Freezing drug substance – taking control over large volume pharmaceutical freezing
In the manufacturing process of drug substances and during their long term storage, freezing is a necessary step to preserve product quality. However, various process parameters in freezing and thawing methods considerably influence the critical quality attributes (CQA) of biologics. It is decisive how drug substances are cooled, for example at what freezing rate and whether the freezing performance can be precisely controlled. Additionally, the choice of drug substance container affects the freezing outcome. Beyond product quality, cost and time reduction in process chains must also be taken into account for employing an efficient drug substance management.
Freezing bulk drug substances – why take the effort?
Freezing drug substances or active pharmaceutical ingredients is necessary to maintain product quality and enable safe transport for CDMOs, pharma manufacturers or biotech companies without risking product integrity. There are legal regulations that must be taken into account to guarantee the safe handling of bulk drug substances.
Freezing allows for storage of large volumes of biopharmaceuticals until demand arises. At the same time, cryopreservation reduces the risk of structural changes and mechanical damage to protein or cells during transportation. When freeze thaw logistics is outsourced to CDMOs – due to cost reduction and more streamlined processes – such production steps become essential.
Main considerations along the freezing process of large volume drug substances
In order to maintain identity, purity, potency of biologics, several aspects have to be considered in process development. This includes the impact of freeze and thaw rates. The speed at which freezing is performed can have a big impact on a drug substance’s efficacy. Fast freezing rates have resulted in lower levels of cryoconcentration and higher protein stability in protein formulations. Furthermore, the goal of an efficient freeze and thaw technology is to prevent alterations in the drug substance through the minimization of protein aggregation.[[1]] [[2]]
Facing challenges with conventional freezers
Bulk drug substances are typically frozen by using either static or blast freezers. However, plate freezers, are a relatively new approach to freeze drug substances in 2D single-use bags. Controlled-rate blast freezers are equally efficient freezers that are mostly used for bulk-packaged single-use containers, such as single-use bottles.
Compared to the conductive (plate freezer) and convective (blast freezer) technologies, static freezers show comparatively slow and inflexible freezing rates. The heat transfer to the drug substance is ineffective which causes a slow freezing rate. Additionally, it can lead to a low external area compared to volume, which can cause damage in complex proteins and alter protein stability. Protein denaturation can potentially impact product quality attributes: Overall, slower freezing leads to greater cryoconcentration which results in higher zones of protein and excipient concentrations in the center bottom area.
Read more: Cold storage requirements of APIs
Slow uncontrolled freezing vs. fast controlled freezing
With controlled-rate freeze and thaw platform concepts, it is possible to maintain the homogeneity of a drug product, facilitating optimal freezing results for drug substances. Especially for products in larger primary packaging, such as bottles, like vaccines, monoclonal antibodies (mAbs) and viral vectors, homogeneity is of utter importance.
What bioprocess containers to choose
When choosing bioprocess containers for frozen storage, stainless steel vessels or bottles have long been the traditional choice. Whereas, bottles provide better structural integrity, they can limit scalability and require specialized handling equipment. Bulky primary packaging tend to take up too much space in storage, their freeze and thaw process is harder to control and they can lead to process inflexibility. However, bottles are here to stay, and there are options to control the freezing of drug substances in bottles as well.
Read more: Freezing bottles – 5 critical considerations – Single Use Support
In comparison, with its geometry single-use bags can minimize cryoconcentration by fast freezing and thawing of all scales, up to large volumes of pharmaceuticals. Furthermore, single-use bags take up less space and come already fully assembled and sterilized, meaning they are ready to use. Secondary packaging, such as the RoSS shell can provide 2D single-use bags with protection to reduce product loss through breakages.
The choice of primary packaging used during freezing often determines the subsequent cold chain management technologies employed. This is because not all cold chain management solutions are compatible with all types of primary packaging.
Minimizing risks – maximizing resource and cost efficiency
The process of drug product manufacturing as well as the cold chain of biopharmaceuticals can be prone to product loss due to contamination and human or mechanical error. While product integrity and staff safety is one of the main challenges for the biopharmaceutical industry, minimizing costs is an important goal for companies to stay economically competitive – especially during the transition from scale-down models to large-scale production. Single Use Support provides a combined solution to all these challenges through automated filling, freezing, thawing and filtration processes.
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Freezing bulk drug substances with single-use technologies
Handling sensitive drug substances like active pharmaceutical ingredients is an everyday task in biopharma and biotechnology. Single Use Support has developed end-to-end solutions for automated aseptic fluid management as well as solutions for a controlled cold chain management of drug substances at sub-zero temperatures. While these systems are compatible with other types and sizes of single-use systems, additional products have been developed to provide a streamlined process from start to finish.
The RoSS Shell, for instance, is designed to ensure robustness and protection of frozen drug substances in 2D single-use bioprocess containers. Its design helps minimize the risk of product loss. Single Use Support’s aseptic filling systems are aligned with EU GMP Annex 1 to provide a closed system for safe and precise fluid transfers.
Part of the character of Single Use Support’s product portfolio is scalability. The modular setup of each filling platform and freeze-thaw platform allows the products to be scaled to industrial large-scale batches – such as large-scale freezing – as well as for small-scale demands.
Ultimately, an end-to-end process that is compatible with every step of cold chain management – from filling and freezing to storage and thawing – ensures a smooth transition, while also facilitating compliance with relevant quality control standards, such as EU GMP Annex 1.
Sustainable Freezing of drug substances
Sustainability has become a defining metric for today’s biopharmaceutical manufacturers. All freezers manufactured by Single Use Support operate using natural refrigerants, minimizing environmental impact through low refrigerant charge volumes, while maintaining full compliance with safety standards and operational reliability.
Another promising approach is the use of cold compressed air as a cooling medium in freezing technologies, achieving a global warming potential of zero. This feature of eco-friendly cold chain management will soon be available in Single Use Support’s freezers.
Read more: Sustainable Freezing in Biopharma: An Exploration of Natural Gas Usage
References
- Freeze–thaw characterization process to minimize aggregation and enable drug product manufacturing of protein based therapeutics, http://dx.doi.org/10.1038/s41598-021-90772-9, Published 2021-05-31
- Large-Scale Freezing of Biologics: Understanding Protein and Solute Concentration Changes in a Cryovessel—Part I, https://www.biopharminternational.com/view/large-scale-freezing-biologics-understanding-protein-and-solute-concentration-changes-cryovessel-par, Published 2010
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