November 8, 2022 PAO-10-022-CL-08
The success of the Moderna and Pfizer/BioNTech mRNA vaccines for SARS-CoV-2 has cast a bright spotlight on mRNA technologies. While only a few companies pursued mRNA vaccine and therapeutic development before the COVID-19 pandemic, that number has swelled to include startups, emerging biotechs, and established biopharma firms. Many mRNA programs are advancing through preclinical and clinical development, targeting a wide range of diseases.
When starting out in mRNA medicines, companies ranging from startups to major pharma often lack the capital, operations, personnel, or know-how to successfully scale the required quality of manufactured mRNA drug substance and formulated drug product. Christian Cobaugh, founder and CEO of Vernal Biosciences, is leveraging his experience and understanding of success factors in the mRNA field to create a contract development and manufacturing organization with a singular focus on manufacturing high-purity mRNA test material and medicines for clients. Describing Vernal’s approach, Cobaugh said, “We first set out to create plug-and-play platform technologies to ensure that the mRNA products we manufacture result in predictably high levels of purity. Often, our projects start with the design of sequences to improve purity and potency, de-risking the mRNA’s manufacturing journey from discovery to commercialization. Even with discovery-stage projects, we are able to baseline the process knowledge and parameters that will speed up subsequent scale-up and clinical manufacturing projects.”
The nascent nature of mRNA technology means that there is only limited experience in mRNA production scattered across the outsourced manufacturing sector. Even though existing CDMOs are opportunistically adding mRNA capabilities, being the new players, most of them are still figuring out scale-up, critical quality attributes (CQAs), and process parameters, with a limited understanding around regulatory considerations for mRNA medicines.
Beyond the post-pandemic supply chain issues challenging the entire industry, another significant issue facing drug developers exploring RNA medicines is the variation in quality from one CDMO to another. Manufacturers of research-use only (RUO) materials may not be fully aligned with their clients in terms of the appropriate level of quality assurance and transparency for RUO programs, particularly as developers looking to advance RNA programs from RUO into clinical trials require a comprehensive understanding of the processes and methods used. Any misalignment or lapse in transparency increases the risks associated with the program as it advances.
At Vernal Biosciences, our commitment to excellence is rooted in the fundamental principle of “quality in / quality out,” meaning that the single most important activity to consistent quality output is ensuring that all raw materials entering our operations are of the highest quality. With our dedication to quality and complete transparency, we track activities from the outset, so that clients understand what work is being accomplished, even at the earliest development stages. As part of delivering superior process transparency to our clients and adhering to Good Manufacturing Practices (GMP) from the beginning, we maintain clear documentation of the experiments and testing performed, as well as the results obtained, as their projects advance to different phases of development and manufacturing. We are leveraging artificial intelligence (AI) and big data analytics to establish correlations between specific sequences and their stability with specific manufacturing activities to ensure that quality is structured into our processes from the very beginning.
One of the industry-wide challenges that Vernal helps developers navigate is a lack of full clarity in regulatory expectations. While the U.S. Food and Drug Administration (FDA) and other regulatory bodies have established basic regulatory guidelines for biologic manufacturing, they do not provide specifics regarding how to apply them, putting the responsibility on CDMOs to determine how quality will be monitored and controlled at each step in their programs. Each manufacturer must build upon the guidelines to establish the specific quality requirements for each product and process, and they must do so with the expectation of further evolution of regulatory demands as more drug candidates progress to late-stage clinical trials and commercialization. There are regulatory guidance documents for mRNA vaccines, but most of these remain in draft status. The U.S. Pharmacopeia is also developing a draft USP chapter for RNA. As a result, there is some alignment and understanding of the testing required and what a quality target product profile (QTPP) for RNA products should comprise. However, the relatively small number of products approved to date makes it difficult to understand the regulatory expectations with a high degree of confidence, with respect to both RNA drug substances themselves and to formulated lipid nanoparticle (LNP)–mRNA products.
