Opportunities and Challenges of Selective Laser Sintering 3D Printing in Personalized Pharmaceutical Manufacturing

Introduction

Three-dimensional printing (3DP) is a path breaking technology, which will undoubtedly open a new era in pharmaceutical manufacturing science. The International Standard Organization (ISO) defines 3DP as: “Fabrication of objects through the deposition of a material using a print head, nozzle, or another printer technology.”¹ It is based on additive manufacturing technology in which three-dimensional objects are created by joining materials layer by layer from a digital computer aided design file. 3DP offers flexibility, versatility and agility for pharmaceutical manufacturing. Possibly, fewer manufacturing steps and lesser number of excipients are required than conventional manufacturing processes.²

The use of 3D printing in the medical device industry has increased enormously and the number of medical devices manufactured using 3DP has exploded. More than 85 3DP medical devices, including hearing aids, hip cups, knee trays, dental crowns, etc. have been approved by the Food and Drugs Administration (FDA).³ In comparison, the pharmaceutical industry has been slow in embracing the technology primarily due to technical and regulatory challenges. So far, only one printed dosage form, Spritam® which contains levetricetam, has been approved by the FDA.⁴ The dosage form is highly porous causing it to disperse in the mouth in a matter of seconds even without consuming water. This attribute makes it a very attractive option for patients who have trouble with chewing or swallowing. Further, the lag time for onset of action is reduced due to fast disintegration and absorption of the drug into systemic circulation through the oral mucosa.^4,5

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The 3D printing methods most relevant to pharmaceutical manufacturing include Fused Deposition Modelling (FDM), Binder Jetting (BJ), Selective Laser Sintering (SLS) and Stereolithography (SLA). The salient features of these technologies are enumerated in Table 1. Briefly, the manufacturing process comprises of designing a digital model of the desired 3D product. The digital design is converted to a readable format, stereolithography (STL) file. The 3D printing software, typically a slicer, converts the STL file into a series of thin layers with print instructions. The printer head or laser moves during the printing process as dosage form (printlets) is built in successive layers on a built platform. Post processing steps may be required depending on the technology employed.²

Selective Laser Sintering

SLS embodies one of the latest and advanced technologies for manufacturing printlets. The essential components of a SLS system are a spreading platform, powder bed, and a laser system (laser and a scanner). After the powder is evenly spread over the building platform, the laser draws specific scanning patterns on the powder surface, which are predesigned depending on the characteristics of the finished product. The powder is sintered by softening or melting of the thermoplastic polymer. Subsequently, the powder bed moves down by a height of one-layer thickness while the reservoir bed moves up to deposit a new powder layer onto the previously sintered layer followed by laser sintering. The process of powder layering and sintering are repeated till desired printlets are formed (Figure 1).⁶

SLS has many advantages over other additive manufacturing methods. For example, no solvent is used. Therefore, it is suitable for drug candidates which are sensitive to aqueous and organic solvents. SLS does not require post processing treatments such as drying, UV curing, etc., meaning that printlets can be immediately dispensed and consumed. In comparison to other processes, SLS does not require a filament form of raw material, polymerizable monomer, or a liquid binder. However, SLS requires formulation components to be thermoplastic and thermally stable. Further, the polymers should be biocompatible, biodegradable and GRAS (Generally Recognized as Safe) listed.6 Additionally, the mixture needs to have laser-absorbing components to enhance the laser absorptivity of the powder mixture (e.g. Candurin® gold sheen [silicon dioxide coated with ferric oxide]). Colouring agents approved by the FDA can also be used as laser absorbing agents in low concentration (≤3%).

The critical process parameters in SLS include laser power, bed temperature, layer thickness, and powder properties such as particle size, particle size distribution, shape, and density. These parameters play crucial roles in dimensional accuracy, quality of the surface/subsurface, mechanical properties, and other critical quality attributes (CQAs) of printlets.^2,6 The powder bed is preheated to reduce the laser energy required for sintering. Internal stresses and thermal deformations can be remarkably reduced when thermal gradients are minimized (often in proportion to the laser energy density supplied), as the printlet undergoes less cooling between layers than if the printing was done at room temperature. The net powder bed temperature is the outcome of interaction between laser beam properties, scanning pattern and thermal properties of powders. Laser energy required for sintering is determined by the type of the material and thickness of the powder layer. In SLS studies done to date for manufacturing pharmaceutical printlets, a Sintratec Kit printer has been used, which has a constant laser power of 2.3W.7-12 Therefore, the only parameters that have been changed to adjust the laser energy are the scan speed and hatch distance. Having a lower scanning speed increases the contact time between the powder bed and the laser beam, which generates a high laser energy density ensuring a high degree of sintering/melting that generally results in denser printlets. Conversely, porous printlets would be formed at high laser scanning speed. High scanning speed results in less energy transmission to the powder, culminating in less powder sintering. Hatch distance, which is the distance between two consecutive scanning path vectors, should be optimized vis-a-vis laser beam diameter and energy density. Large hatch distances may result in incomplete sintering and consequently mechanically weak structures. On the other hand, too small hatch distances may induce thermal deformation.^2,6,10 Though the thermal energy absorption can vary based on powder composition, the volumetric energy density can be determined by:

