3D Printing: A Review on Technology, Role in Novel Dosage Forms and Regulatory Perspective

 

Hemanth KG1, Hemamanjushree S¹, Abhinaya N¹, Raveendra Pai², Girish Pai K¹*

1Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal, Karnataka-576104, India.

²Formulation Development, Glenmark Pharmaceuticals Limited, Taloja, Maharashtra-410208, India.

 

ABSTRACT:

The existence of 3D printing (3DP) ways back to 1992, and its sound presence in the pharmaceutical industry was made in 2015 by the launch of 1^st 3D printed drug, Spritam was manufactured by Aprecia Pharmaceuticals. Implementation of 3DP is escalating in the number of industries, including the pharmaceutical industry. The purpose of this review paper is to briefly discuss types of 3DP and their role in formulating novel dosage forms. Binder jet printing, VAT polymerization, powder bed fusion, and material extrusion are briefly explained along with an example of their implementation in the formulation of the dosage form. A few novel dosage forms which can bypass the first-pass metabolism and how 3D printing is useful in formulating them as been discussed. It also includes a comparison of the process of 3D printed tablets and conventional methods of manufacturing. The significance of 3D printing in novel dosage form and augmenting 3DP with hot-melt extrusion (HME) method is discussed. The regulatory concerns in adopting this technology on a large-scale are addressed. 3DP technology could rapidly print transdermal needles, buccal patches, and different shapes of vaginal rings and proved it can be a versatile tool in formulation technology. As the pharmaceutical industry involves stringent regulations, certain aspects need to be considered by regulatory authorities before implementing this tool into commercial-scale manufacturing.

 

 

 

INTRODUCTION:

“What you were taught 10-20 years ago is fast becoming obsolete. Upskill yourself and recreate your world,” as said by Nicky Verd, our society has followed to evolve. Starting with the first industrial revolution being “The Age of Mechanical Production,” the second industrial revolution as “The Age of Science and Mass Production,” followed by the third industrial revolution “The Digital Revolution.” Each of the revolutions had a significant change in the industry. Now it’s time for the fourth industrial revolution, i.e., the era of 3D printing that will revolutionize the manufacturing industry, not limiting to the pharmaceutical sector ¹.

 

Charles W. Hull invented 3D Printing, also known as additive manufacturing (AM), rapid prototyping (RP), or solid-freeform (SFF) technology ^2,3. He was also the pioneer of one of the 3D printing method, stereolithography ⁴. The technology was first executed by the Massachusetts Institute of Technology in 1992. 3D printing is based on computer-aided design (CAD) models created by the user and manipulated by a terminal computer ⁵. It is an additive manufacturing process from which the digital files, created by a 3D scanner or CAD software, are converted into physical objects.

 

The printing method has been tailored to a wide spectrum of applications in automotive and aerospace industries (Rolls-Royce, a British supplier, and provider of power systems for the aircraft and automobile sectors, has announced plans for 3D printing of aerospace components using quad laser technology from SLM Solutions) ^6,7, transistor circuits ⁸, biological material including protein and cells⁹, drug delivery systems ¹⁰, architectural world ¹¹ and food industry (3D printed food like pizza)^12,13. Researchers have 3D printed artificial corneas that mimic the human eye using the stem cell bio-ink, a breakthrough that can significantly decrease the need for eye donations¹⁴. However, forming, machining, casting, and molding remain as traditional methods of industrial manufacturing.

 

The pharmaceutical industry is conservative, regulated, and prefers well-developed production procedures and designs to guarantee product stability. But the pharmaceutical sector can revolutionize how drugs are being manufactured for individual patients by leveraging innovative techniques and help in manufacturing procedures¹⁵. 3DP of pharmaceutical products is a potential game-changer for the pharmaceutical industry. This opens up unique opportunities to adopt the innovative principle of product design. For instance, the size and shape of the product can be tailored because of the ability of 3DP, which fetches an option to design the inner structure of the product. Mass customization and patient-centered medicine strategy can be achieved by implementing this innovative 3D printing technology ¹⁶. 3DP plays a very important role in serving the small-scale supply chain. For instance, in the manufacturing of orphan drugs ¹⁷.

 

We live in a technological age; we are on the verge of the next industrial revolution, were living in a cloud-based globe of computing, NFC payments, and 3DP, once a fantasy, have now become a reality ¹⁵.

