July 31, 2023 PAO-07-23-CL-04
With the robust efforts across the industry to rapidly and efficiently advance mRNA therapeutics, a broad range of risks must be considered and mitigated. Drug developers and their manufacturing partners are driven to develop robust, efficient, reliable, and scalable manufacturing processes in the context of competitive market pressures. Regulatory guidelines for evaluation of the safety, quality, and efficacy of mRNA therapeutics and vaccines are evolving, with draft guidances likely to become formalized in the near future.
Risk management at BIOVECTRA begins with a quality-by-design (QbD) approach to ensure deep understanding of critical process parameters (CPPs) and critical product quality attributes (CQAs). Manufacturing processes are then designed based on these principles.
Another component of BIOVECTRA’s risk-management approach involves relying on a team of experts with a broad array of knowledge and experience. In addition to quality assurance, engineering, analytics, process development, and manufacturing, science and technology groups participate in risk assessments, applying their diverse perspectives to ensure the best possible process designs.
A third element of the BIOVECTRA risk-management strategy considers, through project management exercises, what risks are associated with advancing our internal platforms and/or client projects.
Underlying these three aspects of our approach to managing the risk of mRNA manufacturing is the implementation of process automation solutions wherever feasible in the new production facility, including the use of process analytical technologies (PATs) to monitor CPPs.
Automation has been proven in other industries to result in more robust processes and to facilitate more streamlined program advancement. For mRNA projects, automation also has the potential to reduce development times, allowing clients to move from preclinical R&D to clinical trials efficiently, which is highly desirable as drug developers race to be the first to market with these next-generation therapies.
Indeed, given that mRNA synthesis typically requires the same process conditions and reagents (e.g., nucleotides, enzymes, DNA substrate) with only the genetic sequence of the DNA varying, it can be straightforward to automate. A bioreactor with inline PAT providing feedback on the temperature, pH, conductivity, and other factors allows careful control of the process. Purification can then be performed via automated filtration followed by chromatography with real-time fraction UV analysis, followed by ultrafiltration, concentration, and buffer exchange.
The pressure for biopharma companies to invest in artificial intelligence, robotics, and digitalization to improve process performance is likely to continue to rise. BIOVECTRA believes that the maturation of the mRNA field (and the pDNA field by association) creates opportunities for leading-edge manufacturers to leverage these technologies, as well as continuous processing. AI can help to predict process outcomes and lead to safer, more efficient, and more productive processes.
One solution we are exploring is the digital twin, in which robotics sensors and AI allow collection of real-time process data that is then used to generate a simulation of that specific process. The simulation is then used to analyze process performance and identify areas for improvement and to predict potential issues before they occur. For mRNA, digital twins could be deployed for processes, such as microbial fermentation to generate pDNA, in vitro transcription to produce mRNA, and formulation.
The key to success for contract development and manufacturing organizations (CDMOs) is to listen carefully to their customers regarding their needs and to then create the optimal solutions that address those pain points. One of the biggest issues for mRNA developers today is the fragmented nature of outsourcing services. Often, developers must work with multiple CDMOs that only support one step of the process — pDNA, mRNA drug substance, or mRNA–lipid nanoparticle (LNP) drug product.
Some larger companies have attempted to address this issue by acquiring smaller CDMOs that specialize in each of these areas. However, these acquired businesses often remain as separate companies in different locations, each with its own team. Material must be shipped from one site to the other and be handled by an entirely different team, which can create the same kind of inefficiencies as tech transfers between different CDMOs.
At BIOVECTRA, all aspects of mRNA–LNP manufacturing exist at one facility under one roof. The entire GMP manufacturing train is located in a single building, and client projects from pDNA production to mRNA–LNP fill/finish are supported by the same team of experts. Internal production of pDNA also simplifies the supply chain and gives us greater control over timelines. We have also overcome the ubiquitous bottleneck associated with limited fill/finish capacity by establishing in-house capabilities.
