December 1, 2008 (Vol. 28, No. 21)

Companies Need to Safeguard Their Resources by Setting Up Efficient Storage Systems

Biotech and pharmaceutical companies are not yet fully comfortable thinking of biological samples as assets. However, new biomarker discovery initiatives as well as large-scale genome projects and disease consortia have encouraged the biobank movement, forcing the rapidly changing industry to think hard about what it will be doing with its samples in five, ten, twenty, or one hundred years. So now it’s time to really answer the questions of where and how to store the samples.

Researchers from around the globe recently convened in Philadelphia to share information about emerging biobanking practices. Having a consensus on the importance of maintaining such banks, “Biorepositories 2008” attendees engaged in a lively discussion about sample collection and storage on a practical level.

It was made clear that storing dubiously labeled samples in dubiously maintained -20º or -70ºC freezers may not be the most effective storage choice. These days, researchers looking for biobanking solutions have a number of sophisticated systems and solutions to choose from. It’s an exciting time to be setting up a biorepository, because the time scales are literally as large as your imagination. Samples collected and stored today may lead to scientific discoveries generations later.

There are many ways to establish a biorepository. One angle of attack is for companies to set up their own, on-site sample-storage systems. This is happening at companies that already have millions of samples, as well as companies that are just getting started and may only have a single freezer.

Eric Koenig, senior manager of molecular technologies at Millennium: The Takeda Oncology Company, explained that Millennium set up its sample-management system (SMS) five years ago, prompted by exciting developments in technology that it knew it would want to exploit later for sample analysis. The company collaborated with Labvantage to set up an integrated SMS for every sample tested within Millennium. This new system replaced a network of sample-storage systems that had evolved over a ten-year period and provided the company with state-of-the-art storage for samples and a system for tracking the sample’s location and chain of custody.

IT solutions are absolutely crucial for any SMS, said Koenig. It would be absolutely disastrous if a key sample could literally not be found within a repository of millions. IT tools including bar-code systems and robotic sample handling help to minimize errors in record keeping, as well as minimize human handling that could compromise the sample integrity.

“The whole point of this is to integrate traceability for all of your samples. If they are well-tracked and annotated, they are usable and reusable resources,” Koenig explained.

A sample that is lost in storage (either because it is corrupted or because it literally can’t be found) is a tangible loss to the company. This is why some companies are choosing to outsource their sample storage. Samples can be stored at the company site or off site. Most researchers, however, prefer to keep their samples close.

Sample integrity and traceability are an integral aspect of a biorepository structure.

Validation Systems Vital

Biostorage Technologies will set up a freezer-based storage system at the client site, and then monitor it for them. Freezers are a common fixture in industry and academic laboratories, but for most researchers freezer storage is an out-of-sight, out-of-mind situation. They don’t think about the validation process required for long-term storage of their precious samples.

“One of the first things that companies should discuss is implementing protocols and standard operating procedures to ensure validated systems are in place,” pointed out Jennifer Benner, manager of quality systems for Biostorage. “This includes shipping containers, storage units, and monitoring systems. The FDA requires that companies maintain documented evidence that provides a high degree of assurance that a specific process is going to give you the same results. This means that the freezer is the correct temperature within certain tolerable limits, and that every location inside the freezer is the correct temperature within tolerable limits.”

Biostorage Technologies provides temperature-monitoring devices that ensure that the temperature has been maintained in a container through its entire chain of custody, from laboratory to a dry ice container for shipping, to its final resting place (the biorepository).

Many of Biostorage Technologies’ clients are working in FDA-regulated environments, but regulatory oversight is something that smaller research laboratories aren’t always accustomed to thinking about. “I think the industry is about to turn the corner and realize that the FDA and other regulatory environments are a lot more interested in storage than they used to be,” added Benner.

Liquid Nitrogen Cooling

Steve Deal, associate director for U.S. commercial operations for The Automation Partnership (TAP), talked about how TAP is addressing one of the major challenges in using robotic sample-handling devices in a sample-storage system. The company’s solution to the problem that mechanisms do not function at -80ºC is a box-within-a-box system that allows the bots to operate at -20ºC, while minimizing sample exposure to higher temperatures. The system also minimizes operator exposure to lower temperatures, according to Deal.

