3D Printing: A Perfect Storm for Pharma Industry and Regulatory Agency

3D printing or additive manufacturing is a process of creating three-dimensional solid objects from a digital design. The process involves printing sequentially thin layers of the building materials until the object is created. The earliest 3D printing technologies came about in the 1980s. Over the past decades, 3D printing has proved itself to have the potential of revolutionizing the way we make almost everything. Nowadays, 3D printing has been employed in aerospace, manufacturing, construction, medicine, and biomedical engineering. Spritam®, the levetiracetam tablets made by 3D printing technology was first approved by FDA in 2015, which marked a new chapter of making drugs. 3D printing is largely for oral solid medications accounting for the majority of marketed drug products. More over, 3D printing is able to print small batches for small patient populations. The patient-specific or personalized 3D-printed medicine tailors treatments to the individual characteristics of each patient. Its simple and decentralized production process enables locally controlled supply chain without security issues such as contaminations and frauds, but on the other side, bings in new compliance and regulatory challenges. The 3D-printing drug manufacture has created a perfect storm for the pharmaceutical industry and its regulatory agency.

3D-printing Technologies in Pharmaceutical Applications

Although not yet fully commercialized as the traditional formulation technologies, the following methods are widely used in making 3D-printed drugs [Ref. 1]: Extrusion Molding Printing (EMP), Drop On Powder Printing (DOP), Selective Laser Sintering (SLS), Stereolithography (SLA), and Electrohydrodynamic Printing (EHD). In all techniques, the printing is executed by following the model parameters preset by a computer design. Among these established methods, DOP and EMP are well studied and have become common practices [Ref. 2]. For instance, DOP is successfully employed in the production of Spritam® tablets. However, Each method has its own pros and cons, and requires further fine-tunes or big-leaps in resolving technical incompetency.

The EMP technology has two branches based on molding materials, the fused deposition modeling (FDM) and semisolid extrusion molding (SSE). In FDM method, a semifluid state of drug-loaded polymers is formed by heating, which is then extruded from the printing nozzle. The desired product is formed after solidification. The cheap and simple operation process has made FDM the most frequently used technique. However, the high heating temperature, usually over 150 °C, is not suitable for thermal-liable APIs without adding low-melting point excipients or water in the drug-loaded filaments. In contrast, the SSE technology does not involve heating process, and can be a good surrogate technique for temperature-sensitive APIs. It extrudes semisolid paste under the pressure of screw gear rotation via a syringe-based print head, and deposits the paste in layers to form the object. One of the disadvantages of SSE is using organic solvents in preparing the paste, which can lead to the residual solvents in the printed products.

DOP is similar to wet granulation used in tablet preparation with regard to solidification mechanisms. DOP sprays droplets containing binders from the print head onto the powder bed. The API can be dispersed either in the liquid or solid phases, e.g. discharging excipient binder onto API-loaded powder. After printing one layer, the platform is lowered vertically, and the new powder layer is spread over the previous layer. The procedures are repeated until the dosage form is complete. This print-glue approach offers reduced formulation complexity, as similar binders are compatible with a broad range of APIs. The method is relatively low cost, easy to scale up and produces tablets with high porosity. The limitation of DOP is its low resolution and high fragility. Post-processing is needed to eliminate residual solvents and recovery of the unprocessed powder.

In SLS, CO2 laser beam instead of binder droplets in DOP is applied to sinter the selected regions of powders in each layer with precision. SLS offers high-resolution, solvent-free, single-step 3D printing. Its process chamber is generally kept between 40 and 50 °C, filled with inert nitrogen to protect from oxidation. While its precision enables manufacturers to greatly control the microstructures of the drug products produced, SLS process is relatively slow and prone to break down APIs and excipients with high-energy laser, thus, the SLS process needs to be verified for drug degradation and mechanical properties.

SLA uses ultraviolet lasers to polymerize photosensitive resins in layers, repeating until the desired dosage form is created. It has the best resolution of 3D printing, facilitating precise structures. There are a couple of drawbacks of SLA technique: it requires post-processing to eliminate resin toxicity, the equipment is costly, few approved resins are available for the pharmaceutical field, and efficiency is low.

EHD is an emerging 3D-printing technology that can pattern fibrous material by digitally controlled deposition to create customized geometries and well-ordered complex structures. EHD 3D printing enables micro to nano-scale fiber engineering and alignment. EHD offers small-scale manufacturing to tailor medicines to meet individual patient needs by printing a vast array of APIs of predefined amounts in a specific pattern on a porous film. EHD applications are limited by low solubility, residual solvents in the dosage form, and high requirements for solution properties.

The technical, compliance, and regulatory challenges

In spite of the unique advantages of 3D-printing drug manufacture, its process and control must comply with stringent pharmaceutical standards to assure the printed drug products meet the characteristic requirements for safety, identity, strength, quality, and purity. As the structure design of a dosage form evolves during formulation development, the modeling software must be continuously updated, in addition, mechanical adjustments to the printing equipment and control systems are required to fix and prevent instrumental malfunctions such as nozzle clogging or binder leakage, which involves computer software verification, instrument qualification, and change controls.

