Cold-Chain Considerations for Manufacturing today’s Advanced Biologics Cold Chain Integrity and Capabilities

Cold-Chain Considerations for Manufacturing today’s Advanced Biologics

Cold Chain Integrity and Capabilities

The ways CDMOs exhibited flexibility and agility to overcome the challenges of mRNA vaccine production. Examining the lessons learned, he provides his perspective on the strategies taken to deliver a better program and highlights the importance of remembering key lessons as we move forward.

Lee Seungheon

Product Logicstics Specialist, Samsung Biologics

The biopharmaceutical industry’s reliance on the technical experience and manufacturing capacity of contract pharma continues to grow as demand for all biologic drugs surges around the world.

Manufacturing advanced biologics compliantly requires mastery of aseptic containment, as well as temperature-controlled cold-chain systems for product integrity and quality. Most biologic modalities require temperature-controlled environments and packaging solutions to preserve product integrity and assure safety quality and efficacy. It also requires operational excellence and an understanding of every aspect of commercial biologic drug substance and product manufacturing to it.

The COVID-19 pandemic highlighted the challenges of ultra-low temperature storage and distribution as messenger RNA (mRNA) technologies required exacting cold-chain temperature controls at every step and highlighted the challenges of ultra-low temperature storage and

distribution. Other biologic modalities including autologous and allogeneic cell and gene therapies (CGTs) are also coming into the scene. These therapeutics involve several steps to accomplish and require exacting cold-chain control throughout production and distribution.

Monoclonal antibodies need a reliable cold-chain

Monoclonal antibodies (mAbs) are synthetically derived molecules that are used to mimic the body’s own natural antibodies. In 2021, the global mAbs market was valued at $185 billion in 2021 and is projected to exhibit a compound annual growth rate (CAGR) of 11.30% from 2022 to 2030. Rising investment to treat chronic diseases such as cancer and cardiovascular disease is increasing the demand for all biologics, but especially mAbs. Similarly, increased application of targeted mAb therapies and rising awareness among patients and physicians is expected to significantly contribute to the market’s tremendous projected growth.1

Used to treat many immune-compromising conditions, mAbs antibodies are relatively fragile and if not stored properly, they can become irreversibly damaged. Most of the industry agrees that temperatures above 65°C will likely result in damage. Most antibodies however should retain functional activity if kept refrigerated at 2 to 8°C for up to 12 months.2

Emerging mRNA technology demands cold-chain integrity

mRNA vaccines are one of the rare commercial drug products that must be stored and shipped frozen within a precise temperature range. From a cold-chain perspective, having to maintain such extremely low temperatures while storing and shipping the finished drug product has challenged the contract development and manufacturing organization (CDMO) industry to a significant degree.

Seasonal vaccines, such as those that use adenoviral vectors, for example, are typically stored and shipped at 2°C - 8°C (35.6°F - 46.4°F). mRNA vaccines, on the other hand, are far more challenging, needing sub-zero storage and shipping, potentially down to -80°C (-112°F) or even lower. Some emerging biologics are expected to require temperatures as low as -180°C (-292°F).3

The crux of cold-chain custody

The crux of cold-chain supply management is to maintain desired product quality through strict temperature controls from warehousing to final shipment. In the case of ultra-low temperature storage and transhipment, it can be technically and operationally quite daunting to flawlessly deal with every storage and logistical requirement these products' temperature requirements demand.

Maintaining a consistent temperature in storage or processing can be particularly challenging. Temperatures have to be precisely controlled for long periods and generally can be vulnerable to even the slightest incursion of ambient air.

Furthermore, more rigorous controls are required when mass-producing commercial vaccines. In this case, finding experienced and well-equipped contract partners wellversed in cold-chain supply management will be critical to the success of any biotech trying to deliver their mRNA-based vaccine or therapeutic safely and successfully to patients.

Among industry peers, Samsung Biologics played a notable role in the global, collective effort to end the pandemic. By outsourcing messenger RNA (mRNA) vaccine production to prominent CDMOs, Pfizer/BioNTech, Moderna, AstraZeneca, J&J, Novavax, and others were able to manufacture and distribute more than 14 billion doses to the world in less than a year.4 Several advanced CDMOs were already well-versed in sophisticated lipid formulation techniques, a key element of mRNA vaccine delivery. This is the kind of expertise CDMOs had at the ready and it is likely that without this experience built-in, the industry’s swift and effective response would not be the reality it became.

