March 9, 2023 PAO-02-23-CL-09
Unlike most typical recombinant protein and antibody drug substances, mRNA is inherently fragile and prone to degradation. The phosphodiester bonds in the backbones of single-stranded mRNA molecules are cleaved via transesterification by 2'-hydroxyl groups, a reaction that can be catalyzed by water. Ribonucleases (RNases), enzymes widely present in the environment, and other ribozymes also catalyze phosphodiester bond cleavage.
During manufacturing, RNase contamination control is crucial to ensure the manufacture of high-quality mRNA products. Gamma-irradiated, single-use equipment is strongly preferred to avoid possible contact with problematic enzymes. Samples and mRNA products must be stored at low temperature (–20 to –70 °C) to suppress degradation reactivity.
Encapsulated mRNA payloads are also typically unstable at room temperature. The temperature during LNP manufacturing must be closely monitored and controlled. In addition, carefully controlled and dedicated processes for freezing and thawing must be developed, as the timeline for both can affect the final particle size and encapsulation efficiency. The temperature-dependent sensitivity of mRNA–LNPs must also be addressed via controlled low-temperature storage and handling.
Sourcing of raw materials and single-use consumables, meanwhile, requires careful approaches and strategic relationships with suppliers. Specialty lipids and tailor-made plasmid DNA are high-value raw materials; suppliers must be selected under strict quality standards, and business transactions must be handled appropriately. Unit price, delivery, and quality dispute terms should be closely evaluated when establishing supplier agreements.
Some critical raw materials also require strict storage and handling conditions to ensure that their high quality is preserved. As a result, flexible temperature-controlled storage areas covering a range of temperatures are required to ensure that not only mRNA drug substances and mRNA–LNP drug products, but also other key raw materials, can be securely stored while maintaining their quality.
The COVID-19 pandemic created additional supply challenges. Soaring demand for both plasmid DNA and other raw materials (e.g., lipids, capping reagents, etc.) required for mRNA production, as well as components for single-use systems, led to shortages that persist today. For instance, when the pandemic emerged, only few suppliers produced GMP-grade plasmids at large scale. Consumables were, meanwhile, increasingly used at manufacturing scale not just for mRNA vaccines but also for COVID-19 therapeutics and many non-COVID biologics.
In the face of this skyrocketing demand, vendors responded quickly to expand existing production capacity and build new manufacturing facilities, albeit not quickly enough to meet demand and avoid inevitable delays for drug manufacturers. Much of that new capacity has recently come onstream or will in 2023, and supply issues are therefore somewhat alleviated today and should continue to improve going forward.
COVID-19 impacted all aspects of the global pharmaceutical supply chain due to lockdowns, raw material supply shortages, lower shipping container availability, route closures, reduced personnel, less frequent commercial air traffic, and many other factors. Prioritization (out of necessity) of the COVID-19 therapeutics and vaccines ahead of existing APIs and drug products made it even more challenging for biopharma companies and their outsourcing partners to secure inventory, even for raw materials. Enhanced collaboration, proactive monitoring technologies, and implementation of innovative supply chain management strategies helped streamline sourcing and reduce risks.
The effects of this supply chain crisis continue to linger. Production scheduling remains challenging because there is often no assurance as to when raw materials will be available. With few qualified raw material suppliers offering products suitable for GMP manufacturing, demand for GMP-grade, mRNA-specific raw materials has increased dramatically, as have lead times. A lack of specific raw materials can force the use of substitutes/alternatives, but the risks of doing so — when possible — must be clearly understood before manufacturing is initiated. Use of unqualified raw materials can cause risks of degradation if appropriate low-temperature storage space is insufficient.
Difficulty accessing single-use consumables owing to high demand and limited supply also continues to affect production scheduling. Lead times for these materials have increased more than twofold in some cases. The heavy reliance of mRNA manufacturing on single-use equipment for contamination control may well expand the need for localized production of single-use technologies to minimize supply shortages and to enable suppliers to maximize business opportunities.
