Moving Forward with GMP 3D Printing for Drug Products

Additive manufacturing, which is commonly called three-dimensional printing (3DP), offers the potential for manufacturing specialty dosage forms and personalized medicine in either a centralized, industrial environment or in distributed, point-of-care supply. The recent development of small-footprint, good manufacturing practice (GMP) 3D printers using various types of 3D-printing technologies further opens the possibility of portable and flexible point-of-care manufacturing, which could include in-hospital clinical trials.

Interest in 3DP technology for point-of-care supply is growing, says Thomas Kipping, head of Drug Carriers, Life Science business of Merck KGaA, Darmstadt, Germany. GMP equipment for distributed manufacturing should be simple to use, require low maintenance, and have easily cleaned, interchangeable product-contact parts, he suggests. Advances in automated quality control are especially
beneficial for GMP manufacturing. “Visual tools confirming the right geometry of the prints combined with enhanced analytical technology are already available, leading to 100% in-process control [and] resulting in higher safety for patients,” says Kipping.

New materials designed for 3DP could help advance 3DP technology adoption. “Standard polymer grades are often used as a basis for formulation development. These excipients are, in most cases, initially developed for other application fields and can only provide limited design space for developers,” Kipping points out. He says Merck KGaA is investigating the requirements for polymeric excipients and particle design for different types of 3DP technologies, including melt-drop deposition and selective laser sintering approaches.

As 3DP technologies are moving quickly from concept stage to industrial use, attention to quality controls is crucial. “Close collaboration between regulatory bodies, engineers, formulation developers, and respective quality functions is required to ensure a successful implementation,” concludes Kipping.

Developers have been refining pharmaceutical 3D printers for several years, and several types of GMP printers and systems have become available.

Material extrusion 3DP

FabRx, created by University College London researchers to develop pharmaceutical 3D printing, launched the M3DIMAKER GMP printer in 2020 (1). The printer is designed to prepare personalized medicine in hospitals and pharmacies or to manufacture small batches for preclinical or clinical trials, says Alvaro Goyanes, CEO and co-founder of FabRx. He says that the printer is in use in several clinical trials around the world, including one in the Gustave Roussy hospital in France, a center for cancer research in Europe.

The M3DIMaker is a material extrusion type of 3D printer that melts a material and deposits it in layers on the printing bed to build up the desired structure. The machine has three different types of printheads that can be used, depending on the form of the input material. In fused deposition modeling (FDM) the API and other ingredients are combined in an extruder and formed into a filament in a separate manufacturing step, and then the filament is melted and deposited in the FDM printer. In direct powder extrusion (DPE), ingredients in powder form are fed directly into the 3D printer. Semisolid extrusion (SSE) extrudes a gel or paste from a syringe under pressure (2). SSE operates at a lower temperature than FDM or DPE, which makes it suitable for thermosensitive drugs.

GMP features of the M3DIMAKER include in-line quality control procedures and camera monitoring of the process. “These are tools that are controlled by our software to assure that each ‘printlet’ (3D-printed tablet) contains the dose that it should have. It is based on the use of balances, cameras, and near-infrared (NIR) spectroscopic methods,” explains Goyanes.

Melt extrusion deposition

Triastek, a 3D-printing technology platform company based in China, invented a melt extrusion deposition technology, trademarked as MED, for pharmaceutical manufacturing. MED technology continuously converts powder into a softened, molten state, which is then deposited layer-by-layer to produce objects with well-designed geometric structures, explains Xiaoling Li, chief scientific officer at Triastek and professor at the University of the Pacific in California. He says it can be used to process thermosensitive APIs and print tablets at room temperature. The technology can be used to solve drug-delivery challenges. “Using MED technology, combinations of complex drug release profiles can be accessed by varied, layered structural designs and high-precision processing,” says Li. “Tablets can be precisely delivered to a specific, hard-to-reach gastrointestinal region to release APIs at the designed onset time, release rate, and specific amount.”

Two of Triastek’s own 3D-printed drug products, T19 (for rheumatoid arthritis) and T20 (for cardiovascular and clotting disorders), have received FDA approval under investigational new drug applications, and the company has started pharmacokinetic (PK) study trials with a clinical contract research organization. “The results of these pilot PK trials will help guide the formulation optimization to establish the to-be-marketed formulation. Once the formulation is finalized, Tristek will perform large-scale production for pivotal clinical studies to support NDAs [new drug applications],” explains Li.

Triastek announced a partnership with Eli Lilly in July 2022 to use 3D-printing technology to create a structure that permits targeted and programmed release of drugs in the gastrointestinal tract (3). MED has the ability to create a multi-layered tablet with controlled release of each layer. The joint research project will study how excipient properties and process parameters impact drug chemical and physical stability, which influence the release profiles of APIs.

The company’s GMP, mass production-scale MED 3D printing system uses a 32 printing-nozzle array design that is capable of manufacturing 3D printed tablets with three different materials at a production rate of approximately 132 kg/72 hours, which is similar to the production rate of manufacturing a 150-kg batch of coated tablets. The array design enables mass production using multiple materials to fabricate complex structures. “The design enables scale-up to meet the manufacturing demands of a blockbuster product, or scale-down to manufacture a smaller quantity of a rare disease product,” says Li.

