In this podcast, I talked with Claire Jarmey-Swan, Global Product Manager, Pall Corporation about the evolution of freeze-thaw technologies and how these new methods can streamline the process, minimize loss and maintain the highest product quality.
Show Notes
We began the interview by discussing how freeze thaw is becoming an increasingly important topic as companies look for ways to improve current methods. I asked Claire what is driving companies to look for these improvements. She explained that currently around 60% of drugs and vaccines include a freeze-thaw process. In addition, by 2024 there is expected to be more than 400 new drugs and vaccines that require cold storage. With biotech companies outsourcing around 81% of their fill finish requirements, this has created a need for shipping bulk drug substance either by road or air, thus robust storage and transport is critical. This kind of robust solution requires an industrialized end-to-end storage and shipping solution.

One key consideration that she identified was the impact of extractables and leachables. She pointed out that maintaining the same biocontainer bag film throughout the entire bioprocess workflow in upstream, downstream, bulk drug substance filling and freezing, and even during formulation and filling reduces risk in this area. She emphasized that the ability to utilize pre-qualified biocontainer bags protected by robust shells throughout the process train is optimal. Robust shells protect biocontainer bags and reduce the risk of loss.

Another important consideration is fast and controlled freezing and thawing to maximize homogeneity of the drug substance. In addition, transport shippers need to ensure sub zero temperatures can be maintained for multiple days and meet ISTA or ASTM shipping standards.
Current Methods for Freeze Thaw
Next, I asked Claire if she could describe current methods for freeze-thaw. She told me how bottles have been used historically to store, freeze, and ship drug substance. However, the use of single-use biocontainer bags protected by shells is rapidly growing because the system permits flexibility and a closed system that enables fill, freeze, thaw, and drain to take place in controlled not classified (CNC) or even warehouse environments. This is more challenging with bottles, as they often need to be filled using laminar flow because a closed system cannot be maintained.

For freeze-thaw technologies, blast freezing is the oldest technology used in the industry and there is now a move to plate-based freezing and thawing, which offers fast and controlled freezing.

I followed up by asking Claire if she could talk about the challenges of blast freezing in bottles. She explained, that in blast freezing warm air rises and cold air descends, the standard convection practice. In this method, the airflow is not well controlled, which results in low surface heat transfer. The airflow in uncontrolled environments leads to unpredictable and deviating freezing kinetics. This can happen even within the same run and up to 56% of protein viability can be lost.

Blast freezing also takes 2-5 times longer than controlled plate freezing which takes 5-8 hours. The slow freezing that occurs in blast freezers results in cryoconcentration and a lack of drug substance homogeneity. Proteins, vaccines, and excipients form concentration gradients near the freeze front and get excluded from the ice liquid interface. This can lead to pH shifts and phase separation among the components, resulting, for example, in protein structure damage. Controlled fast freezing results in smaller ice crystal formation and scale up offers the same thermal parameters.

Space is also a consideration, Claire pointed out that the amount of cold storage space required for frozen bottles is large and costly. In contrast,