Cold chain management has become strategically imperative for the industry in general, with mRNA-specific logistic route management becoming truly essential for mRNA manufacturers. Effective management of cold-chain logistics for mRNA vaccines and therapeutics requires precise coordination from start to finish, including temperature monitoring, real-time tracking for traceability, and well-trained and skilled logistics personnel, to ensure retention of efficacy.
Manufacturers of conventional biologics (recombinant proteins and monoclonal antibodies) have cold chain capabilities, but they are not typically set up to support the extreme temperatures often required for mRNA–LNP products. In order to adapt to global supply chain shifts, contract development and manufacturing organizations (CDMOs) have thus expanded their cold chain and fill/finish offerings to address the additional requirements for new modalities, such as mRNA.
Multiple types of storage capabilities, each with appropriate standard operating procedures, have become essential. Notably, mRNA–LNP products must be carefully frozen and thawed in blast freezers that provide storage at temperatures from –20 to –70 °C, a process typically achieved using control-rate freezers, which require management and operational resources to be effective.
Flexibility in primary packaging is also important for mRNA product developers, as is validation of drug products. If all handling of the mRNA–LNP product takes place on site with little likelihood of temperature variations that, if they do occur, can be more easily controlled, static validations are suitable. Off-site drug product–handling activities (e.g., transport) require dynamic validations, because greater variation in conditions, including temperature shifts, are expected.
CDMOs that offer end-to-end support for the entire mRNA workflow can more easily overcome some of these challenges due to their experience across the entire spectrum (from sourcing raw materials, reagents, and single-use equipment to implementing and monitoring temperature controls across each phase of development and distribution). The supply chain is also greatly streamlined by eliminating the need to work with numerous vendors, saving both time and cost.
Equally important, risks are significantly reduced. Having mRNA drug substance manufactured at one site, then transferred to another for encapsulation, and a third for fill/finish introduces opportunities for product loss given the fragile nature of mRNA. Every time the material experiences high-temperature excursions, it is possible that quality, efficacy, and safety can be negatively impacted.
Ideally, mRNA drug substance should be either transferred directly to the LNP formulation step or used immediately after thawing and stabilization to achieve maximum yield and purity of the encapsulated payload. With mRNA drug substance manufacturing, mRNA–LNP drug product production, and final fill/finish operations located within the same facility and supported by on-site analytical services — as is the case at Samsung Biologics — drug and vaccine companies can have much greater confidence that their products will be safely and securely manufactured with the highest quality and efficacy while avoiding common supply chain challenges.
Samsung Biologics’ clients also benefit from its ability to achieve biologic product approvals from global regulatory agencies including the U.S. FDA and the EMA, among others. The company has also repeatedly demonstrated capabilities with respect to validated processes for the manufacturing, packaging, and shipping of products that require cold-chain distribution within a wide range of temperature-controlled environments, as well as storage and handling of raw materials that require cold chain management. The depth of knowledge and expertise gained from this experience has direct applicability to mRNA–LNP product shipping and supply.
End-to-end support also facilitates scale-up of mRNA drug substance and drug product manufacturing, which will become increasingly important as the many candidate vaccines and therapeutics in the clinical pipeline advance to later development stages and ultimately to commercialization. The ability to perform all activities from lab to commercial scale at one facility eliminates unnecessary time loss, cost, and risks associated with the transfer of materials from one site to another.
Samsung Biologics and its clients have benefited from an approach to sourcing that emphasizes ongoing open communications with both suppliers and customers. For all activities, including sourcing, client satisfaction is a constant driver.
Each client works with a dedicated team of technical experts that includes representatives from procurement. At weekly supply meetings, project updates are shared, followed by a brainstorming session to lead to the best-case scenario and establish specific action items. In addition, client product forecasts are converted to raw material forecasts, which are then quickly shared with vendors to enable sufficient supply at the right time.
Samsung Biologics also applies a concurrent engineering concept to tech-transfer projects, with dedicated experts remaining engaged with a project throughout its lifetime. This approach ensures that the people with the most knowledge about the process are involved in technical discussions with the client and can help to ensure on-time delivery by resolving any quality or other issues that arise. In addition, the supply chain management team communicates directly with the technical and manufacturing teams in order to overcome challenging supply issues. The end result: tech-transfer projects (both conventional biologics and mRNA) are typically completed within six months, faster than the industry average.
