Quality and safety in medical 3D printing

Introduction

The AM/3DP (additive manufacturing/3D printing) is a type of manufacturing technique wherein the final object is formed by successive addition of layers of materials such as plastics, metals, drugs, cell culture etc. using the 3D printer (see Fig. 5.1 ) . According to United States Governmental Accountability Office (GAO), 3D printing can create 3D structures from digital models by AM process . It has a wide range of applications in various fields including healthcare, automobile, aerospace, food, chemical, and toy industry (see Fig. 5.2 ). In the healthcare industry, 3D printing has been used to produce various dosage forms of drugs, prosthetics, medical devices, and artificial tissues and organs. 3D bioprinting is the fabrication of a functional artificial tissues or organs via a 3D printer such as Regenova by layer-upon-layer addition of cells, biomaterials using bioinks such as endotoxin-free low-acyl gellan gum (see Fig. 5.3 ). For example, Spritam, ^a

a Levetiracetam, an antiepileptic drug.

the first 3D-printed drug approved by FDA has encouraged tremendous research in the development of various medication by the use of 3D printing technology . This innovation comes with various challenges to be looked upon to combat the disruptions that can possibly occur ( , p. 146).

Various disruptions in healthcare and manufacturing due to 3D printing are predicted to occur. For more than 20 years, applications of 3D printing were restricted to prototyping. In the recent years, many of the 3D-printed objects have been introduced in the market of healthcare and manufacturing such as medical devices (prosthetics), dental instruments (crowns, bridges), artificial organs (kidney, heart) for research purposes, implants, and many others. By 2019, 3D-printed objects will be a part of our daily life, “located” in or on the body of more than 10% people in the developed world. 3D printing will play a crucial role in more than 35% of the surgical procedures requiring prosthetics, implants, artificial organs, and other 3D-printed objects. Advancement in technology and innovations will lead to 10% of spurious drugs and pharmaceuticals manufactured using 3D printer .

3D printing can increase the quality of deliverable healthcare services, as it is capable of manufacturing personalized products suited for a particular individual. It can print medicine in various shapes, sizes, doses, and dosage forms with desired and prespecified characteristics, including drug release profile and fixed dose combination (FDC). Formulations prepared in an individualized manner are likely to increase drug safety and reduce toxicity and various other side effects caused by inappropriate drug dose. Likewise, the ability of 3D printers to fabricate the medicine at the point-of-care (PoC) avails a range of therapeutic options, which removes the barrier for healthcare personnel in choosing the best-suited approach. Further, it is capable of producing various medical devices, implants, anatomical models, artificial organs, among others, covering a large potential for overall betterment of healthcare services and healthcare education. The first FDA-approved drug product demonstrated the commercial applicability of 3D-printed products in August 2015 following which a large number of medical devices have been produced via 3D printing. Therefore, the continuous innovation and developments in 3D printing technique and its applications seem promising in terms of revolutionizing healthcare and improving quality of life ( , p. 151).

Since 1993, continuous assessment of the process on a detailed basis has been carried out by disclosing some of the limitations in the new technology. Biomedical 3D printing nowadays not only has major applications in pharmaceutics, medicine, and dentistry, but it also involves strict regulation and social challenges. Legislation has to be adapted in order to characterize the new terminology of the new technology. Furthermore, issues like 3D data ownership, privacy and the protection of intellectual property rights must be faced. Quality and Safety standards also must be addressed, to ensure the well-being of humans. On the other hand, the use of the new technology, the high offer of new materials and the technology itself is indisputably extremely challenging for various reasons. For instance, transplantation of a 3D-printed organ would be most welcome, given the lack of suitable donors. Lastly, there is always the prospect of new technology (high-end) new jobs ( , pp. 147–152).

Quality assurance in medical 3D printing

In recent years the development of relatively cheap desktop 3D printers has led to a booming 3D printing industry. Now, with the arrival of commercially available biocompatible and sterilizable 3D prints, local medical 3D printing labs emerge in hospitals worldwide . Studies show that medical 3D printing can be in many different ways of great added value for all kind of specializations. Three main applications are defined :

• Anatomic models : The added value of 3D-printed anatomical models is threefold:

  • a valuable tool for physicians in patient–doctor communication ;

  • serve as a tool for resident education and surgical training ; and

  • allow development for optimal surgical planning .

Furthermore, the quality of the preoperative plans based on 3D prints is shown to be higher than that of digital 3D-rendered images .

