The Growing Future of Drug Manufacturing

The bio/pharma manufacturing industry is an ever-growing and evolving landscape, where emerging modalities and shifts in the field drive technological innovation. Advances in the field are clear to see from the approval rates by regulatory bodies, such as FDA’s Center for Drug Evaluation and Research, which approved 55 novel drugs in 2023 (1) for a variety of conditions. Therapeutic areas such as oncology and immunology are expected to dominate spending worldwide until 2027 (2) thanks, in part, to product innovations, improved patient outcomes, and increasing incidence of disease. Along with this market growth, cell and gene therapies, messenger RNA (mRNA) vaccines, and other new advancements have spurred innovations in every aspect of the pharmaceutical industry, including manufacturing of both small-molecule and large-molecule drugs.

Regarding current technological developments, Daniel Spurgin, director of Strategic Partnerships at ReciBioPharm, points to an industry need for speed, specifically through artificial intelligence (AI). “We’re seeing a rise in the utility of AI to monitor, control, and predict processes. However, AI technologies are only as good as the data they are trained on. Tightly controlled real data [are] essential to realizing the power of digital technology,” Spurgin says. “Autonomous decision-making allows processes to advance to next-unit operations without the need for quality gates and human intervention. In some cases, traditional release panels may be required based on regulatory positions, but the ability to autonomously advance processes would drastically improve the speed and quality of drug manufacturing, which is why FDA is funding MIT and ReciBioPharm to develop such capabilities for RNA modalities.”

Melanie Langhauser, team lead, Process Development DSP and Analytical Development, Ascend Advanced Therapies, has similar thoughts on the focus of the industry. “The biggest developments in manufacturing technology are focused on improving the productivity and efficiency of production processes while simultaneously boosting quality and reducing cost, particularly in the advanced therapies space, where robust, cost-effective, scalable processes are essential to future success,” she says. “Reducing the manufacturing costs is one important goal in our field, but what is even more important for our clients is to shorten the time to market.”

Unmet needs and market direction

The bio/pharma market is moving towards greater integration of data analytics, machine learning, and AI, according to Oladimeji Fashola, chief technology officer, Quantoom Biosciences. This shift comes from a desire for process optimization, predictability, and a need for real-time decision-making. “Manufacturers are also focusing on personalized care vaccines/therapies,” he adds.

This focus is also seen by Cyrill Kellerhals, COO, Andelyn Biosciences, who states that personalized medicines require small batch manufacturing for increasingly smaller patient populations. He points to the emerging need to “tailor efficacy and limit side effects based on individual differences.”

But in the adeno-associated virus (AAV) manufacturing space, Langhauser reveals that current processes fall short. Manufacturers and equipment suppliers have been hard at work developing solutions, which include new engineered AAV serotypes, cell lines designed to produce AAV vectors, more efficient transmission systems and offline assays, and purification technologies designed specifically for viral vectors. Langhauser says that “the small intermediate volumes of the gene and cell therapy area are driving a clear need for equipment manufacturers to develop good manufacturing practice (GMP)-ready devices or solutions. And step by step, the manufacturers recognize that and develop solutions for the gene and cell therapy area.”

“What we still need,” Langhauser says, “are scalable single-use filtration solutions. [Because] a lot of filters are coming from the antibody world the first single-use filters are much too big for the advanced therapies space. We need smaller filters and filter holders in a single-use format. And to have a scale-down model of these filters for later robustness studies, we are up-scaling the filters more than necessary (the maximum capacity of these filters is not reached). So, we underload the filters even if we receive lower step yields.”

Avi Nandi, head of US Cell and Gene Therapy, SK pharmteco, also points to rising informational technology demands. “Manufacturers will need improved IT infrastructure to enable an integrated facility, accessible aggregate data repositories, automation and IT engineers, investment into analytical tools, and consider options to reduce overall [cost of goods sold] (like optimized suite design and process workflows to enable higher throughput operations as demands increase with more commercial approvals).”

New modalities and their impact

In regard to the impact of new modalities, such as cell and gene therapies and mRNA, Fashola says, “The emergence of cell and gene therapies alongside mRNA vaccines has catalyzed substantial innovation not only in manufacturing technology but also in regulatory paradigms governing drug approval and market entry. Advancements are evident across scientific areas, particularly within cell and gene therapies, where techniques such as CRISPR [clustered regularly interspaced short palindromic repeats]-Cas9-mediated gene editing of stem cells are revolutionizing treatment modalities by correcting genetic mutations.”

“Furthermore,” he states, “mRNA technology has unveiled countless therapeutic possibilities, including vaccines targeting historically challenging diseases like HIV and cancer, thus representing a significant stride forward in biomedical intervention.”

Spurgin stresses the impact of cell-free DNA and bio-catalysis agents as critical raw materials for mRNA and cell and gene therapies. “Historically, plasmids have largely been derived from E. coli [Escherichia coli], which often requires significant development time and comes with a technology limitation (larger plasmids are more challenging to produce from E. coli),” he says. “The emergence of a cell-free plasmid DNA process significantly reduces those barriers. The same can be said about the emergence of enzymes and their use in manufacturing. They are making modalities such as xRNA more efficient, cleaner, and faster to manufacture.”

Advanced therapy medicinal products (ATMPs) can be more complex to understand and manufacture, specifies Nandi, who also points to more complexity in predicting clinical outcomes. ATMPs tend to have high cost of goods sold, aggressive timelines, and poorly understood product safety and efficacy. “As such, the technologies are diverse and rapidly evolving in response to improved understanding of these molecules with respect to product design, delivery vehicles, raw materials, cell lines, scalable technologies, analytical tools, etc.”