The small-footprint GMP MED 3D printer can also be used for clinical-trial manufacturing and for personalized medicines. “We see a future with our technology where patients can follow directions to print their own customized tablets,” says Li.

All GMP MED equipment integrates process analytical technology (PAT) to provide digital detection of product quality related attributes, says Li. NIR is used to measure mixture homogeneity, and a photographic monitoring system identifies the physical properties of the tablets; nonconforming tablets can be automatically eliminated.

In-blister printing

Aprecia Pharmaceuticals has launched a small-footprint 3DP technology that uses binder jetting to form 3D-printed tablets directly in blister packaging cavities. Z-Form technology expands the formulation capabilities of Aprecia’s original ZipDose technology, which is used to make the FDA-approved rapidly-disintegrating Spritam (levetiracetam) using open-bed binder jetting 3D-printing equipment. Z-Form enables formulations with multiple powder and liquid blends, multiple APIs, micro doses of API, particles engineered to enhance solubility and bioavailability, particles coated to modify the drug release profiles, and special markings for anticounterfeiting, says Kyle Smith, president and chief operating officer of Aprecia. A patent-pending containment system enables use of highly potent compounds. The Z-Form Flex printing system can produce a range of finished dose formulation options, such as orally disintegrating, sublingual, buccal, and swallow-intact formulations.

Forming the tablet directly in the blister packaging offers several benefits, one of which is the ability to eliminate material waste and produce yields of 99%, reports Smith. Another benefit is flexibility—each individual blister cavity can have a custom formulation and tablet volume/size.

“Z-Form Flex allows researchers to produce small batches of tablets with different formulations or the same base formulation in different strengths,” explains Smith. “Rapid and efficient drug prototyping enables faster entry into first-in-human studies with a close-to-commercial dose form. This [technique] enables speedier transition to proof-of-concept trials or facilitates a quicker failure to conserve valuable time, money, and resources. The flexibility to modify formulations quickly and accurately through customized, layer-by-layer precision dosing at the individual blister cavity level better supports dose ranging and
adaptive clinical trials.”

Traceability features—barcodes on the blister cards and a QR code on each cavity—facilitate both clinical development and personalized drug delivery. “This digital fingerprint enables precise chain of custody throughout the supply chain,” explains Smith.

The small footprint of the Z-Form Flex—approximately 4 ft by 10 ft—lowers costs and environmental impact of construction and operation, says Smith. In addition, the GMP equipment is designed for easy cleanability and quick changeovers of less than 8 hours for better efficiency with small-batch production. The Z-Form Flex platform is designed for a wide range of production volumes, from one blister pack up to 2000 to 3000 finished blister package units/hr, with minimal to no scale-up.

Aprecia plans to further refine the platform by scaling it down to a laboratory version (Z-Form Lab) and up to high-volume GMP commercial production (Z-Form Pro). Both systems are currently in the design phase of development, and the intent is for Z-Form Pro to match the serial output of conventional process trains.

The platform’s PAT architecture uses non-destructive, in-line analytical assessment of product and process quality attributes. PAT data will be used in product and process development, and to establish in-process controls and product specifications that will enable real-time release.

“In terms of large-scale manufacturing, Z-Form Flex sets up the potential for continuous CGMP manufacturing and real-time release,” contends Smith. “Many of the discrete steps involved in conventional manufacturing, such as granulation, drying, and compression/encapsulation, are now contained within a small, compact footprint and occur within the blister cavity. Deployment of a revolutionary planar motion system enables all units of operation to happen simultaneously, so 3D-tablets are formed within three minutes. While drying times are product-dependent, the primary package is often completed within 60 minutes from start to finish, including final inspection and blister card lidding.”

“Aprecia is already performing feasibility studies with pharmaceutical companies using development-scale versions of the Z-Form Flex machine. We are now reaching an inflection point of adoption for our technology,” concludes Chris Gilmore, CEO of Aprecia. He says that Aprecia continues to search out companies with the “appetite and vision to be market disruptors”.

Gilmore believes the ongoing platform innovations at Aprecia are quickly advancing small-scale customization and personalization while also
establishing a solid foundation for addressing unmet need in large-scale, mass production.

References

1. FabRx, “FabRx’s Pharmaceutical 3D Printer for Personalised Medicines,” Press Release, April 6, 2020.

2. FabRx, “Semisolid Extrusion: A Disruptive Technology for the Medical and
Pharmaceutical Fields,” Press Release, April 1, 2021.

3. Triastek, “Triastek Announces Research Collaboration with Lilly to Explore the Application of 3D Printing Technology in Oral Delivery of Drugs,” Press Release, July 13, 2022.

About the author

Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Article details

Pharmaceutical Technology
Volume 46, Number 12
December 2022
Pages: 24-27

Citation

When referring to this article, please cite it as J. Markarian, “Moving Forward with GMP 3D Printing for Drug Products," Pharmaceutical Technology 46 (12) 24-27 (2022).