Moving Forward with GMP 3D Printing for Drug Products

Additive manufacturing, which is often known as three-dimensional printing (3DP), affords the potential for manufacturing specialty dosage varieties and personalised drugs in both a centralized, industrial surroundings or in distributed, point-of-care provide. The current growth of small-footprint, good manufacturing observe (GMP) 3D printers utilizing numerous varieties of 3D-printing applied sciences additional opens the opportunity of moveable and versatile point-of-care manufacturing, which may embody in-hospital scientific trials.

Curiosity in 3DP expertise for point-of-care provide is rising, says Thomas Kipping, head of Drug Carriers, Life Science enterprise of Merck KGaA, Darmstadt, Germany. GMP tools for distributed manufacturing must be easy to make use of, require low upkeep, and have simply cleaned, interchangeable product-contact elements, he suggests. Advances in automated high quality management are particularly
useful for GMP manufacturing. “Visible instruments confirming the proper geometry of the prints mixed with enhanced analytical expertise are already out there, resulting in 100% in-process management [and] leading to greater security for sufferers,” says Kipping.

New supplies designed for 3DP may assist advance 3DP expertise adoption. “Normal polymer grades are sometimes used as a foundation for formulation growth. These excipients are, usually, initially developed for different utility fields and might solely present restricted design house for builders,” Kipping factors out. He says Merck KGaA is investigating the necessities for polymeric excipients and particle design for several types of 3DP applied sciences, together with melt-drop deposition and selective laser sintering approaches.

As 3DP applied sciences are transferring rapidly from idea stage to industrial use, consideration to qc is essential. “Shut collaboration between regulatory our bodies, engineers, formulation builders, and respective high quality features is required to make sure a profitable implementation,” concludes Kipping.

Builders have been refining pharmaceutical 3D printers for a number of years, and several other varieties of GMP printers and methods have turn into out there.

Materials extrusion 3DP

FabRx, created by College School London researchers to develop pharmaceutical 3D printing, launched the M3DIMAKER GMP printer in 2020 (1). The printer is designed to organize personalised drugs in hospitals and pharmacies or to fabricate small batches for preclinical or scientific trials, says Alvaro Goyanes, CEO and co-founder of FabRx. He says that the printer is in use in a number of scientific trials all over the world, together with one within the Gustave Roussy hospital in France, a middle for most cancers analysis in Europe.

The M3DIMaker is a cloth extrusion kind of 3D printer that melts a cloth and deposits it in layers on the printing mattress to construct up the specified construction. The machine has three several types of printheads that can be utilized, relying on the type of the enter materials. In fused deposition modeling (FDM) the API and different components are mixed in an extruder and shaped right into a filament in a separate manufacturing step, after which the filament is melted and deposited within the FDM printer. In direct powder extrusion (DPE), components in powder type are fed immediately into the 3D printer. Semisolid extrusion (SSE) extrudes a gel or paste from a syringe beneath strain (2). SSE operates at a decrease temperature than FDM or DPE, which makes it appropriate for thermosensitive medicine.

GMP options of the M3DIMAKER embody in-line high quality management procedures and digicam monitoring of the method. “These are instruments which are managed by our software program to guarantee that every ‘printlet’ (3D-printed pill) accommodates the dose that it ought to have. It’s based mostly on the usage of balances, cameras, and near-infrared (NIR) spectroscopic strategies,” explains Goyanes.

Soften extrusion deposition

Triastek, a 3D-printing expertise platform firm based mostly in China, invented a soften extrusion deposition expertise, trademarked as MED, for pharmaceutical manufacturing. MED expertise constantly converts powder right into a softened, molten state, which is then deposited layer-by-layer to supply objects with well-designed geometric buildings, explains Xiaoling Li, chief scientific officer at Triastek and professor on the College of the Pacific in California. He says it may be used to course of thermosensitive APIs and print tablets at room temperature. The expertise can be utilized to resolve drug-delivery challenges. “Utilizing MED expertise, combos of advanced drug launch profiles may be accessed by different, layered structural designs and high-precision processing,” says Li. “Tablets may be exactly delivered to a selected, hard-to-reach gastrointestinal area to launch APIs on the designed onset time, launch price, and certain quantity.”

Two of Triastek’s personal 3D-printed drug merchandise, T19 (for rheumatoid arthritis) and T20 (for cardiovascular and clotting problems), have obtained FDA approval beneath investigational new drug functions, and the corporate has began pharmacokinetic (PK) research trials with a scientific contract analysis group. “The outcomes of those pilot PK trials will assist information the formulation optimization to determine the to-be-marketed formulation. As soon as the formulation is finalized, Tristek will carry out large-scale manufacturing for pivotal scientific research to help NDAs [new drug applications],” explains Li.

Triastek introduced a partnership with Eli Lilly in July 2022 to make use of 3D-printing expertise to create a construction that allows focused and programmed launch of medicine within the gastrointestinal tract (3). MED has the power to create a multi-layered pill with managed launch of every layer. The joint analysis challenge will research how excipient properties and course of parameters impression drug chemical and bodily stability, which affect the discharge profiles of APIs.