In 3D-printing formulation, the physicochemical properties of the excipients are extremely critical to the quality of printed dosage forms. For FDM procedures, the carrier excipients are modified to prepare low-temperature filaments to prevent drug degradation and improve drug loading. For SLA and SLS, the excipients of photopolymers and laser sinterable materials are selected, but these excipients are not included in the FDA’s Generally Recognized As Safe (GRAS) list [Ref. 3]. Comparing with traditional formulation processes, the availability of excipients that can be used for 3D printing is limited. These 3D-printing suitable excipients might not be certified for pharmaceutical grade, and have compatibility issues or toxic/adverse side effects. Generally speaking, more of non-toxic, stable, biodegradable, and pharmaceutically certified excipients need to be developed to support commercialized 3D printing formulation.

The inherent nature of 3D printing is stacking layer-by-layer of polymers or powders, results in rough surface or insufficient adhesion strength. The printing procedures can also affect content uniformity, hardness, and friability, which should be listed as quality control parameters in the specifications of solid dosage form with specification limits appropriate for the decentralized, small batch 3D-printing production. Removing the residual solvents and unprocessed powders in the post-processing should be handled properly accordingly to EHS policies. Overall, the 3D printer, the printing process, the operation procedures, the API and excipients, and personnel training should be validated as a complete quality system to ensure all practices meet cGMP requirements.

With respect to the regulation, on top of the aforementioned issues to be addressed, there are many other questions surrounding how 3D-printing formulation should be monitored and controlled for quality. Imagining the 3D-printed drug is customized to the patient in a hospital or in a clinic, whether this is classified as a manufacturing process or compounding will result in different regulatory requirements. In such a circumstance, healthcare specialists will have to undergo thorough training in using various 3D-printed drug formulation technologies, learn to recognize quality defects, and assess possible adverse effects in the just-made medicines. Although FDA has authorized the first 3D-printed tablets, neither guidelines nor regulations are available governing 3D-printed drug products. FDA has issued its guidance on Technical Considerations for Additive Manufactured Medical Devices in 2017 [Ref. 4] to provide the Agency’s initial thinking on technical considerations specific to devices using additive manufacturing, the broad category of manufacturing encompassing 3-dimensional (3D) printing; however, the guidance states “Not all considerations described will be applicable to every device, given the variety of AM technologies, materials, and devices made with additive manufacturing”, thus, it should not be applied to 3D-printed medicines, as its safety, effectiveness or efficacy have to be assessed separately. FDA’s thinking towards 3D-printed drugs is currently being shaped and is yet to be publicized in a similar manner [Ref. 2].

The development trend towards a mature technology

The capability of 3D printing in fabricating personalized medicines based on clinical needs has gained interests across pharmaceutical industry as its opportunities, benefits and successes become more and more apparent. After obtained FDA’s approval on Spritam®, Aprecia Pharmaceuticals forged a long-term collaboration with R&D firm Battelle to further advance its 3D printing equipment. FabRx has also been active on the printed drug development front - having produced personalized medicine for children with rare metabolic disorder maple syrup urine disease (MSUD), and launched its M3DIMAKER 3D printer in 2020. Merck has become a major player in the pharmaceutical 3D printing arena. Merck is taking plans to establish 3D printing for clinical trial supply including scale up to commercial production. In early 2021, a Chinese 3D printing pharmaceutical company Triastek has received IND clearance from FDA for its first 3D-printed rheumatoid arthritis tablets.

3D printing has revealed its potential in transforming the way pharmaceuticals are manufactured and turn the personalized medicine into reality. To shift from the traditional batch production to continuous additive manufacture, installing a reliable and robust process analytical technologies (PATs) and implementing quality by design (QbD) principles are essential to monitor and ensure the critical quality attributes (CQAs) of each single personalized drug product continuously and at all times [Ref. 5]. The applications of PAT and QbD in 3D-printing formulation and manufacture will make the technology more mature, robust, and comply with the stringent pharmaceutical standard and regulatory requirements. The adoption of 3D printing in pharmaceutical industry will become ever more widespread. With the collaborations between industry, academia, and regulatory agency, it is highly anticipated that combining this innovative 3D printing technology with PAT and QbD will deliver high-quality, regulatory-compliant, customized therapeutics to the specific patient populations.

References:

1. Balfour H, 3D printing – current pharmaceutical applications and future directions, European Pharmaceutical Review, September 14, 2021

2. Vilcinskas, K, 3D printed drugs between emerging innovations and current challenges, PreScouter, June 2020

3. Cui M, etc., Acta Pharmaceutical Sinica B 2021: 11(8): 2488-2504

4. FDA, Technical considerations for additive manufactured medical devices – Guidance for industry and food and drug administration staff, issued on December 5, 2017

5. Gadsby M, PAT minimizes regulatory concerns around 3D-printed medicines, synTQ, January 5, 2021

About the Author:

Eric Sun, Ph.D., a seasoned pharmaceutical professional, has diverse experiences in both U.S. and China pharmaceutical industry. He has led research and development, clinical supplies, compliance, and regulatory filing activities at big pharmas, startups, and CROs/CDMOs.  His recent interest has been channeled to improve the overall R&D productivity and success rate ensuring the delivery of the beneficial therapeutics to the clinic in an optimum timescale with minimum safety concerns.