Manufacturers of medical devices or of pharmaceuticals or biologics know that establishing a cleaning validation protocol is a challenge. Combination devices that combine traditional device substrates with an active drug delivery system present unique regulatory and assembly challenges. There are critical considerations in customizing cleaning validation protocols and in both defining and maintaining appropriate surface quality.

REGULATION OF DEVICES AND DRUGS
As with any medical device or pharmaceutical product, quality must be carefully controlled and is regulated. A challenge for combination devices is that the quality regulations for medical devices and drugs must be met simultaneously. In the United States, different portions of Federal regulations govern pharmaceuticals and medical devices. Pharmaceuticals are regulated through 21CFR210/ 211. If the drug is a biologic, derived from living organisms, it is regulated through 21CFR610. Medical devices are regulated through 21CFR820. Pharmaceutical manufacturing must use and document current good manufacturing processes (cGMPs).¹ Medical device manufacturing requires a quality management system (QMS).² With cGMP, the “how-to” of the process is specified; withQMS, the emphasis is on “how do we know that it is correct.”

FDA is required by Section 503(g) of the Federal Food, Drug, and Cosmetic Act (FDCA) to assign a lead center that will have primary jurisdiction for pre-market review and regulation of a combination product. The FDA has addressed the area of combination devices and has established the Office of CombinationProducts (OCP). The OCP neither reviews nor specifies any methods to validate the cleanliness or safety of a combination device. The OCP is primarily a steering organization, designed to determine which branch of the FDA should have primary jurisdiction over a new device. The OCP performs this assignment by determining the primary mode of action (PMOA).³ That is, it determines whether the primary mechanism for the device is pharmaceutical (e.g., delivering a drug) or a medical device (e.g., keeping an artery open). It also determines which of these mechanisms poses the greatest challenge to demonstrating safety and considers several other factors. Based on these determinations, the OCP assigns an applicationto the FDA division most suited to review it.

The PMOA may not always provide a good basis for selecting which of the requirements stated in the drug, biologics, and device regulations should apply to a particular combination product in specific circumstances. Whichever FDA division reviews the application, for the product to be manufactured successfully and reliably, the device fabricator must be exquisitely concerned with the surfaces and with contamination control.

IS IT CLEAN ENOUGH?
The answer may be yes for classic implantable devices. The question needs to be rephrased: is it clean enough now that a biologic or pharmaceutical is present? Issues arise as to how the combination of biologic and classic materials impacts the cleaning process and also how cleaning impacts the interaction of the drug and product with each other. Related issues include when to clean,how to clean, and how to minimize contamination during assembly.

Proximal to the biologic or pharmaceutical
One area involves preparing the surfaces immediately proximal to the biologicor pharmaceutical. In general, surface residue must be minimized to a level that assures that the biologic or pharmaceutical will not be compromised. This may make a difference in the activity of the medicine due to local or possibly systemic immune responses the body may have to the medical device portionof the combination device.

Materials compatibility must also be reconsidered. Any cleaning or manufacturing process has the potential to react with or to modify the surface. The challenge for combination devices, as well as for other newer medical devices, is to define what the surface ought to look like. Perhaps a limited, controlled level of surface modification or controlled incompatibility is called for. For example, trace amounts of residue are often removed by plasma cleaning immediately prior to application of a specific engineered coating. Plasma cleaning might be the appropriate surface pre-treatment prior to application of certain pharmaceuticals or biologics. Plasma also has the potential for surface modification; this attribute is often used advantageously as a sort of controlled incompatibility. Chemical cleaners containing caustics, corrosives, or chlorine often modify the surface of devices that may positively or negatively impact the system as a whole. Some surface modification may make implantation easier in one example but weaken the device in another. Also, this change may alter the interaction the drug has with the device. It likely becomes a more complex issue to select cleaners when they are being used on combination products. An MSDS alone may not contain all the relevant information needed to determine the impact of a cleaner on the device. Therefore, being able to partner with a knowledgeable supplier becomes more important.⁴