Establishing robust processes requires a comprehensive approach to process development. BIOVECTRA has always placed an emphasis on not only creating strong teams but supporting them with great manufacturing science and technology to enable the seamless advancement of programs from process development to GMP manufacturing. This approach positions us to evaluate and implement comprehensive process solutions, including new automation technologies that accelerate process optimization and reduce risks associated with commercial production.
As BIOVECTRA moves to automated approaches, we will continue to rely on a QbD approach. Design-of-experiment (DoE) principles will continue to guide process development efforts, with knowledge about key process parameters that impact impurity generation and product yield used as key inputs into AI algorithms that perform predictive analysis.
BIOVECTRA has constructed a brand-new facility that will come on stream for GMP manufacturing in 2023. We have scales from shake flasks and smaller lab-scale equipment up to the 1,000-liter scale for pDNA and the 30-liter scale for mRNA drug substance and complementary scales for mRNA–LNP drug product. Two separate fill/finish lines provide capacity for over 20,000 vials per day each, which equates to nearly 70 million doses per year of a typical mRNA vaccine.
The offering of sub-liter to 30-liter scales for mRNA drug substance and complementary scales for mRNA–LNP drug product manufacturing was selected on the basis of expected demand for these materials and the nature of the processes involved. Developers of mRNA products are driving extremely hard to improve translational efficiency and reduce dose sizes (e.g., through targeted delivery) to reduce the cost of these drugs and vaccines. In vitro transcription reactions, meanwhile, are typically completed in just three hours, allowing numerous runs to be completed per day. In addition, this type of smaller batch-based approach reduces risk, given the expense of the raw materials.
If there is a need for production of mRNA and mRNA–LNP products in larger volumes, BIOVECTRA is well-positioned to respond. We perform fermentation reactions at up to the 17,000-liter scale — the largest capacity in North America. Indeed, we have extensive experience overcoming scalability challenges for both biologics and small molecule manufacturing, experience that will translate well to mRNA and mRNA–LNP production.
While mRNA technology has been under development for several decades, there are still many opportunities for improvement. As a CDMO offering end-to-end mRNA therapeutic and vaccine services, it is essential that BIOVECTRA maintain awareness of evolving technologies in the field and be prepared to implement new production processes leveraging novel technologies.
One of the biggest areas of innovation today revolves around targeted delivery of mRNA to specific cells and/or tissues. The goal is to find solutions that will eliminate safety concerns around potential negative responses to PEGylated lipids and other components in LNPs and increase the efficiency of delivery, thus reducing the required dosage level.
Potential solutions closely followed at BIOVECTRA include the linkage of antibodies to mRNA–LNPs that can bind to specific receptors on the surfaces of specific cells (similar to antibody–drug conjugates) and the use of alternative forms of RNA, such as circular RNA, that can only be expressed in certain cells or tissue. Other efforts focus on increasing the ability of LNPs to stabilize mRNA, thus prolonging the time the active is present in the body.
With decades of experience in producing many types of biologic and small molecule drug substances and drug products, BIOVECTRA is well equipped to manufacture all different types of RNA modalities formulated in different delivery systems. We can express a large spectrum of biomolecules, perform cross-linking reactions with small molecules, and synthesize a wide range of lipids.
The complexity of mRNA processes contributes to the manufacturing risks, which in part relate to challenges with assaying a wide variety of impurities in addition to fully characterizing the mRNA molecules themselves. Current regulatory guidances emphasize ensuring consistent, high quality of mRNA products, which can be assessed using several techniques, including high-performance liquid chromatography, mass spectrometry, gel electrophoresis, and sequencing techniques, among others. In addition to thorough characterization of the mRNA active, detailed impurity profiling, sterility analysis, and stability determination must be completed.