 

3DP process:

A typical 3DP process starts with creating a design of the intended final product. This can be either achieved by creating the product design using CAD software or by scanning the pre-existing object by 3D scanners, which is intended to be 3D printed.

 

1. CAD software:

a) Open-source software (OSS) relates to the program that allows free use of the technology accessible on the Internet. Many users and organizations can edit, change, or remove the file. Since the app is available to the public, this helps in continually upgrading, changing, and growing as more individuals are encouraged to focus on its development ¹⁸. E.g. Blender, SketchUp, OpenSCAD, TinkerCAD etc. ¹⁹.

 

b) Closed source software (CSS) is contrasted to OSS, which means the program that utilizes the proprietary technology is secured. Only the original program developers can view, duplicate, and change the information. In a case of proprietary source applications, you won't purchase the program but just pay to access it ¹⁸. E.g., Adobe suite, Autodesk inventor, Catia, PTC creo, Rhinoceros, Maya, Solid works, etc. ¹⁹.

 

2. 3D Scanner

The CAD design can also be created using the 3D scanner. We create the digital file of the pre-existing three-dimensional physical object, which intends to be recreated. This method captures detailed information about the texture, color, and shape of the scanned object ²⁰. 3D scanners are classified based on their design, technical specifications, and field of application.

 

3. Desktop 3D scanners:

These types of scanners get accommodated on a desktop. They are of two types, closed-frame desktop 3D scanner in which the user can place the object to scan in a closed environment, and the other type is open-frame desktop 3D scanner where the user places the object to be printed on the rotatable platform on which the camera is focused. Desktop 3D scanners are usually accompanied by a turntable. Turntable facilitates by rotating the object to be scanned, and contemporarily the camera scans and captures the 3D structure of an object.

 

4. Handheld 3D scanners:

These are portable scanners that are used when it is difficult to reach the scanning areas. These may be wired by connecting to the computer via USB or wireless. These can capture 3D objects of various sizes ²¹.

 

5. 3D scanning mobile phone apps:

Application installed on the mobile phone is used to scan the object. Here the camera and inertial sensors of the mobile phone are the hardware that decides the overall performance of a 3D scan ²¹.

 

Based on the application, the feasible 3D scanner is used to create a 3D design. Once the 3D design is constructed, it is saved in specific file formats. The various file formats used for saving 3D designs are .stl (Stereolithography), .obj (Wavefront OBJ), .mb (Maya Scene), .ply (Stanford PLY), .u3d (Universal 3D) etc. ²². This 3D design file is loaded into a slicing software that cuts the model into many horizontal layers. Later this data is communicated with the 3D printer, which prints as per the design created ²³.

 

CFD and 3D printing:

The creation of the 3D printed model depends on the flow of extruded material from the printer nozzle. CFD can solve fluid mechanical problems involved in 3D printing. It is a branch of fluid mechanics that involves broad-spectrum numerical problems solving complex three dimensional and time-dependent flow problems ^24,25. It can be employed to prevent overfill and underfill of 3D printed models. It can leverage the simulation of material extrusion through a printer nozzle and provide an optimized deposition strategy, thereby achieving the accuracy of the printed model ²⁶.

 

Types of 3D Printing:

The taxonomy is implemented by the American Society for Testing and Materials (ASTM), an organization that sets technical standards for materials, products, and systems. The classification of 3D printers relies on the type of material used, the technology of disposition, and the process of layering of material, which results in the characterized formation of the product. Based on the additive process ASTM classifies 3DP technologies like material extrusion, powder bed fusion, material jetting, binder jetting, vat polymerization, sheet lamination, and directed energy deposition and is depicted in Table 1. ².

 

Table 1: Classification of 3DP by ASTM

 

1. Binder jet printing:

It is the 1^st patented 3D printing method, which also finds its commercial application in the manufacturing of fast disintegrating tablet-Spritam by Aprecia pharmaceuticals which is US-FDA approved and patented as Zipdose technology ²⁷.

