3d Printing: What's in Store for Medicine in the Future

3D printing technology is a globally emerging technology in the field of medicine which has a great potential of improving the quality of life and changing the way in which pharmaceuticals are manufactured. By layering material into a product, 3D printing technology generates complex geometric structures through a digitally controlled process.

Ashwin Kuchekar

Associate Professor, Head of Career Services and Placement, MIT World Peace University School of Pharmacy

Shalmali Shirish Cholkar

MIT World Peace University School of Pharmacy

3D printing technology, also known as additive manufacturing, is a digitally-controlled technique of fabricating a product by layer-wise addition of the feed material to generate complex geometric structures. This technique has wide applications in the field of mechanics, consumer goods, electronics, aeronautics, medicine, the food industry, and various other fronts.

The manufacturing process of pharmaceuticals has progressed from batch process to continuous process and now to printing.3D printing technology started gaining increased attention in the pharmaceutical field after the USFDA approval of the first 3D printed pill Spritam® by Aprecia Pharmaceuticals in 2015. This technology has been utilized for the printing of medical devices, dental implants, artificial organs, research prototypes, tailored dosage forms, drug fabrication, and specialty surgical instruments. It offers great flexibility which justifies its use in a wide range of settings including educational institutions, hospitals, and even households. Globally, numerous industry experts have predicted the use of 3D printing technology for centralized manufacturing of pharmaceuticals, veterinary medicine, and in the early phases of clinical trials over the span of the next 5 years.

Fundamental principles of 3D printing

Principles and techniques of 3D printing:

3D PRINTING

Powder solidfication

Liquid solidfication Extrusion

3D printing of pharmaceuticals can be carried out using feed materials like particles, particle colloids, plastic powders, polymers, polymer solutions, gels, polymer-particle composites, or continuous thin sheets.

1. Powder solidification is carried out by the techniques like selective laser sintering and binder jetting.

• Selective laser sintering: This 3D printing process involves the use of a laser beam to fuse the powder particles in successive layers to create the final structure. However, there are chances of degradation of the drug due to the high process temperature generated due to the laser. • Binder jetting: It involves the use of binder material to successively join the layers of powder leveled on a powder bed.

2. Liquid solidification is carried out by the techniques of stereolithography and inkjet printing.

• Stereolithography: It involves the use of a light beam to cause layer-wise solidification of a photosensitive resin placed in a tank. The dosage form can be fabricated from bottomto-top or top-to-bottom. This technique is capable of attaining a good resolution of the printed product and also the speed of printing. As heat is not generated during the printing process, this process is suitable for printing dosage forms containing thermolabile drugs. • Inkjet printing: This process of 3D printing involves heating the ink fluid with the help of a micro-resistor, creating a bubble of vapor that expands and forces the ink to drop out of the nozzle.

3. Extrusion of the feed material is carried out by techniques of fused deposition modeling and semisolid extrusion.

• Fused deposition modeling: This is the most widely used and investigated method of 3D printing of dosage forms. It involves layer-wise deposition of a molten polymer filament of a thermoplastic polymer. This technique is not suitable for dosage forms containing drugs that can undergo thermal degradation. The critical process and equipment parameters for this type of 3D printing include the printer nozzle size, layer height, build platform temperature, printing speed, and printing pattern.

• Semisolid extrusion: It involves the extrusion of plastic semisolid material from a syringe by a pneumatic, mechanical or solenoid-based system. The material hardens on cooling.

Disposable or pre-filled syringes can be used for printing the dosage form.

Procedure of 3D printing:

3D printing starts with the creation of a virtual 3D design of the object using digital design software like AutoCAD, SolidWorks, Autodesk, etc. The steps involved in the 3D printing process are mentioned in the following figure.

Application of 3D printing in pharmaceuticals:

3D printing is a promising technology to help achieve the goal of precision medicine and personalized therapy. Immediate-release tablets, chewable tablets, orodispersible films, solid self-emulsifying formulations, microneedles, and hydrogel patches are some of the dosage forms which can be fabricated using 3D printing. A polypill containing multiple drugs in the same dosage form can be printed which will avoid polypharmacy and improve patient compliance. Incompatible drugs can also be fabricated in the same dosage form. The release profiles of the multiple drugs can be modified by using the appropriate release-modifying polymers for the individual drugs. Customized implants and prosthetics can also be printed as per the individual patient’s needs.

Steps involved in 3D printing

Pros and Cons of 3D printing of pharmaceuticals:

3D printing technology is a computer-controlled process that eliminates the need for manual labor thereby decreasing the incidences of human error in the process. This method minimizes the wastage of the feed material. It is capable of fabricating complex dosage forms and dosage forms containing multiple drugs with much

STEP 02

Conversion of 3D model to.stl digital file format

STEP 04

Movement of print head in X- Y axis to form 2D base of 3D object

STEP 06

Post-processing of printed 3D object STEP 01

STEP 02

STEP 03

STEP 04

STEP 05

STEP 06

STEP 01

Virtual computer aided design (CAD) 3D design

STEP 03

Conversion of .stl file to G file by slicing 3D design into series of 2D horizontal cross-sections

STEP 05

Movement of print head in Z axis to sequentially deposit layer on top of the base of 3D object