Where, ED is the energy density, PL is the laser power, dL is the laser diameter, hS is the hatch distance, and vs is the beam speed, or the laser scanning speed.^13,14

The particle size and thickness of the effective powder layer significantly influences the laser sintering process. The large difference between particle sizes of formulation components can induce segregation. The powder must demonstrate good flowability for uniform spreading on the platform. High packing density of the layer is desired for better printlet density. The particle sizes that provide good flowability and sintering for SLS is typically in the 50-100 µm range. Layer thickness (slice thickness) typically used in SLS varies from 50 to 500 µm, and significantly influence printing resolution, surface roughness, etc.¹⁰ Having a smaller powder layer leads to better layer fusion, as there is less material in thin layers that must be sintered per layer by the laser. Better layer fusion due to having thinner layers also leads to higher mechanical strength and lower porosity.

Challenges of SLS Technology

Various challenges, both technical and regulatory, prevent their widespread application in pharmaceutical manufacturing. Formulation components endure preheating and localized heating phases during the sintering process which may accelerate the degradation of formulation components including drug candidates. Therefore, thorough evaluation of thermal stability behavior during the SLS process is obviously necessary to understand the degradation mechanisms. To reduce the risk to CQAs, thermolabile drugs would require processing at low temperature and lower laser power or alternatively faster scanning speed can be used. Low temperature melting thermoplastic polymers such as polycaprolactone is preferred for such applications.^6,10 The recycling of unbound powder which has been exposed to the processing conditions remains a major challenge. The recycled powder may undergo changes in CQAs and therefore, unbound/uncured material may not be suitable for recycling suggesting significant process losses.² Mechanical properties of 3D printed tablets can be manipulated by formulation and process variables. Therefore, these characteristics would entail a great deal of material and process-related research for various dosage forms. Another challenge impeding the acceptance of this technology is the lack of cGMP compliant 3D printers. Therefore, compliance to CFR 21 part 211 requirements could act as a stumbling block. Further, there is no regulatory guidance available for drug products manufactured by 3D printing. However, existing regulatory framework can be utilized for submitting new drug applications [(NDA (505(b)(1) or 505(b)(2))] or abbreviated new drug applications (ANDA(505(j))].²

Finally, the current 3D printing technology is a slow process and cannot match the mass production output of conventional rotary tablet presses or capsule filling machines. Current 3D printers can process only a few hundred dosage forms per hour, while in comparison a 77 station tablet press can produce 831,000 tablets per hour.¹⁵ However, it is the manufacturing of personalized medicine where 3D printed dosage forms hold immense potential.

Applications in Fabricating Personalized Medicine

3DP technology has the potential to digitize the compounding of pharmaceuticals and print personalized medicines for patients on demand and therefore complete the missing cog in the telemedicine wheel. The current compounding practices used in pharmacies to supply personalized medicines are not significantly different from the age-old practices. Current compounded pharmacies can be easily upgraded with minimal investment to produce 3D printed drugs. In fact, the existing infrastructure in the majority of these pharmacies is generally adequate to start the production of 3D printed dosage formulations.

Personalized medicines are generally required for pediatric populations, geriatrics or patients exhibiting allergy to certain formulation components.² The pediatric population is physiologically heterogeneous. They are categorized into neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years) and adolescents (12 years to <16 years).^16,17 The rapid developmental and physiological changes seen in the pediatric population affect the pharmacokinetics of drugs significantly and hence the dosing needs vary from one pediatric group to another. Consequently, age appropriate formulations with flexible dosing options are required that not only deliver a specific dose, but also should be palatable to ensure adherence to the dosing regimen. Unfortunately, adequate age appropriate formulations are not available and often adult doses are extemporaneously manipulated in compounding pharmacies to cater to the needs of the pediatric population. However, quality, stability, pharmacokinetics, and compliance to other CQAs are major concerns with extemporaneous preparations that raise serious concerns on safety and efficacy of such formulations. With 3DP, personalized medicines can be prepared to meet the individual patient needs by printing individual doses, dosage forms containing multiple drugs and dosage forms exhibiting a particular rate of drug release. Similarly, geriatric patients can benefit immensely, who are often on multiple medications at any given point due to the age-related changes in physiology and multiple comorbidities.² Consequently, geriatric patients are at high risk of developing adverse effects due to polypharmacy. Additionally, polypharmacy is responsible for non- adherence to the medicines and has been shown to be responsible for frequent emergency visits to the hospital.² 3DP can be used to print both mono as well as multidrug formulations that are easy to swallow. The compliance to dosing regimen can be increased and as a result adverse effects may be reduced. Instead of dispensing a cocktail of multiple pills, a once a day personalized polypill can be printed based on a physician’s prescription.²

