Additive manufacturing is one of several novel manufacturing technologies that have created a new world of opportunities for medical device manufacturers, but these opportunities come with significant liabilities. The latest draft guidance from the International Medical Device Regulators Forum (IMDRF) indicates that verification and validation (V&V) of the medical device production system (MDPS) is a complex matter, as is the question of who assumes the regulatory responsibility for the maintenance and use of these systems.
In our most recent blog, we discussed the IMDRF draft’s provisions for personalized medical devices (PMDs), but the draft guidance covers both the PMD and the MDPS. Manufacturers who are intent on setting up an MDPS at the point of care may find a willing series of customers in the form of hospitals with a high volume of implant surgeries due to the modern emphasis on personalized medicine, but this is a complex regulatory space with uneven clarity at present.
A number of terms and acronyms are found in this guidance, which starts with the MDPS, defined as the combination of the resultant medical device (RMD) and the medical device production process (MDPP). The IMDRF stated that the risk classification of the MDPS should be determined by the risk classification of the RMD, a fact which may influence the range of device types the user will seek to manufacture.
There are a number of interesting questions regarding V&V, such as a few novel considerations under human factors validation. The IMDRF indicates that a practical approach to V&V overall commences with the RMD, only after which the developer can validate the MDPS. The draft guidance states that this validation task may be more complex than the process required for the validation of a conventional production system used at the manufacturer’s own facilities. This V&V should assess the variability in the manufacturing process associated with:
- The function of the MDPS in the environment of intended use;
- The elements of the MDPP (including software and post-production equipment);
- Instructions for use;
- Qualification for installation, operation and performance (IQ/OQ/PQ); and
- Human factors and the MDPS interface.
Among the methods available to validate the MDPS are simulated use testing, on-site testing and human factors testing, although user competence testing might be substituted for human factors testing, depending on the risks associated with the end device and the production system. This is only the process used to validate the system at the site where the system is manufactured and/or assembled, however. Once the system has been delivered to the site of use, IQ and OQ, and staff training will be required, as will any systems needed to ensure that the MDPS stays in a validated state. This will require establishment of monitoring processes for manufacturing parameters and a standard operating procedure for corrective action.
Dual Risk Management Systems an Option
Risk management for the MDPS can be evaluated under ISO 14971, but the IMDRF draft recommends that a comprehensive risk management plan account for both the intended use and any reasonably foreseeable misuse. The manufacturer of the MDPS can use a separate risk management plan for the production process and the manufactured device, but a comprehensive risk management plan may be a better option for identifying any weaknesses in the in the design of the MDPS as well as the robustness of the entire process and resulting products over the product life cycle.
A site-specific risk management plan may be required at the time of commissioning, depending on the preferences of the regulatory authority of jurisdiction where the system is installed. The users of the MDPP may be responsible for that risk management plan per the IMDRF draft guidance, although there may be contractual arrangements in which the manufacturer of the system would assume that responsibility.
The draft guidance provides some recommendations for the user facility requirements, which would include an assessment of:
- Power supply;
- Clean room level;
- Air flow/air turnover;
- Water supply;
- Compressed air; and
- Anti-static flooring.
Facility-specific requirements may vary by regulatory authority, some of which may mandate the manufacturer of the system to conduct human factors validation, for which IEC 62366-1 might adequately serve as a standard (incidentally, the FDA recognizes this standard). In some environments, this might also require an assessment of the intra- and inter-user variability in the quality of the finished product. The clinical evidence requirements may be fulfilled by a comparison to another MDPS-manufactured device or a device manufactured by traditional means, but IMDRF provided no prescriptive language in this portion of the draft.
As we discussed in our previous blog, the current regulatory picture for these point-of-care manufacturing systems is fragmented, which introduces some uncertainty as to the harmonization potential of this IMDRF guidance. While we at Enzyme do not pretend to offer legal advice, there is also some concern that the question of liability under tort law is not well developed, which may be a disincentive to go down this path.
The countervailing consideration is the increasing pressure on manufacturers and physicians to respond to a patient’s more or less unique needs, such as the wide degree of variability in the geometry of the femoral neck and head, and the implications for device configuration for total hip arthroplasty. The demand for these patient-specific devices promises to grow in the coming years, and the reliance of this latest IMDRF guidance on internationally recognized standards suggests that it might serve as a good regulatory starting point for any manufacturer intent on providing such products in multiple markets.