 

The platform serves as the base for the pre-determined 3D design of formulation. As shown in Fig. 1 and Fig. 2, the design is built up by the addition of a layer-by-layer of powder with the help of roller and subsequent addition of binder from the inkjet nozzle. The deposition of binder can occur by two mechanisms: through the thermal head, the head is comprised of the cartridge, which acts as a reservoir of ink (binder liquid), and a resistive element. When the current pulse is passed through the element, there is internal temperature rise and drop binder is ejected by vaporization, nucleation, and expansion^2,28. The other mechanism is by a piezoelectric system, which comprises an electromechanical device where the piezo crystal produces pressure oscillations in fluid when current is passed and thereby ejecting the ink droplet through the nozzle. The advantage of the piezoelectric system is that it doesn’t depend on the thermal properties of the ink, and it aids in the life of print head since it doesn’t create thermal stress on fluid and the working system ^2,29. The binder serves its cause of addition, thereby hardening the system. This procedure is repeated successively to build up the predetermined 3D model. The downstream process includes drying for removal of volatile solvent residuals and removes excess powder deposited during printing, thereby signifying the wastage of powder. The overall process of Binder jet 3D printing is shown in Fig. 3.

 

Yu DG et al. ³⁰ formulated paracetamol fast disintegrating tablets (FDT’S) using binder jet printing. Using colloidal silicon dioxide as a fast disintegrating agent, they were able to achieve average disintegration time of 21.8 ± 5.4 seconds and cumulative drug release of 97.7% in initial 2 minutes hence thereby concluded that 3DP has potential application in the formulation of FDT’S.

 

Fig 1: Schematic representation of Binder jet printing

 

Fig 2 Schematic representation of print head with ink deposition system

 

Fig 3 Schematic representation of overall Binder jet 3DP process

 

2. VAT Polymerization:

Vat polymerization is a familiar term for a range of 3D printing techniques. The basic principle involved in VAT polymerization is selective solidification of the liquid photopolymer present in vat or container by an appropriate type of radiation or LASER beam. The major types of vat polymerization processes include SLA, DLP, CLIP, lithography-based ceramic manufacturing (LCM), and two-photon polymerization (2PP) ³¹. Here we discuss the most frequently used type of VAT polymerization method, i.e., SLA.

 

SLA: The method uses liquid photopolymers, which are low molecular weight acrylates, epoxy macromers, or monomers, which results in the formation of very rigid, glassy, and brittle 3D printed designs. The principle involved is the solidification of liquid resin is by photopolymerization, where a cross-linked polymer structure is formed by exposing the liquid resin to visible or UV light.

 

The laser beam is projected for a specific depth in a pre-designed pattern. As a result of this liquid resin solidifies due to polymerization and adheres to supporting platform. In the subsequent step, the build platform moves vertically into the vat as much as the thickness of the first layer. The platform continues to move downwards, and layer by layer polymerization of liquid resin takes place until the 3D structure in the CAD file is formed ^31,32. This solidification can take place by two methods based on the illumination of light and orientation of build platform: Bottom-up and top-down ³².

 

In the top-down method, the build platform moves vertically down into the vat, and the light is illuminated from the top, where layer by layer solidification of the liquid resin occurs on top of the platform. Whereas in the bottom-up method, the light source is illuminated from the bottom of the VAT and moving platform on the top ².

 

Economidou SN et al. ¹⁰ fabricated novel microneedle arrays of insulin using SLA. Microneedles were printed by polymerization of biocompatible resin in consecutive layers. Inkjet printing was also used to form thin layers of insulin and sugar alcohol, which were used as carriers. In-vivo animal trials were conducted and achieved lower glucose levels within 60mins, demonstrating excellent hypoglycemic activity.

 

3. Powder bed fusion (PBF):

PBF is a birds-eye view term that covers SLS, DMLS (Direct metal laser sintering), and SLM. These methods have a similar printing process where thermal energy generated by printer heating system and laser beam fuses the powder particles and differ in the starting powder material used. SLM needs the highest thermal energy supply, and SLS needs the lowest thermal energy ².

 

SLS: uses a laser to selectively combine the powder particles to create a 3D structure in a predefined design. SLS printing setup consists of a powder bed and reservoir, a roller, and a radiation source (laser) [33]. The initial stage of printing involves a thin layer of powder on the building platform, followed by laser irradiation. As the sintering takes place, the building platform moves downwards, and the reservoir platform moves upwards while the roller transfers a thin layer of powder to the building platform. This process of transfer of powder takes place until the predefined 3D structure is formed. Excess powder on the structure is removed by using compressed air or brushing [3].

