Additive manufacturing, commonly referred to as 3D printing (3DP), enables the production of specialized dosage forms and personalized medicines in centralized industrial settings or distributed consumables at the point of care. The recent development of small-scale Good Manufacturing Practices (GMP) 3D printers using various types of 3D printing technologies further opens up opportunities for portable and flexible point-of-care manufacturing, which may include clinical trials in a hospital.
According to Thomas Kipping, head of drug delivery at Merck KGaA’s life sciences division in Darmstadt, Germany, interest in 3DP technology for point-of-care delivery is growing. He recommends that GMP distributed manufacturing equipment be easy to use, low maintenance, and have easy-to-clean, interchangeable product-contact parts. Advances in automated quality control are especially useful for GMP manufacturing. “Visualization tools to confirm the correct print geometry, combined with advanced analytics, provide 100 percent process control [and] improve patient safety,” Kipping said.
New materials developed for 3DP could help the adoption of 3DP technology. “Standard polymer grades are often used as the basis for developing formulations. In most cases, these fillers were originally developed for other applications, which gave developers limited development space,” notes Kipping. Merck KGaA is studying polymer filler and particle design requirements for various types of 3DP technologies, including droplet deposition and selective laser sintering techniques, he said.
Attention to quality control is critical as 3DP technology moves rapidly from concept stage to industrial application. “Ensuring successful implementation requires close collaboration between regulators, engineers, formulators, and the relevant quality departments,” concludes Kipping.
Over the years, developers have improved pharmaceutical 3D printers and several types of printers and GMP systems have been released.
FabRx was founded by researchers at University College London to develop pharmaceutical 3D printing and launched the M3DIMAKER(1) GMP printer in 2020. FabRx CEO and co-founder Alvaro Goyanes said the printer is designed to make personalized medicines for hospitals and pharmacies, or to produce small batches for preclinical or clinical trials. The printer is being used in several clinical trials around the world, including at France’s Hospital Gustave Roussy, a European center for cancer research, he said.
The M3DIMaker is a material extrusion 3D printer that melts material and stacks it in layers on a print platform to create desired structures. Depending on the shape of the input material, the machine can use three different types of printheads. In Fused Deposition Modeling (FDM), API and other ingredients are combined in an extruder and formed into filaments in a separate manufacturing step, which are then melted down and applied to an FDM printer. In direct powder extrusion (DPE), powdered components are fed directly into the 3D printer. In semi-solid extrusion (SSE), the gel or paste is extruded from a syringe under pressure (2). SSE operates at a lower temperature than FDM or DPE, making it suitable for thermosensitive preparations.
GMP M3DIMAKER features include online quality control procedures and production chamber monitoring. “These tools are controlled by our software to ensure that each ‘fingerprint’ (3D printed pill) contains the intended dose. It is based on the use of balances, cameras and near-infrared (NIR) spectroscopy,” explains Goyanes.
Triastek, a China-based 3D printing technology company, has invented a melt extrusion technology for pharmaceutical manufacturing under the brand name MED. According to Xiaoling Li, chief scientist at Triastek and a professor at the University of California Pacific, the MED technology continuously converts powders into a softened molten state, which is then applied layer by layer to produce objects with carefully designed geometry. Thermally sensitive API and printed tablets. This technology can be used to solve drug delivery problems. “Using MED technology, a combination of complex drug release profiles can be obtained through a variety of multilayer structures and high-precision processing,” Li said. “Tablets can be precisely delivered to specific, hard-to-reach areas of the gastrointestinal tract, releasing APIs at a predetermined onset time, release rate, and predetermined volumes.”
Two of Triastek’s own 3D-printed drugs, T19 (for the treatment of rheumatoid arthritis) and T20 (for the treatment of cardiovascular disease and blood clotting disorders), have been approved by the FDA as part of a research application for a new drug, and the company has begun clinical trials. drugs. Kinetic (PK) is a research and development organization under a test contract. “The results of these PK pilot trials will help optimize the formulation to create a market-ready formulation. Once the formulation is complete, Tristek will begin mass production for key clinical trials in support of the NDA [New Drug Use].” Lee explained the way.
In July 2022, Triastek announced a partnership with Eli Lilly to use 3D printing to create a structure that allows targeted and programmed release of drugs in the gastrointestinal tract (3). MED has the ability to produce multilayer tablets with controlled release of each layer. This collaborative research project will investigate how the properties of excipients and process parameters affect the chemical and physical stability of the drug product and hence the release profile of the API.
The company’s MED 3D printing system for GMP mass production is designed with a set of nozzles of 32 printers and is capable of producing 3D printed tablets from three different materials with an output of about 132 kg/72 hours, which is the same up to a batch of 150 kg. Coated tablet speed. Array designs can be mass-produced using multiple materials to create complex structures. “The design can be scaled up to meet the production needs of blockbuster products, or scaled down to produce fewer rare disease products,” Li said.