“When someone opens the door of an upright freezer commonly seen in hospital and pharma laboratories, the first thing that happens is the -80ºC temperature falls out into the warmer area, and samples are exposed to warmer temperatures that have a potentially negative impact on the samples,” said Deal. “With sample integrity in mind, TAP developed a patented drawer-access system that utilizes individually sealed drawers rather than a single large-door design. Thus, only a single drawer needs to be open at any time in order to pick or place samples.”

TAP’s flagship system is based on liquid nitrogen cooling, not mechanical cooling. This has a number of advantages. One is that it’s possible to achieve a true -80ºC temperature. Mechanical cooling systems generally either fall short or are working hard to get that cold. Another advantage is that energy usage is actually lower, which reduces cost and is a more environmentally friendly solution.

Mechanical refrigeration is still available from TAP, if that suits the customer’s needs better, but the liquid nitrogen system represents its most cutting-edge technology, and from a long-term perspective is less likely to become outdated.

A completely different take on biostorage comes from GenVault. David Wellis, Ph.D., president and CEO, gave a presentation on his company’s storage technologies.

For many years, the state of the art for biobanking has been cryostorage. But considerations of cost, energy usage, and standardization led GenVault to think outside the box and tackle dry room-temperature storage.

Dry room-temperature storage of samples is a practice dating back to the discovery of DNA itself. Rosalind Franklin and Maurice Wilkins, codiscoverers of the structure of DNA, used dry room-temperature handling techniques, which improved the resolution of their images the more the humidity was reduced.

DNA is surprisingly stable when stored this way, and, according to Dr. Wellis, GenVault has updated the method for the twenty-first century for a simple and energy-efficient small- to large-scale biobanking strategy. It also has a new chemical matrix, Gentegra, launched in September of 2008, to stabilize purified DNA and, soon, RNA molecules for room temperature storage.

GenVault’s technology has attracted interest from institutions such as the CDC and the Health Ministry of Canada. In the latter case, in a comparison of GenVault’s dry-storage technology with traditional cold storage and dry-ice shipment, it was found that the dry method was better at preserving the blood-borne antigens of interest, Dr. Wellis explained.

GenVault also includes a molecular bar code, Gencode, to augment a conventional bar code based sample-management system. Gencode is a series of unique oligonucleotides that travels with the sample, and can be checked independently of other sample ID information. Human error is a major source of error and information loss in sample management, largely unacknowledged by science but critical for law enforcement and diagnostic applications.

“We cannot yet replace all types of freezer-based sample storage,” said Dr. Wellis. But, for those types of samples that work well at room temperature—they can happily coexist, enhance, and back-up traditional freezers for a mixed-phase biobank.”

The establishment of a biorepository is a bet that there will be better uses for your samples in the future, and better ways to extract that information. There are already many examples of the value of biobanking, such as the discovery of Gleevec through the exploitation of Novartis’ biorepository. In addition, many of the technologies for analysis of samples are advancing at an incredibly rapid rate. Whereas in the past, sequencing of a large number of samples was inconceivable, now next-generation sequencing technologies are bringing that dream closer to reality.

For many researchers, freezer storage is an out-of-sight, out-of-mind situation, as is clearly the case at this unidentified research institution.

Single-Molecule Sequencing

Patrice Milos, Ph.D., vp and CSO of Helicos BioSciences, spoke about future technologies that will unlock the potential in biorepositories.

Helicos has a single-molecule sequencing technology that does not require amplification or other handling methods that introduce bias. Technologies such as these bring to the realm of possibility studies that in the recent past would have been wildly ambitious, Dr. Milos added.

In one example provided by Dr. Milos to demonstrate the importance of sequence information, it was possible to zero in on a novel gene variant of cytochrome P450 2D6 in a drug metabolism study by going back to the original DNA sample and sequencing it. An individual had a drug response that could not be accounted for using known variables, and because the company had an archive and access to new sequencing technology, it was possible to characterize this previously unknown genotype.

“Biorepositories provide a critical component in addressing the challenges of discovering and developing new medicines,” Dr. Milos concluded.

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