To Be Continued...
Hovione’s New Jersey-based site has provided process development and small volume API manufacturing since 2002. In the years since its inception, the site has expanded its portfolio to include particle engineering capabilities and the handling of highly potent compounds. And in 2017, the company introduced continuous drug product manufacturing to its roster. Here, we speak with experts at Hovione, including Alexandra Adao (Head of Quality Assurance Continuous Manufacturing), Jose Santos (Head of Drug Product Continuous Manufacturing), Nuno Matos (Head of Quality Systems Management), and Sarang Oka (Process Development Engineer), about the promises and pitfalls of continuous manufacturing and how the facility is faring since it became operational.
This article is part of our special focus on "traditional" pharma: The Small Molecule Manufacturer (read more here). You can find more articles from The Small Manufacturer here.
Why is continuous manufacturing such an important strategy for drug manufacturers?
For years, the industry has struggled to shorten drug development cycles but many have found themselves limited by the capabilities of batch operations. Requiring less space and resources, continuous manufacturing offers companies the opportunity to manufacture drugs in one facility with a single rig. A major advantage of continuous is that rigs can run for longer when larger batches are needed without the need for scale-up. This could lead to potential savings in API over the course of the entire development cycle (although the API requirement in the early stages of development may be higher). The ability to run development in the same site also means that there is no need to transfer analytical methods and it cuts out the back and forth that often comes when such services are outsourced to other companies.
Big pharma companies are leading the way in proving that the equipment required for continuous operations can also help in lowering footprint. Pfizer’s PCMM (portable, continuous, miniature and modular) platform and GEA’s CDC50 are also strong examples of the portability of continuous manufacturing equipment and its ability to be used in train with minimum modifications to manufacture using dry compression, dry granulation or wet granulation. PCMM and CDC50 have also been used to alternate between tableting and capsule filling.
Is continuous an inevitability for pharma?
The future of manufacturing in the pharmaceutical industry will need to be continuous, given the push for much more aggressive time to market, enhanced process understanding, and the need to have a higher level of scrutiny of the process – and its impact on the API and resulting product quality. Batch manufacturing can no longer remain the status quo.
The fact that regulators are also becoming subject matter experts by investing in equipment, software for process modeling, and partnering with the leading innovators in the field is also a clear indicator of where the industry is heading.
Why was it important for Hovione to expand into continuous manufacturing?
We have installed a continuous manufacturing rig for drug product in 2017 because we believe in the enormous potential this technology brings to the patient. Continuous is giving the company the chance to explore new avenues that weren’t possible within the framework of batch manufacturing operations. For instance, we now have the opportunity to open new routes for the manufacturing of pharmaceuticals that weren’t feasible within the context of batch manufacturing; to eliminate or reduce the need for scale-up, providing a smoother pathway from development to market launch; and to enhance product quality on the basis of improved process understanding.
In a single shift of our rig, which can be prepared to operate in one of three model (dry granulation, wet granulation, and direct compression), we can process more than 100 kg of coated tablets. The process is heavily supported by process analytical technology, which forms the basis of a control strategy with the potential to segregate material throughout the rig, and ultimately enable real-time release.
What are the most significant lessons learned since the site became operational?
One of the initial challenges we ran into was trying to put together a team with the right skillset. Unlike the teams created to deal with our batch manufacturing operations, our new team dedicated to continuous manufacturing needed a strong background in process modeling, automation, control, and PAT. Our existing teams not only had to adjust to a new way of working, but also to new colleagues whose range of expertise differed from their own.
Moreover, because of the steep learning curve, development is expected to be more challenging when compared with batch operations, with development phases taking more time. But the potential of continuous to be much faster than batch in the full cycle of drug development is obvious, as development is always conducted in the same equipment and at the same scale. Though our experience is still limited, our overall equipment effectiveness (OEE) scores for continuous have already surpassed those for our typical batch processes.
Another key challenge for us as a CMO was efficiency. How would change over from one product to another affect our capabilities? Changeover is known to have a direct impact on OEE, the relative amount of useful time in the rig. Rigs consist of hundreds, if not thousands, of parts, so changing over is a complex process.
A strategy that we are planning to adopt is to minimize the number of equipment change overs. An example of this is to bundle batches together in longer campaigns with reduced cleaning between batches. We also have ongoing initiatives (including the creation of functionalized work instructions and SOPs, and the use of advanced scheduling methods) to help us address our existing constraints in terms of people and physical space for both cleaning and assembly.
What technological innovations would help increase uptake of continuous manufacturing?
The best route for process development is still unclear, since running a full-scale continuous manufacturing process is API intensive. There is still a debate as to whether a scaled-down development rig is the right approach (some equipment manufacturers are making steps in that direction), or if there should be increased investment in robust methods to identify API surrogates, so they can be used in lieu of the API during development.
It is clear, however, that more industrial examples are required to decrease the perceived risk of continuous manufacturing – existing communities of practitioners are currently working towards such a goal by working together to populate databases of process performance and materials.
