Facilities of the Future: Meeting the Demands of Breakthrough Therapeutics

Medical Ampoule Production Line at Modern Modern Pharmaceutical Factory. Glass Ampoules are being Filled. Medication Manufacturing Process. | Image Credit: ©IM Imagery - stock.adobe.com

Through the systematic incorporation of innovative equipment, the pharmaceutical industry can push the limits of efficiency, agility, and quality, giving patients faster and more cost-effective access to groundbreaking therapies. Several key, cutting-edge features and technologies are leading the way for the next evolution of pharmaceutical manufacturing, facilitating benefits like increased flexibility, more efficient quality assessment, and more seamless management of therapies across the production line.

Flexibility and smaller batch sizes through single-use technology

Traditionally, the equipment and facilities used in pharmaceutical manufacturing have been purpose-built, meaning they were engineered for specific products or modalities. While this allowed facilities to consistently produce a specific therapy or dosage form, purpose-built equipment lacks flexibility and cannot adapt quickly to new production needs. In contrast, today's pharma industry must navigate supply chain fluctuations while generating therapies that are increasingly complex and personalized. To adapt to these market trends, manufacturers are increasingly moving toward flexible, cost-effective single-use systems (SUS) that can enable the production of multiple therapies within one facility, maximize production efficiency for smaller batches, and maintain high product quality and safety standards.

As opposed to reusable stainless-steel or partially disposable systems that must be manually cleaned and sterilized between batches, the equipment in SUS is meant to be utilized once before disposal (1). At a high level, SUS improve throughput by increasing the speed at which a line can be switched over to accommodate the production of a different batch or product. As far as environmental impact, SUS can reduce the need for chemicals, water, and energy needed to sanitize equipment regularly (2). Moreover, work continues to improve sustainable behaviors across the manufacturing lifecycle, such as recycling single-use waste (3).

Facilities that use single-use technology, such as the 2023 International Society of Pharmaceutical Engineering (ISPE) overall Facility of the Year Awards (FOYA) winner, have streamlined production thanks to the reduced risk of contamination (4). Manufacturers that utilize single-use equipment are positioned to expand the number of modalities and therapies that can be produced in a singular facility in response to market demands and therapy approval.

Increased product integrity and flexibility with closed systems

Closed-system designs are another advancement that facilitates flexibility while potentially improving product integrity. Closed systems are built and operated to keep a product from being exposed to the room environment during manufacture (5). This technology is exciting because of its ability to help ensure product integrity, reduce contamination risk, and improve facility agility. As additional benefits, closed systems tend to have fewer steps and operational interference, streamlining processes and reducing process time. They can also improve worker safety through the reduced need for human intervention in processes. The future of pharmaceutical manufacturing will likely continue to build on the benefits seen by closed systems.

Faster access through continuous manufacturing

Traditional pharmaceutical manufacturing is often bogged down by operational challenges that limit the capabilities of facilities and slow production speed, preventing patients from accessing the therapies they need. Continuous manufacturing can help overcome this problem.

Continuous manufacturing takes processes that have been previously developed or licensed as step-by-step batch operations and adapts them into a continuous flow (6). In a continuous manufacturing flow, steps where the manufacturing process must be held for sampling and testing can be removed. Furthermore, because operations can be sustained for extended periods, continuous manufacturing can decrease cycle times, increasing the amount of product manufactured using the same equipment. This could drive down operating costs while sustaining product quality, ultimately speeding up access to therapies.

While continuous manufacturing has begun to be implemented more extensively, adoption varies across modalities (7). Implementation of continuous manufacturing for small molecules, for example, has the potential to move faster because of the well-characterized and defined nature of the processes. In comparison, large molecules pose a challenge because of their more complex manufacturing processes.

To facilitate widespread adoption, there are some factors that must be overcome across modalities (8). When changing a step-by-step process into a continuous flow, manufacturers must find ways to control and/or verify critical process parameters are being met while the new process runs. To implement continuous manufacturing on existing, licensed products, extensive comparability testing must be performed, in addition to completing necessary filing and approvals. The time and cost associated with this can be a daunting hurdle. This is especially true for new therapies, where the necessary equipment, technologies, and process understanding required for creating a continuous flow must be built from scratch. As a result, the implementation of continuous manufacturing is still in development for many commercial processes and facilities.

