3D Printing for Pharmaceutical Medical Devices An Introduction to Risk Considerations
By Tim Sandle, Ph.D.
Over the past decade, the implementation of single-use technologies for the manufacture of pharmaceutical and medical devices has introduced benefits in terms of design, sterility assurance and reduced energy consumption, in areas such as sterilization and cleaning. In the pharmaceutical sector, these technologies introduce a new way of thinking in terms of design space and process flow.1 Types of single-use technologies relevant to aseptic processing include tubes, capsule filters, single-use ion exchange membrane chromatography devices, single-use mixers and bioreactors, product containing sterile bags instead of stainless steel containers (sterile fluid containment bags), connection devices and sampling containers.2 With medical devices, more niche products tailored to individual patient needs can be produced at lower cost and with better compatibility.3 Interest in such applications grew from 2015, when the FDA approved the first 3D printed product. This change in design and production has been facilitated by the advent and improvement of 3D printing.
Since then, advances in 3D printing have led to new developments in biomedical science, such as the 3D printing of thick, vascularized, perfusable cardiac patches to serve as a functional heart.4 Application areas in pharmaceuticals include drug delivery systems, such as controlled release and microneedles; pharmacy dispensing aids and drug eluting devices, including for patients who require special personalized medications for long-term care; and single-use disposable technologies.
With medical devices, innovations have been faster because it is an ideal technology for the manufacture of parts in industries that do not generally operate in economies of scale, such as medical implants. Three examples of innovations falling under “medical devices” include: printing cranial composites of polylactic acid-based plastics that differentiate MS tumors from cancers or false positives; open source prostheses; and assist with jaw replacement surgery by printing plastic skull renderings designed for accurate jaw bone measurements. With each, 3D printing can provide accurate measurements to medical production facilities, saving time critical to patient prognosis.
What is the 3D printing process?
3D printing (or additive manufacturing, as opposed to subtractive processes in which material is cut, drilled, milled or machined), is the process by which digital 3D design data (as a computer model) is used to build a physical structure, where the component is formed in layers by material deposition.5 Materials can be plastics, composites or biomaterials and these vary in shape, size, stiffness and color. More recently, the printing of hollow systems to carry different drug formulations has expanded the versatility of 3D printed applications. Drug delivery can be assessed using a fluorescent dye to visualize product pathway through filaments and implants. The steps required for 3D printing are simple, based on the commonly used fused deposition modeling method:
- The first step is melt extrusion at the required processing temperature (usually above 100°C).
- The second stage subjects the extruded cooled filaments to heating and melting during printing through a nozzle at even higher temperatures.
An alternative method is stereolithography, in which ultraviolet light is shone into a vat of ultraviolet-sensitive photopolymer, tracing the object to be created on its surface.
The complexities relate to the design concept, computer programming (which may include the development of algorithms) and the selection of materials. With the latter, some risks are presented, and these are discussed below.
The main risk elements include material degradation and an alteration of the mechanical properties of the plastic, which could cause the polymers to bend under the stress of the additive manufacturing process. These risks require a review of appropriate materials, the assignment of critical attributes, and a controlled process for purchasing and releasing materials. Additives may be needed to prevent the desired materials from becoming brittle. Desired materials include plasticizers or solubilizers (designed to promote flexibility). As part of quality-by-design assessments and subsequent quality control assessments, the following should be considered:6
- The appearance of the manufactured item, such as discoloration
- Flexibility, where the item can be subjected to different forms of tensile testing
- Mechanical strength
To fully understand the above hazards, you must understand and document the identified risks for material sourcing and for each stage of the manufacturing process, as well as the mitigations for those risks. Assess these risks both after printing and after any sterilization process, given the stress induced by sterilization technologies. It is important to continue evaluations throughout the shelf life of the product. An understanding of the intended use of each individual device should frame the overall consideration of risk. Later, you should identify and assess any changes to the device, manufacturing process, or process deviations for any potential risks that might be introduced.
Another risk you need to assess with both the base material and the use of additives, catalysts, bonding and curing agents, uncured monomers and plasticizers is toxicology. This includes the risk posed by leachable impurities. This should be extended to account for any risk of residual build material, such as excess starting material or support material, remaining on the finished device. To assess these risks, careful consideration of the materials and the reaction of the materials in the presence of the product is necessary as part of an extensive biocompatibility assessment. These considerations should be framed by the risk profile with respect to the intended user of the material (for a medical device) or with respect to a specific product, when used in pharmaceutical processing.
While 3D printing promises many innovations, there are currently some limitations. Restrictions include:
- Limited materials, as the current selection of raw materials is not exhaustive
- Restricted build size related to types of 3D printers available
- Post-processing, which is limited by the extent to which fabricated materials can be shaped
- The effect of sterilization methods
- Large volumes
- Part structure
- Design inaccuracies
- Regulatory approval stages
The future is bright for 3D printing in pharmaceuticals and medical devices
Greater progress has been made with single-use systems than with drug delivery.seven However, the types of limitations listed above are not, in the longer term, insurmountable as technology and understanding advance. As with any new technology, progress sometimes continues to be uneven. Overall, however, as an area of advanced automation and design, the application of 3D printing is only going to grow.
- Hodgkinson, M. (2014) Improving Microbial Control and Sterility Assurance in Aseptic Processing by Implementing Single-Use Technology, American pharmaceutical journal, at: https://www.americanpharmaceuticalreview.com/Featured-Articles/158936-Enhancing-Microbial-Control-and-Sterility-Assurance-in-Aseptic-Processing-by-Implementing-Single-Use-Technology/
- Sandle, T. (2017) Establishing a Contamination Control Strategy for Aseptic Processing, American pharmaceutical journal, at: https://www.americanpharmaceuticalreview.com/Featured-Articles/335458-Establishing-a-Contamination-Control-Strategy-for-Aseptic-Processing/
- Sandle, T. (2017) Find out how 3D printing can save your life, Open Health News, at: https://www.openhealthnews.com/news-clipping/2017-06-30/read-how-3d-printing-can-save-your-life
- Sandle, T. (2018) Tiny 3D printed heart made with blood vessels, DX Log, at: https://dxjournal.co/2019/04/tiny-3d-printed-heart-fabricated-complete-with-blood-vessels/
- Bucchi M. Saracino B. (2016) Visual Science Literacy: Images and Public Understanding of Science in the Digital Age. Common Sci. 38: 812-819
- Alhijjaj, M., Belton, P. and Qi, S. (2016) An investigation into the use of polymer blends to improve printability and regulate drug release from pharmaceutical solid dispersions prepared via 3D printing fusion deposition modeling (FDM), EUR. J.Pharm. Biopharma., 108: 111-125
- Seoane-Viaño, I., Trenfield, S., Basit, A., Alvaro Goyanes, A. (2021) Translating 3D Printed Pharmaceuticals: From Hype to Real-Life Clinical Applications, Advanced Medication Administration Reviews, 174: 553-575
About the Author:
Tim Sandle, Ph.D., is a pharmaceutical professional with extensive experience in microbiology and quality assurance. He is the author of over 30 books on pharmaceuticals, healthcare and life sciences, as well as over 170 peer-reviewed articles and some 500 technical articles. Sandle has presented over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.