Evolving Methods of Bulk Freezing
Unlocking potential with single-use bags: From outdated CryoVessels to state-of-the-art plate freezers The freezing method with multi-use cryogenic containers, also called cryovessels, has been used for decades. The open stainless-steel container is still largely in use but will be replaced bit by bit by new technologies. Why? Because the risk of contamination is much higher with cryovessels. It is barely scalable. It is not possible to control the freezing process. And the total cost of ownership is high. New technologies improve process efficiency and product quality. Examples are plate-based freezing and thawing platforms for single-use bags as primary packaging (see infographic) or controlled blast freezers for bottles. These are innovative solutions that are paving the way for the evolution of bulk drug substance freezing. What level of ROI do you think could be achieved compared to cryovessels? Evolution of bulk freezing with single-use bags How it began: CryoVessels and their scope of application The use of cryovessels in biopharmaceutical manufacturing revolutionized the freezing process of bulk drug substances. 30 to 40 years ago. The method has a long history, with advances in cryopreservation technology and vessel design contributing to improved freezing protocols. However, the use of cryovessels for freezing bulk drug substance also comes with some drawbacks. These include the need for specialized equipment, the potential for cryovessel-related challenges during scale-up, and the need for careful handling and storage conditions. Manufacturers are limited to the temperatures down to max. -50°C and must accept long freezing times of up to days until the biopharmaceutical liquids are frozen entirely in the bulky shape of the cryovessel.[[1]] Cryovessels - learn more Switch to single-use: Blast Freezing to be established The open architecture of cryogenic steel containers has intensified the need for closed systems. Single-use technologies appeared to be the freezing method that would further reduce the risk of contamination and make the freezing process more sterile, safer and, as now proven, more sustainable.[[2]] Bulk products are now filled into single-use primary packaging in which it is frozen. This type of primary packaging includes single-use bags, bottles and other custom single-use containers. After filling into single-use bioprocess containers, they have been placed into static or blast freezing devices. Blast freezing is a commonly employed technique in the biopharmaceutical manufacturing of large volumes to achieve faster and more uniform freezing of biomaterials than with cryovessels. This method involves subjecting the samples to high-velocity cold air. However, particularly static freezers have their limitations. Since they’re originally designed to hold ultra-low temperature with air circulation, freezing in static freezers can lead to cryoconcentration, where solutes accumulate in unfrozen regions, potentially impacting product stability and quality. The same applies to uncontrolled blast freezers. Only temperature-controlled blast freezers perform precise control over the freezing process that overcome the challenges in maintaining consistent freezing conditions in different scales. For good reason controlled blast freezing is still widely applied when freezing drug substances in bulk packaging, such as bottles or bulk-packaged 2D containers. [[download-1-email-detailed]] Plate-based freezing with single-use bags: Advanced freezing for large volumes Freezing with plate-based platforms offers the advantage of direct surface contact with the single-use bag by using stainless-steel lids and their superb heat transfer properties as the only separators. While cooling energy is dispersed through air in blast and static freezers, the energy in plate-freezers transfers directly to the liquid. Direct surface contact facilitates the temperature-control inside the single-use bag and regulates the last point of freeze within the recommended scope of controlled cooling rate. The single-use bag is carried in the protective RoSS® shell. The secondary packaging around the bioprocess container enables state-of-the-art plate-based freezing with direct contact between the bag and the cooling medium. Advantages of plate-based freezing Compared to traditional and older methods of freezing biopharmaceuticals in single-use bags, plate-based bulk freezers, such as RoSS.pFTU XL, enables: Scalable freezing performance from 10mL to 50L single-use bags Control of freezing at a cooling time of less than 10 hours to -80°C of all sizes of 2D single-use bags Closed system to safeguard sterility throughout aliquoting, freezing, storing, shipping, etc. Full automation in compliance with cGMP and 21 CFR Part 11 Customized freezing rates ensuring highest product quality after cold chain management Less manual intervention, less documentation/validation, shorter process cycles Plate freezing: learn more Table 1: Comparison of drug substance freezing with cryovessels or plate-based freeze thaw platforms, when filled into 2D single-use bags and protected in the RoSS® shell. CryoVessel Platform Plate-Based Freeze Thaw Platform RoSS.PFTU XL Comments Fast Freezing × ✅ The RoSS.pFTU XL achieves controlled freezing to -80°C in less than 10 hours. Low Footprint × ✅ Optimized for a maximum volume on the lowest footprint needed Vendor-agnostic primary packaging ⁓ ✅ Full freedom on choice of your primary packaging supplier to ensure a closed system. Modularity & Scalability × ✅ Scalable freezing with the RoSS.pFTU plate-freezers from 1L up 500L nominal volume per batch Minimum Manual Handling ⁓ ✅ Fully automated freezing process & simple loading/unloading of the palette-size racked Product Viability × ✅ Higher product quality with controlled plate-freezing preventing the effect of cryoconcentration. Entering new realms of freezing large volumes In step with the biotech industry, supporting process solutions are also evolving. Novel therapies require an advanced manufacturing process. The requirements for each product are constantly changing, whether in the commercial production of monoclonal antibodies (mAbs) or antibody-drug conjugates (ADCs), or preparation and processing fluids, such as buffer solutions. These sometimes complex needs can now be answered on a product-specific basis. The freeze-thaw industry has evolved from rigid processes through rigid stainless-steel vessels. Plate-based freezing with single-use bags, but also improved blast freezing with bottles allows manufacturers to adjust the freezing rate, processing volumes and endpoint temperature to meet their needs. Previously unthinkable. Cryovessels are still in use mostly because of their history. Even though the majority of biomanufacturers still have them in day-to-day operation, the technology is outdated and not efficient. The future of freezing and thawing large volumes in single-use bags belongs to plate-based freezing in biomanufacturing. ROI of controlled bulk freezers vs. CryoVessels The benefits of controlled freezing extend beyond just process performance. When the total cost of ownership (TCO) is considered, including cleaning, validation, labor requirements, consumables, equipment replacement, and product loss risk, freezing with single-use technologies can offer a significant economic advantage over traditional cryovessel-based approaches despite their capital expenditure (CAPEX). In one manufacturing case study, Single Use Support's controlled plate freezing platform RoSS.pFTU reached the break-even point shortly after one year. Thanks to its reduced operational expenditures (OPEX), the platform generated savings of more than 2 million EUR after two years of operation. Download the case study to see the complete ROI calculation and key cost drivers. [[download-2-email-detailed]] Bulk freezing & storage as one end-to-end process Bulk freezing is evolving beyond faster rates and tighter process control: As batch volumes grow, manufacturers face the challenge of managing frozen drug substances efficiently across the entire cold chain. In many facilities, freezing and ultra‑cold storage are still treated as separate steps, leading to fragmented workflows, increased handling, and unnecessary transfers. A more efficient approach is to connect freezing and storage into one continuous process. By aligning capacities, entire batches can remain intact throughout freezing, storage, and downstream logistics. This reduces manual handling, simplifies batch management, and supports more consistent cold chain operations.For facilities handling larger volumes or diverse formats, integrating freeze‑to‑store workflows improves scalability without expanding footprint. Ultimately, the next step in bulk freezing is optimizing the entire batch lifecycle – not just the freezing step. More about freeze & ULT storage processes References Large-Scale Freezing of Biologics: A Practitioner’s Review, Part 2: Practical Advice, https://, Published 2009 Streamlined life cycle assessment of single use technologies in biopharmaceutical manufacture, https://pubmed.ncbi.nlm.nih.gov/35007778/, Published 2022
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