Quality with less waste through process analytical technology

Assessing the quality and safety of a therapy throughout its production is another area ripe for technological advancement, particularly process analytical technology (PAT). PAT includes at-line or in-line technologies that sample, test, and analyze products to ensure quality benchmarks are being met. PAT can provide timely measurements of quality and performance to ensure final quality while eliminating the need to pause the process, sample the product, and send the samples for analysis. Not only does PAT potentially save manufacturers time, but it can also reduce waste, a valuable development for personalized therapies that must be produced in small batch sizes. After encouragement from FDA in the early 2000s (9), PAT is now widely viewed as an important and necessary shift for pharmaceutical manufacturing that goes hand-in-hand with other innovations, such as continuous manufacturing.

The implementation of PAT provides vast amounts of real-time data on the manufacturing process, enabling optimization and defect detection. When real-time data are available, manufacturers readily see if a process is deviating from expected performance parameters and take corrective action if needed. In the long term, PAT provides data that can help build operational knowledge that allows for continuous improvement in the manufacturing process.

Much like continuous flow processing, PAT is widely known but its degree of implementation differs between modalities. While some core technologies exist, PAT is generally more widespread in small-molecule oral solid dose manufacturing. In comparison, the implementation of PAT in manufacturing large molecules or more complex therapies—such as biologics and cell and gene therapies (10)—is in an earlier stage. There are several reasons for disparities in implementation, but the complexity of different manufacturing processes adds a distinct layer of difficulty. Additionally, it is challenging for many manufacturers to find or develop PAT sensors or devices that are robust enough to operate commercially. This challenge is particularly acute when considering that lab-based processes and equipment must be adapted outside lab-based settings for manufacturing use. Despite these challenges, ongoing innovation has made it possible for some facilities, including several ISPE FOYA category finalists and winners in recent years, to implement PAT, indicating that the momentum for this technology is growing (11,12).

Innovation across the industry through digitization and digital twinning

Implementation of the technologies discussed thus far has been facilitated by the increasingly common use of fully digital validation, paperless manufacturing operations, and automation. Across the industry, the digitization of information, records, and processes continues to serve as the foundation for innovation.

Looking into the future, technological innovations like the implementation of digital twins will be valuable in providing predictive insights into the manufacturing process for more complex or unique therapies (13). A digital twin is a digital, virtual simulation or model of an actual facility, combining data, machine learning, and AI. Importantly, digital twins are often connected to real-world sensors and thus built and trained on real-world data. Manufacturers can use a digital twin to model or simulate manufacturing processes to predict outcomes. A digital twin can also provide predictive analytics to find areas of the manufacturing process that could be high-risk, pose a problem, or are critical to success. Digital twins are already used to plan and evaluate facility designs, simulate risky scenarios, and train staff. Despite the challenge of building a robust and accurate digital twin, their value and ability to empower manufacturers to make data-driven decisions and avoid future problems makes them an exciting innovation in digitization.

Into the next evolution of pharmaceutical manufacturing

Continued progress across many therapeutic areas is thrilling in a field that often moves slowly and cautiously. However, the technology and processes used to shepherd advanced therapeutics through development to commercialization must also evolve. Luckily, innovators have risen to the challenge, bringing hope for accessible, quality therapies of the future.

References

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8. National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on Chemical Sciences and Technology. Continuous Manufacturing for the Modernization of Pharmaceutical Production: Proceedings of a Workshop. Washington (DC): National Academies Press (US). Continuous Manufacturing for the Modernization of Pharmaceutical Production: Proceedings of a Workshop. 2019 Jan. 30. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540224/
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10. Wang, B.; Bowles-Welch, A.C.; Yeago, C.; Roy, K. Process Analytical Technologies in Cell Therapy Manufacturing: State-of-the-Art and Future Directions. IJAMT. 2022 4 (1) DOI: 10.1002/amp2.10106.
11. Kim, E.J.; Kim, J.H.; Kim, M.; Jeong, S.H; and Choi, D.H. Process Analytical Tools for Monitoring Pharmaceutical Unit Operations: A Control Strategy for Continous Process Verification. Pharmaceutics 2021 13 (6).
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About the author

Scott Billman is vice president Global Engineering, Real Estate, and Facilities, at Solventum.