Material Characterization and Medical Device Regulation

In recent FDA public statements and guidance documents, the agency appears to be raising the bar for fully identifying the materials used in medical devices. Complete identification goes beyond merely giving a generic name because such names can often cover a wide range of materials with varying primary ingredients, other added and/or inadvertent constituents, and physical differences over a range of geometric scales. Geometry takes on a particular role for highly porous materials in which the very definition of materials becomes ambiguous. Is the materials the macroscopic entity with its pores, or is the material only what is bridging the pores? In addition, manufacturing can alter materials such that even starting with the same material at the source doesn’t guarantee the same performance once the material is made into a device.
 
On February 12, 2016, the FDA released a draft guidance (DG) on “Characterization of Ultrahigh Molecular Weight Polyethylene (UHMWPE) Used in Orthopedic Devices.” Since guidance documents present FDA’s current thinking on the subject matter, it might be said that DGs provide what the FDA is thinking about thinking. Guidance documents are also nominally non-binding since they are not regulations. The FDA uses the word “recommends” and its variants rather than “requires” in guidances to reflect that they are not officially requirements. The strategy, however, of not following a guidance document will no doubt involve some extra hurdles. If a guidance document is non-binding then a DG has even less official authority but might none-the-less be viewed as FDA expectations. In this regard, some DGs have long life times including “Implementation of the Biomaterials Access Assurance Act of 1998,” which has been a draft since 2001.
 
Even before the current DG on UHMWPE, it was clear that simply identifying material as polyethylene was not good enough because molecular weight matters in bearing surface performance and only ultrahigh molecular weight material is suitable. But even an UHMWPE designation is not good enough to fully define the material. For example, internal consolidation plays an important role in wear resistance and two materials of identical chemical composition could have very different wear characteristics. For this and related reasons, the DG recommends reporting the starting resin manufacturer’s identification, concentration and indication of antioxidant or other additives, resin consolidation method, radiation dose and type, time and temperature of post-consolidation thermal anneals, compression ratio of mechanical anneals, and the terminal sterilization method.
 
In the DG, the FDA identifies different types of UHMWPE being used in orthopedics including “conventional,” highly crosslinked, highly crosslinked with vitamin E, and “non-conventional.” Crosslinking establishes small-scale structure; materials with different amounts and distribution of crosslinking can be expected to have different performance. In an example from a different context, crosslinking of the silicone gel in breast implants was found to have an important effect on gel or gel component leakage. It is interesting that “progress” in this regard went from firm (more crosslinked) gels, to more viscous gels, and then back to firm.
 
Mechanical Properties of UHMWEPE
The FDA notes that for some properties, such as tensile properties, impact resistance, and density, acceptance criteria in ASTM F648, “Standard Specification for Ultra-High-Molecular-Weight Polyethylene Powder and Fabricated Form for Surgical Implants” would be acceptable. This standard, however, only addresses a subset of possible properties and allows for some variability. The FDA therefore recommends that other properties, such as biaxial mechanical properties, fatigue crack propagation resistance, and consolidation, be directly measured in comparison to other applications. Additional properties to be provided for highly crosslinked materials include total absorbed radiation dose, percent crystallinity, melting temperature, aging oxidation index, trans-vinylene index, and free radical concentrations. With the addition of vitamin E comes an analysis of stability and effects on wear.
 
Biocompatibility of UHMWPE
The FDA notes that Class II devices with “identical” materials and manufacturing processes might avoid specific biocompatibility testing. In this context, “identical” might mean that it is the same product from the same material manufacturer, perhaps as identified by that manufacturer’s catalog number or other descriptor. But even this assumes a degree of consistency and quality control that establishes that today’s material is exactly the same as yesterday’s, and that both are homogeneous. Note also that “identical” is one of those words that shouldn’t be modified by an adjective (i.e., “almost identical” subverts the meaning of identical). The DG also states that the addition of antioxidants raises concerns regarding the biocompatibility of the antioxidant itself and the biocompatibility of radiation-induced degradation products. Thus, variations in antioxidants are a deviation from identical and might require more thorough testing.
 
In an interesting departure from a more narrow view of “biocompatibility” of meaning only ISO 10993 type testing, the DG includes the consideration of the body’s response to wear debris, which it identifies as critical. Further, the DG says that it may be possible through “exhaustive testing” to demonstrate that the antioxidant and its degradation products are not bioavailable. “Exhaustive testing” might well be a daunting, if undefined, term.
 
Other Examples
Another example of FDA’s interest in more complete material characterization is a January 2016 Guidance Document on Implanted Blood Access Devices for Hemodialysis. In that Guidance, the FDA recommends providing a source identification number for the resin along with any colorants, plasticizers, lubricants, mold release agents, additives, or coatings. Also to be identified is the chemical tolerance of the device to repeated exposure to commonly used disinfection agents. The latter reflects the long-standing problem of different access devices requiring different disinfectants while being intolerant to others. This has resulted in inconsistent instructions-for-use along with confusion in the clinical setting.
 
Beyond direct FDA activities, the exact nature and source of the polypropylene used in pelvic mesh has been the source of considerable discussion and ongoing litigation. This includes allegations of device manufacturers using subterfuge to obtain material from a source unaware the material was destined for a “permanent” implant as that source would not have sold it for that purpose and even warned against such use.
 
Metallic materials have perhaps received less attention from the variability perspective although new manufacturing methods, such as 3D printing and very porous structures (e.g., trabecular metals) raise new questions about mechanical properties, biocompatibility, and overall device performance.
 
Conclusion
The FDA may, in general, be increasing its requirements (or recommendations) for the proper identification of exactly what materials are being used in medical devices, how those material have been processed, and whether or not they are the same or different from what has been used in the past.
 
It is also good to remember that the FDA is not the only source for determining what the right thing to do is. Good science and engineering might itself call for knowing more clearly exactly what material was started with, what was done to it and how that affects performance, and acknowledging what was known or unknown about how it will actually perform in an application.