Integrated Freezing Solutions to Minimize Risk and Preserve Product Quality
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Hosted by: Brandy Sargent
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.
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, biocontainer bags protected in shells can be stacked, thereby increasing cold storage density and decreasing the cost of storage.
Plate Freezing and Scale-Up
We then discussed scale-up in plate freezing. Claire said that plate freezing in biocontainer bags can easily be scaled up and that consistent temperature kinetics have been demonstrated during freezing in small volumes of 50 mL biocontainer bags up to larger 10 and20L biocontainer bags. The average number of hours to last point of freeze is almost identical across all volumes and the temperature curves for freezing and thawing are similar irrespective of volume. In contrast, the average number of hours to last point of freeze with conventional blast freezing technology increases as the volume increases.
Integration and Automation of Freeze Thaw
I then asked her to describe how modern freeze thaw methods could be integrated into existing processes and what benefits could be gained from this type of integration. She described how a – technology gap has been identified between downstream and fill finish integrations. The challenge of companies employing products from multiple sources creates numerous threats and disadvantages including a lack of robustness, limited number of platform qualifications, no comprehensive validation packages, and a lack of scalability or reassurance of supply. The best way to streamline the process and enable an integrated solution is to select a supplier that offers a one stop solution for biocontainer bags and protective shells, filling units, freeze-thaw units, and a validated transportation solution. This provides a solution that integrates seamlessly with downstream and fill finish processes. It also provides the added benefit of minimizing extractables and leachables through utilization of the same biocontainer film and maintaining a closed system throughout.
I then asked her how a company should get started if they want to employ plate freezing in their operations. Claire recommended starting small and scaling up. This can easily be done using plate based freezing. One could use a lab scale plate freezer to establish optimal freeze-thaw conditions with low volumes and then the same kinetics can then be transferred to large plate freezers without the need to revalidate the freeze thaw process. Recipe driven automation allows the user to create a program and select specific freeze-thaw conditions as required, then run the preset program time and time again.
To Learn More
I closed the interview by asking Claire how companies could learn more about new freezing technologies and employing these methods. She recommended that they visit the biotech section of the Pall website https://www.pall.com/en/biotech.html or contact their local Pall representative to discuss requirements further.
Learn more about how your freezing choices affect your drug substance – download Pall’s whitepaper