Nandi points to two main outcomes of ATMP development, the first being manufacturing success and the second being clinical data to validate manufacturing platforms. “We’re entering a time,” he says, “where clinical data, namely phenotypic determinants of response, will inform design of next-generation manufacturing technologies.”

Continuous manufacturing developments

In the continuous manufacturing space, Langhauser states that continuous processing for viral vectors is still in the beginning stage. “Companies are exploring the use of perfusion for intensifying the cell culture process prior to transfection. Making the transfection step continuous would be challenging, but for processes levering stable producer cells, running in perfusion mode is certainly possible. There is also potential for use of continuous chromatography techniques, while large-pore membrane and fiber-based media can enable process intensification, if not fully continuous operation. Some companies are already using single-pass tangential flow filtration to reduce process times and increase product recovery.” She stresses, however, that for continuous process development to be successful, one must have a “deep understanding” of the process. Process analytical technologies (PAT) and real-time monitoring are essential to keep continuous processes in control.

Spurgin concurs with the need for PAT and real-time monitoring. “Classical batched manufacturing contains a list of offline quality assays that gate manufacturing steps,” he says. “These transfers of samples and information are wasteful and slow and can negatively impact product quality where intermediates are unstable. Moving analytics from the lab and into the manufacturing stream aligns process steps with quality tests. Inline PAT can provide streamlined product characterization, real-time process monitoring and progression.”

The utilization of continuous manufacturing is on the rise, especially in the production of cell lines to create materials for vaccine and cell and gene therapy manufacture, according to Fashola. “This entails the use of continuous E. coli fermentation reactors that integrate with downstream processes for harvesting, lysis, purification, and filtration. Conversely, in the realm of mRNA vaccines, there is a concerted effort to enhance cost-effectiveness, throughput, and efficacy. To achieve these goals, continuous processes are being implemented from initial IVT [in-vitro transcription] reaction through purification to encapsulation.”

Rise in digitalization

AI has surged in a variety of industries in the past few years, including the pharmaceutical industry. Langhauser sees the technology growing in both drug development and manufacturing. “However, to be effective, AI systems must be constructed using large quantities of robust and truly representative data, otherwise any output they provide will be inaccurate and likely result in poor decision making,” she stresses. “As more processes are automated and the type of reliable data needed to build relevant AI models [are] generated, an inflection point will eventually be reached where AI systems will be able to predict everything from the general, such as the best combination of process steps, to the detailed, such as optimal process parameters, to the mundane, such as ideal preventive maintenance schedules.”

According to Spurgin, full-scale AI adoption still faces barriers. “AI is currently being leveraged across many early-stage drug discovery activities. The ability to select, screen, and characterize potential candidates was fairly easy to implement with no regulatory burden. It is different in the case of late-stage projects,” says Spurgin. However, he says that even though “AI’s most powerful use is in the manufacturing space,” regulators and manufacturers have been conservative with its implementation.

Regulatory considerations

The perspective of regulators on the implementation of new and advancing technology is an important factor, agrees Langhauser. She believes that industry must show how technology can provide greater yield, improved quality, and faster time to market, all at a lower cost. “[FDA] is very interested in emerging technologies that will accelerate process development, improve quality, and lower costs,” she confirms. “The best approach is to collaborate with the agency, and if the new technology is provided by a supplier rather than developed in house, proactively seek to collaborate with the supplier as well as regulatory authorities so the technology that results truly is fit-for-purpose and regulators are aware, not only of the benefits, but of the entire effort involved in bringing the technology to the point where it is validated and proven to be appropriate for GMP manufacturing.”

“Product and manufacturing costs need to be carefully monitored and managed,” says Kellerhals, “to ensure continuing excellence and quality while being optimized for efficiency. Technology development is often faster than the regulatory environment, and in a risk adverse industry, adoption of new technologies can be challenging, and more so as you go from evolutionary new technologies to revolutionary new technologies.”

Kellerhals continues, “Decisions must be data driven—what are the advantages, what are the risks, what is the timing, and what are the quality and regulatory questions that must be addressed before a new technology is introduced and accepted.”

Challenges for manufacturers

Advances in technologies can still lead to setbacks, warns Kellerhals. “Often, new analytical technologies provide breakthrough abilities to better develop or characterize new drugs, but there can be lags in time before those technologies or instrumentation are mature enough to be implemented in GMP settings,” he states. “This results in challenges implementing the newest or the best analytics in early phase clinical productions.”

“The biopharmaceutical industry is conservative in nature, so some technologies, particularly those that may raise questions from regulators, are slow to be adopted,” says Langhauser. “Manufacturers must weigh the risks associated with regulatory uncertainty against the benefits any new manufacturing technology may bring.”

“Looking specifically at technology challenges for viral vectors, the biggest hurdle for those companies using transient transfection, given the inherent nature of this process, is boosting the titer while simultaneously achieving selectivity for full capsids, and doing so at large scale,” Langhauser adds. “Progress has been made … but there is much more to do.”

References

1. CDER. Novel Drug Approvals for 2023. FDA.gov. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023
2. Statista. Projected Top Therapy Areas Worldwide in 2027, by Spending. Statista.com (accessed March 21, 2024). https://www.statista.com/statistics/281951/top-therapy-classes-in-developed-pharmaceutical-markets-by-spending/

About the author

Daria Husni is assistant editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®

Vol. 48, No. 4

April 2024

Pages: 14, 16-17

Citation

When referring to this article, please cite it as Husni, D. The Growing Future of Drug Manufacturing. Pharmaceutical Technology® 2024 48 (4).