Speakers during the 2021 PDA Annual Meeting session “Developing and Manufacturing Vaccines through Lessons Learned from Other Biologics” explored new frontiers in vaccine development and manufacturing.
Among the specific topics discussed were:
- QbD principles for biologics and vaccines
- A novel, rapid analytical method for vaccine fingerprinting
- An innovative biologics case study assessing risk in lyophilized drug products.
In addition, members of the PDA Vaccine Interest Group presented an overview of the forthcoming PDA technical report on vaccine development and lifecycle management.
Development times for biologics need to be accelerated, according to M. Amin Khan, PhD, End-to-end Vaccine and Drug Development Experience, but there are many hurdles to overcome — technical, clinical, and regulatory. Yet industry’s response to the COVID-19 pandemic has demonstrated that rapid product development is possible. It entails prior knowledge and understanding of structural biology, global coordination of and priority access to regulators, at-risk investments in manufacturing, and streamlined clinical trials.
“Quality by Design is the key enabler,” stressed Cristiana Campa, PhD, GSK, “because it fosters a deeper understanding of what is critical, what level of CMC risk is acceptable and, hence, which elements can be actually streamlined.” Those elements can then be employed in designing product and manufacturing processes to develop a safe, effective medicine quickly and efficiently.
Using a vaccine example, Khan and Campa stressed the criticality of comparability and development of computational models in reducing the time factor. By basing a new product on the evolving knowledge from similar products, analytics and processes, risk-based approaches focused on product quality can be developed that may be acceptable to regulators.
Khan and Campa illustrate the principles and strategies involved in the new PDA book they developed, Quality by Design—An Indispensable Approach to Accelerate Biopharmaceutical Product Development. In it, authors from major pharmaceutical companies and well-respected academic institutions share their expertise with case studies in biotherapeutics and vaccines about how QbD principles have been implemented to produce safe and efficacious products.
70% of Vax Manufacturing is QC
Up to 70% of the manufacturing process for vaccines is quality control, according to HORIBA Scientific’s Linda Kidder Yarlott, PhD, and Karoly Csatorday, PhD.
Their presentation explored the tools that could be used to acquire the necessary information to produce a successful vaccine in less time than traditional methods. ”Industry’s goal should be one to two days,” Yarlott said, which is possible “by using multivariate sensors and multivariate analysis.”
Comparing six standard optical approaches for sensitivity, selectivity, and confounding factors, they determined that adding an Absorbance and Transmission spectrometer into the fluorescence EEM instrument allowed real-time correction in time and space, providing much better resolution and sensitivity. This A-TEEM™ molecular fingerprinting works very effectively with vaccines, she said, as it acquires data on all those factors simultaneously.
To validate the A-TEEM™ method, Yarlott and Csatorday simulated a product-release test on four different multicomponent commercial vaccines that were similar enough to stress the capabilities of the differentiation. Analysis showed that the A-TEEM™ method met all the criteria for success: It could be performed in minutes, it could clearly differentiate the four vaccine formulations, and it proved to be both validatable and repeatable according to USP standards.
“The new applications in biopharma almost demand new tools,” Yarlott said, “and the existing toolkit out there may not solve all the problems. So it’s up to the people who develop the tools to think carefully about what the problems are for the industry, and it’s up to the industry to keep an eye out for the tools that help with particular problems. These things are critical for us to work together in order to solve the problems to advance things as quickly as possible.”
The case study that Diego Zurbriggen, West Pharmaceutical Services, and Samantha Singer, Lyophilization Technology, Inc., presented detailed how to create a well-designed lyophilized product by considering product design, formulation, lyophilization cycle and container closure system (CCS). They evaluated all stressors for their effect on a product’s manufacturability and suitability for use, product quality and patient safety.
Stressors should be evaluated throughout the entire product and process development, Singer said. She also noted that “the lyol product is the only dosage form where the product packaging has a direct influence on the success of the outcome of the process. So, the [selected] container closure system needs to remain integral for the life of the product.”
Zurbriggen concluded that risk mitigation requires a holistic approach. “It’s a balancing act,” he said. Not only do the FDA guidances on suitability of use need to be considered, which include chemical and physical testing, but the components also need to perform appropriately in the manufacturing environment.
“Analytical testing produces a great deal of data,” Zurbriggen said, but it is important to focus the data being generated on what addresses the question being asked, such as the manufacturability questions. He also encouraged the audience to leverage existing knowledge. “If you have used certain components before, look back at how they behaved. Reach out to your suppliers, your CMOs, your CROs…to anyone who might have knowledge you can leverage.”
Sabrina Restrepo, PhD, Merck & Co., Inc. and co-lead of the PDA Vaccines Interest Group, discussed the PDA draft technical report, Strategies for Vaccine Development and Lifecycle Management.
She said the group focused on the diversity of vaccine platforms, so the tech report addresses the complexity of managing the vaccine lifecycle, especially as manufacturing processes, control strategies, supply change management, and global regulatory expectations change. “We can always create advances to develop new treatments,” Restrepo said, but each advance “creates the complexity of managing the particular purposes or development processes specific to the platform.”
The Task Force encourages companies to not just think about acceleration, but “to think through their strategy from product and process development to lifecycle management.” In highlighting the approval process, the tech report distinguishes the difference between approval for “Emergency Use” and final approval, which can affect the supply chain and expiry dating. It discusses key considerations in choosing a control strategy, examines the benefits and challenges of comparability assessments, and recommends some best practices. The tech report also covers both the regulatory and nonregulatory aspects of lifecycle management.
“There are a lot of interesting vaccines now, more than there were a year ago and vaccines are a very complex and diverse group of products; it’s important to apply as many of the principles of modern biologic development as you can,” said Jane Halpern, PhD, consultant and co-lead of the PDA Vaccines Interest Group. In the report, “we talk about specifications, and we talk about the regulatory challenges, which are extensive when you’re trying to license a vaccine and maintain the vaccine distribution around the world.”
Restrepo provided an overview of the group’s activities for 2021.The draft technical report will be ready for peer review and publication this year and the Group has hosted several post-conference sessions. Restrepo welcomed all PDA members to participate. She encouraged them to share their expertise in the development of vaccine-related webinars and to participate in other collaborative PDA vaccine initiatives.