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Industry progress improves freeze drying/lyophilization: technological advancements lead to higher quality products.

As the freeze drying/lyophilization process has progressed over the past few years, the industry has encountered advancements in technology has can improve the process. Whether it is exploring alternatives to glass vials or utilizing the latest control systems ensuring quality and reducing waste, the freeze drying/lyophilization process offers users technological advancements to produce quality products.

Processors can see advancement in the use of isolators and barrier equipment. With the ever increasing regulatory requirements, processors are encountering the use of isolators or barrier equipment to reduce contamination. "LSNE performs a risk assessment and acquires a toxicology review of all incoming compounds so we can be sure that we are using the proper level of containment to minimize personnel exposure and cross-contamination," says Christine Palus, vice president of sales and marketing for Lyophilization Services of New England.

Additional safe handling efforts are required as the need for smaller and more sophisticated freeze dryers continues to grow. "As technology progresses, drug potency increases and the amount of product in the vial is reduced," says T.N. Thompson, president of Millrock Technology, Inc. "Smaller vials are being used and the value of the product is increasing ... The higher potency drugs also drive the need for safer handling and the need for isolators and sterilization."


In order to optimize lyophilization cycles while minimizing risks, DSM Pharmaceuticals, Inc. looked toward freeze dryers with oversized condenser capacity and liquid nitrogen cooling where isolators and barriers minimize risks from operator intervention or contamination.


While traditional glass vials have remained a mainstay in the lyophilization process, some people in the industry note the potential use for other materials. Utilizing other materials would offer several benefits. Lars Waldmann, process development manager at Pharmalucence, Inc., recognizes that one benefit to a glass vial alternative is the possibility to reduce the number of broken vials. However, he also notes the concern about the age and viscosity of plastics.

According to Jeremy Griffin, with Grand River Aseptic Manufacturing, glass vial alternatives include container systems manufactured from plastic or with a special coating. "The technology looks pretty promising, but it is still waiting to be scrutinized by regulatory agencies," he says.

Palus has seen some movement away from traditional glass vials, specifically towards the Crystal Zenith resin vials. "They are a good alternative since their dimensions are similar to the standard glass vials, and they can be filled on our automated vial filling line," she says. "Since the vials are made out of break-resistant materials it can help reduce the risk of vial breakage during shipping."


Another option available for vials is a system incorporating the stopper in the caps. "Typically, the stoppers and caps come separately," says Joe Redford, formulation and preparation team lead at Grand River Aseptic Manufacturing. "However, systems are coming out with the stopper in the cap. So, during the lyophilization process the capping takes place at the same time--eliminating risk."


Griffin notes that this system saves in production time because the material does not have to be processed twice. However, one drawback is that it requires custom equipment.

While non-glass vials limit breakage, processors may encounter a few drawbacks to using the product. "The biggest drawback to using a non-glass vial is that additional material capability studies are required and there is a risk of extractables and leachables," Palus says. "Additionally, because the vials arrive pre-sterilized, there are some different handling procedures."


The industry has seen several new control systems emerge over the past few years resulting in a significant impact on processing. These control systems ensure that the safest and most effective product is delivered to the market. One area processors have seen improvement is in controlled nucleation.

"The freezing process has always been considered the foundation of the freeze drying process, yet it has never been properly controlled," Thompson says. "Simply placing vials on a shelf and lowering the shelf temperature leads to heterogeneous nucleation and non-uniform crystal growth."

Millrock Technologies has improved nucleation with its FreezeBooster, a controlled nucleation that nucleates all the vials at the same time, temperature and rate to produce a consistent point for freeze control across the entire batch. It also has AccuFlux, a heat flow control for controlled crystal growth.

Providing the highest yield for customers has led DSM to develop new systems. "We have developed new systems and process flows designed to detect and eliminate quality issues to prevent impact on the product," says Wayne Edgerton, director of manufacturing and packaging production at DSM Pharmaceuticals, Inc. "We use automation when applicable to control and monitor our process to help maintain the highest quality standards."