• Surgical models : 3D-printed surgical guides are widely used in specialties such as orthopedics, traumatology, oral and maxillofacial surgery, plastic surgery, and several other invasive surgical fields. Patient-specific surgical navigation guides offer a boost in surgical precision and reduction of surgical time, leading to lesser chance for infection and a faster recovery .

• Implants and prostheses : Development of implants and personalized prostheses is the most important and most valuable application of 3D printing in the field of orthopedics, up to now. Several individual cases of 3D-printed cranial, dental, and spinal implants have been reported .

With this rapidly growing new in-hospital technology, there's an urge and necessity for methods of quality control and quality assurance. Apart from a recent paper from Ref. ; where a methodology is provided for quality control of the in-house 3D printing workflow for unsterilized anatomical models, no literature on the quality control of the complete process, encompassing the various applications, is known. During the different phases of 3D printing, there is the possibility of errors occurring. These errors may be due to human factors such as miscommunication or failure of other factors which are inherent to the workflow step. By optimizing the workflow and a proper definition of the responsibilities, the human errors can be minimized or completely taken away, whereas the inherent errors can only be minimized and monitored. Specifically ( , pp. 670–672),

• 1.

  Qualitatively induced errors : Without a well-defined 3D printing workflow strategy, the quality of the 3D printing process cannot be assured. The process definition contains a typical 3D printing workflow with six steps ( Fig. 5.4 ):

  • a.

    the selection of 3D printing cases (based on the clinical value, cost-effectiveness, and a risk assessment),

  • b.

    image acquisition (responsibility of the radiologist and medical physicist),

  • c.

    segmentation (reconstructing images is a collaboration between a technologist with anatomical knowledge, the requesting physician, and a medical engineer),

  • d.

    engineering (development of molds or guides, the smoothing and the supporting of the printable),

  • e.

    3D printing (a task for the medical engineer), and

  • f.

    preparation for use (supports by a medical engineer, checked and validated by the requesting physician and if necessary sterilized at the central sterile service department (CSSD)).

  

An overview of the process see the next figure ( Fig. 5.5 ):

• Quantitatively induced errors : these concern the following:

  • Image acquisition and segmentation: A critical step in each patient specific 3D print is the image acquisition. As the commonly used imaging modalities already own a QC program the quality control of the image acquisition is left out of the scope of this report. However, it is evident that from patient to digital scan, this is the first inherently error-inducing step in the process. Slice thickness and reconstruction kernels are the most important parameters at this stage. The segmentation is called the process of restricting the reconstructed volumetric images into the region of interest only. Within each of these packages segmentation can be achieved through various methods (Hounsfield units to slice per slice contouring). For a successful quality assurance program these induced errors should be insightful and easily monitored over time.

  • 3D printing : It is evident that from CAD drawing to 3D print, the 3D printer induces errors due to the discrete layers that build up the model. The printer's resolution and accuracy are the parameters that could lead to unexpected dimensional errors.

  • Sterilization: For several 3D printing purposes, sterilization of the finished product is necessary. Possibilities are surgical instruments, surgical guides, and implants. In high-temperature steam sterilization, the 3D print is exposed for 3 minutes to temperatures of 134 °C. ^b

    b WIPrichtlijn, http://www.rivm.nl/dsresource?objectid=330dd0f8-e6b8-4621-86b17a039ac83d42&type=pdf&disposition=inline .

    Today, it is unclear if significant shrinkage, expansion, or deterioration of the print occurs at these temperatures.

For example, a case study in 2009 by Sampat et al., suggested that the rapid release and absorption of a baclofen compounded formulation may lead to toxicities in the targeted populations and that a reduced frequency of dosing is a suitable alternative for improved therapeutic outcomes . Therefore, a modified release pediatric formulation, enabling individualization of dosage, could be the most suitable strategy to improve the therapeutic outcome of baclofen, with minimal side effects in the targeted population. Scoutaris et al. ; reported the development of chewable indomethacin 3D printed tablets (“Starmix”) for the pediatric population using HPMCAS . However, there are limited/no reports on the use of PVA for the development of pediatric population-specific 3D-printed baclofen formulation. Thus, the purpose of the present work was to develop and characterize a modified release baclofen minicaplet using FDM 3D printing technique and systematically investigate the effect of different printing parameters on drug release using a 32 full factorial design. The overall process of hot melt extrusion to 3D printing of minicaplet and potential advantages of 3D-printed minicaplets in pediatric population have been schematically represented in the next figure ( , pp. 107–108) ( Fig. 5.6 ).