Vernal Biosciences’ practice of introducing only quality materials into the process makes it possible to replicate them and generate the same quality constructs as projects advance to later development stages. Taking the time to understand the critical materials used in the process and how they impact the CQAs of the product facilitates the development of robust processes that produce the same material every time. Vernal also works closely with the FDA, which recognizes that mRNA is still an emerging field, in terms of what the CQAs should be and which aspects of manufacturing processes are critical.
The quality in / quality out approach, combined with a robust quality system in place that includes thorough vetting of vendors and the use of the right quality materials minimizes manufacturing risks and ensures the production of high-quality products. Similarly, partnering with vendors, establishing redundancies, and building flexibility into the supply chain for basic materials, taking into account the high-level dynamics of this global market, is crucial.
With Vernal Biosciences, customers can also minimize the risks of late-stage failures. Our AI and predictive software help accelerate mRNA sequence and process optimization, supported by the extensive practical experience and expertise of the scientific team. Vernal does not simply take the client’s construct and produce it at the appropriate quality grade — we provide advice on where issues might arise and recommend changes that will increase the chances of success with that sequence (or a variant thereof).
Vernal also has an established template system for process development and optimization, which ensures not only that the processes are optimized but that the data gathered are optimal and compatible with the data architecture. The use of these vetted protocols is supplemented by an extensive review system to ensure that processes are implemented correctly and that issues are identified and addressed. A final review is then conducted to assess the results of the process. In addition, each data entry is retained in a combined system, so the status of every process and the work order associated with it are known and accessible. The work orders also have their own templates in which every single process that goes into a production run is tracked.
At Vernal Biosciences, the different quality expectations for research grade versus GMP materials leads to the implementation of phase-appropriate development and manufacturing activities. The benefit to clients is speed-to-market with streamlined, accelerated progress toward late-stage clinical trials and marketing authorization. Accelerating therapeutic development, however, cannot result in any compromise on quality. With the phase-appropriate risk-based approach that Vernal takes, increasing quality expectations and requirements are applied as the program advances through different phases of manufacturing. Sourcing of materials, operator training, and other activities are performed according to GMP requirements, and the levels of tracking and tracing increase as the regulatory requirements increase.
When a product advances into early clinical phases, the expectations for quality assurance as outlined in FDA and EMA guidance documents on how to manufacture materials under principles of GMP are followed, which essentially involves layering on additional testing (for critical materials and product release) and documentation, as well as auditing and confirming approved vendors. Risk assessments used to determine which materials are considered as critical are documented, along with a description of how they are being tested and how quality is controlled and assured. With this approach, the manufacturing process remains fundamentally the same, but the levels of documentation and quality control increase.
Vernal Biosciences has a quality mindset that pervades all activities, spanning every team at the organization. Quality simply cannot be the sole responsibility of the quality department; it is the responsibility of every single employee, and it must be woven throughout the culture of the company. An assurance of traceability of all materials, including trending capability, provides deep knowledge of processes to all stakeholders. All unexpected events/results are thoroughly investigated to identify the root cause(s). This foundation of quality culture will be tremendously helpful as the company expands into GMP manufacturing to ensure that more stringent quality controls can be easily implemented and maintained.
With its headquarters in Burlington, Vermont, Vernal Biosciences is just three hours from the biotech hub in Cambridge, Massachusetts, but offers a living and working environment very different than that found in a large city. Construction of the new manufacturing facility for GMP mRNA drug substances is underway and targeted for completion by May 2023. The new commercial-scale, sterile fill/finish facility for GMP mRNA and LNP drug products is in the planning stages, with construction set to begin in 2023 and the site expected to be operational in the second quarter of 2024.
Judith Adair McCorry is the Senior Vice President for Quality at Vernal Biosciences. She has over 20 years of experience in Quality Control and Quality Assurance for pharmaceutical and biotech companies. Judith has held increasing leadership roles leading transformational changes to quality systems in support of commercial manufacturing at companies including Pfizer, PPD, and Merck, among others. She earned her B.S. in biochemistry from the Indiana University of Pennsylvania and a Master’s in leadership development and an MBA from The Pennsylvania State University.