A combination device is a product created by combining drugs and/or biologics with devices or a product created through a combination of drugs and biologics.1 We will discuss the first category of devices, in part because of their growing popularity. One example is the drug-eluting stent, but there are a host of possible combination devices. It has been estimated that 30% of developmental products are medical devices combined with pharmaceuticals or biologics.2 Combination devices that meld traditional medical devices with drugs or bio-logics pose additional challenges and quality requirements in a number of areas, such as surface definition, contamination control, and management of active components.
STATIC MEETS DYNAMIC
A traditional medical device (implantable or not) is made of metal or composite or other stable materials. Certainly, particularly for implantables, the surface finish must be designed to interact amicably with the host (usually a person). Stents must be non-thrombogenic (must not cause clots). Implantable teeth must exhibit adequate osseointegration (so that, for example, bone knits with an implanted tooth). However, such devices are meant to be static,with little to no change over time.
A classic device may have a stellar record of performance. This proof-of-the-pudding, this record of performance, may be combined with non-specific surface testing to indicate quality and consistency. Typical “workhorse” residue testing may include particulate determination, non-volatile residue (typically by extraction, evaporation of the extract, and gravimetric determination), and total organic carbon (TOC). These tests provide an overall indication of residue, but they do not necessarily provide sufficient information about theinteraction of the drug or biologic with the device surface.
In contrast, pharmaceuticals and biologics are dynamic; they are active within the host. Dynamic, active materials are inherently less stable than the traditional materials used for classic devices. Additional care is needed when the twoare melded.
Active drugs, chemicals, reagents, and blends are potentially prone to degradation, particularly in the presence of heat, humidity, light, microbial action, and other chemicals.3 Biologics are even more likely to be damaged by environmental, microbial, and chemical activity. Where may these potentially damaging chemicals come from? One potential source is the “hard” surface of the device. Non-specific residue tests may not provide sufficient information about specific contaminants. TOC testing, for example, provides information about the total amount of covalently-bound carbon on the surface. However, TOC includes only organic compounds; some process chemicals are inorganic. In addition, the total level of carbon may remain relatively constant, but the specific organic compounds may vary. Therefore, TOC testing may not provide an adequate picture of the surface.
The concept of zero contamination is unrealistic; surface residue is a fact of life. Understanding the residues, eliminating process chemicals that contribute harmful residue, and taking steps to control the level of specific residues are important for a robust combination device. While determination of particulate levels and non-volatile residue are valuable, they are not likely to be sufficient for combination devices. In developing and monitoring the fabrication of combination devices, analytical tests that speciate (that identify the residue or class of residue) are valuable tools in validation, in establishing baselines, and in process control.
ANALYSIS WITHOUT PARALYSIS
We periodically discuss the features, benefits, and limitations of various analytical techniques. Recently, in this publication, we compared two surface analytical techniques, and we indicated that the choice may depend on company resources and on the skill and experience of the analyst.4 However, no single analytical technique is applicable to all situations. The fact that the expertise and equipment to perform X-ray photoelectron spectroscopy or scanning electron microscopy are available on-site does not mean these are the correct techniques to use to monitor your combination device. Perhaps the analysis of an extract using infrared spectroscopy would be more informative. Selecting the appropriate techniques, careful experimental design, and realistic interpretation of the findings are critical to the cost-effective production of robust, consistent combination devices. Therefore, we suggest pro-actively developing solid,supportable analytical protocols.
Because the assembled device will contain active and, therefore, potentially labile material, it is important to also establish stability testing for the assembled device. Such protocols may be performance-based, and they may also include analytical testing. In the future, such protocols may be simplified by exploiting the fact that biological materials share common chemistries. The theta surface, a concept developed by Robert Baier,* relates surface forces to the non-polar properties of aqueous biological media,5to predict and monitor the properties of both the static and active portions of the device. Understanding the theta surface would allow development of optimal conditions for adhesion or of release of biomaterials from a surface withoutdetailed knowledge of the specific biological component.
CONTROLLED: ENVIRONMENTS, PROCESSES, AND PRODUCT DESIGN
Because it is devoted to critical applications, Controlled Environments Magazine is a very logical platform for discussing combination devices. To build on this introduction, we expect additional discussions of this important topic. A combination device is inherently more complex than the sum of its parts. Therefore, controlled environments and controlled processes become essential, even at early stages of assembly. Such control encompasses a host of activities. A few examples include controlled atmosphere for production, air monitoring for particulates and for thin film contamination, enhanced incoming inspection and certification of process chemicals, controlled characterization of water,controlled fabrication processes, as well as critical cleaning and drying processes that characterize the composition and level of residue. Sterilization protocols will also have to be monitored and controlled. Of course, all of this process control involves communication and coordination throughout what is oftenan international supply chain.
Finally, because product performance depends on controlling residue and assuring stability, considering design for manufacturability along with design for product performance will support the production of effective, rugged, stable combination devices.
*Bob Baier was a contributing author to this column in the August, 2004 issue, “Microbes and Boulders”.
- Kramer, M., “FDA’s Office Of Combination Products: Roles, Progress & Challenges”, Journal of Medical Device Regulation, 2005, 2(3), 3 http://www.fda.gov/oc/combination/jmdr2005.html.
- Combination Products: Navigating the Two FDA quality Systems,” Microtest White Paper 2007 http://www.microtestlabs.com/combinationpaper/0750506ComboWhitePaper.pdf.
- Van Buskirk, G. E., “A GMP Compliant Quality System for a Combination Product,” Reguatory Affairs Focus Magazine, January, 2005.
- Kanegsberg, B. & E. Kanegsberg, XPS or AES? (Parts 1 and II), Controlled Environments Magazine, October and November, 2007. 5. Baier, R., “Surface Behaviour Of Biomaterials: The Theta Surface For Biocompatibility”, J Mater Sci: Mater Med (2006) 17:1057–1062.
Barbara Kanegsberg and Ed Kanegsberg are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of The Handbook for Critical Cleaning, CRC Press. Contact them at BFK Solutions LLC., 310-459-3614; email@example.com; www.bfksolutions.com.