By McKenzie E. Cato* & Allyson B. Mullen –
On May 10, FDA issued the long-awaited draft guidance, “Technical Considerations for Additive Manufactured Devices.” In October 2014, FDA held a public workshop on AM devices, “Additive Manufacturing of Medical Devices: An Interactive Discussion on the Technical Considerations of 3D Printing.” Since then, this draft guidance topic appeared on FDA’s priority guidance list in 2015, but was removed without explanation in 2016, leaving some to wonder about its status. The draft guidance states that it intends to “outline considerations associated with [additive manufacturing (AM)] processes” and provide “recommendations for testing and characterization for devices that include at least one AM fabrication step.” AM is “a process that builds an object by iteratively building 2-dimensional (2D) layers and joining each to the layer below, allowing device manufacturers to rapidly alter designs without the need for retooling and to create complex devices built as a single piece.” AM is a category of manufacturing which encompasses “3D printing.”
The most common AM methods used in the manufacture of medical devices are:
- Powder fusion: Selective melting or sintering of layers of powder (metal or polymer)
- Stereolithography: Selective light curing (by laser or projection system) of a vat of liquid material
- Fused filament fabrication: Melting of solid filament which solidifies in place
- Liquid-based extrusion: Ejection of a liquid, which solidifies via light exposure, solvent evaporation, or other chemical process
This layer-building fabrication process allows manufacturers to create anatomically matched devices using a patient’s medical imaging. It also allows manufacturers to easily create internal channels, geometric support structures, and porous materials.
The draft guidance is divided into two general parts: (1) Quality System Considerations; and (2) Device Testing Considerations (i.e., premarket submission considerations). Below we provide a high-level summary of each.
Quality System Considerations
The draft guidance provides technical manufacturing considerations for each step in the manufacturing process of an AM device. Because there are many different combinations of processing steps used in AM technology, FDA recommends that manufacturers create a production flow diagram “that identifies all critical steps involved in the manufacturing of the device, from the initial device design to the post-processing of the final device” and a “high-level summary of each critical manufacturing process.”
The basic manufacturing process of an AM device is illustrated in the draft guidance by the following flow chart. Each step in this process is addressed in turn.
The design process may include standard sizes and models or anatomically matched devices designed from a patient’s medical imaging.
The AM process, compared to other manufacturing techniques, introduces increased variability into the design process for standard-sized devices (e.g., due to pixilation of features in the device design), so FDA recommends that manufacturers identify and document manufacturing tolerances of the machine.
Regarding patient-matched designs, FDA recommends that manufacturers identify clinically relevant parameters, the range for alteration of these parameters, and which of these parameters may be modified for patient-matching. Patient-matched designs have the added variability of reliance on the accuracy and resolution of medical imaging. Additionally, any procedure or software used to make manipulations to device design based on a patient’s anatomy should contain “internal checks that prevent the user from exceeding the pre-established device specifications documented in the device master record.”
The software workflow stage involves optimization and conversion of the device design into a format from which it can be printed.
Errors in file conversion can affect the dimensions of a final finished device. Manufacturers are advised to test all file conversion steps with simulated worst-case scenarios. Final device files that are used for printing should be archived in a standardized format, such as Additive Manufacturing File (AMF) format, described in ISO/ASTM 52915.
The draft guidance identifies several additional preparatory processes that are typically accomplished using build preparation software:
- Build volume placement: Placement and orientation of devices or components within the build volume can affect device or component quality.
- Addition of support material: Some AM processes require temporary support structures. The location, type, and number of supports can affect the properties of a final device or component.
- Slicing: Most AM techniques involve a layer-building process. Manufacturers should document their choice of layer thickness, which should reflect a balance of accuracy, quality, and printing speed.
- Build paths: The path traced by the energy or material delivery system can affect device or component quality. Manufacturers should maintain consistency of build path between identical devices.
- Machine parameters: Proper calibration and preventive maintenance are key factors to achieve low rejection rates of devices and components.
- Environmental conditions: The ambient temperature, atmospheric composition, and flow patterns can impact the final properties of a device or component. Manufacturers should establish procedures to control environmental conditions within the build volume.
Concurrently with the software workflow stage, material controls are established for the materials used to print the device.
Manufacturers should document the following information about each starting material used and any processing aids, additives, and cross-linkers: (1) the identity of the material, (2) the material supplier, and (3) the incoming material specifications and material certificates of analysis (COAs) and the test methods used for the COAs. The specifications for starting materials should be based on the AM technology used. For example, if the starting material is a solid powder, the specifications may be particle size and size distribution.
The post-processing phase includes cleaning, annealing, post-printing machining, and sterilization. Manufacturers are advised to document all post-processing steps and include a discussion of the effects of these steps on the final device. Manufacturers should identify any potentially detrimental effects of post-processing steps and describe mitigations implemented.
Process Validation and Acceptance Activities
The draft guidance suggests the following methods for ensuring consistency of quality:
- In-process monitoring of parameters such as:
- temperature at the beam focus,
- melt pool size,
- build-space environmental conditions,
- power of the energy delivery system, or
- status of mechanical elements of the printing system;
- Manual or automated visual inspection with defined acceptance criteria;
- Non-destructive evaluation; and
- Test coupon evaluation.
Revalidation may be necessary if there are changes to the manufacturing process or process deviations (e.g., software changes, changes in material, physically moving the machine to a new location).
