Robust by Design – How to Build a Reliable Freezing Container
Downstream Processing
Jan 10, 2023
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5 min read
A robust freezing container is the first line of defense against deviations in the cold chain. In this blog post, we discuss how a philosophy of 'robust by design' enabled us to develop our next generation of Celsius® containers.
Freezing and thawing of bulk drug substances (BDS) are common operations in modern biopharmaceutical processes. In addition to the specificities of the freeze-thaw process, these operations must also consider the handling, shipping, and storage of frozen goods.
Despite their pervasiveness across biologics manufacturing, freeze-thaw processes are not immune to challenges, especially as new technologies and modalities continue to emerge and manufacturing networks become increasingly global. These advances require changes to how cryopreservation processes are performed and how the biopharmaceutical cold chain is managed.
Freezing containers are the foundations of a reliable cold chain. When selecting the freezing container, assurance of robustness is essential. Loss of product due to lapses in the cold chain (which could include temperature fluctuations, loss of container integrity, and | or leakage) account for a significant loss of BDS. This creates a significant financial burden, compromises patient safety, and interrupts drug supply chains.
The Dangers of an Unstable Cryochain
Loss of product integrity creates efficacy and safety concerns.
Drug products are increasingly versatile, with newer modalities often particularly sensitive to temperature fluctuations.
Losses of an estimated $35 billion per year due to temperature control failures in the pharmaceutical industry [1]
The World Health Organization estimates that up to 50% of vaccines are wasted every year [2]. Scaling up, this could translate to a loss of 1 billion COVID-19 vaccine doses [3]
Sartorius engineers have been working to re-imagine the next generation of Celsius® freezing containers by implementing quality-by-design (QbD) principles to ensure our containers are robust throughout their entire lifecycle. QbD relies on a solid understanding of materials, processes, and products and harnesses routine monitoring and control to ensure quality is built into the manufacturing process.
Our developmental approach for our Celsius®cryopreservation containers follows three pillars of robustness-by-design.
Three Pillars of Robustness-by-Design in Freeze-Thaw Containers
Material Properties Comprehensive characterization of candidate materials is essential to ensuring robust container design. Freezing containers must withstand temperatures as low as - 80°C. Therefore, material properties have been evaluated at low temperatures early in development to ensure the best resources are selected to build robust containers.
This allowed us to finalize the material selection for the new container design based on their robustness despite low temperatures, tensions, and impacts.
Design Simulation Once material properties have been evaluated, design simulations can help adapt the container design to ensure the minimum level of stress to the most sensitive areas.
These simulation studies informed the "cassette" design of the Celsius® FFT | FFTp bags, which consists of a semi-rigid bag composed of two polyester plates and a bag assembly protected by a surrounding shell, which offers security and more uniform freeze and thaw.
Material characterization and design simulations allowed our engineers to identify the components and areas requiring further protection and the best materials to offer that protection. As a result, they were able to adapt the container design according to the simulation runs without lengthy real-life design iteration cycles. The overall protection packaging was improved to immobilize these components and reduce potential stresses.
To confirm what was observed during design simulations relevant application testing must be performed to ensure the design meets real-life requirements.
Application Testing
Demonstrating robustness requires a deep understanding of standard, variant, and worst-case product life cycles. This informs a rigorous testing protocol, which should include subjecting the container to shocks, vibrations, and the temperature ranges it is likely to encounter during its lifecycle (Figure 1).
Figure 1 - Proving robustness requires deep application knowledge and understanding of the product life cycle under real conditions of use. Hitting the product with a hammer, for example, is not representative of the risk it may encounter during a process. However, dropping the product when placing it in storage is a possibility.
The final lifecycle study included filling, liquid handling, freezing, frozen handling, shipping, unpacking, frozen handling after shipping, thawing, liquid handling after thawing, and draining (Figure 2). Leak tests and inspections are used to test product integrity and ultimately confirm robustness.
Figure 2 –Lifecycle testing should cover all aspects of a freeze and thaw process
Routine Monitoring and Control
Continuous monitoring of process performance and product quality ensures that QbD principles are maintained and that mandatory compliances are met.
In-process controls are essential for the production of freezing containers because they directly interact with precious drug products. As a result, the containers must possess a very high integrity assurance level, supplementing their intrinsic robustness guaranteed by their design and extensive qualification according to their lifecycle.
Building a Reliable Tailor-Made Solution for Frozen Storage and Handling
Material expertise, insights from design simulations, and real-life application testing guided our development of the next generation of Celsius® freeze and thaw solutions. This approach ensured they were purpose-built to ensure reliability across the lifecycle of the freezing container, supporting a robust cryochain.
2. WHO. (2005). Monitoring Vaccine Wastage at Country Level. Immunization, Vaccines and Biologicals, 1–63. Retrieved from https://apps.who.int/iris/bitstream/handle/10665/68463/WHO_VB_03.18.Rev.1_eng.pdf?sequence=1&isAllowed=y
3. United Nations Environment Programme. (2020). Why optimized cold-chains could save a billion COVID vaccines. United Nations Environment Programme, 2020–2021. Retrieved from https://www.unep.org/news-and-stories/story/why-optimized-cold-chains-could-save-billion-covid-vaccines
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