Pros & Cons of 3D printing

Low printing speed Generation of toxic nanoplastic byproducts Viscous feed — clogging of nozzle Poor mechanical strength of printed dosage form Degradation of API due to processing heat High cost of specialized equipment Training required to handle instruments Poor appearance

Flexible dosing range Cost-effective Simplify treatment Alter drug release profile in multidrug formulations On-demand fabrication of tablets; can be done directly in blister pack Fabricate dosage form with fine details and complex geometry Less wastage of feed Computer-controlled process eliminates need for manual labour Faster method of fabrication of dosage form

ease. This simplifies the treatment therapy and increases patient compliance. The dosing range can be customized as per the needs of the individual patient. It is a faster and more convenient method of fabricating a dosage form. The dosage form can be printed and handed over to the patient at the point of care. On-demand fabrication of the dosage form can be done directly in the packing material itself which decreases the unit operations involved in the packaging of the dosage form. However, this technology can potentially generate toxic nanoplastic byproducts. The mechanical strength of the printed dosage form can be weak and has a poor appearance at times, which can affect patient compliance. The viscous feed material can sometimes lead to clogging of the printer nozzle in case of extrusion processes. The 3D printer is high-cost specialized equipment and requires trained personnel to handle the instrument.

Limitations and challenges of 3D printing:

3D printing faces certain limitations and challenges to be used for manufacturing pharmaceuticals which have hindered the full-fledged large-scale usage of this technology for producing medicines. In the case of pharmaceuticals, there is a very limited number of materials that are compatible and suitable for the 3D printing process. The polymers used in formulating pharmaceutical dosage forms do not possess the desired mechanical strength, thermal stability,

and rheological behavior to be suitable for 3D printing. The process of 3D printing is a low-volume production process and the printed dosage form or medical device requires postprocessing at times. In addition to this, there is a lack of batch-to-batch equivalence in the printed dosage form which poses a challenge to compliance with the regulatory guidelines.

Challenges & Limitations of 3D printing

CONTROL OF DRUG LOADING

BATCH-TOBATCH EQUIVALENCE COMPATIBILITY & THERMAL STABILITY OF MATERIALS,

CHALLENGES & LIMITATIONS

ADHESION OF PRINTED LAYERS

PLASTICITY AND RHEOLOGICAL PROPERTY OF MATERIAL FILAMENT

POST PROCESSING

LOW VOLUME PRODUCTION

WIDE RANGE OF PROCESSING TIME

4D printing technology:

Moving a step forward, 3D printing technology is further advancing to develop biopharmaceuticals by utilizing 4D printing technology. 4D printing technology is a modified form of 3D printing technology which uses stimuli-responsive materials, low-strength smart polymers, shapememory materials, self-healing materials, metals, and nanocomposites. Utilizing 4D printing technology, a real-time material response can be obtained. Such material is capable of responding

to multiple environmental circumstances and stimuli which may be internal (pH, temperature, biomolecules) or external (magnetic field, ultrasound). The material can also produce a predictable response to an event or stimuli locally. By printing biocompatible materials or living cells (organ-on-chip), 4D bioprinting can serve as a means of fabricating biological structures that can respond to external stimulation by changing shape or functionality.A wide variety of applications for this technology exist, including drug delivery systems, wound therapies, tissue engineering, and organ regeneration.

The difference between 3D and 4D printing technology lies in the feed material utilized. 3D printing utilizes thermoplastics, powders, gels, nanomaterials, etc whereas 4D printing uses stimuli-responsive, shape-memory, and self-healing materials to fabricate dosage forms and medical devices. 3D printing utilizes digital information for the fabrication of a structure. On the other hand, 4D printing utilizes digital information for the deformation of a structure. The 4D printed product undergoes a change in its dimensions, structure, or appearance in response to a stimulus which does not occur in the case of most 3D printed products.

These advanced technologies need further development and optimization to overcome limitations concerning compliance with regulatory guidelines and large-scale manufacturing to increase their commercial applicability.

AUTHOR BIO

Dr. Ashwin Kuchekar is an Associate Professor and the Head of Career Services and Placement at the School of Pharmacy, Dr. Vishwanath Karad MIT-WPU in Pune. He completed his M. Pharm. in 2009 and Ph. D. in 2015. In 2012, he received the Senior Research Fellow (SRF) Award from the Council of Scientific Industrial and Research (CSIR). He is a trained specialist in Lean Six Sigma Black Belt (LSSBB). He has 7 years of industrial experience in reputed pharmaceutical companies such as Piramal, Lupin, and Abbott Healthcare. He has a unique blend of statistics and formulation development, Quality by Design with exposure to branded and generic product development. He has practical experience in the Design of Experiments and product formulation and process optimization

Shalmali Shirish Cholkar specializes in Pharmaceutics. Being creative and thinking out of the box has enabled her to turn imagination into reality. Pharmaceutical polymeric excipients, 3D printing of pharmaceuticals, hot melt extrusion, packaging material of pharmaceuticals, QbD in pharmaceutical process and product development, and Lean Six Sigma in pharmaceutical process optimization and performance enhancement are some of her research interests. Currently, she is developing a robust polymer combination platform for the 3D printing of pharmaceuticals.