3d printing of pharmaceuticals depth analysis

3D printing or additive manufacturing has gained a lot of attention in Pharmaceutical industry thanks to its ability to customize the pharmaceuticals. This presentation discusses various aspects of the 3D printing of pharmaceutical products right from its invention to the current market landscape and pharma players. It also discusses the science, present and future of 3D printing in pharma industry.

1. 3D PRINTING OF PHARMACEUTICALS Presented by V. Sravani

2. What is 3D printing?​ How it is started?​ Why do we need it?​ How it works?​ What are the applications and challenges ?​ Who are doing it?​ What are the products of this technology?​

3. What is 3D Printing? C onstruction  of a 3D object  from a CAD model or a digital  3D model It can be done in a variety of processes in which material is deposited, joined or solidified under  computer control  with the material being added together typically layer by layer.

4. How does it works? Design of 3D object with computer-aided design software and optimization of the geometry according to printer specification Generation of an printer recognizable format like STL file  Processing of STL file in slicer software which converts model into a series of thin layers  and produce G-Code file containing instructions tailored to a specific type of 3d printer Printing G-Code file with 3D printing software

5. Jamróz M. et al., Pharm Res (2018) 35: 176_ The development of 3D printed object

6. How it is started? Fused deposition modeling Patent by Scott Crump 1990 2000 3DP drug loaded delivery devices with pharma grade excipients (DOS method) 2010 FDM printed tablets Bilayer tablets and multi drug delivery device printed by paste extrusion 2016 Spritam - first 3DP drug approved by FDA. (levetiracetam) Selective laser sintering patent Tablet printed by SLA, SLS ODF printed by FDM In Vivo evaluation of 3DP implants (DOS) 1984 Stereolithography First 3DP placebo tablets (DOS method) Jamróz M. et al., Pharm Res (2018) 35: 176_ Timeline of significant breakthroughs in 3DP_ modified from refernce

7. 3D printing Technologies Powder based systems Drop on powder, Binder jetting  Selective laser sintering Liquid based systems   Drop on Drop deposition   Stereolithography Extrusion based systems    Fused deposition modelling    Semisolid extrusion 

8. Powder jetting/Drop on solid deposition Developed by MIT in the 1980 Zipdose  technology developed by Aprecea SPRITAM -  first FDA approved 3D printed tablet API was dissolved in ink and distributed in powder bed. Droplets of ink sprayed from print head bind the layer of free powder bed while unbound powder particles act as a support material preventing from collapsing of overhang or porous structures.  After each step the formed object is lowered and a layer of free powder is applied by roller or powder jetting system and process is proceeded

9. Powder jetting /Drop on solid deposition Possibility of precise location of exact dose of drug or modifying excipients within powdered bed to obtain several compartments with different composition or mode of action. Allows preparation of fast disintegrating tablets with dose up to 1000 mg  The high porosity of structures resulting from PB 3D printing is associated with poor mechanical resistance. Examples Implants with levofloxacin or in combination with rifampicin.                        The chlorpheniramine tablets with modified release                                       Acetaminophen tablets with linear release profiles                                          Implant Isoniazid.

10. What problem does SPRITAM solved?? There is no increased efficiency, but Allows manipulation of drug's composition according to the requirements compared with traditional press and die pill-making More dissolvable pills rapid disintegration even for higher doses. Easy to swallow for patients.

11. Selective laser sintering A powder is irradiated by a laser beam that results in the fusion of the powder at the irradiated parts. Subsequently, the build platform is lowered, and a roller deposits a thin, fresh powder layer on top of the previous material.  The following irradiation results in the next layer being generated.   Promising method to obtain porous, rapid disintegrating as well as modified release dosage forms without binding agent.  High drug loading, high resolution, easy to scaleup Chances of degradation of materials due to high energy input and post processing and inefficient power usage. Paracetamol tablet with Kollicoat ® IR or Eudragit® L100–55, fluorouracil T-shaped IUS

12. Drop on drop/Polyjet technology Droplets of ink sprayed from the nozzle are deposited on the thin layers and cured by cooling air or in presence of high energy light.  Used in modified release dosage form formulation High resolution and high quality surface of products Limited excipients, additional material required for support due to the absence of powdered bed  Matrix tablets containing beeswax and fenofibrate  Ropinirole HCl tablets 