Patheon has encountered process analytical technologies that have been developed mainly for lyopilotunits where the development of lyophilization parameters is preformed. It includes in-process monitoring, NIR/FTIR, micro-gravimetric, thermocouples, lyophilizer headspace monitoring pressure rise testing/MTM, and pirani vs. chamber pressure.


Another area where controls have seen advancements is in the push to streamline lyophilization cycles exposing the product to lyophilization for specific times. "Basically they are exposed only for the time they need to be rather than the old mentality of it needs to this much time to freeze and add an hour," Griffin says. "The cycles that are run with products will be very specific, and there won't be slack in that. This technology will allow users to reduce waste and increase quality."

Wireless technology for temperature mapping is another control system Griffin has encountered and hopes to see accepted for production within the next few years.


As the demand for freeze drying/lyophilization continues to grow, the future of the service will result in possible technological changes to adjust and meet the industry standards. From creating systems that conserve energy to improving temperature distribution, processors will find the freeze drying/lyophilization process improved in various areas.

Waldmann predicts the next five years will lead to a greater focus on energy and utility conserving systems in the market. "Currently, control systems follow the architecture of PLC system for actuation of the mechanical components of the lyophilizer or loading systems, which connects to a PC or HMI," he says. "With microcontrollers becoming more powerful and capable to drive HMIs we may see an elimination of the PC and instead control the whole system by a microcontroller."

Representatives from Patheon, Inc. also believe that new process technologies for fast, continuous freeze-drying will move forward in the next five years. They believe the rationale is behind the need for economic drying processes for large scale production, mass production of MABs and the need for bulk storage as an alternative to frozen solution.

The addition of fully automated loading systems in isolator or RABS is another possible option in the future of freeze drying. "Cycle optimization will be a key component to our success to open up additional capacity in the freeze dryers," Edgerton says. "As technology improves with thermal transfer and cooling capabilities the newer freeze dryers should be able to handle more aggressive cycles that will help with improving cycle times."



Waldmann also expects to see more manufacturers of lyophilizers to offer loading systems for barrier applications. "Right now there are still a significant number of manufacturers that do not offer automated loading systems for lyonhilizers." he says.

Thompson foresees the next five years resulting in process control and PAT as the major considerations for freeze dryers. "Today, the freeze drying process is an open loop control with very little monitoring in-situ," he says. "Processing companies may not know there is a faulty run until the freeze drying run is completed. New technologies will enable complete control of the freeze drying process including: Controlled Nucleation, Controlled Crystal Growth during freezing, Product Temperature Control instead of shelf temperature control, the ability to determine the end of freezing and the end of primary drying, and the ability to verify that the process has executed properly."

With changes made to freeze dry technologies, Griffin notes that there is always room for improvement with temperature distribution within shelves. "Temperature distribution within shelves is a constant design consideration when they are building lyophilizers that is huge for product quality," he says. "If shelf stability and uniformity with lyophilizers can be nailed down that would be huge for the product."

Thompson also notes that FreezeBooster controlled nucleation and AccuFlux heat flow control will become the preferred method of control for the freeze drying process. "With the ability to measure and control the heat flow, the product can be properly and consistently frozen," he says. "The shelf temperature can be optimized during primary drying to shorten the cycle while maintaining product quality."

While the demand for lyophilization continues to grow, Palus anticipates a continued shortage of lyophilization capacity at CMOs. "Due to the increased demand for lyophilization against a backdrop of some capacity being removed from the market due to regulatory considerations, we anticipate that there will most likely continue to be a shortage of lyophilization capacity at CMOs," she says. "Lyophilization is a complicated science and not every company with a lyophyilizer can successfully develop or execute the process so we believe we will see certain companies emerge as lyophilization experts."

* By Kimberley Schmitt, Associate Editor
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Author:Schmitt, Kimberley
Publication:Pharmaceutical Processing
Date:Jul 1, 2013
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