Wet, Wet, Wet

In the UK, CPI is collaborating with GlaxoSmithKline and AstraZeneca to establish a small-scale continuous wet granulation manufacturing facility for oral solid dosage forms. The facility is due to be completed in Q3 2020 and will be available as a national, open-access centre for contract development. The facility is part of a project called PROSPECT CP (Proving Real-world Scalable Predictive Tools/Technologies for Complex Particles).

“One of CPI’s strategic themes is predictive design and manufacturability, which includes exploring the use of PAT-enabled, model-based process control to help speed the adoption of digital manufacturing technologies across the whole formulation industry,” says Jacquin Wilford-Brown, Principal Scientist at CPI. “PROSPECT CP is one component of this, seeking to create a facility to remove risks and barriers, and speed up development of new solid products. The initial demonstrator is in the pharmaceutical space, building on our previous work and linking forward to the Medicines Manufacturing Innovation Centre.”

Tablets remain the most prevalent drug delivery method and wet granulation is often used for APIs with challenging processing properties, as some molecules are simply not amenable to direct compression approaches. In recent years, CPI has noted that more and more pharma companies are expressing interest in continuous technologies. Given that the UK Medicines Manufacturing Innovation Centre is running a project focused on direct compression, it made sense for CPI and its partners to look at twin-screw wet granulation.

“We aim to create, test and validate a national open-access contract development facility for process development and optimization of oral solid dosage forms, based on twin-screw wet granulation interfaced with a range of real-time measurements,” says Wilford-Brown. “Broadly speaking, we want to generate process understanding to support the development of new products and processes and establish control strategies for commercial manufacturing processes for drug products approaching registration. This will also allow us to understand and demonstrate the value of novel materials or excipients, and assess new and existing process analytical tools in real-life manufacturing scenarios.”

De-risk and improve production

Despite more companies showing interest in continuous manufacturing, Wilford-Brown believes that we are only part way along the technology adoption curve. Many pharma companies have existing assets based on batch manufacture. Although many agree that continuous processing offers advantages, new capital investment for continuous technologies may be difficult to justify. Similar considerations also apply to the adoption of PAT. “Integration of PAT is fantastic once it works, but it can be difficult to get to that point. Possession of the right PAT probe without the correct presentation method does not enable appropriate process control, so capital expenditure on PAT alone doesn’t guarantee success,” says Wilford-Brown.

To monitor a continuous process, manufacturers need to be able to access a representative portion of samples from the process with appropriate resolution. As a continuous process is, by its nature, continuous, it can be difficult to “break” into discrete portions that would enable real-time monitoring of the critical quality attributes of a product at the right point in the process. “There are a number of hurdles to effective implementation, but the prize is massive! Tighter quality specifications and more robust medicines manufactured at a lower cost, with the future potential of real-time release. On top of that, modeling approaches can be used to highlight the best points for PAT monitoring. By combining novel technologies, it is possible to effectively de-risk production,” says Wilford-Brown.

The pharma sand pit

One of the big roles of the new facility will be to act as a “sand pit” where companies can test new ideas without impacting their current manufacturing lines – particularly new PAT technologies. For continuous wet granulation to get a foothold in pharma, in-line PAT will be essential in giving manufacturers immediate feedback on a process and control in real time. “Specifically, PAT enables the Model Based Controller (MBC) to predict the necessary process changes before the product goes out of specification, driving less waste. Without the pertinent chemical and physical information, linking the critical process to product parameters, we would not be able to effectively do this,” explains Wilford-Brown. “Ultimately, we want to reduce or even remove the need for end-of-manufacture testing, so that product release is faster and the therapies reach patients much more quickly. PAT is also a major focus of the UK’s Medicines Manufacturing Innovation Centre.”

The facility will include a range of different PAT techniques, such as NIR spectroscopy, Raman spectroscopy and particle sizing technology. But the real intention is for the facility to be a platform for the evaluation of emerging PAT tools.  

GSK and AstraZeneca will bring their technical knowledge and strategic guidance to the project. Both companies have significant experience in the use of various PAT tools, advanced process control and continuous manufacturing. They will also be ensuring that the focus is kept on developing a capability and a service that will be appropriate and relevant for the pharmaceutical industry.