13. Stereolithography Involves the curing of the polymers using ultraviolet (UV) light (60,61) or digital light projection technique (DLP)  to initiate a chemical reaction in the photopolymer which causes the gelation of the exposed area.  Process is repeated layer after layer to build the entire parts of the object .  High level of accuracy and resolution Tissue engineering  and the fabrication of implantable devices  potential health hazards from the use of resins due to carcinogenic nature  Time consuming Hydrogels containing up to 30% w/ w of water, and 10% w/w of ibuprofen

14. Semisolid extrusion (Pressure assisted syringe) Layer-by-layer deposition of semi-solids  through a syringe based tool-head Semi-solids (gels or pastes) are formulated by mixing optimal ratios of polymers and appropriate solvent(s) in order to obtain a viscosity suitable for printing Tablets, polymeric structures, multi active solid dosage forms. High loading of drug, mild process, broad range of excipients Low resolution and efficiency, post processing Developing a cardiovascular treatment regime with one pill incorporating 5 drugs in different immediate and extended release profiles Floating tablets Dipyridamole

15. Fusion deposit modeling Object is formed by layers of melted or softened thermoplastic filament extruded from the printer’s head Material is heated above its softening point inside the head is extruded through a nozzle, and deposited layer by layer, solidifying in under a second. Thermoplastic polymers such as PVA have been utilized as drug carrier FDM 3D printing combined  with hot melt extrusion (HME) to increase the range of polymers that can be adapted with FDM and achieve higher drug loading. Ex: Tablets Theophylline,  Oro dispersible films Aripiprazole, Indomethacin T-shaped IUS, indomethacin subcutaneous rods, progesterone intravaginal rings

16. Advanced melt drop extrusion The polymer is melted in a heated plasticizer barrel in which a screw rotates and transports the material to the nozzle tip.  When the polymer melt reaches the polymer reservoir, pressure is applied via translational movement of the screw, and droplets are discharged via a piezo actuator which can operate at a very high frequency of up to 250 hertz High accuracy for melt-based printing systems as the droplet geometry can be precisely defined. No post process curing required and high equipment diversity Low dose loading

17. Different dosage forms developed using 3DP K. Al-Litani, T. Ali, P. Robles Martinez et al. summary of 3D printed implantable device used in women’s health applications

18.     3DP Technique                             Polymer Drop on drop deposition Stereolithography Selective laser sintering Fused deposition modelling  Extrusion based printing Poly caprolactone, Poly ethylene oxide, Eudragit E, Eudragit RL, PVP, Poly (di-lactic acid)(PDLLA), Microporous dicalcium phosphate dehydrate PVA, PEDGA, PEG, formlabs PEO, Eudragit, EC Kallicoat IR R (75%PVA and 25% PEG copolymer) Eudragit L100-55 (50% methacrylic acid and 50% ethyl acrylate copolymer)  Kollidon VA 64 and microcrystalline cellulose, cyclodextrin. PVA, Eudragit RS, PCL, PLLA, EC, PVA  HPC, PVA-PEG graft copolymer PEG, EVA,  PVPA, PVA-g-PEG, HPMC, PLA  PLGA (Poly lactic –co-glycolic acid), PVA, Cellulose acetate, HPMC, Sodium starch glycolate, HPMC matrix                    Polymers used in 3D Printing 

19. SEM images of tablets and strands produced using melt drop deposition_ Merck

20. What are the limitations of conventional dosage forms? Stability issues Swallowing impairment and choking in children below 8 Potentially toxic excipients (solvents like propylene glycol,sodium benzoate) Inappropriate dosing adaptations by crushing and splitting the tablet and capsule Poor dose flexibility regarding age and weight Diverse requirements of dosing regimen Adverse reactions in children to excipients. Need of administering many tablets in certain cases-Poly pharmacy.

