Mark Gordon is product manager at Trelleborg Sealing Solutions Healthcare and Medical

Mark Gordon

This article presents some examples of combination devices being tested or currently in use along with factors for consideration when developing them.

	Silicone has long been a favorite material of medical product designers who value its stability, physical properties, and biocompatibility.  For these reasons, medical grade silicones are commonly used across a wide variety of medical devices and drug delivery products. 

	In addition to the physical properties that make silicone a preferred material for medical devices, its chemistry and cross-linking characteristics make it an ideal material to use in many drug delivery applications.  Combination products include combinations of two or more of these three components: medical devices, drug, and biologics.  For this article, the combination of a medical device and active pharmaceutical ingredient (API) will be considered.  

	An API can be used with a medical device to enhance the performance or safety of the device, or both.  A good example of this would be a collar added to a pacemaker lead that is made from a mixture of silicone and Dexamethasone. The Dexamethasone enhances the function of the pacemaker lead by reducing the inflammation and swelling post-implantation at the surgical site. 

	On the other hand, medical devices can be used as a delivery method for an API. Inhalers and insulin pumps are good examples of devices that focus on drug delivery, with the drug and the device acting independently.  

	Implanted contraceptives combine a drug reservoir with a rate-release control membrane to elude a hormone in a closely controlled range over a lengthy period of time. In this case, the device function and the drug are functionally intertwined, with the drug and device attributes being combined to provide the specified therapeutic dose.  An API may be combined with polymers in many ways; two of the most common are mixing an API with a polymer, such as silicone, prior to manufacturing the component or drug formulation, or adding the drug to the component after component fabrication. Each of these approaches have advantages and limitations.  

In most controlled-release drug delivery applications, the API is added to the base polymer before the polymer is formed into its final shape. When the materials to be mixed are combined in a closely controlled process, the end result is that the final dosage is controlled well within dosage specifications.  In many manufacturing operations, material handling and mixing are completed in single-use, disposable vessels so that safety and contamination controls can be more easily implemented. Single-use systems are one way that the burden of validated cleaning methods is reduced, especially during early preclinical and clinical development. 

	At commercial scale, dedicated equipment and manufacturing cells are frequently used so that cross-product and cross-facility contamination risks are more readily controlled. At all stages, containment and cleaning plans must be designed and implemented as part of a risk-based hazard assessment.  

. There may be several advantages to adding an API to a previously manufactured product. Some of these advantages are: the manufacturing process for the initial product may continue without modification, the handling of the API/solvent mixture is performed in an isolated environment separate from the remainder of the facility, and the product lead time is relatively short compared to a product where the API is mixed with the polymer prior to shaping. There are several predicate products to be found, so development paths can be shortened. 

	The first step in developing a silicone implant to which the API may be added is by working with a silicone component manufacturer with an understanding of the silicone and the API chemistry in general, and the drug solubility in particular. Understanding the drug solubility is critical to determine which solvent is best for the application. The API must be dissolved in a solvent that can permeate the silicone.  The device is immersed in the solvent/API solution, and in this way, the solvent can penetrate the silicone material molecular chains, with the drug molecules left behind after the solvent flashes off.  Chloroform is a commonly used solvent; toluene and acetone are also options.

	The length of immersion is determined by a number of factors, including the type of drug, the overall device design, the thickness of the silicone wall, the density of silicone being used, and the size of the part. Typically, a short series of controlled tests (two to four) are completed to determine the optimal immersion time and establish a range of immersion times and concentrations of the drug/solvent combination. 

	There are limitations to this process; the content control and uniformity of the API in the component will be less than when adding an API to the base polymer; the drug content as a mass ratio is generally lower; and the total time of drug release is limited to shorter times (e.g., days or weeks). 

	Bio-absorbable devices for drug delivery

	Polyvinyl acetate (PVA) and ethyl vinyl acetate (EVA) are bio-absorbable polymers that can be used to help control the rate of release of a variety of drugs. Small-scale implants that are completely absorbed once the drug has been fully released have the potential to reduce post-surgical infections and increase medication compliance.

	Similar technology is under development for ophthalmic applications. Rather than prescribing eye drops, which have a low rate of patient compliance and are prone to dilution from tears, a drug delivery on-lay containing medication may be placed under the eyelid by a physician. It would deliver a minute amount of medication (measured in micrograms per day), and the polymer wafer is absorbed at the same rate as the drug.

	These devices can be used for delivering minute amounts of a drug over a period of days or weeks. Typical drug delivery rates range from 10–20 micrograms per day, and the drug reservoir may hold 2–100 milligrams in total.

	Key considerations for combination product development

	When designing any device combining a polymer with an API, one of the first considerations is whether the device will stay in the body or be absorbed. Silicones, for example, are meant for long-term use, while PVAs or EVAs are bio-absorbable.

		Whether the dosage is flat or varied (i.e., a bolus of drug immediately after device implantation followed by a tapering dose)

		The frequency of the dose that will be dispensed

		The overall length of time the drug will be dispensed. 

	It’s important to work with a vendor experienced with combination devices to determine the viability of a proposed new device. Look for a vendor prepared to take a project from early-stage feasibility through development, clinical trials, and commercialization. The contract development and manufacturing organization selected to be a development partner must have the quality systems required for cGMP manufacturing, which starts with a commitment from upper management to high level quality systems and safety standards. 

	As with any new technology, the vast proportion of formulation work comes at the initial stages of developing a combination product. Pharmaceutical scientists must develop hypotheses and work with development and manufacturing partners to align with therapeutic, quality, and commercialization goals.  Additionally, devices with multiple APIs may begin appearing on the market, leading the way to personalized drug therapy in the future. 

	As these devices are tested, improved upon, brought into clinical trials, and commercialized, the methodologies for creating them should be established early in the development program.  It is crucial to characterize the manufacturing processes as early as possible to achieve quality and economic value for new medical and drug products.  

	When referring to this article, please cite it as A. Gaillard and M. Gordon, "Designing Combination Products," 

Pharmaceutical Technology Outsourcing Supplement

	Andrew Gaillard is global director, and Mark Gordon is product manager, both at Trelleborg Sealing Solutions Healthcare and Medical.

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API can be mixed with silicone and other polymers to create drug-delivery combination products. 