The need for cold storage is growing, as is the choice of available storage equipment. Alex Esmon, Thermo Fisher Scientific, reviews specific design features that can be crucial for efficient storage at each stage of drug development and production
Benchtop ultra-low temperature freezer for clinical trial samples
Whatever the stage – development, manufacturing or delivery – pharmaceutical and biotech companies need cold storage equipment that is reliable, consistent, stable and accurate. Just as a safe deposit box protects personal valuables that are difficult or impossible to replace, the right cold storage equipment helps ensure that samples, reagents, cells, enzymes, drugs and biologics are stable, safe and secure.
A typical chemistry research lab stores thousands of chemical reagents for months or years, depending on the frequency of usage. To prevent decomposition and maintain the original concentration, some reagents require refrigeration. Often reagents near (or in) solution form are flammable. Flammable liquids that need refrigeration must be stored in specialised refrigerators or freezers designed to prevent ignition of flammable vapours.
Flammable materials refrigerators and freezers have all electrical components outside the refrigerator so the interior is spark-free. Helpful design features include thresholds, self-closing doors, magnetic door gaskets and special inner shell materials that control or limit the damage in case a reaction occurs within the storage compartment.
Explosion-proof refrigerators and freezers are used in areas where flammable vapours might develop, such as solvent storage or dispensing rooms. Explosion-proof refrigerators are designed so that no operating components are exposed to outside flammable vapours. Explosion-proof models require special hazardous-location wiring according to local wiring codes.
Small molecule drug discovery programmes rely on chemical synthesis of new molecules. Such processes are technically challenging, require expensive reagents, and take significant time for completion. These factors mean it is critical to preserve the new molecule’s composition. To ensure stability over several months, the molecules are typically stored in lab refrigerators (+4°C) or freezers (–20°C/–30°C).
In addition, pharma companies own proprietary libraries containing scores of chemical compounds or biologics, which are used in high throughput screening campaigns. The integrity and composition of the library samples must be preserved over several years.
Cold storage is vital in biological research labs for storing materials such as enzymes, cell lines, cell media, DNA stocks, micro-organisms, and tissues safely in their viable form; refrigeration needs vary depending on the application. To attain reliable and reproducible data, the integrity of the chemical samples and biological materials must be ensured. To save precious time and cost, having reliable cold storage on hand is critical.
It is important to monitor refrigeration units closely to ensure samples do not get damaged by temperature fluctuations
It is important to monitor refrigeration units closely to ensure samples do not get damaged by temperature fluctuations. Sometimes, when freezers are not managed carefully, frost can build up around the doors. This can reduce the effectiveness of the seal, leading to increased energy consumption and warming of precious samples. Auto defrost cycles are particularly susceptible to temperature fluctuations and as such, a manual defrost freezer may be more appropriate for the application.
High-performance freezers, such as Thermo Scientific Revco laboratory freezers, are designed to provide defrost programmes that monitor temperature differences across the evaporator, run defrost cycles only when necessary, and create minimal temperature increases in storage compartments. This design may also reduce energy consumption.1
Among ultra-low temperature freezers (–40°C and below), –80°C freezers are the most widely used, and reliability and security of the storage unit are paramount. They are used for storing particularly sensitive proteins, other biological samples cell lines, and for long-term storage of yeast or bacterial stock.
A upright ultra-low temperature freezer
Samples stored in –80°C freezers are highly sensitive and are hard to replace from a time and cost perspective. Because of the sensitivity of the samples, compartmentalisation is a key feature in –80°C freezers. Thermo Scientific offers large ultra-low temperature freezers that offer a variety of interior compartments. Other helpful features in ultra-low temperature freezers are built-in temperature and event data storage. These features are particularly important for regulatory compliance.
Traditionally, –80°C freezers needed 220V power supply. These freezers were large, noisy and heavy due to bulky insulation and generated heat, and caused circuit breakdowns at voltage peak points. Newer versions are available that use regular 110V power, which helps circumvent these issues. Cryopreservation systems are used for long-term preservation of mammalian cell lines, bone marrow, cord blood, organs and tissues. Cell lines are a valuable resource and their replacement is costly and time-consuming. When a small surplus of cells becomes available they are frozen in a cryoprotective agent and preserved for long-term storage.
