Here are two questions that illustrate our changing times in the pharmaceutical industry.
The first question is: “What is the most common cold chain storage temperature in use in the pharmaceutical industry?”
- refrigerated storage (+2°C to +8°C)
- -135°C to -149°C
- -150°C and colder
The second question is “What is the fastest-growing cold chain storage temperature in use by the industry?”
- refrigerated storage (+2°C to +8°C)
- -135°C to -150°C
- -150°C and colder
The answer is that currently, the most common storage is ultra low temperature storage, but the fastest-growing is cryogenic, in vapor phase liquid nitrogen. This transition is huge.
Pharmaceutical products were—until recently—a chemical in a pill or bottle and were taken with a drink of water, from a teaspoon, or injected by needle. The majority of these finished agents were chemically stable compounds that could be kept at room temperature for years. The drug substance, the intermediate stages in the development and manufacture of these products, typically required refrigeration within a tight temperature range of +2°C to +8°C and usually had a short shelf life. Maintaining this tight temperature range is a challenge, but the nature of this drug product resulted in only short-term storage and the need for storage capacity was relatively modest.
Today, we are focused on developing advanced therapies that are derived from human cells, and either retaining or changing some specific living, complex molecular attributes. These materials are also very sensitive to temperature change and are most often frozen at -70°C to -90°C (and increasingly in LN2). Additional differences: these materials are often aliquoted prior to being frozen, may be in storage for a much longer period of time, and are of far higher value—in some cases, irreplaceable.
The volume of materials in ultra cold storage has already overtaken refrigeration, and this has created unexpected challenges for those Companies and Researchers coming from a small molecule background. There is a big difference between managing drug substance under refrigeration and managing drug substance at ultra low temperatures (between -70°C and -90°C) or in LN2, and the difference goes well beyond temperature. Additional factors have to be accounted for, depending on the nature of the material and its end use, and this is the source of the challenges. Often a key question is around cold chain distribution: how does one ship material ultra cold or cryogenic, and ensure that the material arrives at the same temperature it is stored at? Chain of temperature data and chain of custody in handling is imperative to the Pharmaceutical industry of today. These additional factors partly explain the much higher cost of these therapies as well. The three primary issues are: capacity, regulatory, and risk. We’ll look briefly at all three.
Capacity: Storing materials for a longer period creates need for additional space; storing drug substance at ultra low temperatures has a multiplying effect on that need for extra space. For instance, ultra low freezers necessitate a larger footprint for the escape of heat from the compressors. Additional freezers also require additional temperature monitoring probes and preventive maintenance activity. This equipment also creates a need for additional HVAC capacity to keep compressors from overheating, and the facility as a whole will need additional power supply and back-up generators. LN2 tanks also have a larger footprint per unit of material stored. LN2 storage does not require the same level of additional HVAC capacity, but these tanks must have a bulk supply of available LN2 for continuous refill to maintain correct operating temperature. Bottom line: biologically derived therapies require a substantial capital investment, and this is only for storage.
Regulatory: Biologics are heavily regulated, which is to be expected as most are injected directly into a patient upon thawing. Bio-pharmaceutical company Quality Assurance Departments are understandably focused on the regulations applicable to the development and manufacture of the therapies, not on storage and distribution issues. However, the transition to biologically based therapies and the associated regulations for storage and logistics have place QA departments in the position of needing to rely on regulatory agencies (FDA) to provide quality assessments of service providers, including such critical issues as chain of custody and chain of temperature data. Bio-pharma companies are struggling to catch up with the increasingly demanding regulations concerning storage and cold chain logistics of advanced therapies.
Risk: Bio-pharmaceutical companies know they must manage risk, but they may not know what managing risk actually entails. For instance, many know to split inventory between two different facilities, but may not consider that the two facilities must be on two different power grids. In addition, a risk mitigation plan is only as good as the threat assessment on which it is based.
With high value biologics, the cost of a mistake could be catastrophic. Losing a lot of small molecule drug substance is undeniably expensive, but the cost of losing a batch of advanced therapies could put a company out of business. If the therapy is autologous, it could cost a patient’s life. As you can see, there is a large difference between small molecule therapies (managing drug substance at refrigerated temperatures), and biological, or large molecule therapies (managed at ultra low or cryogenically frozen temperatures).
The cost of storing material at ultra cold temperatures (-80°C) is one of the most significant operational expenditures of a biorepository and affects the long-term sustainability of biobanks. Although mechanical ultra low freezers have become more energy-efficient and offer greater storage capacity for a given footprint, these units still represent a high energy cost.
Download this eBook to learn more about Biobanking and the importance of risk mitigation.