 

Fina F et al. ³³ constructed paracetamol loaded cylindrical, gyroid lattices, and bi-layer tablets using Eudragit (L100-55 and RL) (EUD L and EUD RL), polyethylene oxide (PEO) and ethyl cellulose (EC) as polymers. They demonstrated that SLS is also a 3DP technology that is feasible in customizing the drug release profile, which in conventional practice could avoid changing the formulation composition instead it could be achieved by changing the 3D design.

 

4. Material extrusion:

The material extrusion method involves layer by layer fabrication of a 3D model using FDM, 3D plotting, multiphase jet solidification (MJS), and precise extrusion manufacturing (PEM). FDM involves the melting of materials, and other methods are assisted by pressurized micro-syringe for non-melted liquid materials through the printer nozzle³⁴. This method of 3D printing extrudes the material filaments through the heated nozzle of the 3D printer. Initially, polymer filaments made of acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA) were used, but due to the expansion of research in 3D printing, polyvinyl alcohol (PVA), ethylene-vinyl acetate and hydroxypropyl cellulose (HPC), etc. are also explored. The materials extruded are melted when passed through the nozzle and hardened on cooling ³⁵.

 

FDM: is a form of material extrusion 3D printing technique focused on the deposition of successive layers of softened / molten thermoplastic materials ³⁵. In this method, the pre-determined 3D model is printed by moving the printer head through specific directions and keeping the nozzle tip at a specific temperature, which melts the polymer filament. Fig. 4., gives an overview of material extrusion 3D printing.

 

Fig 4: Overview of material extrusion 3D printing method

 

Two methods can achieve the presence of the drug in polymer filament. The first method is by impregnation of the polymer matrix in a highly concentrated drug solution. The drug then gets loaded by passive diffusion into the tedious polymer matrix. Thereby this method is expensive in drug loading and inefficient because an inadequate amount of drug is being trapped by passive diffusion. Another method involves the application of HME. The raw materials are loaded through the hopper of HME, and polymer filaments are extruded as products. The shape and diameter of filaments can be altered by changing the nozzle of HME. The polymer filaments soaked in drugs can be printed into different dosage forms ^36,37. This 3D printing technique is versatile and alters the dose of the drug. Varying the 3D design and altering the in-fill density leads to achieving the altered drug dose ^31,38.

 

Chai X et al.³⁹ printed floating sustained-release tablets of domperidone using fused deposition modeling 3D printing technique. Since domperidone is an insoluble weak base, it is formulated as a floating sustained-release tablet, which would increase bioavailability and decrease the frequency of administration. Hydroxypropyl cellulose filaments along with domperidone were prepared by the hot-melt extrusion process, thereby achieving the drug loading. The optimized formulation containing 10% domperidone with 0% infill showed sustained release and achieved 10 hours in vitro floating. The results showed that FDM is a promising technology to manufacture hollow tablets utilized as floating drug delivery systems.

 

3DP in Bypassing the first-pass Metabolism of The Drug:

With the emerging trend of 3D printing utilized in the manufacture of tablets ⁴⁰, it also has potential in the manufacturing of novel dosage forms which can bypass the first-pass metabolism; for instance, transdermal patches, ophthalmic inserts, rectal and vaginal implants, buccal patches, parenteral injections, etc.

 

1. Transdermal patches:

Transdermal delivery is a great alternative to the enteral route of drug administration. It is advantageous as it bypasses the first-pass metabolism, pain caused by hypodermic injections, disease transmission by needle re-use, patient compliance, and treatment can be terminated at any time by the patient. Microneedles are third-generation transdermal drug delivery systems that pierce into the skin painlessly and give extended-release ranging from small molecules, proteins, and nanoparticles. And microneedles are coated or encapsulated by drug formulations, which provide rapid or controlled release of proteins and vaccines ⁴¹.

