This article compares the different documentation requirements of biocompatibility for 510k submissions with a technical file submission for CE Marking.
A couple of my clients recently received requests for additional information as part of their technical file submission for CE Marking. Both clients had titanium implants, and they submitted the same justification of biocompatibility for 510k submissions as they were now submitting for their technical file. They were providing a one-paragraph description of materials used and referencing the ASTM specification for implant-grade titanium. Both clients already had CE Marking for similar devices, and the wording of the justification for not conducting biocompatibility testing on the full device was identical to the previous submissions.
“Justifications are no longer permitted”
One of my clients questioned whether there was a new EN standard for implant-grade titanium that they might need to comply with. Their auditor told the other client that the Notified Body would no longer accept justifications for not conducting biocompatibility testing.
On behalf of my clients, I scheduled a meeting with their Notified Body to obtain clarification and to make sure that the policies for documentation of biocompatibility had not changed. The Notified Body had three important points to make:
- Justifications are PERMITTED as it states in EN ISO 10993-1:2009
- Competent Authorities noticed that some of the justifications accepted in the past were not sufficient
- What the FDA accepts for biocompatibility for 510k submissions is not sufficient for a technical file
FDA requirements of biocompatibility for 510k submissions
In 1995, the FDA published a biocompatibility guidance document. That guidance document includes a decision tree that asks a series of questions related to biocompatibility for 510k submissions that is intended to help manufacturers determine which biocompatiblity testing may be required for 510k submission of their new or modified device. The following questions are the critical items covered in that decision tree:
- Is the material the same as a marketed device?
- Same manufacturing process?
- Same chemical composition?
- Same body contact?
- Same sterilization method?
- Is the material metal, metal alloy, or ceramic?
- Does it contain any toxic substances (e.g., Pb, Ni, Cd, Zr)?
- Does the master file have acceptable toxicology data?
In the past, I recommended that clients with titanium implants prepare section 15 of their 510k submissions by answering each of the questions above. 99% of the time, the predicate device is substantially equivalent to the 510k submission device with regard to the first five questions. Except in the case of coated implants, there was seldom a Device Master File to reference, and the metal was compliant with the ASTM standard for titanium implants–including the concentrations of heavy metals.
For other medical devices that were not made of just titanium or some other implant-grade metal, the manufacturer was forced into conducting biocompatiblity testing. In these cases, I directed the clients to follow the biocompatibility testing matrix published by the FDA.
New Draft Biocompatibility Guidance from the FDA
In 2013, the FDA published an FDA 2013 draft guidance document for biocompatibility with additional requirements for biocompatibility documentation and testing. The newer draft guidance appears to be the current expectation of the agency for 510k submissions, but the draft guidance has not been finalized yet.
The new 2013 draft guidance document from the FDA indicates that biocompatiblity testing reports must be provided with 510k submissions instead of merely summarizing the testing performed. The FDA clarifies in the draft that materials will not be evaluated alone, and the full device must be evaluated for biocompatibility instead. The FDA also specifies that the device evaluation must be for a sterilized device if the device is intended to be delivered in a sterile state to users/patients. This draft incorporates new ideas regarding toxic chemicals, such as colorants. The FDA also suggests that manufacturers discuss their testing plans with the FDA before starting the biocompatibility testing.
Despite the changes proposed in the 2013 draft guidance, there are no changes to the requirements of biocompatibility for 510k submissions if the device is a metallic implant that is substantially equivalent to a predicate device.
Technical File Differences for Biocompatibility
In theory, there should be very few differences between biocompatibility for 510k submissions and technical file requirements for CE Marking, because the FDA recognizes ISO 10993-1:2009, and the content of the standard is nearly identical to the European national version of the standard. For European CE Marking, the expectation is for the technical file to include documentation of conformity with the current state of the art for biocompatibility (i.e., EN ISO 10993-1:2009). Summary Technical Documentation (STED) is preferred by Notified Bodies to reduce the time and costs associated with the review of the technical documentation.
A STED that explains how your biocompatibility evaluation conforms to a harmonized European Standard is quite different from a justification based upon substantial equivalence. Notified Bodies expect you to review each of the elements of the harmonized standard and explain how you address it in the STED. In Clause 7 of EN ISO 10993-1:2009, there are seven elements recommended for a biological safety assessment:
- the strategy and program content for the biological evaluation of the medical device;
- the criteria for determining the acceptability of the material for the intended purpose, in line with the risk management plan;
- the adequacy of the material characterization;
- the rationale for selection and/or waiving of tests;
- the interpretation of existing data and results of testing;
- the need for any additional data to complete the biological evaluation; and
- overall biological safety conclusions for the medical device.
The fourth element of the biological safety assessment will undoubtedly include a reference to the implant-grade titanium that you are using. However, you also must address additional questions that are posed in Figure 1 of the standard. Issues that should be addressed in your biological safety assessment include:
- Are there any additives, contaminants, and residues remaining on the device?
- Are there any substances leachable from the device?
- Are there any degradation components of the device?
- Are there other components, and how might they interact with the final product?
- What are the properties and characteristics of the final product?
If you conducted a cleaning validation, you need to reference that process validation report. If you did the testing of EO residuals, you need to reference the ISO 10993-7 test report.
The message the Notified Bodies are sending you is that they agree that implant-grade titanium is biocompatible. Still, you need to systematically write a justification for not conducting the testing in accordance with the EN standard, and you have to cross-reference to your objective evidence throughout the STED.