In December, the U.S. Food and Drug Administration (FDA) issued guidance on Technical Considerations for Additive Manufactured Medical Devices. The guidance represents FDA’s efforts to provide regulatory direction about additive manufacturing (AM)—the broad field of 3D printing—of medical devices. Specifically, AM makes objects by sequentially building 2-dimensional layers and joining each to the layer below. AM enables diverse design models without the need to retool or create complex manufacturing machines to build components. The FDA guidance focuses on technical aspects of AM, and is organized into two topics: (1) design and manufacturing considerations; and (2) device testing considerations. The guidance notes that FDA “does not comprehensively address all considerations or regulatory requirements to establish a quality system for the manufacturing” of AM devices. Instead, FDA recommends testing and characterization for devices that include at least one additively‑manufactured component or additively‑fabricated step. The guidance also reflects the agency’s current thinking on AM for medical devices.
AM is a rapidly growing technology with numerous applications in medical devices. Representing a step toward personalized medicine, AM can facilitate anatomically‑matched devices and surgical instrumentation by using the patient’s own medical imaging (these are referred to as “patient-matched devices”). AM can create complex geometric structures that would otherwise be impossible to manufacture, or too costly to manufacture under traditional manufacturing approaches. These technologies can prove life-saving. For example, in 2012, after receiving emergency clearance from FDA, medical staff at the University of Michigan used AM processes to create a bioresorbable tracheal splint that they used to rescue an infant suffering from a collapsed bronchus due to severe tracheobronchomalacia. The splint was implanted in the infant’s airway, expanding the bronchus and allowing for future proper growth. Within weeks, the infant was off ventilator support and breathing normally. AM saved the baby’s life.
Recognizing the benefits of AM, FDA is preparing for “a significant wave of new technologies that are nearly certain to transform medical practice.” The FDA Commissioner does recognize that novel aspects of the AM process lack substantial clinical histories and experimentation. Accordingly, use of AM techniques in sensitive medical contexts poses challenges, and FDA anticipates that manufacturers may struggle in “determining optimal characterization and assessment methods for the final finished device, as well as optimal process validation and acceptance methods for these devices.”
So far, FDA has reviewed more than 100 medical devices that were manufactured using AM techniques. FDA also recently approved a drug for seizures that was 3D-printed to create a more porous matrix than the drug would have had if manufactured using traditional means. This allowed the drug to dissolve more rapidly in the mouth. FDA further anticipates that AM can lead to treatments for burn wounds and even artificial replacement organs.
Design and Manufacturing Process Considerations
FDA anticipates that its standard premarket submission process will apply in equal force to AM devices as it does to traditionally-manufactured devices. Accordingly, for Class II and III devices (and select Class I devices), manufacturers “must establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met per 21 CFR 820.30 Design Controls.” The FDA further expects manufacturers to “establish procedures including validation of the manufacturing process of AM devices to ensure that the device can perform as intended.” Especially where the final result of a process cannot be fully verified by subsequent inspection and testing, the process must be “validated with a high degree of assurance and approved according to established procedures.”
Because several AM technologies and processing steps can be used in medical devices, the guidance urges manufacturers to “clearly identify each step in the printing process.” In this vein, FDA recommends use of production flow diagrams coupled with high-level summaries of each critical step to help ensure product quality. Each described process step should include “a description of the process, and identification of the process parameters and output specifications.” Delineated, step-by-step descriptions of each process should be well documented to allow the manufacturer to identify and remedy any root causes of failures from manufacturing defects; absent such detailed process instructions, defects can be difficult to pinpoint and correct. Because AM processes can be quickly modified and adapted to specific use-scenarios, dimensional specifications for the final device or component, as well as manufacturing tolerances of the manufacturing machine, should be properly documented.
Additional considerations come with patient-matched devices, which may not have a “standard‑sized template” (since they are contoured to individual patients) and may be modified by clinical staff, the device manufacturer, or third parties in response to clinical inputs. Because of this customizability, manufacturers “should clearly identify clinically relevant design parameters, the pre-determined range (min/max) for these parameters, and which of these parameters can be modified for patient-matching.” The guidance specifically recommends, to the extent applicable, that manufacturers address: (1) effects and necessity of imaging; (2) clinical and patient interactions with design models; (3) maintenance of data integrity of complex design files; and (4) the (cyber)security of personally identifiable information.
FDA provides that “AM typically involves interaction between several software packages, often from different manufacturers[.]” As a result, errors in file conversions and software interactions can negatively impact the quality of the AM process and final device. For this reason, FDA recommends that manufacturers “verify the critical attributes and performance criteria of [their] final products as part of the software workflow validation to ensure expected performance, especially for patient-matched devices.”
