddressed unless serving as an immediate threat. To avoid downtime and to limit the number of “surprises,” manufacturers should consider sourcing and involving a consultant or other partner who can provide insight and direction throughout production. This is especially helpful when the drug company creating the combination product has little familiarity with devices and could benefit from an adviser weighing in. Having an ally who can ask the hard-hitting questions will help minimize the risk of disagreements over standards or other potential barriers to market.
- Industry resources: Leaning on other regulatory resources like the International Congress of Harmonization (ICH) may also be useful for companies pursuing combination products. The ICH offers guidelines on risk management that touch upon life cycle, quality agreement systems, and more, all harmonized among the FDA and European and Japanese markets. The FDA often endorses these guidelines and encourages manufacturers to apply them as a starting point — especially for globally marketed products.
Growing Potential For Combination Products
While the path to launching a combination product is far from one-size-fits-all, pharmaceutical companies that pursue this category stand to win big on several fronts. For drug companies transitioning from patented to generic, marketing a combination product can bring new life to an existing drug. The company can extend the lifespan and reach of a drug with a new delivery format that offers convenience benefits for the patient. If packaged and administered correctly, the products can also promote better outcomes, delivering the drug to its target with potentially fewer side effects.
About The Author:
Jerry Martin is an independent consultant to pharmaceutical manufacturers and equipment suppliers for filtration, single-use manufacturing, marketing, business development, and regulatory compliance. He was previously SVP, marketing and global scientific affairs, for Pall Life Sciences, where he served the pharmaceutical, biotech, medical device, and vaccine industries for over 37 years. He is currently chairman emeritus of the Bio-Process Systems Alliance, the single-use manufacturing trade association, and a member of the USP Expert Panel on Plastic Systems Used for Manufacturing Pharmaceutical Products. He holds an M.Sc. in microbiology from the University of Toronto.
Find More Answers At PACK EXPO East
Regardless of application, the changing landscape of combination products offers tremendous room for innovation in packaging and production techniques. Pharmaceutical companies aiming to launch a new combination product or simply bolster their industry knowledge can find the latest technological solutions and guidance on best practices at PACK EXPO East (March 3-5, 2020, at the Philadelphia Convention Center). Owned and produced by PMMI, The Association of Processing and Packaging Technologies, the show offers attendees the opportunity to glean insights from more than 400 exhibiting companies. The show will also offer educational programming and opportunities as well as feature up to 7,000 attendees to network with industry peers. Register and learn more at www.packexpoeast.com.