The 3DP manufacturing processes can be executed in a resource limited environment such as pharmacy, clinic or space and thus it enables ‘on-demand’ or ‘just-in-time’ pharmacy capability. While preparing printlets in pharmacy and hospital setting, certain criteria laid in sections 501(a)(2)(B) (concerning cGMP requirements), section 502(f)(1) (concerning the labelling of drugs with adequate directions for use) and section 505 (concerning the approval of drugs under new drug applications or abbreviated new drug applications) of the Food, Drugs and Cosmetic Act (FD&C) may be exempted.^18,19 It is to be noted that for sterile products, compliance to cGMP is mandatory.

SLS can be used in fabricating specialized dosage forms such as orally disintegrating (ODT), sustained, extended release, dual release profiles, abuse deterrent formulations and amorphous solid dispersion (ASD). The technology offers unique capabilities which are difficult to achieve in traditional manufacturing. For instance, ODT prepared by traditional manufacturing methods are limited by the tablet weight 500 mg and should disintegrate within 30 sec. The 3DP technology can produce highly porous structures which can disintegrate in a few seconds and meet disintegration time requirements of less than 30 sec. Similarly, ASD of poorly soluble drugs can be fabricated in a one step. Traditional manufacturing involves multiple steps such as preparing ASD by spray drying or hot melt extrusion followed by capsule filling or tablet compression. SLS can produce ASD dosage forms in a single step with very low crystalline fraction, which can be further controlled by process and formulation variables.

References

1. ISO / ASTM52900-15, Standard Terminology for Additive Manufacturing - General Principles - Terminology, ASTM International, West Conshohocken, PA. 2015.
2. Rahman Z, Barakh ASF, Ozkan T, Charoo NA, Reddy IK, Khan MA. Additive manufacturing with 3D printing: progress from bench to bedside. AAPS J. 2018; 20(6):101.
3. Jacobson M. Lessons for medical device manufacturers using 3D printing. Med Device Online. July 18, 2018. Available at: https://www.meddeviceonline.com/doc/lessons-for- medical-device-manufacturers-using-d-printing-0001. Accessed November 10, 2020.
4. Spritam® FDA label, January 22, 2019. Available at: https://www.accessdata.fda.gov/ drugsatfda_docs/label/2018/207958s008lbl.pdf. Accessed November 10, 2020.
5. Rahman Z, Charoo NA, Kuttolamadom M, Khan M, Printing of personalized medication using binder jetting 3D printer. In: Faintuch J, Faintuch S, eds. Precision Medicine for Investigators, Practitioners and Providers. Elsevier, 2020:474-480.
6. Charoo NA, Ali SFB, Mohamed EM, Kuttolamadom MA, Ozkan T, Khan MA, Rahman Z. Selective laser sintering 3D printing - an overview of the technology and pharmaceutical applications. Drug Dev Ind Pharm. 2020;46(6):869-877.
7. Barakh Ali SF, Mohamed EM, Ozkan T, Kuttolamadom MA, Khan MA, Asadi A, Rahman Z. Understanding the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering 3D printing. Int J. Pharm. 2019;570:118651.
8. Allahham N, Fina F, Marcuta C, Kraschew L, Mohr W, Gaisford S, Basit AW, Goyanes A. Selective laser sintering 3D printing of orally disintegrating printlets containing ondansetron. Pharmaceutics 2020;12(2):110.
9. Awad A, Yao A, Trenfield SJ, Goyanes A, Gaisford S, Basit AW. 3D printed tablets (printlets) with Braille and Moon patterns for visually impaired patients. Pharmaceutics 2020;12(2):172.
10. Fina F, Goyanes A, Gaisford S, Basit AW. Selective laser sintering (SLS) 3D printing of medicines. Int J Pharm. 2017;529:285-293.
11. Atheer A, Fabrizio F, Sarah JT, Pavanesh P, Alvaro G, Simon G, Abdul WB. 3D printed pellets (miniprintlets): a novel, multi-drug, controlled release platform technology. Pharmaceutics 2019;11 (4):148.
12. Fina F, Madla CM, Goyanes A, Zhang J, Gaisford S, Basit AW. Fabricating 3D printed orally disintegrating printlets using selective laser sintering. Int J Pharm. 2018;541:101-107.
13. Chatham CA, Long TE, Williams CB. A review of the process physics and material screening methods for polymer powder bed fusion additive manufacturing, Prog Polym Sci. 2019;93:68-95.
14. Drexler M, Lexow M, Drummer D. Selective laser melting of polymer powder - part mechanics as function of exposure speed. Phys Procedia. 2015;78:328-36.
15. Siew A. Increasing tablet production with multi-tip tooling. Pharma Tech. 2015. Available at: http://www.pharmtech.com/increasing-tablet-production-multi-tip-toolin. Accessed November 10, 2020.
16. Joseph PD, Craig JC, Caldwell PH. Clinical trials in children. Br J Clin Pharmacol. 2015;79(3):357-369.
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18. FDA guidance on pharmacy compounding of human drug products under section 503A of the Federal Food, Drug and Cosmetic Act 2016.
19. FDA guidance for industry - Orally disintegrating tablets, 2008. https://www.fda.gov/ media/70877/download. Accessed November 10, 2020.

