Abstract
The ATTUNE™ Knee System (DePuy Synthes) comprises of a tibial insert that is made from AOX™, an antioxidant-stabilized polyethylene. The antioxidant used in AOX is pentaerythritol tetrakis [3-(3, 5-di-tertiary butyl-4-hydroxyphenyl)] propionate (PBHP). A biological risk assessment of the degradation products arising from PBHP has been performed. This assessment focuses on the requirements of ISO 10993–1:2009, ISO 14971:2007, and the Medical Device Directive 93/42/EEC.
Because the orthopedic implant is a permanent implant, consideration has been given to all relevant endpoints defined by ISO 10993–1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process. Comprehensive biocompatibility testing including long-term (26 weeks) subcutaneous implantation has been conducted which confirms the biosafety of the polyethylene compound[1]. In addition to the biological safety testing completed, the overall safety and the associated toxicological risk of exposure to degradation products of PBHP has been given due consideration.
The guidelines for the Threshold for Toxicological Concern (TTC) provided by The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group were used in the assessment[2]. This working group is a collaboration of chemists and toxicologists from the U.S. Food and Drug Administration (FDA), industry, and academia.
The TTC principle allows safety assessment in the absence of substance-specific hazard data, based on very low levels of exposure to that substance. A Margin of Safety (MOS) is calculated as the ratio of the threshold safety value to the actual exposure quantities determined and used in the assessment. A MOS value greater than 1 is typically judged by risk assessors and regulatory bodies to be unlikely to cause harm and the risk may be considered low.
The identity of the degradation products as well as the corresponding 30-day leachable quantities from a water:acetone extraction media has been previously reported [3] and provided here (Table 1). The amount of leachables determined from Table 1 for all products were well below the TTC of 150 ng/device and hence no toxicological risks were identified for these compounds.
In order to further examine the toxicological risk assessment, aggressive extraction using Dynamic Head Space (DHS) extraction was done and analytical testing was performed on the degradation products of PBHP using gas chromatography/mass spectrometry (GC /MS). These estimated quantities along with literature information from biological safety studies of the chemicals that were identified from the quantitative GC/MS analysis of degradation products of PBHP were used in the review and toxicological assessment per the methodology described in ISO 14971 and ISO 10993–18.
The extraction and analysis confirmed the same sixteen compounds previously identified. The quantities and the calculated margins of safety are summarized (Table 2).
In conclusion, upon review of actual test results of PBHP degradation products (Table 1), there is little probability that these organic degradation products would cause a systemic reaction and not be safe. Thus, the potential biological hazards identified in ISO 10993–1:2009 due to the quantified leachables have been verified to be minimal with a high Margin of Safety relative to the Threshold of Toxicological Concern.
