The bio and pharma manufacturing industry happens to be an ever-growing as well as evolving landscape, wherein the emerging modalities and shifts in the field drive technological innovation. Advances within the field are clear to see from the approval rates by regulatory bodies, like the FDA’s Center for Drug Evaluation and Research, that went on to approve 55 novel drugs in 2023 (1) for a spectrum of conditions. Therapeutic areas like oncology and immunology are all set to dominate spending worldwide until 2027 (2), thanks, in part, to product innovations, enhanced patient outcomes, and an increasing incidence of disease. Alo2ng with such kinds of market growth, cell and gene therapies, messenger RNA-mRNA vaccines, and other new advancements have spurred innovations in all aspects of the pharmaceutical industry, including manufacturing when it comes to both small-molecule and large-molecule drugs.
In reference to the current technological developments, the director of strategic partnerships at ReciBioPharm, Daniel Spurgin, goes on to point out an industry need for speed, especially by way of AI. He says that they are seeing a rise when it comes to the utility of AI in order to monitor, control, and predict processes. But AI technologies are only as good as the data they get trained on. Tightly controlled real data is indeed essential so as to realize the progress of digital technology, says Spurgin. Autonomous decision-making goes on to enable processes to advance to next-unit operations sans the need for quality gates or human intervention. In some areas, traditional release panels may as well be required based on regulatory positions, however, the ability to autonomously go ahead and advance processes would go on to drastically improve the speed as well as the quality of drug manufacturing, which is why the FDA happens to be funding MIT as well as ReciBioPharm to go ahead and develop such capabilities for the RNA modalities.
The team lead for Process Development DSP as well as Analytical Development at Ascend Advanced Therapies, Melanie Langhauser, happens to have similar thoughts on the focus of the sector. The biggest of all the developments within manufacturing technology happen to be focused on improving the productivity as well as the efficiency of production processes while at the same time boosting quality and reducing cost, especially in the advanced therapies space, where robust, cost-effective, and scalable processes are indeed essential for future success. Decreasing the manufacturing costs happens to be one important goal in the field, but what happens to be even more important for the clients is to shorten the time to the market.
Unmet requirements and market direction
The bio and pharma markets happen to be moving towards a greater integration of data analytics, machine learning, and AI, as per the chief technology officer at Quantoom Biosciences, Oladimeji Fashola. This shift happens to come from a desire for process optimization, predictability, as well as a need for real-time decision-making. It is well to be noted that the manufacturers are also focusing on personalized care vaccines as well as therapies, he adds.
This stress also happens to be seen by the COO of Andelyn Biosciences, Cyrill Kellerhals, who states that customized medicines need small batch manufacturing for increasingly smaller patient populations. He points out to the fact of emerging need to tailor efficacy as well as limit the side effects based on individual differences.
However, in the case of the adeno-associated virus- AAV manufacturing space, Langhauser goes on to reveal that the present processes kind of fall short. Manufacturers as well as equipment suppliers have indeed been hard at work developing solutions, which go on to include new engineered AAV serotypes, cell lines designed so as to produce AAV vectors, more efficient transmission systems as well as offline assays, and also purification technologies designed especially for viral vectors. Langhauser opines that the small intermediate volumes of the gene and cell therapy area happen to be driving a clear need for equipment manufacturers in order to develop good manufacturing practice-ready devices or solutions. And step by step, manufacturers also acknowledge that and develop solutions for the gene as well as the cell therapy area.
What one still needs, as per Langhauser, is a scalable single-use filtration solution. Due to the fact that a lot of filters happen to be coming from the antibody world, the first single-use filters happen to be much too big for the advanced therapies space. One indeed needs smaller filters and filter holders in a single-use format. And in order to have a scale-down model of such filters for later robustness studies, they happen to be upscaling the filters more than necessary; the maximum capacity of such filters is not yet reached. So, one goes ahead and underloads the filters even if they go on to receive lower step yields.