Certain sample types require the use of special freezing (and thawing) techniques to ensure the best possible viability – in these cases, controlled rate freezers, such as Thermo Scientific’s CryoMed series, can provide the control needed to allow for the nuances of samples such as hESC, PBMC, sperm or oocytes.
Benchtop –80°C freezers are popular for use in clinical trials due to user convenience and portability. They are often used to store specimens from clinical trials, including cells, serum, urine, cerebral spinal fluids, and biopsy of tissues. These units can also be used to store specimens short term, for 1–2 days.
These freezers feature easy maintenance and configurability of temperature settings and accessories to best fit the applications, processes or experiments that are being performed. When space is tight, internal racking/compartment systems simplify the organisation of the samples inside.
Temperature sensors and alarms can be connected to a central network that can send out alerts, e-mails, or text messages to relevant personnel
Built-in or wireless temperature sensors and alarms are essential to protect clinical samples and are most useful if they are connected to a central network that can send out alerts, e-mails, or text messages to relevant personnel. Wireless systems, such as the Thermo Scientific Smart-Vue wireless monitoring solution, can monitor critical laboratory equipment parameters and send out instant notification of power or mechanical issues 24 hours a day. There are wireless monitors for parameters such as temperature, relative humidity, CO2 concentration and differential pressure. Smart-Vue is compatible and scalable with multiple brands and equipment, so that new equipment can be easily added. Notification options include audio and visual alarms, e-mail, text messages, telephone and fax alerts. All data is continuously logged to assist with regulatory compliance.
Cryopreservation systems are sometimes used in clinical research for storing items such as cell lines. Cell lines used for specific applications are very specialised and proprietary and may be highly valuable financial and intellectual assets. Thermo Scientific CryoPlus cryopreservation systems have keyed locks for added security and safety as well as a tri-colour liquid level monitor so that the level of liquid nitrogen in the system can easily be seen at all times without opening the cabinet. To aid in sample tracking, some facilities use tubes that are laser-etched with unique 2D barcodes that can be read by barcode readers.
Creating an unbroken temperature-controlled supply chain from manufacturing to drug delivery and application is essential for temperature-sensitive products. Whether being manufactured for a small, specific population or for millions of people, companies must adhere to Current Good Manufacturing Practices. These practices, which include proper storage, are enforced by the US Food and Drug Administration.
The pathway from manufacturer to end user often involves many parties and different modes of transportation. Yet it must maintain the integrity of the product in its packaging during storage and distribution and all parties bear responsibility for ensuring they handle the drug products in a way that does not affect the product identity, strength, quality, purity or safety.2
During manufacturing, it is important to store media within appropriate temperature parameters. High-performance refrigerators are designed to meet the needs of the cell culture process by providing the proper environment during standard use (i.e. door opening events). It is also important to be able to store and protect sensitive, flammable materials, solvents and intermediaries.
Some laboratories use temperature-controlled cold rooms for large-scale storage but these airtight rooms can be a safety hazard, can grow mould and may offer no redundancy in case of failure. Refrigerators address most of these disadvantages.
The shift toward more products being sold directly to consumers has increased the need for temperature-controlled packaging
During packaging, the shift toward more products being sold directly to consumers has increased the need for temperature-controlled packaging. Today’s options range from insulated packaging, dry ice or wet ice (crushed ice or refrigerant packs that contain water mixtures with specific freezing points), to high-performance shippers with controlled compression lids, vacuum-insulated panels, and +5°C phase-change material that provides consistent temperature control.
It is also important to monitor temperatures throughout delivery, especially during long journeys. In most cases, the product leaves the manufacturer’s chain of control when it enters distribution. Thus, manufacturers may attach temperature-monitoring devices to ensure that the desired temperature is maintained.
From early research through to drug distribution, cold storage plays a critical role in protecting valuable materials, samples and products. The time and financial investment made to bring a drug to market are substantial and should be protected by reliable, stable, and accurate cold storage systems.
1. Gordon Shields and Jeff Schneider, Thermo Fisher, 7 April, 2009, www.labmanager.com/?articles.view/articleNo/3325/title/Greening-Cold-Storage/
2. Desmond G. Hunt, US Pharmacopeial Convention, Date unknown, www.pharmacopeia.cn/v29240/usp29nf24s0_c1079.html