 

Caudill CL et al. ⁴² printed microneedles on a transdermal patch using CAD files, which were developed SolidWorks 2014 for designing the structure of the needle. The pyramidal microneedles were composed using polyethylene glycol dimethacrylate (PEG) with 2.5 wt% TPO as a photoinitiator. The dimension of needles was 1000μm tall and 333μm wide at the base. The CAD files were designed delicately before fabrication to print 1000μm tall microneedles. Post creation, IPA was used to wash-off the residual resin on microneedles and was cured for 5 minutes using a Phoseon FireJet™ FJ800 UV LED lamp. They used CLIP, a novel additive manufacturing technique, were UV light aids to photo polymerize the liquid resin. The microneedles were made of polyethylene glycol and coated by model proteins such as ovalbumin, bovine serum albumin, and lysozyme. CLIP microneedles quickly released protein-coated cargo in solution on penetration into the porcine skin. They concluded that there was sustained retention of protein in the skin over 72hr when applied to live mice. The conventional methods of microneedle formulation are limited to the efficiency to quickly create microneedles along the high degree of control over their design parameters, which can be achieved by using 3DP.

 

2. Buccal patches:

The buccal drug delivery system is a novel drug delivery system which is aimed to increase the bioavailability of drugs, which are affected by hepatic first-pass metabolism. The drug delivery system consists of API, permeation enhancers, and adhesive. The conventional methods of manufacturing include solvent evaporation and HME⁴³. There is a time lag in the conventional manufacturing process due to multistep process involvement such as drug loading, drying, adding backing layers, etc. In this case, there is a potential implication of a 3D printer, which is versatile and timesaving ⁴⁴.

 

Eleftheriadis GK et al. ⁴⁴ used FMD 3D (Maker Bot. Inc) printer to manufacture poly (vinyl alcohol) based diclofenac sodium mucoadhesive buccal films. Xylitol was added into the polymer blend to exhibit its plasticizing character. The potential FDM printer was utilized to develop buccal films. The CAD design of films was created using AutoCAD 2019 (Autodesk Inc., USA), which was a 20x20 mm rectangle of 0.2mm thickness. The extrusion temperature through printer nozzle was set to 200^◦C and 190^◦C. The physicochemical characterization was done by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). The results of SEM found that the surface of polymer filaments was smooth without porous nature, indicating homogeneity of polymer filaments extruded. The printing temperature did not affect the thermal degradation of polymer or drug. XRD diffractogram confirmed the successful molecular dispersion into the polymer matrix. The buccal films printed after the addition of chitosan to PVA filaments showed three times an increase in permeation parameters. The results of the overall study confirm the potential of implementing 3D printing in formulating buccal films.

 

3. Vaginal rings:

These are polymeric drug delivery systems that are used to administer the drug, which exhibits local or systemic effects ⁴⁵. Vaginal rings are devices majorly used for delivering hormones to overcome their bioavailability issues. Though there are several marketed vaginal rings, e.g., Estring, Femring, NuvaRing, and Progering, they lack the customization of dose and shape in compliance with the patient's need. This need can be addressed by 3D printing technology ³⁶.

 

Fu et al.³⁶ printed different shapes of progesterone vaginal rings using the FDM 3D printing technique. The polymer matrix was made of PLA and polycaprolactone (PCL) and progesterone. The polymer filaments were formed by passing the polymer matrix through the single screw extruder. The CAD design of vaginal rings was developed in AutoCAD 2007. The filaments were passed through the 3D printer nozzle, and rings were printed according to the CAD design. Different shapes such as ‘O,’ ‘Y,’ ‘M’ were printed, and the drug release profile was studied. All the formulated shapes exhibited sustained drug release were ‘O’ shaped formulation exhibited maximum drug release. This shows that AM is a future technology that can be used in marketed formulations to solve the unmet need.

 

3D Printing in tablet Manufacturing:

Tablet manufacturing is one of the well-established solid unit dosage form process ⁴⁶. 3D printing of tablets can be explored as an initial step in adopting this new technology in the pharmaceutical industry. Fig. 5. gives an overview of conventional tablet manufacturing vs. 3D printing tablet manufacturing process

 

Fig 5: Conventional tablet manufacturing process vs 3D printing assisted tablet manufacturing process

 

Disadvantages of conventional tablet manufacturing:

·         Involves time-consuming unit operations, wastage of raw materials, and require human resources in each step ⁴⁷.

·         The minimum batch size for large scale tablet manufacturing is one lakh as recommended by the regulatory agency ⁴⁸.

·         Since various critical process parameters have to be optimized, continuous batch manufacturing is a challenge.

