There is no question that mRNA mannufacturing is not easy. Besides testing their safety and efficacy, biopharmaceutical companies must also design a protocol for scaling and manufacturing the drug for regulatory approval and commercial use. This creates an immense pressure to expeditiously develop streamlined chemistry, manufacturing and control (CMC) strategies.
That is why in this article we will explain what a CMC strategy is and the challenges in the mRNA manufacturing.
What is CMC Development?
CMC Development means all research and development activities conducted in respect of the Manufacture of Products, including chemistry, manufacturing and control (CMC), creation of master and working cell banks, test method development and stability testing, process development, manufacturing scale-up, qualification and validation, quality assurance and quality control processes and techniques.
What is the Purpose of CMC?
Before you’re ready to test your medicinal product on humans, you must develop a CMC process to ensure quality manufacturing standards have been established. This information is required in Module 3 of the Clinical Trials Application (CTA), such a the Investigational Medicinal Product Dossier (IMPD) in Europe and the Food and Drug Administration´s (FDA´s) Investigational New Drug (IND) application in the US, as well as EU marketing authorization applications and FDA new applications (NDAs) or Biologics License Applications (BLAs).
The primary objective of CMC is to assure the quality of the finished product during all phases of development. Regulatory authorities need to see detailed standards to ensure consistency of identity, safety, quality, stability, and strength between the product used for clinical trials and product batches produced for commercial purposes on an ongoing basis.
You might be interested in reading: Manufacturing Strategies for mRNA Vaccines and Therapeutics
Are CMC Practices Required?
The answer is YES.
All biopharma companies with investigational products have to follow the specific details of their CMC process for every phase of the product lifecycle, including technology transfer and line extensions. The problem here is to know which steps and variables in the manufacturing process need to be controlled and why, in order to obtain a comprehensive understanding of the necessary CMC strategy.
But, what happen if CMC practices are not followed or if they do not meet current regulatory requirements? The marketing authorization will be considered non-compliant and will be withdrawn.
On the other hand, the regulatory requirements are constantly evolving, so you’ll need to update your CMC strategy to stay compliant with current guidance from the agency.
CMC Challenges in mRNA manufacturing
As we move toward a future where the mRNA therapy will play a vital role in patient care, there are several areas of consideration where biopharma must focus to minimize bottlenecks and drive mRNA manufacturing.
The diversity of mRNA presents its own CMC development challenges, as there are many variants of interest that will be manufactured at different scales, from the large scale required during the pandemic down to much smaller scales for personalized mRNA therapeutics.
The lack of standardization and cost-effective techniques for manufacturing and analytics for product characterization, create CMC development challenges for mRNA-based products.
For example, the mRNA molecule and the impurity profile can differ from product to product, calling on different purification strategies to ensure the removal of impurities downstream while preserving the mRNA molecule. Many of today’s resins and membranes have low capacity for large mRNA molecules and poor resolution for impurities due to their similarity to the target product. This means there is the need to develop improved solutions to accommodate downstream mRNA purification.
Another critical issue to establish is the setup, manufacturing, and control of the lipid nanoparticle (LNP) that are critical in mRNA manufacturing, because the protect the mRNA from degradation and enabling more efficient delivery to the target tissue cells.
For all this, the biopharma industry needs regulatory authorities to provide a framework for compliance to streamline CMC development and ensure the safety and quality of novel products.
You might be interested in reading: Consider cGMP to minimize the Risks and Accelerate Your Development Milestones
The factors that make a strong CMC strategy
To prevent complications with the regulatory agencies, companies should consider more than one CMC strategy throughout product development and perform continuous improvement to optimize their approach. This will help them mitigate the risks and satisfy regulators to bring much-needed relief to patients.
Successful CMC strategies share many common elements, like robust testing, rigorous monitoring and meticulous data collection. Also in a successful CMC strategy, the development process is monitor to identify potential sources of risk. To reduce risk, the CMC plan should be stage-gated, and scientific justification must be provided for all important decisions made from process development to product release and expiry dating.
Companies should begin designing their CMC strategy as early as a disease target is developed and should continue refining it through the entire development process.
Should You Work With a CDMO?
Working with a global partner experienced in regulatory strategy and CMC development (https://53biologics.com/mrna-services/ )can help you appropriately analyze and document the manufacturing processes, active substance and drug product characteristics, and testing to ensure the product is safe, effective, and consistent.
Biopharmaceutical companies do not have to go at it alone. With the help of a contract development and manufacturing organization (CDMO), a company can optimize the CMC process, for efficient and reliable biological production and release.
CDMOs have experience to bring biologics to market and can lend this experience to smaller companies in need of guidance. CDMOs understand how to develop risk-based and scientifically justified CMC strategies that the regulatory agencies may favor.
CDMOs also bring scientific, technical and regulatory knowledge to the table, offering the scientific justification that biopharmaceutical companies need as they establish their production, analysis and validation plans. Their guidance will increase the chance of regulatory success without too much do-over.
Also CDMOs can also reduce costs, because they can help companies understand the cost of each CMC step and how their decisions will impact the budget, making it easier to keep costs down while increasing the chance of reaching the market.
Conclusion
An effective CMC strategy is a key component of any successful commercial drug-product development program, particularly one with an accelerated timeline. Choosing the right CDMO partner and involving them early in the development process can make the difference between project success and failure. This work showed the successful use of 53Biologics´ embedded CMC strategy to attain regulatory approval on immediate-release tablets despite numerous potential regulatory hurdles and an aggressive timeline.
53Biologics combines technological innovation with world-class manufacturing and process excellence. The company’s decades of experience in formulation, drug development, and process engineering, including in-depth CMC and Regulatory Affairs knowledge, have been used to address an array of product-development challenges. 53Biologics also provides integrated product development, analytical method and modelling development, and phase-appropriate manufacturing services.
Do you want to learn more? Arrange a meeting with our CMC strategy team.
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