How Tech Can Drive In-House API Manufacturing
By Life Science Connect Editorial Staff
Active pharmaceutical ingredient (API) production strategy is largely guided by advances in manufacturing technology and execution strategies that drive cost-effectiveness. Still, in recent years, API strategy has increasingly been influenced by the impacts of geopolitical tensions, trade disruptions, and public health emergencies.
In response, pharmaceutical companies continue to pursue the benefits offered by advanced manufacturing technologies (AMTs). However, bolstering capacity, ensuring high quality, and reinforcing supply chain security by nearshoring/reshoring manufacturing or adding in-house production are increasingly part of drug makers’ plans not only to survive, but to thrive as global operators.
The Case For Reinvigorating In-House Production
The COVID-19 pandemic and subsequent global strife have highlighted vulnerabilities in pharma supply chains. Further, demand for many medicines is increasing, leading organizations to invest in capacity by expanding existing facilities and building new ones. Expanding in-house capability enables greater visibility and control over timelines, reduces logistics complexity and exposure to global bottlenecks, and enables faster response to demand shifts. Additionally, in-house manufacturing allows for easier process integration, encouraging closer collaboration and innovation between R&D and manufacturing teams, all while building deep organizational capabilities in terms of talent and culture.
AMTs’ Game-Changing Potential
AMTs consist of production equipment, such as continuous flow reactors, and testing tools, including process analytical technology (PAT). AMTs implementing continuous flow chemistry utilize a significantly smaller manufacturing space footprint compared to batch processing, even with the addition of PAT, and can make API production more efficient and cost-effective.
Still, AMTs must be carefully considered because they not only impact manufacturing operations, they also influence activity in training, QA, and QC. Accordingly, it is vital that drug producers do not frame their needs in terms of technology, but approach challenges from a business standpoint and consider potential technological solutions more holistically. For example, continuous flow is a great technology, objectively, but it may not address a particular process or business concern in terms of building efficiency or cutting cost. Micro batches or advanced catalysis may be the right answer instead.
Moreover, a 2024 PharmaACE survey examining real and perceived barriers to investment in, and implementation of, AMTs revealed that pharmaceutical companies see the biggest barrier to AMT implementation as capital investment. Changing mindset from a batch process to a continuous flow process is also perceived as a key barrier. That is an organizational, cultural, and intellectual barrier, and training can be a powerful tool in helping bridge what is possible today versus what the industry will require in a few years. More widespread education about AMT benefits and specialized training by both equipment manufacturers and third parties, such as government entities and the API Innovation Center (APIIC), can be applied to overcome these barriers.
How Facility And Staff Impact The Tech Decision
Taking a broader view of technology solutions can reveal that options like added automation, fewer manual touchpoints, improved repeatability, and paperless operations will be easier to implement and more impactful than fully retrofitting or building a facility around AMTs. Working toward electronic batch records and real-time data capture can accelerate batch review and release timelines on the back end. Therefore, it can be more feasible both economically and logistically to overlay analytical tools like PAT on current processes than it is to implement major process changes. PAT enables high purity and yields, streamlines process control, and can facilitate greener chemistry.
Drug producers also must consider how the technologies and training required to add API manufacturing to their current space or build a greenfield space differ from those necessary to produce the finished dosage form. Each API generally constitutes a unique chemistry with its own sequence, intermediate profile, purification requirements, etc. Drug products tend to comprise more established, standardized formulations and presentations. This is not to say drug product production is not challenging — just that, from an API platform perspective, more process, equipment, and facility evolution has been necessary to accommodate the variety of advanced medicines coming through the pipeline. Keep in mind what the end user will need in terms of facility, equipment, and operator training.
Consider, too, that batch and continuous flow production each utilize various inputs and outputs that need to be calibrated/optimized to work effectively within the organization’s specific workflow, regardless of the reactor system. In addition to time and cost savings, useful metrics in assessing process effectiveness can include waste output, power and water usage, and how personnel are utilized. Depending on the application, using digital twins to computer model processes and using simulation software to troubleshoot can support greater process understanding and benefit optimization efforts.
New Facility Construction Vs. Retrofitted Sites
Building new facilities and retrofitting existing facilities are vastly different jobs, but both strategies are viable. For example, APIIC research indicates that the U.S. has significant idle manufacturing capacity, with some sites at about 50% utilization or lower, and that about 30 billion additional doses could be produced domestically using existing infrastructure. In many of these cases, when, it can be less expensive to retrofit an existing facility by implementing AMTs or preparing to produce a new API than it would be to build a new one — especially if the site already performs API manufacturing or production that adheres to similar principles. Retrofitting also provides drug developers with an opportunity to reshore medicines previously produced elsewhere, easing oversight.
A new site can take longer to plan and build, but generally provides more immediate up-front benefits versus retrofitting, which often requires staging various elements of the build — integration that may take years, particularly when electronic systems and data connectivity are part of the upgrade. New builds generally are preferred for novel production methods: for example, bio catalysis and biosynthesis to make APIs is fundamentally different from traditional chemical synthesis.
Final Thoughts, First Steps
The ability to improve and modernize manufacturing operations and capacity to meet global demand is key to the success of drug producers operating in the U.S. market. Investment in automation, AMTs, and digitization, as well as focused efforts toward advanced training, will drive the industry forward. Regardless of the type of investment — retrofitting old facilities, building new ones, implementing AMTs, or introducing more comprehensive process analytics — pharmaceutical companies in the U.S. must build in GMP compliance from the start, from HVAC to segregation, controls, and people flow.
Then, manufacturers must consider their processes’ technology and automation backbone, ensuring all systems are connected to enable the highest levels of quality and data integrity. Materials in/logistics out must be meticulously tracked and targeted for continuous improvement in terms of efficiency, quality, and cost.
Finally, in addition to training, workforce design is critical. It requires understanding the company’s capability needs locally and in-house, as well as its commitment to quality, because a facility and a supply chain are only as capable as the people running them. AMTs absolutely have the potential to improve quality but, in a practical sense, quality culture is what enables the technology to produce high-quality products.
To learn more, watch Pharmaceutical Online’s virtual event, “Closer To Home: Rethinking API Manufacturing,” on demand. Moderated by Pharmaceutical Online Chief Editor Katie Anderson, the event welcomed Brian Doty, VP of R&D and Programs for the API Innovation Center; Hugh Kelly, Associate VP and Site Head of Indianapolis API Manufacturing at Eli Lilly and Company; and Dennis Hall, VP of AMTs for U.S. Pharmacopeia; to share their expertise and muse over next steps for the industry.