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Agnes Shanley is senior editor of Pharmaceutical Technology.
Research is striving to make pharmaceutical processes more scalable by making them simpler and easier to replicate and control. Advances include 3D printing, as well as miniaturized and continuous processes, all of which are being aided by improved automation and analytics.
For the past two decades, regulators have voiced support for the development of a more flexible, agile approach to developing and manufacturing pharmaceuticals (1). Miniaturized, modular, and continuous manufacturing processes will help speed scale-up, address supply chain complexity, and prevent shortages of important medications, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), noted during a meeting of the US National Academy of Sciences (NAS) in late February 2020. The COVID-19 pandemic, which was then at its earliest stages in the United States, has exposed vulnerabilities and emphasized the need for alternatives, she said (2).
Different approaches are being refined to address these challenges. One area of growing interest is three-dimensional printing (3DP), which allows greater customization of dosage forms, including polydrugs that would incorporate dosages of multiple active ingredients in a single form to enhance patient compliance and overall outcomes. The technology gained a foothold in pharma when FDA approved Spritam, an anticonvulsant manufactured by Aprecia Pharmaceuticals using 3DP technology.
Aprecia offers its 3DP platform for license to other companies. Its technology, ZipDose, uses powder liquid binder jetting to create a wide range of rapidly dissolving dosage forms and other solutions, says CEO Chris Gilmore. The process has been successfully applied to a wide range of drugs ranging in solubilities from Biopharmaceutical Classification System (BCS) Class I to IV, and incorporating a variety of engineered particle technologies, he says.
In 2020, Aprecia formalized a joint collaboration with Purdue University to advance 3DP in pharma. Eric Munson, head of Purdue’s School of Industrial and Physical Pharmacy, expects the collaboration to help drive the formulation and manufacturing of new drugs with properties that are not always feasible using traditional approaches (e.g., rapid dissolution, high drug loadings, and flexible manufacturing scales). Purdue will contribute knowhow to the venture, both in equipment design and drug-delivery science, he says.
Munson sees 3DP helping industry develop clinical trial supplies and create patient-centric dosage forms. “Scalability is potentially a huge step for manufacturing small-scale doses, which can then be easily adapted to large-scale manufacturing,” he says.
Aprecia currently out-licenses its platform to a number of pharmaceutical companies for lifecycle management, line extensions, and new chemical entities, says Gilmore, who envisions that any intellectual property created by the collaboration with Purdue would also also be outlicensed.
Different types of 3DP technologies, such as binder jetting and fused deposition modeling (FDM), may have different applications, Munson explains. “3DP in the pharmacy may involve more FDM-based approaches to avoid powders,”he says, “but also pose challenges with ensuring product quality, such as optimizing dissolution rates and stability. Binder jetting technologies, meanwhile, may allow for high-dose products with fast dissolution rates, and also enable appropriate taste masking of the particles prior to printing,” he says.
Recently, Gilmore says, the company has developed a scored, oro-dispersable tablet medication in excess of 1000 mg that rapidly disintegrates with a very small amount of liquid. Aprecia has also made advancements in modified release and poor solubility products, he says. “At this point, the combination of high-dose and fast-melt capabilities can only be achieved with 3DP, but the platform has the flexibility and precision to do more,” he says.
Other companies are also developing 3DP applications in pharma. In the UK, FabRx, a spinoff of University College, London, is actively working in this area.
Meanwhile, pharma continues to develop more continuous processing routes, mainly in oral solid dosage form (OSD) manufacturing, to improve scalability and efficiency. At February’s NAS meeting (2), Daniel Blackwood, a research fellow at Pfizer’s small molecules drug product design group, discussed the evolution of these efforts at Pfizer.
One driving force has been process intensification, he said, which enables miniaturization, in turn allowing for equipment modularization and portability. He envisions a time when, using miniature, modular equipment, pharma companies might routinely share space and even some manufacturing operations, without violating precompetitive agreements.
Research is also underway to develop miniature manufacturing lines, to optimize flexibility in response to market demands. In 2016, researchers at the Massachusetts Institute of Technology (MIT) developed a prototype line that could allow companies to manufacture specific OSD forms (3).
Various R&D projects are carrying this work forward in different applications. For example, Govind Rao, a professor of chemical and biochemical engineering at the University of Maryland, is working on a portable system that would make FDA-approved biologics at the point of administration in less than 24 hours. The US Defense Advanced Research Projects Agency (DARPA) is funding this work, which would use freeze-dried formulations, adding buffer and DNA to activate them, synthesize RNA, and manufacture protein. Describing the research at the NAS meeting (2), Rao said his team has conducted a demonstration project involving Neupogen (filgrastim)and is working with GE on development of remote bioreactor sensors to monitor analytes, oxygen, and carbon dioxide in small-scale systems in real time (2).
