On May 10, 2016, FDA released a much-anticipated draft guidance (the “Guidance”) concerning medical devices that incorporate additive manufacturing (AM) technologies, a category which includes 3D printed devices. AM technology is proliferating in the medical device space, with approximately 80 medical devices using AM cleared by FDA for the market.
In the Guidance, FDA recognizes the advantages of using AM in medical devices including “facilitating the creation of anatomically-matched devices and surgical instrumentation by using a patient’s own medical imaging” (i.e., “patient-specific” devices and instrumentation) as well as the “ease in fabricating complex geometric structures … that would not be easily possible using traditional (non-additive) manufacturing approaches.” The agency identifies powder fusion, stereolithography, fused filament fabrication and liquid-based extrusion as the most common AM technologies used in the manufacture of medical devices. FDA, however, notes that the unique nature of AM processes and the lack of historical experience with medical devices manufactured using AM pose challenges. Some of the major points raised by the Guidance include:
- AM devices will, by default, generally be held to the same regulatory requirements as traditionally manufactured devices of the same type, though FDA raises the possibility (characterized as “rare”) that “AM may raise different questions of safety and/or effectiveness.”
- The Guidance does not address AM devices incorporating biologics, cells or tissues — the Center for Biologics Evaluation and Research will address those devices.
- FDA believes point-of-care manufacturing (i.e., in the clinical space) may raise additional technical considerations.
- Manufacturers’ quality systems must be applied throughout the design, software workflow, build file, material control, post-processing and testing phases of AM.
- The agency is strongly encouraging AM device manufacturers to use pre-submission procedures to interact with regulators and obtain necessary clarifications.
The Guidance is a “leap-frog” guidance meaning that it is intended to share FDA’s initial thoughts concerning AM — a technology the agency thinks likely to be of public health importance early in product development. The Guidance highlights technical aspects of AM medical devices to be considered through development, production, process validation and finished device testing.
Design and Manufacturing Process Considerations
This section of the Guidance covers technical considerations to be addressed in fulfilling Quality System (QS) requirements for AM medical devices. Manufacturers must both follow procedures to control the device’s design (design controls) and to monitor and control process parameters, for validated processes, to meet design specifications. Because not all specifications are easily inspected or tested for, FDA expects manufacturers to establish procedures (including manufacturing process validation) to ensure that AM devices perform as intended.
For AM technologies, FDA explains that “it is important to clearly identify each step in the printing process” and suggests a product flow chart to help ensure product quality. Manufacturers should consider producing “a high-level summary of each critical manufacturing process step” to help document the AM process. The characterization of each process step should at least include inputs and outputs as well as reflect an understating that optimization of one design parameter can influence another.
The Guidance then discusses each step in the AM design process, which is charted as follows:
Figure 1: Flow chart of the additive manufacturing process.
- For standard-sized device design, FDA recommends a comparison of “the minimum possible feature size of your AM technique, in addition to the manufacturing tolerances of the machine, to the desired feature sizes of your finished device” to ensure that devices and components of the desired dimensions can reliably be produced.
- For patient-matched device design, FDA recommends clear identification of “clinically-relevant design parameters, the range (min/max) for these parameters, and which of these parameters can be modified for patient-matching” as alterations to the final device and how they are made can directly affect the patient. FDA specifically recommends addressing the following, if applicable: effects of imaging, potential time constraints due to changes in anatomy and interacting with design models.
- The agency warns manufacturers not to fall into the trap of considering “patient-matched devices” to be “customized” devices — an AM device must meet independently all relevant statutory criteria under Section 520(b) of the FD&C Act.
FDA makes the following recommendations for the software workflow stage:
- As file conversions can affect patient outcome, all files with conversion steps should be tested with simulated worst-case scenarios. Also, final device files for printing “should be maintained and archived in robust, standardized formats that are able to store AM-specific information...”
- Correct placement and orientation of devices or components in the build volume to ensure best results.
- Analysis of the geometry and other factors that could be affected by support material, if required. In addition, “information about how support material will be used and processed should be included in the Device Master Record (DMR), including documents such as work flow diagrams and work instructions.”
- Documentation of layer thickness, which should reflect a balance of its potential effects, accuracy, quality and printing speed.
- Maintenance of consistent build paths for identical devices and components.
- Establishment and maintenance of “procedures to adequately control environmental conditions within the build volume.”
FDA makes the following recommendations for the material controls stage:
- Documentation of the following information for each starting material, processing aid, additive and crosslinker used:
- “Identity of the material or chemical by common name, chemical name, trade names, and Chemical Abstracts Service (CAS) number,
- Material supplier, and
- Incoming material specifications and material certificates of analysis (COAs), with the test methods used for the COAs.”
- Documentation should be based on the specific AM technology used.
- FDA recommends documentation and discussion of all post-processing steps and their effects on the final device including potentially detrimental effects and ways to mitigate.
Process Validation and Acceptance
FDA makes the following recommendations:
- Perform process verification to ensure and maintain quality for all devices and document monitoring and control methods for validated processes. Test methods used for process monitoring must be validated.
- Identify changes to the manufacturing process or process deviations that trigger the need for revalidation.
- Discuss and document any non-destructive evaluation (NDE) technique used in device acceptance.
- Use test coupons for process validation and identification of worst-case scenarios in the manufacturing process. Document that test coupons are representative.
Device Testing Considerations
The Guidance describes the type of information that should be included in the premarket submission for a device made using AM. Most AM devices require the same type of characterizing or performance testing information required of non-AM devices. FDA expressly acknowledges that the type and amount of data will vary given both the different AM processes and the device itself.
- For patient-matched devices, identify the range of dimensions of the device, describe design variations, and note any critical dimensions or features to be altered to match a patient.
- Describe the type of AM technology used to build the device.
- Include a flow chart describing the AM process including post-processing.
- Clearly identify critical features of the device.
- Complete performance testing on final finished versions of the devices or on coupons that have undergone identical processing.
- Perform a baseline study of the machine/material combination to determine the degree to which the build orientation affects mechanical properties.
- Specify the dimensional tolerances and performance of dimensional measurements for each AM component.
- Take dimensional measurements on samples from multiple build cycles and provide a justification of the sampling scheme.
- Identify all materials involved in the manufacturing of the medical device and the chemical composition of the final product.
- Provide biocompatibility information if necessary.
- Some materials (in Section VI.D.2 of the Guidance) carry specific requirements.
Cleaning and Sterilization
- Validate the cleaning and sterilizing processes to account for the AM device’s geometry and worst-case conditions.
- Describe how the cleaning process adequately removes residual material.
- Describe how the cleaning process adequately removes residual material.
- Include in the premarket submission information showing that all devices are thoroughly cleaned before being given to the end user.
- FDA reminds manufacturers to follow ISO-10993 (Biological Evaluation of Medical Devices Part 1: Evaluation and Testing) for biocompatibility.
Additional Labeling Considerations
- Patient-matched devices should be marketed or have physician labeling with the packaging including:
- Patient identifier,
- Details identifying use, such as anatomical location, and
- Final design iteration of version used to manufacture the device.
- Include a precaution in labeling that the patient should be surveyed for additional anatomical changes prior to procedure.
FDA’s effort in this first, leap-frog Guidance is an important step in making FDA’s expectations more clear to AM device manufacturers. However, it should be regarded only as the opening gambit in a much longer game of bringing clarity and consistency to the evaluation of AM medical devices.