Robust pre-market submissions for medical devices are beneficial to streamline clearance to market and avoid delays and additional costs. FDA provides guidance documents for many products and technologies to communicate current agency rational and to offer transparency on what to include in these pre-market submissions. 

Failure to provide all required information may result in a technical hold, AINN deficiency hold, prolonged interactive dialogue, or worst-case, a not substantially equivalent (NSE) decision. With the increase in additively manufactured devices on the market and the increase in additive implants submitted for pre-market review, additive manufacturing deficiencies are on the rise as well. Predicting the precise combination of requirements for a successful outcome of a premarket submission can be difficult, but relying on historical regulatory data from previous submissions and understanding current FDA stance can help provide a clearer picture while peering into the regulatory crystal ball. 

This article lays out best practices for presenting information surrounding additive manufacturing to the FDA to avoid extended deficiency holds and reduce the impact on the device’s time to market. Analysis of recent deficiency trends and guidance documents provides the clearer path for sponsors looking to read into the future of their premarket submission.

Additive manufacturing (AM) of medical devices has increased in the last 15 years, especially in orthopedic implants. The ability to create porous metallic structures allows devices to have mechanical properties like Young’s modulus and porosity similar to native bone. Additional benefits of additively manufactured implants include the ability to print devices with complex geometries that would otherwise not have been possible with traditional subtractive manufacturing technologies. 

These complex geometries also allow for better osteointegration through porous design on implants. Focus on patient-specific implants has also been made possible using additive manufacturing processes. Despite the many advantages, additive manufacturing of medical implants has left FDA with some apprehension due to the lack of long-term clinical data and potential for larger variability in the printing process. This apprehension had led to the identification of some common deficiencies that may be easier to avoid when understood. 

The regulatory landscape for devices that are additively manufactured have some unique requirements. Applicable FDA Guidance Documents include Technical Considerations for Additive Manufactured Medical Devices Guidance for Industry and Food and Drug Administration Staff – December 2017 and FDA Guidance Document for Testing Orthopedic Implants with Modified Metallic Surfaces Apposing Bone or Bone Cement, and a draft guidance Characterization of Metallic Coatings and/or Calcium Phosphate Coatings on Orthopedic Devices Draft Guidance for Industry and Food and Drug Administration Staff. These guidance documents provide sponsors guidelines for information needed in a premarket submission for their device. 

These documents don’t include specific details on what FDA will accept but are meant to be used as guidelines. There’s no cheat sheet and no one-size-fits-all set of parameters for all devices. Sponsors may look into their crystal ball hoping to glimpse the future from the FDA review team’s eyes. Current deficiency trends show some of the top AM-specific deficiencies include: incomplete characterization of material properties, lack of process validation and control, insufficient mechanical testing or worst-case rationale, and inadequate cleaning and sterilization validation. 

Variability is an 11-letter word for the FDA’s safety concerns. The additive manufacturing process lends more variability than traditional subtractive manufacturing processes, leading to more concern. 

In FDA’s Guidance Document Technical Considerations for Additive Manufactured Medical Devices Guidance for Industry and Food and Drug Administration Staff – December 2017, the agency warns “optimal settings and parameters for a single model of a machine can vary greatly when printing different devices or components. Furthermore, optimal settings and parameters can vary between machines of the same model even when printing the same devices or components.” Some of the common deficiencies on this topic occur when 1) the sponsor has not fully described how the print parameters and positioning of devices within the build chamber may impact dimensions and performance of the final, finished device, 2) not all machine validations are provided, and 3) when justification for a particular printing parameter is not supported with evidence.  

Providing robust validation and justifications for all steps in the validation process helps avoid deficiencies in this area. Manufacturers should provide validation for any machine that could be used to produce their device to reduce concerns with machine-to-machine variability. Manufacturers should also provide justification with evidence on how printing parameters either do not affect the outcome or are worst-case printing parameters for each printer supported by device-specific data. 

For example, if the manufacturer plans to allow powder reuse during manufacturing of their device, they should provide data throughout the reuse process to ensure the final finished device’s mechanical integrity, chemical characterization, and oxygen content is not hindered by the repeated power reuse by conducting performance testing using the worst-case powder reuse cycle. Overall, FDA is not looking for a sponsor to match another device or fit within certain parameters predefined by guidance documents, but looking for sponsors to justify their parameters with supporting evidence.