The in vitro transcription reaction followed by various enzymatic reactions and/or capping reactions creates the need to understand the capping, poly-A tail, and other aspects of mRNA drug substances, as well as the various product-and process-related impurities that can be generated. Many of the methods required are unique to mRNA.
BIOVECTRA’s quality analytics team has developed over 50 in-house methods for determining the structure and quality of pDNA, mRNA, and mRNA–LNP products. These assays are platform driven to the extent possible, with detailed protocols in place to complete any aspects that must be customized for a specific mRNA candidate. Importantly, this work is performed within a robust and proven quality system that has a successful track record with regard to regulatory inspections, including by the U.S. FDA, Health Canada, and Japan’s PMDA.
The most up-to-date mRNA guidance comes from the U.S. FDA, with the latest update occurring in March 2023. Further updates from the FDA are anticipated in the near future. In addition, the WHO — as well as potentially other national regulatory agencies — is expected to issue new mRNA-specific guidelines, possibly before the end of 2023. The U.S. Pharmacopeia has published a second edition of its guidelines for mRNA analytical methods.
At BIOVECTRA, we recognize that mRNA is a new modality with limited real-world data available. Consequently, it is essential during clinical trials of new mRNA candidates to let the data speak for themselves. As more data are generated, agencies will continue to update guidances and share that knowledge.
BIOVECTRA has an internal regulatory group that stays on top of the latest trends and supports clients in their filing processes. They also understand that our customers are at the forefront of the industry, interfacing with the regulatory agencies and consistently reoptimizing their products based on real-time outcomes of animal studies and clinical trials. By partnering with our clients and gathering their feedback, BIOVECTRA is able to optimize and adjust our processes. In fact, interacting with many different clients gives us many different perspectives and allows us to stay on top of potency, safety aspects, and other regulatory concerns, ensuring that we pursue all activities in a compliant manner.
The risks associated with moving from preclinical to clinical to commercial stages for any drug candidate can be magnified if raw materials are not taken into consideration from the outset. One way to reduce that risk is to use phase-appropriate raw materials that are produced using the same processes regardless of whether they are research-grade or GMP-compliant.
To that end, BIOVECTRA offers preclinical materials suitable for animal and toxicology studies and GMP-grade materials for use in clinical trials and commercial production. The only difference between these materials is the additional quality documentation, such as the use of validated analytical methods and validated processes. It should be noted, however, that BIOVECTRA does not offer high-throughput screening services for identification of optimal mRNA sequences. We largely produce GMP material for clients that have selected their lead candidate and are looking for the ideal partner to help them move rapidly move beyond the preclinical stage.
The success of the COVID-19 mRNA vaccines has drawn much attention to their potential for the prevention of a wide variety of infectious diseases. Many companies are also focused on the development of mRNA-based cancer vaccines, which by their nature are personalized medicines. Such autologous treatments are much more complex in terms of batch records, traceability, quality control, and other manufacturing aspects compared with traditional vaccines.
BIOVECTRA recognizes the challenges associated with advancing such personalized mRNA products. Automation will be essential to minimizing the timeline from patient biopsy to treatment while ensuring traceability and documentation. BIOVECTRA anticipates implementing digitalization and electronic batch records in the very near future. We are also moving toward digitalization and barcoding of samples to greatly increase both traceability and safety. We are looking forward to supporting clients in that personalized medicine space through these improvements.
Jessica Madigan, B.Sc. (chemistry, 2008), has 14+ years of experience focused on nucleic acid manufacturing and development. Jessica played a key role at start-up company TriLink BioTechnologies (first CMO/CDMO for mRNA and inventors of CleanCap technology), leading to successful launch of mRNA, plasmid, capping analogs, and modified nucleotide products. Jessica also holds a Project Management Professional (PMP) Certification and successfully managed over 30 API manufacturing projects for mRNA early-phase clinical trials. At BIOVECTRA (2022–present), Jessica supports business development efforts for pDNA, mRNA, and formulation services.
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