Author Biographies

Naseem A. Charoo is the co-founder and chief scientific officer at Succor Pharma Solutions. He has 17 years of experience in pharmaceutical development. He is responsible for leading the R&D efforts to build product portfolio. Prior to joining the company he worked in various organizations in Asia, Africa, Middle East and Latin America. Dr. Naseem earned a MS and Ph.D. in Pharmaceutics from Jamia Hamdard, New Delhi.

Cyrus Funkhouser is a student at Texas A&M working towards his MS in Engineering Technology. He has earned a BS of Manufacturing and Mechanical Engineering Technology at Texas A&M. Prior to entering the MS program, Cyrus has worked on another project regarding medical manufacturing: Design & Control of a Vibration-Added Haptic Device for Minimally Invasive Surgical Simulation. Currently, he is working in a joint effort with the Department of Pharmaceutical Research as well as the Department Engineering Technology and Industrial Distribution to further explore SLS of pharmaceutical tablets.

Dr. Mathew A. Kuttolamadom is an associate professor at Texas A&M University. With a background in design, materials and manufacturing, his recent research has focused on laser-based AM of polymers, metals and ceramics, with a view to tailor bioinspired and graded materials. Over the past 2-years, his team has extensively investigated the selective laser sintering (SLS) of various pharmaceutical formulations, integrated thermal/other sensors to elucidate the process, and comprehensively characterized the printlets.

Dr. Mansoor A. Khan is a professor and vice dean of college of pharmacy Texas A&M University. I served as a director of product quality research and SBRS scientist in FDA for 11 years. I have had the privilege to serve as the FDA representative to EMA (pediatric working group, and pediatric formulations committee), WHO (generic quality and pediatric guidelines committee), USP (expert panel on dosage forms), FIP (Program chair and Keynote Speaker), DOD/DARPA (continuous manufacturing advisory panel), Clinton HIV/AIDpanel(dosageformsexpert), NIH(PIonthe FDA:NIH IAG), and NASA (PI on the FDA:NASA Research Cooperative Agreement). Prior to joining the FDA in 2004, I was a Professor of Pharmaceutics and founding Director of the Graduate Program in the School of Pharmacy at Texas Tech University. Ihavepublishedover 300 peer-reviewedmanuscripts on the various dosage forms, manufacturing sciences and bioavailability-bioequivalence issues related to drug products. I have also been an editor of five texts including “Quality by Design for Biopharmaceutical Product Development”, and book chapters, 200 abstracts/poster presentations, and more than 250 invited presentations world-wide.

Dr. Ziyaur Rahman is an associate professor at Texas A&M University. Prior to joining Texas A&M University, he served as a scientist and reviewer for seven years in FDA. His research focus at FDA was to support Chemistry, Manufacturing and Controls, and the biopharmaceutics sections of NDAs and ANDAs. He was part of the team involved in approval of first 3D printed drug product in 2015. He had had the privilege to serve as grants reviewer, FDA liaison to USP Expert Committee on Excipients and scientist in ‘Immediate Release/Modified Release Work Group’ in FDA. He has received FDA/CDER Outstanding ANDA Review, FDA/CDER Team Excellence, FDA/CDER Regulatory Science Excellence, FDA/CDER Special Recognition, FDA/CDER Group Recognition, FDA/ CDER Leveraging Collaboration and Texas A&M Health “Teaching Team” awards. He has published over 100 peer-reviewed publications and 13 book chapters. He serves on editorial board of Scientia Pharmaceutica, American Journal of Analytical Chemistry, Current Nanomedicine, Pharmaceuticals, and Crystals journals.