Reducing the time-to-release for drug product is a key goal of the industry as it can lower production costs and accelerate speed-to-market. This is why BioPhorum has completed a significant piece of work on the development of in-line monitoring technologies, which are fundamental enablers of real-time product release.
The result is a new and extensive white paper, In-line Monitoring/Real-Time Release Testing in Biopharmaceutical Processes – Prioritization and Cost-Benefit Analysis.
The paper is a huge step forward for the industry and will help it move away from off-line testing in the quality control laboratory to in-line, on-line or at-line testing on the manufacturing floor.
The core sections of the paper are:
- Process workflow
A step-by-step process matrix and ranking methodology were developed to prioritize critical quality attributes and critical process parameter measurements based on ILM-RTRT needs. It describes critical control points for each attribute, which are unit operations where the attribute can be controlled through measurements using feed-back/feed-forward control to ensure an attribute is in a desired range.
- User requirement specifications (URSs)
Technology-agnostic URSs were created for each prioritized attribute based on industry needs, including safety and regulatory requirements for any potential technology to be developed or improved by the industry.
- Business case
This discusses the elements of business-case calculations and the considerations and assumptions for a selection of attributes. Examples act as a guide to help users decide how to evaluate specific scenarios to apply this type of technology.
“From an end-user perspective, the white paper and the URSs provide clear guidance for technology vendors about what specification we need and what the state-of-the-art should look like,” said Ben Wilkes, Lead Scientist, R&D at Lonza. “The paper is specifically phrased on what we need to measure, rather than just generally saying ‘We would like it to do something in this region’.”
The white paper and URSs can be seen as a communication tool that outlines where the industry is now, where we want to be, what the requirements are to get there, and what the benefits are.
Gunnar Malmquist, Principal Scientist at Cytiva (formerly GE Healthcare Life Sciences), suggested that while some of the content in the URSs had existed before, pulling them together into a cohesive document allowed valuable cross-functional discussions between end-users and supply partners. “From a supply partner view, the paper and URSs are excellent starting points for a future proof-of-concept and prioritizing where to put our efforts. Companies outside of the BioPhorum framework could benchmark their technology against the requirements in the URSs.”
One of the major hindrances to ILM-RTRT progress has been trying to articulate a detailed and robust business case. This is why the paper includes a strategy for stating the business case for each attribute to understand the return on investment and the potential benefits created through the development and implementation of a combined ILM-RTRT approach.
“In addition to the technology,” said Michalle Adkins, Director, Life Sciences Consulting at Emerson, “one of the challenges is to get projects approved and funded in organizations. Using the white paper to articulate ILM-RTRT benefits, and to give an example of these potential benefits, is essential to justify a project.”
The functional requirements in the paper cover the technical specifications of the required technology, including accuracy, precision, lower limit of quantitation, frequency of measurement and total measurement time. It was important that these requirements were technology-agnostic so as not to bias the outcome of a URS.
Malmquist said that he found it valuable to walk through the process in a technology-agnostic way, “without running down the rabbit holes of new and exciting technologies”.
Adkins agreed and added, “By not focusing on specific technologies, we hope to help users and supply partners to think a little ‘outside the box’. Instead of building on existing technologies, we want to help them to think about what is possible.”
From an industry perspective, ILM-RTRT is a long-term project and follows the timeline of the 2017 BioPhorum Biomanufacturing Technology Roadmap, which looked 10-years ahead.
Wilkes explained that there had been industry talk and conjecture for many years on how to work towards and achieve ILM-RTRT strategies, without much coordinated progress. “Each company has been working at it from their own point of view so there has been a spread of strategies. The BioPhorum documents provide a cohesive multi-company industry strategy of saying what we think should happen and what it should look like. It’s a unified standpoint to discuss with regulators and supply partners.”
He added that another benefit of the paper was around analytics. “Process innovation is outpacing analytical innovation. We are finding new ways to make more and better products and to make them cheaper. But a potential bottleneck, now or in the near future, is analytics. So a strategy that says ‘This is what we’re going to aim to implement and this is the thought process behind it’ is a powerful document to help analytical development.”
The paper should be seen as the beginning of a long-term effort and act as a driver to start transformative projects. It should foster detailed internal and external discussions on the topics of improved process control, and better or faster release of products.
“The paper and URSs are very good for internal discussions,” said Malmquist. “I’m sure that my company will be able to build on the story and use the framework. I really appreciate the effort that went into the business case and the URSs. Even if we tweak things when we develop something, we can always refer back to this document that is a shared asset between supply partners and end-users. For us, this is really valuable.”
The workstream consisting of 15 end-users, 11 supply partners and an innovation hub is rapidly moving on through the ILM-RTRT journey, which will deliver tangible proof-of-concept demonstrators that meet the stipulations of the URS, for a subset of the identified high-impact attributes.
As ever, the BioPhorum collaborative approach was crucial to the success of developing the paper and URSs.
“The ability to work together has proven very fruitful,” added Malmquist. “There is also is the realization that no company, supply partner or end-user can solve this alone. This is something that can only be addressed by multiple companies working together.”
Adkins also saw significant benefits from working with people who understand the technology behind the instruments. “It’s all about people who understand analytics, automation and process control – as well as the different parts and intricacies of the process. The process of working together to tackle this beast has been a good opportunity to build relationships, while accomplishing the goal of publishing the white paper.”
The white paper provides a basis for evaluating and developing new proof-of-concept ILM-RTRT technologies. To make these a reality, close collaboration between equipment suppliers, technology developers, innovation hubs and biologics end-users will be crucial.
“I think it’s the whole industry working together to start solving some big issues that can really drive the ILM-RTRT forwards,” said Wilkes.
This need for this ‘top to bottom’, industry-wide teamwork is exactly how BioPhorum can play a role in bringing together the right people at the right time, which will be crucial to the success of ILM-RTRT.