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As new manufacturing processes and technologies are introduced to meet demand and overcome challenges, understanding also needs to improve to ensure the right balance is achieved.
Bio/pharmaceutical manufacturers have been required to pivot in recent times because of a number of factors, including the shifting focus of drug development to next-generation modalities, pressurized supply chains, increasing adoption of digitalization, and intensified efforts to be more sustainable (1). One event that has thrown up hurdles and required novel solutions in response has been the COVID-19 pandemic, which has had an influence on all aspects of industry across the globe.
Despite the disruptions and uncertainties caused by the pandemic, the bio/pharmaceutical manufacturing sector has advanced and evolved, balancing the fluctuations correspondingly to mitigate risk and allow for further progression. According to research, for example, the bio/pharmaceutical manufacturing market should witness compound annual growth in the region of 11% between 2022 and 2027 (2), thanks in part to advancing manufacturing technologies.
“There have been a couple of significant shifts in the industry,” stresses Dan UpDyke, strategic marketing manager, Life Sciences, Rockwell Automation. “In years past, it was typical to build purpose-built, single product facilities. These would have fixed vessels and be designed with rigid processes to deliver repeatable results but had limited flexibility. As drug development has shifted to highly specialized treatments with smaller patient populations, the need for flexible and scalable systems has become a focus leading to solutions such as single-use technologies.”
Precision medicine and other next-generation modalities, such as cell and gene therapies, have been a focus for the bio/pharmaceutical industry over the past decade, remarks Bryan Deuber, senior director, Business Development and Strategic Partnerships, Andelyn Biosciences. “In response, outsourced development, manufacturing, and testing organizations have adjusted their models to accommodate the flexibility of serving both relatively small-batch manufacturing and larger indications,” he states. “Many therapeutics behind the recent growth require an extremely skilled workforce, state-of-the-art technologies, and advanced consumables, including plasmids and viral vectors.”
These new modalities and platforms—messenger RNA (mRNA), cell and gene therapies, and so on—also require delivery in multiple dosage forms, such as autoinjectors, syringes, and vials, and new patient distribution models, specifies Sridhar Krishnan, vice president, The Catalent Way at Catalent. “Manufacturers must be able to integrate this wide range of needs into their operations,” he says.
“Most recently, biopharmaceutical manufacturing has been impacted by pressures on supply chain,” specifies Antonio Crincoli, vice president of Engineering, Pharma and Consumer Health, Catalent. “The expectation from customers is for consistent, resilient, and predictable supply chain performance, at a high quality and a reasonable cost.”
Although Jade Byrd, director of Industry Marketing at Agilent Technologies, also points to the drive toward better risk management by the manufacturing community because of the scrutiny over supply chains over recent years, which is reducing the risk of drug shortages, as a key trend, she believes that the most impactful change is the move to continuous manufacturing. “The same number of doses can be produced in much smaller facilities, leading to both reduced costs and less waste,” she says.
“The pandemic had a major impact on pharmaceutical manufacturing, forcing organizations to think differently about treatment manufacturing,” continues Nathan Pettus, president, Process Systems and Solutions, Emerson. “COVID brought supply chain issues to light, and that revelation created a push for more regional manufacturing, instead of making everything in one place. By creating more regional manufacturing hubs, many pharmaceutical manufacturers are significantly de-risking their supply chains to minimize disruptions.”
For Shankar Gupta, chief sales officer, ACG, it is the globalization of the bio/pharmaceutical industry that has led to the advent of new manufacturing hubs with rising cross border sales. “Encouragingly, this growth has brought with it a real focus around quality and inspection,” he adds.
However, according to Thomas Schmidt, marketing director, Digital Solutions, Agilent Technologies, despite the existence of lean Six Sigma and quality-by-design initiatives to ensure better product quality for some time already, these tools have not always been used to their full potential, perhaps as a result of the change management they require.
