PAT minimises regulatory concerns around 3D-printed medicines

Martin Gadsby looks at the opportunities 3D printing creates for the pharmaceutical sector. It discusses how to deliver high-quality, regulatory-compliant drugs by combining this innovative printing technology with QbD and process analytical technology (PAT) frameworks

3D printing was originally developed for rapid prototyping of engineering components, it has developed quickly and now has a high level of proliferation in both engineering design and manufacturing. 

Printing with a wide variety of different media from powders to metals and plastics offers unique opportunities for manufacturers in different fields, including the medical and pharmaceutical sectors.

In drug development and manufacturing, 3D printing is a potential gamechanger, as it gives producers the ability to match drugs to individual patients, optimise the efficiency of their manufacturing and R&D processes as well as improve product quality and consistency.

The opportunities offered by 3D printing in the medical and pharmaceutical sectors have been recognised by regulatory bodies, such as the U.S. Food and Drug Administration (FDA), which acknowledged the impact and growing investments in 3D printing. 

In order to provide initial recommendations on how to provide regulatory-compliant 3D printed medical and pharmaceutical products, the agency recently released its “Technical considerations for additive manufactured medical devices” [1].

Additive manufacturing offers a unique tool to fully customise medicines – mostly oral solid dosage forms – with realistic production costs. In this way, patients can be treated with more specific dosages, release profiles and drug combinations that fully address their individual needs. Even more, this technology empowers pharmaceutical industries to develop medicines with sophisticated bio-functional constructs, which are not achievable with traditional manufacturing practices.

For example, it is possible to 3D print drugs with specific geometries and internal structures to create modified-release dosage forms, whose formulations allow the release of active pharmaceutical ingredients (APIs) according to individual patient requirements. Similarly, 3D-printed polypills – medicines that combine multiple APIs to treat one condition, eg heart disease, have already been approved and commercialised in Europe and the Americas [2,3].

The methods used to produce 3D-printed drugs, or ‘printlets’, conform to conventional additive manufacturing technologies, such as inkjet printing, binder jetting or fused deposition modelling (FDM). In these systems, the product is often built by depositing highly accurate doses of material layer by layer, until a 3D shape is formed. 

As a result, reproducibility is a key feature and conventional pharmaceutical subtractive manufacturing operations, such as milling, granulating or compressing, do not take place in additive manufacturing.

Instead, in FDM, inkjet printing, stereolithography or binder jetting, manufacturers first design a 3D theoretical drug model. Secondly, they choose appropriate printing process parameters, such as layer thickness, extruder diameter, base plate, extruder temperature, printing and extrusion speed. Subsequently, the 3D printing machine reads the models and executes the commands in order to produce the final product.

Therefore, to deliver personalised medicaments with specific drug properties, manufacturers must have a thorough understanding of the different 3D printing processes involved and how they affect the final drug attributes. In this way, they can plan, control and fine-tune the relevant mechanisms to suit.

For example, the creation of tailored release profiles or compartmentalised drugs within one polypill requires a careful design of the different segments and layers within a tablet to achieve the desired pharmaceutical outcomes. After the most suitable layout has been identified, pharmaceutical manufacturers need to define how the layer deposition of APIs and excipient should take place and under which conditions.

Being in full control of the 3D printing process is particularly crucial when low volume batches need to be produced. In these situations, quality control of the finished products are risky practices, which can offset the benefits that additive manufacturing brings to the pharmaceutical sector, i.e. efficiency and speed.

Even more, participants to the FDA workshop invited to identify the guidelines presented in “Technical considerations for additive manufactured medical devices” highlighted the importance of material and process control to ensure successful fabrication [1].

QbD is a prerequisite for additive manufacturing and precision medicine

This need for extensive process understanding and monitoring, typical of additive manufacturing of pharmaceuticals, is the foundation of quality by design or QbD. This model focuses on designing quality into a product from the earliest stages of planning – identifying what are the Quality Target Product Profiles (QTPPs), i.e. the clinical outcome metrics and design criteria that a given medicine should feature.

Manufacturers following the QbD approach can then proceed to determine the drug’s critical quality attributes (CQAs) that define the QTTPs and which critical process parameters (CPPs) affect the product outcome.

Based on these considerations, it is possible to set up a process analytical technology or PAT framework to create a closed-loop control system that monitors CQAs at any point of the manufacturing process via in-line, on-line or at-line analyses and adjusts CPPs accordingly.

In this way, manufacturers can be certain that the end product satisfies a set pharmacological specification and complies with manufacturing standards and regulations, such as Good Manufacturing Practices (GMPs), Good Documentation Practices (GDPs) and Good Laboratory Practices (GLPs). This is why regulatory bodies, such as the European Medicines and the FDA, have promoted the adoption of QbD and PAT frameworks as a way to increase reliability and robustness of manufacturing quality systems.

When PAT and QbD are applied to 3D printing, the conceptual framework remains the same as what is used for conventional subtractive manufacturing.

Nonetheless, it is important to keep in mind that pharmaceutical industries may have to include more or different QTPPs and CQAs than what are required for subtractive manufacturing processes. Even more, as the processes and conditions are dissimilar, the CPPs also differ.

For instance, an extremely important CQA in FDM is the thickness of the printed layer, which is influenced by CPPs such as printing speed and nozzle diameter. Also, porosity of printlets can be defined by infill density (or percentage). 

As a result, common instruments for quality assurance in additive manufacturing, eg accelerometers that measure vibration of the printhead and detect potential anomalies in binder jetting, can be coupled with other non-destructive analytical tools such as colorimetry, chemical hyperspectral imaging, infrared, near-infrared and Raman spectroscopy. 

All these can be integrated in the printing system as in-line, real-time quality control tools to conduct uni- and multivariate analysis and can monitor CQAs and adjust CPPs accordingly.

