Reliable cold chain management for biopharma

Freezing bottles – 5 critical considerations

Freezing drug substances to ultra-cold temperatures is a standard step in biopharmaceutical manufacturing. Yet, beyond simply cooling, it’s the critical quality attributes (CQA), like product safety, consistency, and process efficiency, that truly define success in biopharma. When preparing to freeze drug substances in sterile bottles, it’s essential to weigh several key factors. These considerations help ensure the freezing process not only preserves product integrity but also supports reliable and productive operations. 1. Secure product quality with controlled freezing Controlled and uniform freezing is essential to avoid cryoconcentration – a phenomenon where solutes concentrate unevenly due to ice formation from the outside in. This can lead to protein denaturation and pH shifts, which ultimately impact drug stability and efficacy. Studies show that the “volcano effect” in bottles, where solutes are pushed to the center and top, can cause significant concentration gradients. Manufacturers can minimize these risks by controlling the freezing rate and temperature profile throughout the freezing process including the solidification phase. Product integrity stems from a controlled freezing which can be adapted depending on the specifications of the drug substance, such as cell-based or mAbs. What we learnt about controlled bottle freezing   Figure 1: Visualization of the volcano effect in bottles occurring in uncontrolled freezing, compared to consistent distribution in controlled freezing.    2. Protect bottles to ensure container closure integrity When drug substances or other raw materials, such as buffer or media, are frozen in bottles, the single-use containers must maintain their integrity. Even though they’re called rigid containers, there are vulnerable spots, particularly when the single-use container and assemblies become more brittle under sub-zero conditions.  To prevent leakage or contamination, bottle integrity can remain secure when the assemblies are protected during cold chain handling. Bottle RoSS is the equivalent of the RoSS® shell, which is the protective shell for single-use bags. With Bottle RoSS the tubing on bottles is protected at glass-like sub-zero temperatures with the help of a soft 3D foam which hardens at frozen state. More about Bottle RoSS 3. Static or blast freezing? In general, the choice between static and blast freezing for cooling drug substances in bottles depends on the container format and the sensitivity of the drug substances. Static freezers are meant for storing drug substances at low temperatures, not for freezing them. Using them to freeze bottles can lead to issues like cryoconcentration and product degradation. Even if the freezing time is similar to other methods for small bottles, the lack of control during the critical phase transition still negatively impacts product quality. In contrast, blast freezers with high-speed air convection technology are more effective at rapidly and uniformly freezing drug substances. This technology is particularly effective for biologics stored in bulky containers, such as bottles, as it minimizes thermal gradients and preserves product quality. 4. Role of bottle types and sizes Not all bottles are created equal. Manufacturers can choose among bottles with different types, geometry and size of the bottle, which may impact on freezing efficiency and uniformity. HDPE and PETG bottles have different features affecting the following fluid and cold chain management processes. Same with the sizes that can range up to 20L bottles. Overall, rigid bottles allow for optimal airflow in blast freezers, supporting consistent freezing profiles. Larger containers may require customized airflow systems to ensure uniform temperature distribution.   5. Think end-to-end for closed system efficiency Look left and right before freezing bottles. An efficient and safe freezing process requires an aseptic closed system, beginning with the aseptic filling and filtration stages. This continues through cold chain storage and shipping with a controlled thawing process. Integrating closed systems minimizes contamination risks, streamlines workflows, and ensures that drug substances remain protected at every stage. This end-to-end strategy meets GMP-relevant quality standards, including Annex 1, and operational efficiency, making it the gold standard for working with bottles in biopharma.  Interview: Trends with Single-Use Bottles in Bioprocessing – Single Use Support Mastering filling & freezing of bottles with Single Use Support Uncontrolled bottle freezing processes often struggle to scale, leading to inefficiencies and risks for critical drug substances. With RoSS.BLST, Single Use Support addresses these pain points by enabling seamless transitions from clinical to commercial production – without compromise. Single Use Support’s end-to-end fluid management and cold chain solutions deliver scalable, aseptically closed processes for advanced fluid and cold chain management of bottles, ensuring product safety and regulatory compliance at every step. As the only provider offering fully integrated handling, filling and cooling critical liquids in bottles, Single Use Support empowers biopharma manufacturers to streamline fluid and cold chain management with bottles with compatibility, safety and efficiency. [[download-1-email-detailed]]