Insufficient mechanical testing is also common to bring up deficiencies for additively manufactured devices during a pre-market review. FDA’s current policy is to treat any additively manufactured lattice or porous structure on the bone contacting surfaces—which have the same intended promotion of osteointegration as a coating—as a device coating. FDA’s draft guidance Characterization of Metallic Coatings and/or Calcium Phosphate Coatings on Orthopedic Devices Draft Guidance for Industry and Food and Drug Administration Staff includes recommended non-clinical bench testing to characterize the device’s lattice or porous structure, which include chemical analysis and microstructure characterization. The current recommendation for mechanical testing of metallic coating coupons, which the FDA may require for a printed lattice coupon, is listed in Table 1. 

Suggestions to avoid deficiencies relating to evaluating the device lattice/porous structure is to complete all required testing per the guidance document or to reference a previously cleared device with the identical structure or a master file for the lattice structure itself on file with the FDA.

Analysis of all parameters resulting in the worst-case printing for the devices tested in mechanical testing is another common deficiency topic. One common deficiency for Ti-6Al-4V ELI implants per F3001 states that if the material properties demonstrated by the test coupons from the print build from which the subject implant test samples came are significantly greater than the acceptance criteria from ASTM F3001, the device-specific performance testing may not fully represent the worst-case AM conditions. 

It’s plausible that implants printed from a print built with coupon performance at the ASTM F3001 acceptance levels may be weaker than implants tested for the premarket submission that were printed in the batch and were significantly stronger than the F3001 requirements. With this deficiency, FDA may recommend an adjustment to the ASTM F3001 acceptance criteria to provide confidence that a new worst-case device won’t be produced once released to the market. 

Although this deficiency isn’t necessarily difficult to address, sponsors are continually caught off-guard since the ASTM F3001 acceptance criteria is considered the gold standard and can potentially lead to scrapped batches that fall below the new acceptance criteria but above the ASTM F3001 criteria. Additionally, this deficiency may require sponsors to work with their contract manufacturer to ensure this update to acceptance criteria is adjusted, justified, and maintained moving forward.  

A unique concern for additive manufactured devices is the potential for manufacturing residue or printing powder to remain on the device or be trapped in a complex lattice structure and cause a harmful patient reaction. The FDA’s concern is the potential harm caused if this residue or printing powder is initially trapped then later released into the patient’s tissue. 

Traditional cleaning validations submitted by manufacturers have proven inadequate to address this specific concern for additively manufactured devices. On removing manufacturing residues, the FDA Additive Manufacturing Guidance Document states, “the extent to which manufacturing material residue must be reduced is determined on a case-by-case basis considering characteristics such as manufacturing processes, intended use, materials, type and duration of exposure, intended anatomical location, and type of device.” When testing or using a rationale to support removing manufacturing residue is not provided, FDA’s deficiency language typically states the need to show the “processing and cleaning steps are sufficient to remove manufacturing material, such as feedstock powder.” 

Based on current FDA recognized standards, it is recommended to address this concern by performing ultrasonication testing to release any trapped particles, then characterizing saline through a particulate analysis per ASTM F1877 and comparing results to a cleared predicate device. This characterization is different from a wear debris analysis of fatigue testing samples for which concern of excessive fatigue wear must be mitigated. Providing this testing and justification of results will help deliver evidence the device system includes adequate cleaning procedures and is safe from a biocompatibility standpoint.

While no one can accurately predict the future regarding the FDA, understanding FDA’s expectations is as close as it gets to looking into the regulatory crystal ball. Some key players in the fight include additive manufacturers or regulatory specialists experienced in additive manufactured device submissions. 

Pairing with a manufacturer that produces other FDA-cleared devices may provide some confidence the manufacturer understands the regulatory requirements. Connecting with a regulatory professional experienced in additively manufactured device submissions may provide helpful insight on anticipating and addressing common deficiencies prior to the submission. 

Don’t just react to FDA feedback; be proactive in creating submissions that reflect a deep understanding of regulatory recommendations based on current FDA thinking to bring more innovative additively manufactured devices to patients.

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Hannah Taggart is a forward-thinking biomedical engineer and regulatory specialist with Empirical Technologies who is helping to navigate clients through the complex regulatory landscape to provide innovative and compliant medical devices for their patients.