Advancements in technology and the increasing demand for improved, effective and innovative products to prevent, treat, and in some cases, cure diseases have focused the attention of drug developers on new modalities including mRNA-, DNA-, viral vector- and cell-based therapies and vaccines. In the past few years, advanced therapeutics have gained regulatory approval such as the viral vector-based gene therapies Novartis’ Zolgensma® and Roche’s Luxturna®, and several gene-enabled cell therapies including Kite Pharma’s Yescarta® and Tecartus™. Recently, with the clinical success of Moderna’s and Pfizer/BioNTech’s COVID-19 vaccines, mRNA-based products have come into the spotlight.
As promising as these novel products are, their innovation brings a level of complexity to developing and bringing them through design, clinical studies and to the market. Similar to standard treatments, they require robust, scalable manufacturing processes, a reliable quality-driven supply chain, demonstrable process control and adherence to regulatory guidelines from upstream through the downstream and fill/finish processes. New modalities do not have standard manufacturing processes, so they must be developed and validated to help ensure the products reaching the clinic have the best chance of providing improved patient outcomes.
"You have to take a patient-first approach," Thomas VanCott, Ph.D., Vice President and Global Head of Product Development, Cell & Gene Therapy, for Catalent, said. "We recommend that our partners think early in the process about what their product will look like, what will its critical quality attributes be? From there, we develop the plan and determine the right materials needed to help them bring their product to patients."
Levels of Quality Plasmid DNA
Many of these innovative vaccines and therapies share a common starting material, plasmid DNA. For mRNA- and viral vector-based vaccines and therapies, plasmid DNA is a critical raw material. For DNA-based products, the plasmid DNA can be the active pharmaceutical ingredient.
Understanding which quality level or grade of plasmid DNA is required for manufacturing is essential for the eventual success of a therapy in clinical studies. For example, research grade is typically used for the initial stages of discovery, research and development, preclinical and proof-of-concept studies; however, it is not intended for use in humans.
"Research grade is like spring training in baseball," VanCott said. "It allows you to see how athletes perform before selecting them for the team. Research grade plasmid DNA allows biotech companies to evaluate candidates at a much lower price, then down select the promising prospects."
High quality or GMP-like quality plasmids go through some testing and may receive a Certificate of Analysis, but typically do not undergo a full quality review or have a batch record. These plasmids may or may not be manufactured in a GMP facility but can be used in early phase (Phase 1 or 2) clinical studies.
Ultimately, the end goal is to have a fully CGMP compliant process that encompasses raw materials, manufacturing facilities, validated equipment, testing, complete batch records and quality reviews in order to be used for Phase 3 studies and commercialization.
"Being CGMP compliant is what Catalent’s partners are expecting even for early phase studies", VanCott said. "With expedited regulatory designations, we are seeing clinical timelines that are so fast that clients do not want to risk any complications by being non-CGMP compliant," he added. "Some clients prefer to use CGMP grade plasmids throughout development to help maintain process consistency."
Locking in Raw Materials and Processes
Also critical to the success of cell and gene therapies is locking in processes early. Catalent’s approach, as a candidate moves through development stages, is to lock in the process and materials. By planning ahead, including the use of CGMP grade plasmid DNA and developing a robust, scalable manufacturing process early, clients can avoid extensive and expensive bridging studies for changes made to raw materials, equipment and processes prior to late stage, pivotal studies and commercialization.
Advanced therapies that go down the path of expedited review do so with shortened timelines that compress intervals between Phase 1 and Phase 3. These shortened timelines underscore the importance of planning ahead to meet CGMP chemistry, manufacturing and controls guidelines and the level of quality of critical raw materials used, including plasmids.
The key to success in developing and bringing mRNA-, DNA-, viral vector- and cell-based therapies and vaccines to market is having a partner like Catalent with a global reach and multiple solutions for clients. For plasmid DNA, this includes helping our partners determine if high quality- or CGMP-grade plasmid DNA is right for their candidate’s stage of development. The Catalent team works with its partners to look for ways to streamline the development path to help meet expedited timelines.
From development and manufacturing expertise for plasmid DNA, viral vectors, autologous and allogeneic cell therapies to packaging, storage, and delivery to clinical study locations, Catalent can support its partners at every stage in the candidate’s journey. For more information visit: https://biologics.catalent.com/cell-gene-therapy/.