October 30, 2019
With bulk drug substances playing an increasingly important role in the pharmaceutical and biopharmaceutical industry, the need for a reliable freeze/thaw process as well as safe shipping and storage is more important than ever.
Storage and shipping of large-scale protein solutions are important steps on the way from an active agent to the final end product. If those steps are carried out at a temperature above the solution’s freezing point, this can lead to detrimental shear stress as well as microbial contamination. As a consequence, freezing those agents and shipping them in a frozen state can prevent these issues. In order to do that, many factors have to be considered, such as the precise handling of the supply chain and the cold chain.
At Single Use Support, we have set ourselves the goal to provide the biopharmaceutical industry with solutions that support them in increasing the reliability of storage and shipping and in turn minimizing the loss of valuable high-quality drug substance. To do that, we developed a freeze thaw platform that enables bulk freezing of drug substance and thawing of drug substance, including lab freezer and pharmaceutical freezer.
Freeze logistics in the pharma industry is concerned with the save storage and shipping of drug substances and drug products by putting controlled freeze-thaw systems in place. It aims to ensure safety and product quality.
It is common to freeze drug substances in the development or production of pharmaceuticals, especially proteins, which are extremely delicate when it comes to temperatures. Freezing in general is a key element of the processing of pharmaceuticals and in drug substance logistics because it helps maintain the quality and stability of the drug substances as well as the product.
Depending on the substances and the wanted outcome, it can be chosen between slow freezing and fast freezing (this can be done by putting samples in subzero solvents). Furthermore, freezing is known to be a crucial factor in maximizing productivity and minimizing production costs, because bulk solution manufacturing and storage efforts are separated from the final product manufacture. Additionally, low temperatures are providing longer shelf life, especially of bioproducts in solution-based formulations. Freeze-thaw processes also positively influences the stability of proteins throughout the whole supply chain.
However, the freezing of liquid solutions is a complex process that poses its own challenges and products can suffer under the effects of freezing. Freezing rates that are too slow may lead to Cryoconcentration. This means that excipients and proteins form concentration gradients near of the freeze front, which consequently excludes them from the ice-liquid interface. PH shifts and phase separation are possible, which would result in structural damage of the protein. In other cases – depending on the protein solution to be frozen – the process may result in the formation of aggregates (protein-aggregation) followed by denaturation.
Obviously, these cases are less than ideal, as they will invariably lead to the loss of valuable and potentially life-saving drug substance. Clearly, this dilemma calls for action, and that is where Single Use Support comes in. With our expertise and products, we know how to prevent any damages and negative outcomes.
In summary, freezing can lead to a maximum of protein stability throughout the whole supply chain. But, as discussed, the freeze-thaw process is complex. In order to achieve high-standard and safety, the right equipment has to be chosen, a number of assays have to be conducted and guidelines and regulations (by the FDA and ICH) have to be followed.1 2
Freeze-thaw study protocols contain a characterization of the chosen study, including the study design, methodology, organization of the assay and validation of analytical procedures and are critical for process development. Freeze-thaw studies are supposed to help meet the criteria for quality attributes. Furthermore, they are popular approaches to study the impact of freezing and thawing rates, in order to define process conditions and the evaluation of long-term effects of freeze-thaw processes.
The first step of those assays is to create a study design, which contains selecting a representative formulation and a small-scale container-closure, as well as the definition of freeze-thaw cycles which are needed for large-scale manufacturing. Many aspects can be taken into consideration, such as how other protein formulations or protein concentrations would act or the effects of thawing frozen samples in ambient temperature (active fast thaw protocol) in opposite to room temperature thawing. Additionally, it can be differentiated between high concentration and low concentration stability.
Stability studies or stress tests are applied, which assess how protein attributes change under different circumstances. One example is to test how long-term storage conditions change the stability. Another one is to evaluate extreme temperature changes. Some studies are small-scale studies. Those are done on the foundation of the most representative freeze-thaw conditions. The stability of the product then depends on container-closure and selected formulation.
This way the very delicate protein stability can be tested as well as the effect of freezing and researchers can see if any significant changes have happened to the tested substance or product. An additional test can be done to assess storage components in order to prevent extractables or leachables to come up.
The freeze-thaw process runs through cycles in which it represents a mild homogenization procedure. It is mostly used at the same time as other homogenization methods.
Although, for some solutions more than one cycle has to be done, some are very sensitive to these procedures and can only handle a single cycle. Again, this can be assessed in stress or stability studies. In these assays, products are put through various freeze-thaw cycles. Before a big batch of expensive drug products are being frozen, it is common to first freeze small-scale batches to test the outcome.
In order to achieve the highest quality and safety, not only testing is important, but also the right equipment. We have developed a freeze-thaw platform that is better than any other freezing technologies.
For our research, we performed a series of tests in which we tested the influence of various parameters on the extent of Cryoconcentration and compiled extensive data from literature. This has led to the conclusion that plate freezers – in combination with single use bags – are a predestined solution for the freezing process of protein solutions.
With this seemingly simply combination of two components – plate freezer and single use bags – the protein solution is separated from the cold surface by only a thin polyethylene layer, which ensures an optimal heat transfer from the heat transfer plates to the substance to be frozen.
Furthermore, this method offers a better heat transfer coefficient than bottles that are frozen by using cold air in blast or static freezers. But that is not the only advantage: Plate freezers also cover relatively short freezing distances as opposed to plastic bottles or Cryo vessels made of stainless steel, thus allowing for a fast freeze front velocity and better control of the temperature.
With all these factors in mind and after extensive research and trial-and-errors, we have developed a plate freezer that enables the bulk freezing and thawing of large quantities of solution.
The freezer can handle volumes of up to 300 L that are contained in 50 L single use bags and covers the entire process in less than 2 minutes.
The bags are encased in our RoSS® shells that are constructed of a plastic frame with the base and lid made of stainless steel. This combination of materials not only offers added protection but also facilitates optimal heat transfer rates during the thawing process.
We have designed our plate freezer so it allows for a scalable process, both in terms of last point of freeze and based on protein activity. With our technology we are pushing the freeze thaw technology to the next level. We offer players in the biopharmaceutical industry an advanced and reliable solution for their logistics process – a scalable platform for the a quick and reliable freeze/thaw process of bulk drug substances.
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