“Regulatory expectations are increasing,” emphasizes Krishnan, “and as a result, manufacturers must look to meet the highest regulatory standards to be able to supply to all markets. Accordingly, there is a focus on quality management systems that ensure data integrity and governance, and that digitization occurs with appropriate validation, also, where necessary, that there is segregation of operating systems to eliminate risk of corruption.”
Customers are also placing greater importance on speed-to-market for products and flexibility of supply, notes Crincoli, meaning that manufacturers must be capable of quickly deploying or transitioning manufacturing assets to meet market needs. “It is therefore beneficial if facilities and equipment are designed to handle multiple products or dose forms. Similarly, there must be the ability to quickly move from development to commercial operations through scaling up or scaling out,” he says.
In fact, the speed at which COVID‑19 vaccines were created and manufactured demonstrated to the world that it was possible to launch new products at pace, confirms Pettus. “While much of that speed was enabled by emergency authorization regulation changes and special funding, life sciences companies have now seen what is possible, and they want to find additional ways to safely develop and manufacture other essential treatments much faster,” he states.
Another big movement for bio/pharmaceutical manufacturing has been investment in the digital transformation, adds UpDyke. For many years, technology innovation has been slow, with equipment and processes becoming “standard,” until recently when the business value of digitalization is being realized, he affirms.
Focusing on the fact that companies are looking to operate in more regionalized facilities, work with a greater number of contract development and manufacturing organizations (CDMOs), and develop more niche markets, Pettus points out that they will have many more batches to track and products to manage. “The massive amounts of data generated by these information-intensive methods will need to be contextualized so manufacturers can glean innovative and more efficient ways to ensure they are operating in a cost-effective, reliable, and quality-compliant manner,” he says.
A useful tool that will empower manufacturers to take advantage of additional data not previously collected is process analytical technology (PAT), which enables inline monitoring and real-time release, Pettus continues. “With the application of these technologies—instead of performing sampling processes, waiting for in-process testing before proceeding to the next step, or waiting for final batch test results to proceed with or release the batch—much of the critical process parameter and critical quality attribute data can be collected in real-time during the manufacturing process,” he states. “When critical steps are performed during manufacturing, teams have results before the process step or even the batch is complete, ultimately moving them to more efficient real-time control and closer to real-time release.”
“PAT and an emphasis on process understanding have been embraced by the majority of pharmaceutical manufacturers, and there are several case studies where both artificial intelligence (AI) and machine learning (ML) have led to improved quality or increased yield, even in good manufacturing practice (GMP) facilities,” adds Byrd. However, there are still regulatory hurdles impeding adoption of more modern techniques, she asserts. “[Although] this [situation] has improved over the past several years with the incorporation of engagement possibilities like the Emerging Technologies Team at FDA and the Innovation Task Force at EMA [European Medicines Agency],” Byrd notes.
In concurrence, Schmidt also emphasizes the importance online and at-line analysis has become in recent years. “Our customers want results much closer to product manufacturing and not always in the traditional lab,” he remarks.
Ensuring all equipment is running efficiently and effectively is another pertinent area to balance, according to Pettus. “By monitoring key characteristics of the equipment and the process, potential problems are identified, and appropriate actions can be planned to ensure emerging potential issues are resolved before they cause production problems,” he says. “And with regards to that planning, real-time scheduling software helps manufacturing and support teams to not only make the most of equipment time and production availability, but to also automatically reorganize schedules when there is an aberration—such as a supply chain issue, equipment failure, or other delays—to help ensure on-time production for improved delivery times and profitability.”
“Business continuity is key to any reliable supply chain, which includes ensuring all of a company’s facilities and equipment are available and operate as intended, to meet the flexible demands,” emphasizes Crincoli. In addition, it is just as important for manufacturers to build and select a strong, high quality, supplier base for raw materials and consumables, he adds.
Improvements in manufacturing efficiency can be made through comprehensive quality management systems that focus on digitization, reduce human errors, and improve data integrity, notes Krishnan. “These steps are backed up by having an operational excellence strategy, and a continuous improvement system, but whatever systems are in place, the most important step is a continuous investment in people, and the training of employees,” he says.