Flexibility and experienced operations deliver cold-chains that work

Depending on the incoming drug product, various temperature conditions for storage and shipment are required as each product type needs to be inspected in a different environment. Cold-chain facilities must be capable of meeting each molecule’s unique storage and shipping temperature requirements. For best cold-chain outcomes, flexible cold-chain systems adaptable to fickle environments are required to provide a relevant and competitive offering. This can range from precisely controlling storage temperatures end-to-end to state-of-the-art blast and control-rate freezers that can precisely and rapidly freeze the various types of biologic therapeutics being developed by pharma.

When contracted to manufacture mRNA COVID-19 vaccines for Moderna, one of the first orders of business for our operational teams was to thoroughly evaluate and inspect cold-chain capabilities to make sure Samsung Biologics’ control-rate and blast-rate freezing systems and ultra-low temperature storage facilities were prepared and operating as validated.

Facilities for storing and transferring intermediate products during production as well as facilities for freezing completed biomedicines are a must-have. It is also important to calculate the appropriate facility size considering the production cadence of biomedicines, capacity of refrigeration facilities, and efficient shipping procedures for mass-produced biomedicines.

It is imperative to keep the temperature at an appropriate level between storage and shipment while consistently checking and collecting instant temperature data through statistical analysis and Mean Kinetic Temperature (MKT) calculation. The goal is to maintain a temperature in The crux of cold-chain every section within a required range. supply management is to Any change in shipment temperature is maintain desired product converted into data during shipment, and quality through strict real-time monitoring and data archiving are utilized to record temperature temperature controls changes during storage. Temperaturefrom warehousing to final related technology has greatly influenced shipment the validation work for the cold chain. Technologies that affect the MKT and air circulation inside the equipment and inside shipping containers are utilized during the validation process.

Maintaining critical parameters is especially challenging

Keeping the temperature within a certain range from storage to shipment is crucial. However it’s especially challenging to keep the product at the right temperature while shipping. Just because it left the facility’s control in a frozen condition, shipments are vulnerable to temperature excursions at any time. That’s why it’s vital to minimize the number of entry-and-exit events as well as any external exposure in transhipment.

Shipping container technology has a pivotal job

As biologics need to be stored and then shipped within a limited time to ensure their stability, container technology has also evolved. Shipping cold-chain integrity depends on this aspect of product logistics and distribution to an important degree. Samsung Biologics has acquired enough lightweight, compact shipping containers from its partner to help maintain seamless, cost-efficient cold-chain management. Overcoming the challenges of the COVID-19 pandemic required the global distribution of vaccines. Every dose was transhipped via this key enabling technology, and the industry continues to refine the cold-chain logistics contemporary biologics require to ensure patient access to these extremely beneficial therapeutics.

Most products required to be stored at a refrigerated temperature are shipped by RKN-type packaging solution via air. Essentially portable refrigerators, RKN units are a solution optimized for air shipment designed to fit into aircraft holds, monitor conditions, and precisely maintain temperature. Products required to be stored at a freezing temperature often need individual packaging solutions.

As storing and shipping biologics needs to be completed within a constrained timeline, keeping a seamless cold-chain system operating cost efficiently can challenge even the most adept organizations. Express international shipment via air freight, which usually occurs within less than a week, is growing more expensive due to rising fuel and labour costs confronting air shippers.

Labelling: Challenging the cold chain further

From a cold-chain perspective certain regulatory requirements offer specific challenges to manufacturers. For example, it is particularly technically challenging to conduct labelling in low-temperature environments on frozen primary packaging. Often requiring long manual processes, it can cause both manual processes and product temperatures to rise. It can be operationally daunting to reattach a label at a low-temperature setting once it has been detached. It is also difficult to visually identify the right product among other unlabelled ones, which can cause a quality deviation. Labelling under cold-chain custody is truly problematic to accomplish and requires systems and process expertise to accomplish successfully. Product serialization is another aspect of cold-chain operations adding complexity to the mix. As IDs are added through multiple serializations, operators are mandated to check the batch, quantity, and storage location of the product, often through the organization’s enterprise resource planning (ERP) system. This too adds time complexity and the potential for deviations.

AUTHOR BIO

Lee Seung-Heon is a product logistics specialist in charge of validating storage and shipment of frozen biologics at Samsung Biologics. Lee holds a bachelor degree in aerospace mechanical engineering at Korea Aerospace University.

All things considered for the cold-chain biologics need now

Delivering comprehensive cold-chain integrity for biologics in development and being marketed commercially is challenging but certainly well within the capabilities of most of today’s biologics-focused CDMOs. What will always distinguish one from another is how well the organization pays attention to the details technically and organizationally. Leveraging risk-based, compliant, controlled environments, freezing processes, and standard operating procedures will continue to enable the industry to deliver the desired market and patient outcomes it seeks for its advanced biologic drug products.