mRNA医薬品開発成功のためのCDMOの選び方： CDMOに求められる5つの要素

A critical challenge for raw materials is the need for safety and purity based on regulatory guidelines for products for human use. Raw materials must be free of substances of animal origin, and of beta lactam antibiotics, to eliminate risks of transmissible diseases or viral agents, and risks of allergic reactions and other side effects. Raw material purity is ensured through bioburden and endotoxin testing—and through use of controlled environment, mature quality systems, and extensive quality control testing.

Overall project success depends on selecting the proper quality grade of reagents, identifying appropriate tests to monitor the quality of each intermediate, and selecting the most appropriate formulation, which may include lipid nanoparticle manufacturing. This ensures the lot-to-lot consistency required by industry and global regulatory authorities alike.

To meet this challenge, Thermo Fisher Scientific launched its TheraPure and TheraPure Plus solutions for mRNA production. These are designed to accelerate mRNA vaccine and therapeutics production from preclinical development to commercialization with a portfolio of restriction enzymes, in vitro transcription enzymes, nucleotides, and capping solutions to meet critical process, scale, quality, and regulatory needs. These raw materials are crafted in facilities with thoroughly documented quality systems that are audited by accredited registrars and are manufactured following GMP principles.

Over the past year, the lack of a mature supply chain for mRNA has posed challenges for vaccine production, with the industry moving from manufacturing thousands to billions of doses—a scale-up that would stress any system. Key vendors are working diligently with suppliers to create and scale up manufacture of raw materials such as lipids, enzymes, and resins for purification. Supply is currently a challenge for any vaccine modality, including for simple components such as tubing or filters.

Thermo Fisher Scientific is supporting customers in this space by rapidly expanding capacity for resin production, adding capacity to an existing facility and accelerating build-out of a new facility to double overall production. In 2020, we built a new facility in Vilnius, Lithuania, for industrial-scale single use technology manufacturing. We have manufacturing redundancies in several U.S. locations for reagents used in mRNA synthesis, with the goal of ensuring a stable supply that is accessible from multiple sites on different continents.

An additional challenge is the need for a skilled workforce. Each vaccine is developed, produced, and tested by highly technically skilled people. It has been challenging to find enough people to support the rapid build out in manufacturing, analytics, manufacturing science and technology (MST), tech transfer and chemistry, and manufacturing and controls (CMC). Partnerships with pharma companies should comprise cross-functional teams including raw material developers, process equipment suppliers, analytical experts, formulation scientists, clinical study leaders, and quality compliance advisors.

Capacity has been the primary hurdle for DNA and plasmid production, which mainly uses fermentation, typically with E. coli. Suite dedication is a particular issue, since carrying out a fermentation process in a suite that also runs a mammalian cell culture would lead to a risk of cross contamination. Overall, the plasmid production process is straightforward, starting with fermentation, harvest/lysis/concentration, purification, and formulation. This usually employs a fermenter less than 100 liters in capacity, with relatively small columns of up to 20 liters. For customers with controlled clean space to implement their own plasmid production, we offer Gibco™ fermentation media, single-use fermenters and POROS™ anion exchange and hydrophobic interaction resins.