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On April 26, FDA released a final guidance on Characterization of Ultrahigh Molecular Weight Polyethylene (UHMWPE) Used in Orthopedic Devices1. The draft of this guidance was issued on February 12, 2016. The guidance addresses four different types of UHMWPE: conventional, highly crosslinked, highly crosslinked containing antioxidants, and non-conventional. The parameters of characterization include material description, sterility, biocompatibility, mechanical properties, and chemical properties. For the base material, FDA “recommends” the inclusion of information on starting resin, resin consolidation method, and the terminal sterilization method. Material properties of interest, depending on the type of UHMWPE, include tensile properties, impact resistance, density, crosslinking parameters, percent crystallinity, melting temperature, fatigue resistance, antioxidants used, effect of antioxidant on wear, creep resistance, and surface durability. These many parameters, and the allowable ranges in relevant standards, demonstrate that material characterization is a complex issue.
Yet in the section on biocompatibility, FDA states that “If the subject device uses the identical UHMWPE materials and manufacturing processes as a legally marketed device with a history of safe use, you may reference previous testing experience or literature, if appropriate.” It is not explained exactly what such referencing buys you. The italics "in identical" are FDA’s, but there is no definition given of identical and the word does not appear elsewhere in the standard.
What then makes two pieces of UHMPE identical? This would seem to go beyond the name, any relevant standards, and the supplier. More generally, identical would seem to require that every characteristic of the material (such as those enumerated in the guidance) have been shown to match between the previously used material and the candidate material. This would presumably require proof obtained from testing. And such proof would seem to also require biocompatibility testing--i.e., you have to do all the tests to show that it is identical before you can assert that it is identical. This is reminiscent of an observation under Design Controls pertaining to risk assessment. Under validation (21CFR820.30g) there is a requirement that risk assessment be included “where appropriate.” This of course invites the question, When is it appropriate? The preamble to the regulation provides a partial answer “Risk analysis must be conducted for the majority of devices subject to design controls and is considered to be an essential requirement for medical devices.” A further answer heard from FDA is that in order to determine whether a risk analysis is appropriate, you have to do the risk analysis.
Another component of identical is identified in the use of Master Files, which are supplied to FDA by material manufacturers. However, it isn’t just about the raw material, because FDA recommends that the possible effects of processing, cleaning, and sterilization of the finished device also be assessed. Despite the requirement for “identical,” FDA seems to waffle a bit by allowing for a prior device with “similar location/duration of contact and intended use that uses the same materials and manufacturing processes.” Since biocompatibility is now understood to be application specific, a “similar” use of the same material lowers the bar. FDA also says that, in addition, conformity to a recognized material consensus standard can be declared when applicable. While such conformity may be relevant, it generally would not rise to the level of “identical” since most standards are inexact. For example, ASTM 648, Standard Specification for Ultra-High-Molecular-Weight Polyethylene Powder and Fabricated Form for Surgical Implants, allows for a range of densities and three types with different strengths and other mechanical properties. FDA further notes that antioxidants and wear debris are a consideration for UHMWPE biocompatibility. Wear is at least in part a function of the design of the device and its specific application, which further makes “similar” a loose term.
Implant material science is receiving increased FDA attention as reflected by this guidance, FDA’s general statement on materials2, and the recent draft guidance on Nitinol3. It would appear that FDA will be increasing its scrutiny of regulatory submissions in this regard, and that the “regulatory burden” will increase accordingly.