In the case of mRNA production, Samsung experts focus on eliminating bottlenecks involving single-use components from customized equipment assemblies by working closely with technical experts at external vendors. Early-stage joint communication also accelerates the forecast and ordering process, enabling the completion of tech transfer within six months. Combined, these efforts result in significantly increased raw material readiness.
As a top-10 global CDMO with extensive mAb manufacturing experience, Samsung Biologics has also established close relationships and strong ties with many global suppliers. These relationships have been leveraged to expedite access to important raw materials and single-use components for mRNA production.
In addition to a team approach that emphasizes continuous, transparent communication within Samsung Biologics and between suppliers and customers, multi-sourcing has become an important and successful strategy for addressing supply chain challenges. Sourcing raw materials from multiple suppliers helps ensure access to key ingredients. If some of those different suppliers are local, the security of the supply chain is even greater.
This philosophy has led Samsung Biologics to attract major biopharma raw material manufacturers into Songdo, the city in South Korea in which Samsung’s manufacturing site is presently located. This area is rapidly becoming a key hub for the production of important raw materials and single-use components used in biologics manufacturing, including mRNA–LNP products. Sourcing materials coming from manufacturers in Songdo, Samsung Biologics’ headquarters, helps to minimize lead times. As additional raw material producers establish nearby manufacturing sites, stability of supply will be further enhanced, and Samsung Biologics’ internal efficiency will increase even further.
With today’s distribution network becoming increasingly complex at a time when biopharma companies face new challenges, Samsung Biologics ensures on-time delivery of high-quality mRNA–LNP products leveraging effective sourcing strategies and cold chain capabilities.
Strong and deep relationships with raw material suppliers ensure consistent supply of mRNA-specific raw materials and single-use components. Investment in local supply chain infrastructure facilitates collaboration with not just local suppliers but also global partners and regulators. Dedicated manufacturing capacity ensures the production of high-quality mRNA drug substances and mRNA–LNP drug products, and extensive infrastructure for cold chain supply enables storage and handling of mRNA drug substances and mRNA–LNP drug products at temperatures ranging from –20 to –70 °C. Products and samples are packaged with precision for distribution and stored within temperature-regulated and highly controlled areas in compliance with strict quality standards before being released.
Biopharma companies developing new modalities, such as mRNA therapeutics and vaccines, face uncertainties from two directions. On one end, predicting demand for new classes of drugs is difficult. On the other, for mRNA-based candidates in particular, accessing large quantities of high-quality, GMP-grade plasmids and fit-for-purpose, and single-use assemblies is even more difficult. Added to these uncertainties is the general lack of industry knowledge about producing novel drug substances and drug products at large scale.
Samsung Biologics is tackling these uncertainties head on. The company’s development and manufacturing systems have built-in flexibility and agility, enabling rapid responses to changing market dynamics that influence both supply of key raw materials and quality for final drug products. The localized supply approach provides an ecosystem better equipped to respond to sudden crises. As an end-to-end CDMO, Samsung Biologics also integrates typically segmented production operations into consistent processes — all at one site — that allows for greater control and affords high-quality products. The company is also applying its knowledge and expertise of mAb manufacturing where appropriate, to address challenges to the production of new modalities, such as mRNA.
Hanel Hwang is the Lead of mRNA Manufacturing at Samsung Biologics, where she leads mRNA CMO technical transfer and manufacturing. She has over 16 years of industry experience with a breadth and depth of GMP biopharmaceutical knowledge spanning from quality control to manufacturing. Hanel recently joined this team to help establish the mRNA manufacturing facility at Samsung Biologics and even led the completion of mRNA production in 2022. Prior to joining Samsung Biologics, Hanel held a senior role in Quality Control at Janssen Vaccine Korea. She holds a bachelor’s degree in microbiological technology at Konkuk University.