The head of US Cell and Gene Therapy for SK pharmteco, Avi Nandi, also points out the rising demands of information technology. Manufacturers will require enhanced IT infrastructure so as to enable an integrated facility, accessible aggregate data repositories, automation as well as IT engineers, investment in the analytical tools, and at the same time also consider options in order to reduce the overall cost of goods sold, such as optimized suite design as well as process workflows to help with higher throughput operations since the demands increase with more commercial nods.
New modalities and their effects
With regards to the impact of new modalities like cell and gene therapies and mRNA, Fashola opines that the emergence of cell and gene therapies along with mRNA vaccines has catalyzed substantial innovation not just in manufacturing technology but at the same time in regulatory paradigms governing drug approval as well as market entry. Advancements are quite evident across the scientific areas, especially within cell and gene therapies, where techniques like CRISPR- clustered regularly interspaced short palindromic repeats-Cas9-mediated gene editing of stem cells happen to be revolutionizing treatment modalities by way of correcting genetic mutations.
Moreover, he states that mRNA technology has gone on to unveil countless therapeutic possibilities, such as vaccines targeting historically challenging diseases such as HIV and cancer, hence representing a major stride forward within the biomedical intervention spectrum.
Spurgin goes on to stress the impact of cell-free DNA as well as bio-catalysis agents as critical raw materials for mRNA as well as cell and gene therapies. Plasmids, according to him, have largely been derived from E. coli- Escherichia coli, which often requires major development time and comes with technology limitation- larger plasmids happen to be more challenging to produce from E. coli, he says. The rise of a cell-free plasmid DNA process goes on to significantly reduce those barriers. The same can be said about the elevation of enzymes and their use in manufacturing. They are making modalities like xRNA more efficient, cleaner, as well as much faster to manufacture.
It is well to be noted that advanced therapy medicinal products- ATMPs can happen to be more complex to understand as well as manufacture, notes Nandi, who even points to more complexity when it comes to predicting clinical outcomes. ATMPs happen to have a high cost of goods sold, some aggressive timelines, and poorly understood product safety and efficacy. As a matter of fact, the technologies happen to be diverse and rapidly evolving in response to the improved understanding of such molecules with regards to product design, raw materials, delivery vehicles, cell lines, scalable technologies, analytical tools, and more. It is worth noting that Nandi points to two main outcomes of ATMP development, the first happens to be manufacturing success, and the second is clinical data to validate manufacturing platforms. He adds that they are entering a time where clinical data, especially phenotypic determinants of response, will go on to inform the design of next-generation manufacturing technologies.
Consistent manufacturing developments
In the continuous manufacturing spectrum, Langhauser opines that continuous processing for the viral vectors still happens to be in the beginning stage. There are companies that are exploring the use of perfusion to intensify the cell culture process prior to transfection. Making the transfection step consistent is indeed going to be quite challenging, but for the processes levering stable producer cells, running within a perfusion mode is indeed possible. There also happens to be potential for the use of continuous chromatography techniques, whereas large-pore membranes and fiber-based media can help process intensification, if not completely continuous operation. Some companies happen to be already using single-pass tangential flow filtration in order to decrease process times and increase product recovery, however, in order to make sure of a continuous process development to be successful, one has to have a deep understanding of the process. Process analytical technologies- PAT as well as real-time monitoring are indeed essential to keeping continuous processes under control.
Spurgin goes on to concur with the requirement for PAT and real-time monitoring. Classical batch manufacturing goes on to have a list of offline quality assays that go on to gate manufacturing steps. These transfers of samples and information happen to be wasteful and slow and can, in a way, negatively impact product quality because the intermediates are unstable. Moving analytics from the lab into the manufacturing stream syncs the process steps with quality tests. Inline PAT can go on to offer streamlined product characterization, real-time process tracking, and progression.
