Freeze-drying for IVDs

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Freeze-drying for IVDs
Originally Published IVD Technology June 2004
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Advances in automation have imparted greater control over the lyophilization process.
For reagents that are degraded by water, lyophilization confers greater stability and a longer shelf life. However, the demands of the modern IVD market have presented many challenges to the conventional way in which lyophilization is utilized. Physical characteristics like miniaturization of IVD instrumentation and the ever-shortening product life cycle of IVDs have put an unsurpassed strain on development scientists using lyophilization to stabilize their reagents. Nonetheless, manufacturers have more control over the lyophilization process now than ever before.
To investigate the application of lyophilization in the process of manufacturing IVDs, IVD Technology editor Richard Park spoke with Edward Trappler, president of Lyophilization Technology (Ivyland, PA). In this interview, Trappler discusses the challenges to the lyophilization process posed by advances in the technology of IVDs. He also discusses advances in the lyophilization process and forecasts the future role of lyophilization in IVD manufacturing.
IVD Technology: What have been the biggest advances in the lyophilization process for IVDs during the past few years?
Ed Trappler: Over the past 9 years or so, there has been an increased understanding of the critical aspects of product design and process engineering for lyophilized products. Those aspects include optimizing reagent formulations; designing container closure systems used to hold lyophilized products; and effectively processing lyophilized material with the highest degree of reproducibility, robustness of process, and consistency of finished product.
The article you wrote for IVD Technology in 1995 dealt with reproducibility, consistency, and robustness of product. How have advances in lyophilization addressed those issues?
Those issues have been addressed through the constituents used in a formulation. For example, certain components of a formulation may be needed to stabilize the product or to impart various attributes to the finished product. In addition, the design of a container or closure can have an impact on the long-term stability of a product. Some of the advances in packaging, particularly for field instrumentation, have been fostered by bioterrorism concerns and the need for environmental monitoring.
In terms of processing, we have learned how critical the freezing step is. This step influences how the product behaves during processing as well as how the product would be constituted prior to use. We have recognized that we need to be successful in primary drying to ensure the long-term stability of the product. In addition, we have realized that secondary drying, where we remove the last bit of residual moisture, can be impacted by the success gained in primary drying. In secondary drying, the age-old question of how low in residual moisture is low enough to achieve long-term stability still remains. So the awareness of the relationship between product design and process engineering has increased. In addition, we have made progress in achieving more reproducibility and robustness of the processes.
Evolution of Lyophilization
What have been the latest trends in lyophilization over the past several years?
There have been two principal trends. One has been our understanding to a much greater extent the importance of each of the process steps, from beginning to end. As a result, each of these steps has been refined, starting with first loading the product into the lyophilizer.
The processing conditions for each step are optimized, from the beginning of loading the material until the last bit of product is filled into its containers, which are sealed and then unloaded from the lyophilizer. So a greater understanding of the impact of each of those steps of the process on the long-term stability of the product has been a trend.
The second trend, which has been furthered by technological developments in the IVD industry, is in miniaturization. Historically, a product would have been contained in a traditional container/ closure system?a vial and a stopper, for example. However, recently, we have had to learn to carry out the lyophilization process in unconventional packaging systems. Now we are lyophilizing reagents for IVDs that are in cartridges and ready to be inserted into an automated instrument. That too has presented additional challenges to many IVD manufacturers.
What advances in lyophilization technologies have contributed to controlling the lyophilization processes?
Previously, control of the lyophilizer was entirely manual. It was based on following a standard operating procedure and manually engaging parts of the equipment like the refrigeration units. Under some circumstances, not having control of the chamber pressure was recognized as a critical process parameter.
Process automation, in terms of automated control, is now commonly used to control the equipment. Automated control instrumentation has decreased variation to but a few degrees in shelf temperature and a few micrometers of mercury in chamber pressure.
Challenges
Please describe, in detail, some of the challenges posed by trends in lyophilized products?
Those challenges include learning how to incorporate and accommodate the packaging within not only the freeze-drying process but also the manufacturing process from beginning to end. For example, when product was filled as a liquid into a vial, then a stopper would be inserted on the vial and the vial placed into the freeze-dryer. The product would be stoppered in the lyophilizer.
Now, with miniaturization, new techniques are used for freezing. These techniques involve freezing the product separately in a different container from the one it will end up in. It may even be frozen and freeze-dried in a bulk tray. Then, the product is placed in a lyophilizer. After the lyophilization process, the product is removed from its first container and packaged separately. In addition, maintaining the low residual moisture that is necessary for long-term stability subsequent to the lyophilization process is part of the packaging operation.
Historically, freezing was given little attention?it was considered a part of the process that you need to get through in order to freeze-dry. Now, there is a much greater awareness of the impact of the freezing step. In addition, we have learned that even before the freezing step, the thermal history of the product (e.g., the temperature at which the product is loaded into the freezer dryer, the temperature of the shelves in the freezer dryer, etc.) is important. The freezing impacts the subsequent steps of the process, as well as the behavior and attributes of the finished product. We have gained a greater awareness of the process for conventional container closure systems. Some of the new challenges include working with products that we have not freeze-dried in a specific form, such as Amersham Bioscience?s (Buckinghamshire, UK) microbeads that contain reagents. In addition, because of the advances made in the miniaturization of instrumentation, we still need to learn different approaches to processing such materials.
What challenges do IVD manufactures encounter when lyophilizing their reagents and other products?
The greatest challenge to batch uniformity continues to be the age-old obstacle of nucleation. Nucleation is the formation of the first ice crystal, which sets the subsequent growth pattern and crystallization of the product. Nucleation is a random event yet it has an impact on subsequent processing steps as well as finished product attributes. In either a specific container closure or within a microbead where the freezing technique may be very different, nucleation is still an uncontrolled force in the process, based solely on probability.
How do manufacturers overcome these challenges?
In terms of reproducibility and uniformity of products within a batch, those problems can only be overcome, and are better controlled today than ever before, by rigorousness in process engineering and controlling the processing conditions used for lyophilization. Today we are more cognizant of controlling the shelf temperature, chamber pressure, and time for each step of the process.
Has the emergence of biodefense diagnostics introduced for the lyophilization process?
The development of biodefense technology and expansion of the need for this technology have converged at an opportune time. The demand for miniaturized devices and technology that can be taken into the field has created the necessity of advancing the design of reagents as well.
What are the most pressing issues concerning the lyophilization process for IVDs?
The most pressing issues are validation and meeting regulatory requirements. With ever-increasing regulatory requirements?even if a company has a high degree of confidence in and a great amount of success with a product?if the company has a limited amount of scientific rationale for the processing steps, it may not meet regulatory requirements. So, in many instances, a process may work well and may be sufficiently reproducible, but the growing pressure for more-extensive validation of that process may prevent the product from being marketable.
Will the cost of energy ever be a serious factor in the use of the lyophilization process?
The impact of energy cost on unit cost for IVDs is minuscule. What has a greater impact is dependability of access to electricity. We have seen in the last few years circumstances such as the brownouts in California and the failure of the grid in the Northeast that have had a much greater impact on cost than specific cents per kilowatt hour.
Have exact and definitive regulatory requirements been outlined for the lyophilization process for IVDs?
A great amount