The small size of the GMP MED 3D printer can also be used to produce and personalize drugs for clinical trials. “We see a future with our technology where patients can print their own tablets as instructed,” Li said.
According to Li, all GMP MED devices integrate process analysis technology (PAT) to provide a digital definition of attributes related to product quality. NIR is used to measure the homogeneity of the mixture, and a photographic inspection system determines the physical characteristics of the tablets; tablets that do not meet specifications may be automatically rejected.
Aprecia Pharmaceuticals has unveiled a low-volume 3DP technology that uses binder spray to form 3D printed tablets directly into the cavities of a blister pack. Z-Form technology expands on the formulation capabilities of Aprecia’s original ZipDose technology used to produce FDA-approved fast disintegrating spritam (levetiracetam) using an open binder 3D printer. Z-Form enables formulation with multiple powder and liquid blends, multiple APIs, microdosing APIs, beads designed for solubility and bioavailability, coated beads for modifying drug release profiles, and specialty beads for anti-counterfeiting Mark, President & CEO Kyle Smith said Aprecia’s COO. The patented sealing system allows the use of high performance connections. The Z-Form Flex Printing System can produce a range of finished dosage forms such as dissolvable oral, sublingual, buccal and swallowable finished dosage forms.
Forming tablets directly into the blister pack has several advantages, Smith says, one of which is the ability to eliminate material waste and increase yield by 99 percent. Another advantage is flexibility: each individual blister cavity can be individually formulated and tablet volume/size.
“Z-Form Flex allows researchers to produce small batches of tablets with different formulations or the same base formulation with different strengths,” Smith explained. “Fast and efficient drug prototyping enables early human studies in near-commercial dosage forms to proceed faster. This [technology] could move faster to proof-of-concept trials or facilitate faster failures to save valuable time, money, and flexibility for rapid and fine-tuning formulations with individual layer-by-layer precise dosing at the level of a single blister cavity better supports dose range and adaptive clinical trials.”
Tracking features — barcodes on blister cards and QR codes on each cavity — facilitate clinical development and personalized drug delivery. “This digital footprint ensures an accurate supply chain throughout the entire supply chain,” Smith explained.
According to Smith, the Z-Form Flex’s small footprint of approximately 4 feet by 10 feet reduces construction and operating costs, as well as environmental impact. In addition, the GMP plant is designed for easy cleaning and quick changeover in less than 8 hours, making small batch production more efficient. The Z-Form Flex platform is designed to handle a wide range of production volumes, from a single blister pack to 2,000-3,000 finished blister packs per hour, with little or no scaling.
Aprecia plans to refine the platform, downsizing it to a lab version (Z-Form Lab) and a GMP high-volume commercial production (Z-Form Pro). Both systems are currently under development to align the Z-Form Pro with the serial output of traditional process streams.
The platform’s PAT architecture evaluates product and process quality attributes using non-destructive online analysis. The PAT data will be used for product and process development, and to establish process control and product specifications for real-time release.
“In terms of large scale production, Z-Form Flex creates the potential for continuous CGMP production and real-time release,” Smith stated. “Many of the individual steps of traditional manufacturing, such as granulation, drying and pressing/encapsulation, are now done in a small, compact area and done in a blister chamber. The deployment of the revolutionary planar motion system allows the use of all operating units. can occur simultaneously, so a 3D tablet can be formed in less than three minutes. While drying time varies by product, primary packaging is typically completed in 60 minutes from start to finish, including final inspection and blister card closing.”
“Aprecia is already conducting feasibility studies with pharmaceutical companies using a development-scale version of the Z-Form Flex machine. We are now at a tipping point in the implementation of the technology,” concludes Aprecia CEO Chris Gilmour. According to him, Aprecia will continue to look for companies with “appetite and vision to become market revolutionaries.”
According to Gilmour, the constant innovation of the Aprecia platform is rapidly advancing small-scale customization and personalization, while also providing a solid foundation to meet unmet needs in large-scale mass production.
1. FabRx, “FabRx 3D printer for personalized medicine”, press release, April 6, 2020
2. FabRx, “Semi-Solid Extrusion: A Revolutionary Technology in Medical and Pharmaceuticals”, press release, April 1, 2021.
3. Triastek, “Triastek Announces Research Collaboration with Eli Lilly and Company to Explore 3D Printing for Oral Drug Delivery,” press release, July 13, 2022.
When citing this article, please refer to J. Markarian, “Advancing GMP 3D Printing of Pharmaceuticals”, Pharmaceutical Technology 46 (12) 24-27 (2022).
Post time: Dec-03-2022