The complete utilization of continuous manufacturing happens to be on the rise, especially when it comes to the production of cell lines so as to create materials for vaccines as well as cell and gene therapy manufacture, as per Fashola. This entails the use of continuous E. coli fermentation reactors that go on to integrate with downstream processes in terms of harvesting, lysis, purification, and filtration. Conversely, within the realm of mRNA vaccines, there happens to be a concerted effort to go ahead and enhance cost-effectiveness, throughput, and efficacy. In order to achieve these goals, consistent processes are being executed from the initial IVT-in-vitro transcription reaction by means of purification to encapsulation.
A digitalization enhancement
AI has gone on to see a surge in a variety of industries over the past few years, such as the pharmaceutical industry. Langhauser feels the technology is growing across both drug development and manufacturing. But to be effective, AI systems must be constructed by way of using large quantities of robust as well as truly representative data, or else any output they provide is going to be inaccurate and most likely result in poor decision-making, she stresses. As more processes get automated and the kind of reliable data required to build relevant AI models is already generated, an inflection point is going to eventually be reached wherein the AI systems will be able to forecast everything from the general, like the best combination of process steps, to the detailed, like optimal process parameters, and even to the mundane, such as the ideal preventive maintenance schedules.
As per Spurgin, full-scale AI adoption still happens to be facing barriers. AI is, at present, being leveraged throughout many early-stage drug discovery activities. The ability so as to select, screen, and characterize potential candidates happened to be fairly easy to execute with no regulatory burden. It is pretty varied in the case of late-stage projects, says Spurgin. But he opines that even though AI’s most powerful usage is in the manufacturing space, regulators as well as manufacturers have been quite conservative with its execution.
Regulatory considerations
The regulators’ perspective on the execution of new as well as advancing technology is a vital factor, agrees Langhauser. She goes on to believe that industry must demonstrate as to how technology can go ahead and offer greater yield, enhanced quality, and a faster time to market, and that too all at a lower cost. She affirms that the FDA is very inclined toward emerging technologies that will go ahead and accelerate process development, enhance quality, and lower costs, she affirms. The best approach is going to be to collaborate with the agency, and if the new technology is provided by a supplier rather than being developed in house, proactively look to collaborate with the supplier as well as the regulatory authorities so that the technology that results is a competitive fit-for-purpose and that the regulators are aware, not only of the advantages, but of the overall effort that’s involved in bringing technology to the point where it gets validated and proven to be apt for GMP manufacturing.
Product along with the manufacturing costs have to be carefully tracked and also managed, says Kellerhals, so as to make sure of continuing excellence and also quality while being optimized for efficiency. Technology development happens to be often faster than the regulatory environment, and within a risk-averse industry, the embrace of new technologies can indeed be challenging, and more so as one can go from evolutionary new technologies to revolutionary new technologies.
Kellerhals adds that the decisions have to be data-driven, considering what the advantages are, what the risks are going to be, what the timing is, and what quality and regulatory questions should be addressed before new technology gets introduced and accepted.
Challenges when it comes to the manufacturers
Advances in the technologies can still go ahead and lead to setbacks, warns Kellerhals. Most often, the new analytical technologies go on to offer breakthrough capacities in order to better develop or characterize the novel drugs, but there may be lags in time before that kind of technology or instrumentation gets mature enough to be executed in GMP settings, he adds. This goes on to result in challenges in executing the newest or best analytics within the early phase of clinical production.
It is well to be noted that the biopharmaceutical industry happens to be conservative in nature, and hence some technologies, especially those that may go on to raise questions from regulators, happen to be slow to be adopted, says Langhauser. Manufacturers must weigh all kinds of risks associated with the regulatory uncertainty against the advantages any new manufacturing technology may go on to bring.
Aiming specifically at the technology challenges in terms of viral vectors, the biggest barrier for those companies making use of transient transfection, given the inherent nature of this process, happens to be boosting the titer while at the same time achieving selectivity for the full capsids, and that too by doing so on a large scale, adds Langhauser. The fact is that the growth is there to be seen, but there is much more that needs to be achieved.