·         The shape of tablets is restricted to dies used in tablet punching ⁴⁹.

Advantages of 3D tablet manufacturing:

·         Involves pharmaceutical ink or drug immersed polymer filament preparation, which is fed further into a 3D printer, thereby overcoming various unit operations and reduce resource investment.

·         3D printing can be used in the formulation of dosage forms in FIH trials, which demands a need for inexpensive, rapid small scale production with flexible-dose of drug ².

·         3D printer combined with or without HME can leverage continuous batch manufacturing ⁵⁰.

·         The shape of tablets can be varied by changing the CAD design based on the patient’s age and preference ^51,52.

·         The 3D printer needs a small place to accommodate, which brings the potential to integrate with the healthcare professionals or pharmacists. They can tailor the dose of the drug according to the patient's needs and provide seamless supply and experience ²⁷.

 

Augmented 3d Printing in the Pharmaceutical Industry

HME technology dates back to 1930. It is used widely in the processing technology of plastic, rubber, and food industry. Currently, its application is not limited to the pharmaceutical industry. It is also employed to increase the solubility and bioavailability of thermostable           drugs ⁵³.

 

The major component of HME is an extruder. As shown in Fig. 6 and Fig. 7, it consists of motor, extrusion barrel with one screw (single) or two (twin) screws and die or orifice at the end. The extruder also comprises heaters that facilitate heat for softening or melting of raw materials (polymers). The screws in the extruder are capable of exerting shear pressure and cause extreme material mixing. The friction caused by the screws in the barrel and the heat supplied results in the melting of polymers. Later the screw conveys the molten polymers down the barrel while pressure and temperature are the major process parameters. The shape of the extrudate is dependent on the type of exit dies used in the HME set-up ⁵⁰. The types of exit die to include sheet and film, pellets, granules, and strands, and various auxiliary components are used in the downstream process ⁵³.

 

Fig 6: Cross-section view of single and twin screw extruder barrel

 

Fig 7: Hot melt extrusion process

 

Due to availability and low printing costs, FDM is one of the 3DP methods that is widely used in pharmaceutical sciences ^54,55. FDM involves extrusion of polymer filament through the heated nozzle, and the melted product is printed according to the CAD file design. The drawback of the FDM method is there are no readymade polymer filaments with the desired active pharmaceutical ingredients where in this case, the strands of polymer and active pharmaceutical ingredients produced by HME play a very potential role and serves the need ⁵⁶.

 

Regulatory Perspective:

Compliance with regulatory requirements is a key requirement for the market launch of a 3D printed product ¹⁰. 3D printing's ability to revolutionize manufacturing and drug development has attracted the attention of regulatory bodies across the globe. Hence the challenge of following traditional regulations for introducing 3D printed products as raised. The FDA released final guidance on technical considerations for Additive manufactured devices, which considers the design, manufacturing, and testing of devices ⁵⁷.

 

Aprecia Pharmaceuticals is the pioneer company that has received FDA approval for the manufacturing of orally fast disintegrating tablets (Spritam) containing Levetiracetam used in the treatment of epilepsy. This is considered a milestone in the Pharma sector for the implementation of 3D printing. ZipDose® technology is a 3D printing method employed in the manufacturing of SPRITAM and is similar to conventional powder compaction of mass manufacturing of pharmaceutical tablets ^58,59.

 

For 3D printed dosage forms, regulatory bodies can draw insights from the path of setting up the regulatory framework for approval of AM medical devices, which was issued in December 2017 ^57,60.

 

1. Anticipated questions to be addressed by regulatory agencies for setting guidance for 3D printing of pharmaceutical dosage forms:

a)       Will the law cover the original "Pharmaceutical ink," 3D printer, and end product? If yes, there are few initial pharmaceutical inks which are toxic to humans, but the product is non-toxic as in case of dosage forms manufactured by vat polymerization

b)       Can the FDA control all the various AM technologies? This can be complicated since the materials used in each AM technology are quite distinct from each other

c)       Will there be a need for additional data from clinical trials other than safety and efficacy details followed in conventional clinical trials of drugs? ⁶⁰

d)       Should the CAD software be included under Schedule M2 of the D&C act, as per the regulations of medical devices?