Further, once a device design is complete, manufacturers should consider additional preparatory processes, including:
- placement, orientation, and packing density of devices or components within the build volume;
- use of additional support material or structures for certain design features;
- layer thickness of each “slice” created by the AM machine as related to the layer-by-layer printing process;
- the build path, or path traced by the energy or material delivery system (e.g., laser or extruder);
- required machine parameters and calibrations (e.g., build speed, total energy density, and focal point or nozzle diameter); and
- environmental conditions within the build volume (e.g., temperature, pressure, and atmospheric compositions).
FDA recommends that materials used in AM processes should be well documented and chosen based on the AM technology used, the intended use of the final medical product, and any other information available. Reuse of certain materials (something possible when using AM technologies) is allowed but should be scrupulously documented. Evidence should be provided that reuse will not adversely affect the final device. Any post-processing steps of AM (manufacturing steps occurring after the printing process) that may affect device performance and material properties should also be well documented and include analysis of any effects such steps may have.
As noted above, when a final result of a process cannot be fully verified by subsequent inspection and testing, the process must be validated with a high degree of assurance. For such validation processes, monitoring and control methods of data must be documented. Such methods may include monitoring and documenting parameters such as:
- temperature at the beam focus;
- melt pool data;
- build-space environmental conditions;
- location in the build volume where a device or component was built; and
- power of the energy delivery system.
These same methods may also be helpful for processes that are not required to be validated.
Device Testing Considerations
Generally, FDA advises that AM product performance testing should be implemented in the same manner as if the device were manufactured using traditional manufacturing methods. Depending on the device type, these testing methods may include: “material property testing such as modulus, yield strength, ultimate strength, creep/viscoelasticity, fatigue, or abrasive wear.” Further, performance testing should be conducted on all finished devices following post-processing, cleaning, and sterilization steps. Manufacturers should also conduct tests targeting the “worst-case combinations” of dimensions, features, orientations of the materials, and locations in the build space to ensure adequate product performance. These tests should include a discussion of how the combinations were selected and why each test was conducted. Manufacturers should create and maintain “test coupons” (a representative test sample of the device or component) when evaluating AM products.
Recognizing that AM processes may lead to a wider variance in end products than traditional manufacturing methods, FDA recommends that manufacturers specify and adhere to pre-set dimensional tolerances by measuring representative product samples. Manufacturers should address any variability due to orientation and build location if studies show variance based on these parameters. In order to maintain consistency, product measurements should be made on samples from multiple build cycles and manufacturers are expected to provide justification for the sampling scheme used. Finally, process validation information may help demonstrate negligible variability between products in different build cycles or batches.
Because of the iterative nature of AM, starting materials may be exposed to partial re-melting and solidifications multiple times. This may result in unexpected or undesired material compositions. Because many AM medical devices will be used in sensitive medical contexts (often surgically implanted into a patient), manufacturers should conduct biocompatibility testing and incorporate guidance proffered in “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process’” if necessary. Specific testing (e.g., in vitro degradation testing) may be necessary if the AM device uses an absorbable material.
One of the greatest advantages of AM devices is the ability to make highly complex components and end products. With that advantage comes an inherent disadvantage—AM devices may be exceptionally hard to clean and sterilize. AM also allows porous structures to be produced earlier in the manufacturing process than traditional methods, which may result in greater soiling by subsequent exposure to other AM materials. Accordingly, manufacturers should create work-flows and be able to validate that any remaining material residue will not adversely affect the device’s quality. A summary of this information should be included in premarket submissions to the agency. Additionally, the guidance warns that many end-use facilities will not have access to the equipment or materials needed to implement on-site cleaning procedures designed to remove residual manufacturing materials. Accordingly, only devices that are sufficiently cleaned should be provided to the end user.
Finally, the guidance provides that AM device labeling “should be developed in accordance with applicable regulations, device-specific guidance documents, and consensus standards.” Additional labeling is recommended for AM devices that are patient-matched. FDA recommends that such labeling identify (1) the patient; (2) the products used (e.g., left distal femoral surgical guide); and (3) final design iteration or version used to produce the device. Expiration dates for patient-matched devices should also be included. Because it is possible that a patient may experience an event between imaging and surgery, FDA also recommends that manufacturers include a precaution in their labeling that the patient should be evaluated for potential anatomical changes prior to the procedure.
Though not binding, manufacturers should consider adopting the recommendations included in the FDA’s guidance on AM. As with other FDA guidance documents, future regulations are likely to incorporate and expand on these existing guidelines.