Device Testing Considerations
This section of the draft guidance highlights considerations for manufacturers when preparing premarket submissions for AM devices. The draft guidance indicates that the variability of AM devices, including shape and sizing of patient-matched devices, affects what a manufacturer can and should include in a premarket submission.
Device Description: The device description should identify the range of dimensions of the device, any design variations, any critical dimensions or features that are intended to be altered, and the range of allowable values for alterable parameters. The device description should also describe the type of AM technology used to build the device and a flow chart describing the manufacturing process, including post-processing. The draft guidance provides no additional details as to what level of information regarding the manufacturing technology or manufacturing process will be required in a premarket submission for an AM device. This level of detail will be important for not only AM device manufacturers to understand, but also 3D printer and scanner manufacturers, so that they are able to supply AM device manufacturers with the necessary information for these manufacturing tools.
Mechanical Testing and Dimensional Measurements: The draft guidance indicates the type of performance testing that should be conducted on an AM device will not generally differ substantially from traditional manufacturing methods. Performance testing may include material property testing (e.g., modulus, yield strength, ultimate strength, creep/viscoelasticity, fatigue, abrasive wear). Additionally, manufacturers should conduct performance testing on worst-case combinations of dimensions and features.
Manufacturers should identify the device’s orientation (i.e., anisotropy) relative to the build direction and location within the build space for each performance test, including worst-case orientation. The draft guidance suggests conducting a baseline study of the machine and material combination to determine the degree to which build orientation and location affects mechanical properties. The draft guidance lacks additional information regarding such a baseline study, including what it is or what such a study would entail. Manufacturers should also specify the dimensional tolerances and perform dimensional measurements for each AM component.
Material Characterization: Manufacturers should ensure that there are no unintentionally formed chemical entities that could pose a risk to patient health. In addition, the draft guidance recommends providing specific details and testing to characterize the materials to be used to build an AM device.
It is important to note that the draft guidance does not address use or incorporation of biological, cellular, or tissue-based products in AM. Thus, AM manufacturers intending to use such material should seek guidance from CBER.
Cleaning and Sterilization: The draft guidance states that cleaning and sterilization process validation should account for the geometry of the device under worst-case conditions. The draft guidance suggests that AM devices may carry an increased risk of residual manufacturing material. Manufacturers should describe how the cleaning process ensures adequate removal of residual materials as part of the cleaning validation process. Because of limitations at the end-user facility, the draft guidance recommends that AM device manufacturers perform all final cleaning steps prior to supplying the finished device to the end user. If the AM device is intended to be reusable, the draft guidance recommends inclusion of reprocessing instructions in the device labeling.
Additional Labeling Considerations: Finally, the draft guidance addresses additional labeling considerations for devices that are patient-matched. Such devices should have accompanying physician labeling in the packaging to identify the patient identifier; details identifying use, such as anatomical location; and final design iteration or version used to produce the device. The draft guidance also highlights that the patient for whom a patient-matched AM device is intended may have experienced anatomical changes since imaging was taken to prepare the device. As a result, the draft guidance recommends including an expiration date for AM devices and a precaution in the labeling indicating that “patients should be surveyed for potential anatomical changes prior to” using a patient-matched AM device.
While the draft guidance is a good starting point, it leaves open a number of important questions. For example, the draft guidance provides no information as to who FDA considers to be an AM device manufacturer. Will all hospitals that own a 3D printer now be considered device manufacturers and required to comply with device regulatory requirements? The draft guidance states, “point-of-care device manufacturing may raise additional technical considerations,” which suggests that point-of-care manufacturing could be included in the scope of this draft guidance.
The draft guidance also does not address the distinct challenges of deciding when a new 510(k) may be required for a cleared AM device. 510(k) submissions have not traditionally included information regarding the manufacturing process for the subject device. Thus, manufacturing changes were not generally contemplated in FDA’s 1997 Guidance, “Deciding When to Submit a 510(k) for a Change to an Existing Device (K97-1).” Because of the unique nature of AM devices, however, details of the manufacturing process for these devices will likely be included in most AM device 510(k)s. The draft guidance does not provide any recommendations for AM device manufacturers to aid them in determining when a change to an AM device’s manufacturing process could necessitate a new 510(k). For example, the draft guidance states that the location of AM manufacturing equipment in a build space could potentially affect the mechanical properties of the resulting AM device. Accordingly, could a new 510(k) be required if the manufacturing equipment is moved? What if commercial demand increases and a new piece of equipment is added next to (not in exactly the same location as) the original piece of equipment?
These are just a couple of the undoubtedly infinite number of open questions for AM device manufacturers. Even with FDA’s effort to provide guidance in this area, we suspect that most AM device manufacturers will need to seek device-specific guidance from FDA prior to submitting a premarket submission for a new AM device. Our earlier post on the Pre-Submission process and obtaining early feedback from FDA can be found here.
A final interesting note about this draft guidance: FDA characterizes this draft as a “leap-frog guidance.” Leap-frog guidances are relatively new, only having been used by the Agency a few times in the last couple of years. FDA describes a leap-frog guidance as “a mechanism by which the Agency can share initial thoughts regarding the content of premarket submissions for emerging technologies and new clinical applications that are likely to be of public health importance very early in product development.” We commend FDA for establishing such a process because we hope it provides greater transparency for industry regarding premarket requirements. However, unlike Immediately In Effect (IIE) guidances, another new type of guidance document, for which FDA published a draft SOP in September 2013 (see our post on IIE guidances here), we are unaware of any similar public SOPs for leap-frog guidances. Thus, the specifics of how and when FDA will employ leap-frog guidances is not apparent.