Also funded by DARPA, research underway at MIT is developing miniaturized, automated equipment to speed up chemical synthesis (4).The project began with the goal of harnessing machine language to predict reaction pathways based on published results from the literature, says project co-leader, MIT Professor Klavs Jensen. These efforts continue in research underway with the Machine Language for Pharmaceutical Design and Synthesis, an academic-industry consortium, he says.
Another aspect of this research, however, has been developing an integrated robotic system that would allow for the automation of synthesis reactions (4). The set up uses artificial intelligence (AI) to find the best possible pathways, allowing users to develop recipes for specific reactions. These recipes are then sent to a 2-m³ modular processing unit that features miniature mixers and other process equipment and a robotic arm that automates molecule production. Initial research evaluated results for 15 workhorse APIs. At the time, researchers noted a need for better predictive models for flow chemistry and purification, both of which remains a challenge today, Jensen says. However, since research results were first published, he notes, robotics have been improved, and now include integrated online measurement systems using infrared (IR), Fourier Transform IR, and high-pressure liquid chromatography and mass spectrometry so that key parameters can be measured in real-time, permitting online optimization.
OSD equipment processing manufacturers are working to improve continuous feeding (5,6). Pfizer has already made significant progress in developing continuous direct compression for OSD products. The company is also focusing on increased use of analytics, incorporating sensors to monitor mixing and allowing process control to enable real-time decision making, Blackwood said at the NAS event, noting that computational process modeling and data analytics are key focus areas (2).
Use of process analytical technologies (PAT) has become standard in many pharma development programs, and technology vendors have facilitated efforts by incorporating analytics into more process equipment. For the contract development and manufacturing organization (CDMO), Lonza Pharma & Biotech, PAT is finding increased use, along with more at- and in-line testing, to ensure process compliance, robustness, and faster product release, says Charles Christy, head of commercial solutions for Lonza’s Ibex Dedicate division. Use of Raman and nuclear magnetic resonance (NMR) spectroscopy, refractive index, excipient identification, metabolite monitoring, and cell counts has now become routine, in both process development and manufacturing, he says.
In mammalian cell-culture, Christy says, screening and optimization tools are finding increased use, both in clonal cell line development (e.g., microfluidic technology, such as Berkeley Light’s Beacon system, which screens and selects the best producing clonal cell lines) and in cell culture (e.g., using Sartorius Biotech’s Ambr systems), to speed time to clinic for high yield, robust processes.Single-use technologies are playing a more important role in both small molecules and biologics, Christy notes.Their combination with closed process systems and ballroom processing concepts has allowed facilities to be configured for concurrent manufacturing. In antibody production, for example, they allow the company to configure processes from standard to next-generation formats such as bi-specifics, or to process high titer or other challenging processes, Christy says.
In small molecules, single-use approaches are also proving important in highly active pharmaceutical ingredient (HAPI) manufacturing to improve operator safety and reduce toxic waste streams that would have been generated by traditional clean-in-place (CIP) activities, he says. Christy sees a growing trend to automate processes and expand use of analytics, which is improving efficiency, and reducing errors, manual intervention, and staffing requirements (i.e., overall full-time equivalent numbers). Capsugel, for example, is using AI for online testing, real-time quality assurance, and product release of capsule manufacturing, he says.
As the emphasis on scalability intensifies, technology vendors are collaborating more closely with CDMOs and also expanding their own contract services, with some offering turnkey CDMO services as well as processes and equipment designed to cut down on development time. For example, in OSD development, Adare Pharmaceuticals (formerly Aptalis), which acquired Orbis Biosciences in May 2020, offers platforms that include Microcaps for taste-masking; Diffucaps and Multi Mini Tablets, to control the rate of drug release; and Precision Particle Fabrication technology to control particle size distribution.
On the filling and packaging side, Syntegon (formerly Bosch) Packaging Technology has introduced products that include modular filling systems; microbatch systems for aseptic and HAPI applications; and visual inspection platforms that utilize AI.
The company’s single object data acquisition system, offered in collaboration with Schott Smart Packaging, aims to help users improve product traceability and supply-chain transparency. The company has also expanded its range of pharmaceutical services, including programs that focus more closely on small-to-mid-scale operations.
1. FDA, "Pharmaceutical Quality for the 21st Century A Risk-Based Approach Progress Report," fda.gov, May 2007.
2. US National Academy of Sciences, “Innovations in Pharmaceutical Manufacturing Proceedings of a Workshop—in Brief,” nationalacademies.org, May 2020.
3. J. Markarian, “Solid Dose Continuous Manufacturing Presses on,” PharmTech.com, August 17, 2020.
4.J. Markarian, PharmTech 13(9) (2020).
5. A. Trafton, “Pharmacy on Demand,” mit.edu, March 31, 2016.
6. C. Coley et al, Science 365(6453), (August 2019).
Vol. 44, No. 10
When citing this article, please refer to it as: A. Shanley, "Improving Agility Through Scalability," PharmTech 44(10) (2020), 34-37.
Agnes Shanley is senior editor of Pharmaceutical Technology.