 

2. Assuming the implementation of 3D printing, the following are the topics to be considered by the regulatory body while developing a framework for 3D Printing process

a)       3D printed product design and process: Small scale or large scale has to be defined, which influences the design and process considerations. If it is large scale manufacturing, CMC related regulations have to be followed, thus addressing the safety and efficacy specifications ².

b)       State of Control: 3D printing is less explored in pharmaceutical manufacturing. Hence the process variables such as print head voltage gap, printer nozzle clog, the pace of roller, powder bed alignment, print head alignment, laser power, and temperature need to be well studied to ensure product homogeneity and quality. Throughout implementation, correct process attributes or ranges must be identified. A detailed risk analysis can be utilized to ensure that any effect on product quality in all operating states is identified and handled adequately ².

c)       Raw Material and Intermediate Control: 3D printing involves the layer-by-layer distribution of material; which might affect finished product due to variations in the printability and physicochemical properties of API and excipients in the process of printing. Micromeritics (Surface area, porosity, etc.) is one of the properties of raw material that can affect 3D printing. Some of the other properties of raw materials are flow properties, viscoelastic properties, glass transition point, thermal conductivity, melting point, impurities, degradation properties, solid-state, and moisture. Based on product and process understanding, critical product attributes have to be established, and Process analytical techniques (PAT) monitoring may be included ².

d)       Equipment and Software Workflow: It is essential to take into account the aspects of equipment control in 3D printing; however, most of the 3D printers have their operating principles varying from one another. The key software attributes to consider are software control, predetermined design parameter range, and file format conversions ².

e)       Print Cartridges: They are the filaments loaded with drugs or excipients, which runs through the heated nozzle of a 3D printer, and the dosage form is created. The filaments should comply with standard Chemistry, manufacturing, and controls (CMC) and the manufacturing process with the standard GMP ².

f)        Product Collection and Rejection: Post FDA approval of Spritam, 3D printing, has become the platform for commercial bulk manufacturing. Similar to conventional pharmaceutical manufacturing methods, a state of control for the AM process has to be well established to deal with the scenarios of malfunctioning of printer or software. In the future, there would be a need to optimize the standards in the collection of the product, rejection of product, or rejection of a whole batch ².

g)       Post-processing and Packaging: Post-processing unit operations may include drying, harvesting of unused / unbound powder content, recycling, and packaging when using the powder bed inkjet 3D printer. Identification of the post-processing steps involved in the particular use of 3D printers is a critical research area. Such post-processing operations that affect the quality of the final drug product may not be directly related to the type of 3D printer used. It may be resolved with a thorough understanding of the root cause ².

h)       Equipment Cleaning: Some parts of the 3D printers may be disposable or may be used for one time. The process of cleaning should consider material build, degradation, microbial growth, cleaning agent removal from the 3D printing equipment parts keeping equipment complexity, and product changeover in mind. Also, the frequency, length, and quantity of the cleaning agent should be considered. Establishing the cleaning validation procedure for 3DP equipment and systems could be the same as traditional pharmaceutical manufacturing techniques ².

 

CONCLUSION:

Many innovative technologies are trying to signify their potential in the pharmaceutical industry. This review article demonstrated the capability of 3D printing and gave an overview starting from its history to a regulatory perspective in the pharmaceutical industry. The results of novel dosage forms like transdermal patches, buccal patches, and vaginal rings indicate the potential of 3DP in formulation technology. The regulatory approval of 3D printed Spritam tablets by Aprecia Pharmaceuticals has led to a thunderstorm of research in 3D printing for pharmaceutical applications. As FDA is probing research in 3D printing and trying to establish the standards for its implementation in the pharmaceutical industry, the future of 3D printing is not so far. However, FDA has to address questions related to CAD software implementation, standards of polymeric filaments, SOP’s for equipment cleaning, process workflow, etc. 3D printing has been employed in various sectors like aerospace, automobile, food, and architecture, etc. its role in the pharmaceutical industry is not an exception.

 

ACKNOWLEDGEMENT:

Authors are thankful to Manipal College of Pharmaceuticals Sciences for providing necessary facilities.

 

CONFLICT OF INTEREST:

The authors confirm that this article content has no conflict of interest.

 

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Received on 07.10.2020          Modified on 24.11.2020

Accepted on 29.12.2020         © RJPT All right reserved