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Adapting cold chain and fill-finish capabilities for new drug modalities

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Jeong Jin-hyeok, associated director of Aseptic Filling, at Samsung Biologics, examines the lessons learned following the onset of COVID-19 and highlights how CDMO flexibility is helping to hail in an era of new therapeutic modalities.

Key insights:

In rapid reaction to the COVID-19 pandemic, pioneering drug developers introduced a novel drug modality worldwide in the form of mRNA vaccines. The success of the global vaccine roll-out was facilitated in part through the efforts of contract development and manufacturing organisations (CDMOs) that quickly adapted their capabilities to support mass production.

Revolutionary technologies

From the onset of the COVID-19 pandemic, drug developers reacted quickly to produce essential treatments and vaccines. This global health crisis set the stage for the introduction of a ground-breaking drug modality: mRNA vaccines. Although this technology had been used in treatments for a variety of infectious agents, including influenza, Zika virus, and cytomegalovirus, the pandemic highlighted its potential for worldwide vaccination programs.

Owing to the relatively simple editing involved in adapting mRNA, this technology offers “plug-and-play” applications, opening the door to its use in a wide number of different therapeutic areas. mRNA drugs have now entered the development pipeline targeting even more infectious diseases, from HIV to malaria, as well as autoimmune disorders, rare diseases, and a range of cancers.

The global mRNA therapeutics market reflects this growing potential and rising interest from the biopharma industry, as the market is forecasted to grow from $46.7 billion in 2021 to $101.3 billion by 2026.

Supporting continued mRNA production

For the biopharma industry to meet the rising demand for new mRNA drugs, it will need unending support from CDMOs with expertise and experience. Anticipating this growing requirement, many CDMOs have shifted and adapted their services to expand their cold chain and fill-finish capabilities.

With increasing pressures to accelerate project delivery times, cold chain capabilities are relied upon heavily for mRNA drug development. Rather than spending considerable time ensuring product stability at room temperature in formulation development, shortened timelines can be achieved using cold storage. Shortened timelines were essential to bring vaccines to Phase I and Phase II clinical trials on time when vaccines were in an urgent demand.

Adapting to meet mRNA production demands

To meet the growing needs of mRNA projects on the horizon, development and manufacturing facilities and capabilities must be reassessed with mRNA at the heart. Manufacturers must face the challenges that surround implementing or expanding both their cold chain and fill-finish capabilities, as well as understanding this novel and often unfamiliar technology.

In biologics production, manufacturers will have common cold chain processes already in place, but there are additional considerations they will need to consider when working with new drug modalities like mRNA.

1. Freezing and storage

Temperature ranges used for freezing biologic products are generally standard, but to provide flexibility, especially for new drug modalities, manufacturers should offer access to multiple types of storage capabilities and have the appropriate standard operating procedures (SOPs) in place. For example, having blast freezers whose storage temperature can be adjusted anywhere from -20℃  to -70℃  can help CDMOs support a wider variety of projects.

For some biologics, slower freezing rates can cause cryoconcentration, where freezing from the outside-in causes compression of the bulk material and ultimately damages the molecular structure of the drug. Although this can be a common problem with blast-rate freezers, control-rate freezers can minimise potential damage by controlling the cooling rate at specific points of freezing. In DP production, manufacturers will need to consider the thawing process, for which control-rate freezers can also be used. Control-rate freezers require careful management and operational resources to be effective.

2. Primary packaging

Various types of containers are used throughout biologic cold chain processes and the choice of which will primarily be dependent on the platform used by the product owner. Manufacturers must therefore offer flexibility to mRNA product developers while remaining conscious of how the container materials could impact the product in terms of extractables and leachables.

Manufacturers will also need check for any damage to containers like glass vials during the handling/shipment processes that could lead to product loss as well as deteriorate product quality.

3. Validation

Both static and dynamic handling validations of cold chain capabilities during storage and transport. Static validations will be needed for the on-site handling of drug products (DP), where variations in temperature are unlikely to occur and can be more easily controlled. Contrastingly. dynamic validations are associated with off-site DP handling (e.g., during transport), where greater variation can be anticipated.

Appropriate controls and monitoring of temperature and humidity should be in place for manufacturing, storage, and transportation. In the event of deviation and control failures, there must also be risk management systems and continuity plans.

As most vaccines are in parenteral format, manufacturers will need to ensure that these types of mRNA therapeutics are sterile to minimise the risk of exposing patients to contaminants.

Sterile filtration is the only method that can suitably sterilise vaccine products without impacting stability, a challenge that is also seen in general protein product manufacturing. This is usually conducted in grade A environments using two in-line filters during fill-finish as close as possible to the filling points. Consequently, as the product flows through the lines to the container, the product is sterilised. A thorough control will be required to prevent changes in mRNA concentration that could arise due to filtration clogging.

In the early days of the COVID-19 pandemic, manufacturers were faced with a common problem: unfamiliarity with a relatively new drug modality. Most of those with a background in supporting the production of biologics had predominantly worked with water-soluble drugs, in comparison to mRNA products encapsulated with lipid nanoparticles. 

The unpredictable nature of mRNA drugs meant that these manufacturers had to quickly familiarise themselves with the new technology to determine how fill-finish and cold storage conditions could impact the product characteristics.

In part, manufacturers relied upon transparent and strong communication between the CDMO and the mRNA drug sponsor to form a clear understanding of the technology. By having a trusting relationship, efficient and effective transfer of important information can be achieved, with critical process parameters shared between both parties rapidly. In a public health emergency, this approach can minimise delays, ensuring patients receive critical vaccines in shorter timeframes. With new mRNA products entering the development pipeline, it will be increasingly important to build this trust and transparency between the parties involved in manufacturing.

Looking ahead

The COVID-19 pandemic highlighted three key areas that manufacturers must carefully consider when working with a relatively new technology: fill-finish capabilities, cold chain capabilities, and building a familiarisation with the product. The need for CDMOs that can proactively anticipate these needs and continue to offer flexibility will remain essential. This support will be further necessary for areas set to see rising expansion in the future, including the cell and gene therapy space. 

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