The power of Big Data in 3D printing

Similarly to conventional subtractive manufacturing, it is of utmost importance to implement a closed-loop automated system that can gather, analyse, store, and display analytical and process measurements. This data can then be used to create and validate models, generate predictions based on these models and provide feedback to the 3D printing system. In this way, manufacturers are empowered with clear actionable insights.

What is called for is a process orchestrator, ie a PAT knowledge management software. This tool processes and stores all uni- and multivariate sensor data collected in real-time in-line, at-line or on-line during the manufacturing stages.

Most importantly, it turns this information into process knowledge. To succeed in this, it offers a platform to control CPPs based on quality predictions. By communicating with chemometric models in real-time, it helps manufacturers determine meaningful connections between QTPPs, CQAs and CPPs.

In this way, operators can detect anomalies during production and adjust CPPs on-the-fly to meet set CQAs and QTPPs. In addition, knowledge managers provide a mechanism for continual improvement of the entire manufacturing process – whether it is subtractive or additive.

A suitable PAT knowledge management solution can be developed using proprietary software such as Optimal’s synTQ software platform. They offer a regulatory-compliant, user-friendly platform to detect when a process is moving out of its optimum operating window and correct the relevant CPPs live and in-process.

Taking drug 3D printing to the next level

PAT is fundamental to making a quantum leap in 3D printing of medicines. The main purpose of 3D printing in the pharmaceutical sector is to create products with unique functionalities that cannot be achieved by high-speed conventional manufacturing technologies. 

Nonetheless, optimising process efficiency to reduce costs and speed-up production is fundamental in order to serve the large portion of patients that would benefit from polypill and personalised medicines.

In particular, shortening cycle times is extremely important for the broad acceptance of additive manufacturing. Subtractive drug manufacturing processes can produce over a million tablets per hour [5,6]. 

Even within small-volume continuous preparations, multiple kilograms of medicines can be produced in a day, as is the case for cancer treatment prexasertib monolactate monohydrate [7]. These figures exceed by far what 3D printers can currently deliver in the same time span.

Applying PAT methodology can support the shift towards continuous additive manufacturing. This approach is still in its infancy, but different studies have shown the possibility of successfully implementing such a system and its feasibility [8,9]. 

By adopting this continuous manufacturing approach, 3D printers can reduce production times and costs even further by enabling the real-time release of regulatory compliant drugs.

To shift from batch to continuous production, it is necessary to install a reliable and robust PAT framework that is connected to the entire system. In this way, CQAs of each single personalised drug can be monitored at all times. A consequence of continuous manufacturing is the generation of even larger volumes of process data. Therefore, PAT knowledge management platforms hold an even more central role.

Additive manufacturing is beginning to gain interest within the pharmaceutical industry, as its opportunities, benefits and successes become more and more apparent. Even more, regulatory compliant 3D-printed medicines are already turning into reality, as the FDA granted approval to the first drug products of this kind [10]. 

As its visibility increases and its technology matures, especially strengthening the continuous processing capabilities, its adoption will become ever more widespread.

So will PAT, which is already becoming a new industry standard, as this is the key tool to ensure that personalised drugs fulfil their specific pharmacological and regulatory requirements. By choosing well-accepted PAT knowledge management software, manufacturers can call on a solid, configurable solution to build new production processes for highly customisable 3D printed medicines.

References:

[1] US Food and Drug Administration. Technical considerations for additive manufactured medical devices – Guidance for industry and food and drug administration staff, Issued on December 5, 2017.

[2] Khaled, S.A., Burley, J.C., Alexander, M.R., Yang, J. and Roberts, C.J., 2015. 3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles. Journal of controlled release, 217, pp.308-314.

[3] Tamargo, J., Castellano, J.M. and Fuster, V., 2015. The Fuster-CNIC-Ferrer Cardiovascular Polypill: A polypill for secondary cardiovascular prevention. International journal of cardiology, 201, pp.S15-S23.

[4] Anonymous, 2018. PAT based production management software finds favour with global majors. Available at: https://www.syntq.com/pat-based-production-management-software-finds-favour-global-majors/ [Accessed: 30 August 2019] [5] Anonymous, 2007. Millions of pills: New tablet press for up to one million tablets per hour. Process worldwide, 3, pp.302.

[6] Anonymous, 2014. Rotary tablet press offers maximum productivity with minimum footprint. European pharmaceutical manufacturer. Available at: https://www.epmmagazine.com/technology/rotary-press-offers-max-productivity/ [Accessed: 30 August 2019] [7] Cole, K.P., Groh, J.M., Johnson, M.D., Burcham, C.L., Campbell, B.M., Diseroad, W.D., Heller, M.R., Howell, J.R., Kallman, N.J., Koenig, T.M. and May, S.A., 2017. Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science, 356(6343), pp.1144-1150.

[8] Thabet, Y., Lunter, D. and Breitkreutz, J., 2018. Continuous inkjet printing of enalapril maleate onto orodispersible film formulations. International journal of pharmaceutics, 546(1-2), pp.180-187.

[9] Alomari, M., Vuddanda, P.R., Trenfield, S.J., Dodoo, C.C., Velaga, S., Basit, A.W. and Gaisford, S., 2018. Printing T3 and T4 oral drug combinations as a novel strategy for hypothyroidism. International journal of pharmaceutics, 549(1-2), pp.363-369.

[10] Pharmaceutical Technology Editors, 2015. FDA approves the first 3D-printed drug product. Pharmaceutical Technology, 11(9). Available at: http://www.pharmtech.com/fda-approves-first-3d-printed-drug-product [Accessed 30 August 2019]

Martin Gadsby is Director of Optimal Industrial Technologies.