Pettus also highlights process and knowledge management software, which collates, contextualizes, and standardizes process steps and critical data across the entire lifecycle, as a useful tool for ensuring manufacturing efficiency from process development to full-scale manufacturing. “Ultimately, these are the technologies that will unlock one-click technology transfer in the future, which will be a key component of faster product launches, including individualized treatment,” he adds.
“Time can be saved using modular facilities and equipment that can be assembled offsite, and rapidly deployed,” continues Crincoli. “There is more equipment available with the ability to manufacture multiple forms (i.e., vials or syringes) on the same line, and employing single-use equipment can reduce cycle times while improving the overall speed of manufacturing campaigns. Time can also be saved, for example, when expediting a commercial launch, using strategies such as scaling out rather than scaling up, and again, utilizing continuous manufacturing where it offers an advantage.”
The importance of continuous manufacturing is growing, affirms Pettus, who agrees that it can help eliminate the scale-up issues that were common with the “one-size-fits-all” product development and commercialization process. “Instead of scaling up, continuous manufacturing capacity is increased by scaling out,” he states. “Organizations can use the same continuous manufacturing technology in their product development, clinical trial manufacturing, and commercial manufacturing. As demand increases, they can simply copy the technologies to new manufacturing facilities to increase output or bring manufacturing closer to a population in need, without the additional burdens of scaleup design and its associated technology transfer complications.”
Gupta is also in agreement about the exponential growth of continuous manufacturing and adds that further balance within bio/pharmaceutical manufacturing is being found in terms of opportunities as well. “Customers today are demanding higher quality at a lower cost,” he says. “Therefore, the playing field has levelled for manufacturers, offering scope and opportunity for new players from emerging markets.”
For emerging therapies, such as cell and gene therapies, more work is needed to balance the complexity of processes required to ensure the risk of errors is minimized, Pettus stresses. “Organizations need to find ways to improve the complicated technology transfer process, which is full of opportunities for errors,” he says. “A decentralized manufacturing model will be important for individualized therapies because they will need to be consistently manufactured closer to the patients, all over the world.”
Although, Deuber reveals that despite initial tools being derived from academia and ultimately not suitable for scale-up purposes, within the past five years much work has already been done by industry leaders in the design of advanced instruments to enable drug developers to improve the quality and manufacturability of innovative new medicines, such as cell and gene therapies. “There have been improvements throughout drug development, from molecule screening to purification,” he says. “For viral vectors in particular, suspension platforms have gradually replaced adherent processes to ensure scalability as the cell and gene therapy space expands to include further indications.”
Finally, Byrd iterates the importance of viewing equipment, software, and technology suppliers as valuable resources throughout the value chain, thanks to the expertise they can provide to guide risk assessments and selections of technologies on what is fit -for-purpose. “Vendors often engage with regulators to help them understand the underlying mechanisms in the products they provide and therefore assist industry to gain acceptance for deploying more modern manufacturing approaches that maximize the quality and efficiency of manufacturing processes and reduce costs,” she asserts.
“In an industry that is justifiably risk averse, change needs to be balanced with assuredness,” concludes UpDyke. “As new initiatives come along, there is a lot of work done to understand regulatory, quality, and reliability impacts. A lot of peer review and collaboration, such as the work done through BioPhorum [a global collaboration of industry leaders and subject matter experts], helps to ensure that new solutions are fully vetted and understood.”
1. PMMI. Pharmaceutical Manufacturing: Trends Shaping the Future. Industry Report, March 2022.
2. Mordor Intelligence. Pharmaceutical Manufacturing Market—Growth, Trends, COVID-19 Impact, and Forecasts (2023–2028). Market Report, Jan. 23, 2023.
Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.
Vol. 47, No. 4
When referring to this article, please cite it as Thomas, F. Balancing Change and Certainty in Manufacturing. Pharmaceutical Technology, 2023, 47 (4) 16–20.