The corporate’s GMP, mass production-scale MED 3D printing system makes use of a 32 printing-nozzle array design that’s able to manufacturing 3D printed tablets with three totally different supplies at a manufacturing price of roughly 132 kg/72 hours, which has similarities to the manufacturing price of producing a 150-kg batch of coated tablets. The array design permits mass manufacturing utilizing a number of supplies to manufacture advanced buildings. “The design permits scale-up to satisfy the manufacturing calls for of a blockbuster product, or scale-down to fabricate a smaller amount of a uncommon illness product,” says Li.

The small-footprint GMP MED 3D printer will also be used for clinical-trial manufacturing and for personalised medicines. “We see a future with our expertise the place sufferers can observe instructions to print their very own custom-made tablets,” says Li.

All GMP MED tools integrates course of analytical expertise (PAT) to supply digital detection of product high quality associated attributes, says Li. NIR is used to measure combination homogeneity, and a photographic monitoring system identifies the bodily properties of the tablets; nonconforming tablets may be routinely eradicated.

In-blister printing

Aprecia Prescription drugs has launched a small-footprint 3DP expertise that makes use of binder jetting to type 3D-printed tablets immediately in blister packaging cavities. Z-Type expertise expands the formulation capabilities of Aprecia’s unique ZipDose expertise, which is used to make the FDA-approved rapidly-disintegrating Spritam (levetiracetam) utilizing open-bed binder jetting 3D-printing tools. Z-Type permits formulations with a number of powder and liquid blends, a number of APIs, micro doses of API, particles engineered to reinforce solubility and bioavailability, particles coated to change the drug launch profiles, and particular markings for anticounterfeiting, says Kyle Smith, president and chief working officer of Aprecia. A patent-pending containment system permits use of extremely potent compounds. The Z-Type Flex printing system can produce a spread of completed dose formulation choices, resembling orally disintegrating, sublingual, buccal, and swallow-intact formulations.

Forming the pill immediately within the blister packaging affords a number of advantages, certainly one of which is the power to eradicate materials waste and produce yields of 99%, reviews Smith. One other profit is flexibility—every particular person blister cavity can have a customized formulation and pill quantity/measurement.

“Z-Type Flex permits researchers to supply small batches of tablets with totally different formulations or the identical base formulation in several strengths,” explains Smith. “Fast and environment friendly drug prototyping permits sooner entry into first-in-human research with a close-to-commercial dose type. This [technique] permits speedier transition to proof-of-concept trials or facilitates a faster failure to preserve useful time, cash, and sources. The pliability to change formulations rapidly and precisely by way of custom-made, layer-by-layer precision dosing on the particular person blister cavity degree higher helps dose ranging and
adaptive scientific trials.”

Traceability options—barcodes on the blister playing cards and a QR code on every cavity—facilitate each scientific growth and personalised drug supply. “This digital fingerprint permits exact chain of custody all through the availability chain,” explains Smith.

The small footprint of the Z-Type Flex—roughly 4 ft by 10 ft—lowers prices and environmental impression of development and operation, says Smith. As well as, the GMP tools is designed for straightforward cleanability and fast changeovers of lower than 8 hours for higher effectivity with small-batch manufacturing. The Z-Type Flex platform is designed for a variety of manufacturing volumes, from one blister pack as much as 2000 to 3000 completed blister bundle items/hr, with minimal to no scale-up.

Aprecia plans to additional refine the platform by scaling it all the way down to a laboratory model (Z-Type Lab) and as much as high-volume GMP industrial manufacturing (Z-Type Professional). Each methods are presently within the design section of growth, and the intent is for Z-Type Professional to match the serial output of standard course of trains.

The platform’s PAT structure makes use of non-destructive, in-line analytical evaluation of product and course of high quality attributes. PAT information might be utilized in product and course of growth, and to determine in-process controls and product specs that may allow real-time launch.

“By way of large-scale manufacturing, Z-Type Flex units up the potential for steady CGMP manufacturing and real-time launch,” contends Smith. “Lots of the discrete steps concerned in standard manufacturing, resembling granulation, drying, and compression/encapsulation, are actually contained inside a small, compact footprint and happen throughout the blister cavity. Deployment of a revolutionary planar movement system permits all items of operation to occur concurrently, so 3D-tablets are shaped inside three minutes. Whereas drying instances are product-dependent, the first bundle is commonly accomplished inside 60 minutes from begin to end, together with remaining inspection and blister card lidding.”

“Aprecia is already performing feasibility research with pharmaceutical corporations utilizing development-scale variations of the Z-Type Flex machine. We are actually reaching an inflection level of adoption for our expertise,” concludes Chris Gilmore, CEO of Aprecia. He says that Aprecia continues to look out corporations with the “urge for food and imaginative and prescient to be market disruptors”.

Gilmore believes the continuing platform improvements at Aprecia are rapidly advancing small-scale customization and personalization whereas additionally
establishing a strong basis for addressing unmet want in large-scale, mass manufacturing.

References

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

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

3. Triastek, “Triastek Declares Analysis Collaboration with Lilly to Discover the Software of 3D Printing Expertise in Oral Supply of Medicine,” Press Launch, July 13, 2022.

Concerning the writer

Jennifer Markarian is manufacturing reporter for Pharmaceutical Expertise.

Article particulars

Pharmaceutical Expertise
Quantity 46, Quantity 12
December 2022
Pages: 24-27

Quotation

When referring to this text, please cite it as J. Markarian, “Transferring Ahead with GMP 3D Printing for Drug Merchandise,” Pharmaceutical Expertise 46 (12) 24-27 (2022).