21. What we can do with 3D printing? Increased Product complexity On demand manufacturing Personalized medicine

22. Increased product complexity A drug product’s structure can affect drug release, complex 3D structures create new opportunities for drug delivery. Ex: SPRITAM®, has a unitary porous structure produced by a 3D printing process that binds powders without compression which allows tablets with up to 1000 mg of levetiracetam to disintegrate within seconds when taken with a sip of water. Dissolution rates can be increased by printing high-surface-area shapes and amorphous dispersions by hot melt extrusion Problems associated with occupational exposure to potent APIs, can be solved by powder-free printing processes that encapsulate API in multiple layers of excipients

23. Extremely low-dose products containing as little as 3 ng of API with 10% RSD can be formulated. Control over release kinetics and drug targeting Conjoining osmotic pumps and hypromellose -based MR structures to create a single product with multiple release modalities Varying the infill of poly(vinyl alcohol) products as a means of accelerating or decelerating drug release Stacking six or more distinct layers in a single product for multi- phasic release Printing toroidal SODFs that achieve near-zero-order release

24. S. Borandeh, B. van Bochove, A. Teotia et al._Multi-purposable filaments of HPMC for AM of medications with tailored drug release and timed-absorption using FDM Possible structures of 3DP

25. On demand manufacturing (Mini dispenser units)

26. Rapid printing from digital designs- no intermediate machining  Flexibility in changing design and composition without need of changing the entire setup or machinery Printing at the point of care Reducing the barriers to experimentation during drug product development Drugs with low stability and limited shelf life can be manufactured at the time of need directly Accelerating the drug development process A team from the University of Milan recently used this concept to print and test variations of an injection-molded, delayed-release capsule. This use of 3D printing may enable faster formulation optimization during drug product development On demand Manufacturing

27. Personalized Medicine

28. Tailored doses and dosage forms for potent drugs, growing children. Drug loaded implants  to match the anatomy of patient Polypills that combine different drugs into single pill (with varying doses) Hallow products with variable infill to control the drug release rate Reduced side effects Reduced complications after implantation Increased adherence Reduced metabolic burden for elderly Appropriate drug release

29. SLS has been employed to prepare orally disintegrating printlets with Braille and moon patterns on the surface of the dosage forms to enable visually impaired patients to identify medications . The printlets were also produced in different shapes to offer additional information, such as the dosing regimen. AW Basit & S. J Trenfeild et al 2022 Chewable printlets in different flavours, colours and with different doses of isoleucine for the world-first clinical study using 3D printed chewable tablets to treat children with maple syrup urine disease by FabRx _AW Basit & S. J Trenfeild et al 2022

30. Technical challenges Long printing time compared to conventional manufacturing. Compromised friability and hardness in  fast disintegrating tablets in powder based 3D printing High energy input might degrade starting materials in Selective laser sintering and Fused deposition modelling . Low hardness and high friability in extrusion based printing Post printing modifications  

31. Regulatory Challenges what are the critical parameters affecting the printability of various materials into drug products? What are the critical process parameters for each 3D printing technology? How can we assess the performance of 3D printed drug products? Can we use traditional in vitro testing methods for 3D printed drug products? How can we determine when and how a certain 3D geometric design may not perform as it should? What are the critical factors in 3D-printed design that affect the drug release rates and mechanisms?

32. Companies personalizing treatments with 3D printing

33. References Abdul W Basit & Sarah J Trenfield 3D printing of pharmaceuticals and the role of pharmacy, drug discovery and development. Jamroz et al., (2018)-3D Printing in Pharmaceutical and Medical Applications – Recent Achievements and Challenges James Norman et al., A new chapter in pharmaceutical manufacturing: 3D- printed drug products, Adv Drug Deliv Rev. 2017 Jan 1:108:39-50 Ahmed Zidan, 2017, CDER Researchers Explore the Promise and Potential of 3D Printed Pharmaceuticals Jonathan, Goole, Karim, Amighi , 3D printing in pharmaceutics: A new tool for designing customized drug delivery systems.International Journal of Pharmaceutics K. Al-Litani, T. Ali, P. Robles Martinez et al.  3D printed implantable drug delivery devices for women’s health:Formulation challenges and regulatory perspective Advanced Drug Delivery Reviews 198 (2023) 114859 T. Tracy et al.3D printing: Innovative solutions for patients and pharmaceutical industry, International Journal of Pharmaceutics 631 (2023) 122480 S. Borandeh , B. van Bochove , A. Teotia et al,  Polymeric drug delivery systems by additive manufacturingAdvanced Drug Delivery Reviews 173 (2021) 349–373.

34. Learn to ask questions, because there is no other path to wisdom and change Thank you