Increased testing is one of the best strategies to mitigate the growing number of COVID-19 cases in the U.S., but to date laboratories have faced shortages. Labs are deploying automated, high-throughput sample preparation instruments and techniques to increase testing throughput, but some are experiencing supply chain disruptions at this stage in the workflow, as well.
The Food and Drug Administration Emergency Use Authorizations specify what sample preparation steps can be used for a particular commercial molecular diagnostic or lab-developed test.
An analysis of the 133 authorized SARS-CoV-2 molecular tests currently listed on the FDA’s website shows that approximately 30% use low-throughput or non-automated extraction techniques.
About 17% of the EUA molecular tests use fully automated systems which perform extraction on the instrument.
Half of all EUA tests so far are authorized for some degree of automated extraction — using highthroughput instruments or extraction kits run on robotic liquid handling systems — sometimes also in combination with a low-throughput or manual option.
High-throughput systems can process 24 samples in 40 minutes and 48 samples in 90 minutes.
Some test workflows also incorporate automated sample prep from Qiagen, including the QIAcube and QIASymphony, which runs up to 96 samples in 24-sample batches. The Promega Maxwell family of instruments and the Thermo Fisher Scientific KingFisher are also highly represented in the high-throughput EUAs.
Labs starting from scratch, or with pre-existing flexible systems, may have an advantage in the COVID era.
Los Angeles-based start-up Curative uses a viral extraction kit from Norgen Biotek that it can use either manually or in an automated protocol with a Tecan robot called the Resolvex A200. Tecan also offers viral extraction kits and other sample prep instruments, according to John Laycock, the firm’s director of technology and product development.
Other groups setting up brand new labs are also surveying the landscape to find solutions that might provide flexibility in the face of shortages. Engineer Catharine Klapperich, the associate dean for research at Boston University, is leading the development of a CLIA facility to do high-throughput testing for the BU community. She said the lab is choosing to use the Thermo Fisher Scientific MagMax extraction on a robotic instrument from Hamilton called the STAR. “This is a more flexible option – but the instrument is more expensive,” Klapperich noted in an email.
At MD Anderson Center in Houston, the lab has a lab-developed test with EUA for three different sample prep strategies. A representative at MD Anderson said in an email that there are currently no limitations on the center’s ability to perform COVID-19 testing for patients and employees.
Tim Hodge, director of operations at University Clinical Health, a commercial lab in Memphis, Tennessee said his lab also hasn’t yet had any issues with supply.
The UCH lab is using a SARS-CoV-2 testing platform designed to be modular and scalable, “to meet market demand without being constrained by single vendors for reagents and supplies,” Hodge said in an email.
The custom-designed system uses in-house-developed high-throughput RNA extraction chemistry that is able to be performed on any off-the-shelf liquid handler, but is currently optimized for the Agilent Bravo instrument.
Prior to the COVID-19 pandemic, UCH was developing a cancer diagnostic test. “As the pandemic emerged, we rapidly repurposed the instrumentation and reagents we had in house for the FDA EUA studies,” Hodge said. Then, after issuance of the EUA, the lab performed bridging studies for the replacement of a lower throughput Promega Maxwell RSC instrument with commercially available highthroughput instruments combined with the in-house sample preparation chemistry.
Automated sample prep is a critical component of the overall set-up, Hodge said, in part because manual sample prep is prone to error and not easily scalable.
The lab has seen specimen volumes rapidly increasing, and has been contacted by outside organizations, including other SARS-CoV-2 testing labs, to help them perform testing, he said. “We understand that some organizations that are utilizing commercial kits and commercial instrumentation simply cannot get the reagents and materials because of allocations and other market factors,” Hodge said.
Two months ago, nearly three quarters of labs reported having experienced supply chain disruptions in implementing SARS-CoV-2 testing in an Association of Molecular Pathologists survey. While one out of six labs had not yet had any issues with reagent supplies specifically, nearly half had overcome shortages, and a third were experiencing current supply disruptions in reagents such as RNA extraction kits and buffers.
In response to supply chain disruptions, nearly 90% of labs said they had to either decrease or delay testing. Almost two thirds of labs in academic medical centers and health systems had deployed more than three test methods, and a key factor determining which testing method was prioritized and used was the availability of testing reagents and supplies.
At the University of North Carolina Hospital system, the clinical molecular microbiology lab is using two automated workflows, according to the lab’s director, Melissa Miller. Specifically, UNC’s EUA LDT uses either the Roche MagNA Pure 24 or the bioMerieux EasyMag system, both of which prepare up to 24 samples per one-hour run.
“We would not be able to survive without automation right now,” Miller said. “The volume of testing has steadily increased weekly, and to have the capacity we need to serve our patients we rely on automation,” she said.
The lab initially opted to get its EUA for two extraction platforms in order to increase capacity, but also to provide redundancy should shortages occur. And unfortunately, they have.
“The supply chain of extraction reagents — and even some consumables — has been a major problem,” Miller said, noting that this is impacting COVID-19 testing but also routine molecular testing that the lab needs to do every day.
Miller said that one company had limited the lab’s supply of extraction reagents in order to redistribute them for COVID-19 testing, and that the UNC lab has also found it “near impossible” to buy new extraction instrumentation. “Most are months out for delivery,” she said.
Assuming the lab could get a new instrument, it is not guaranteed reagents. And, once an instrument is available, it needs to be installed, and potentially serviced.
Having even one instrument down can cause a significant testing capacity decrease, and turnaround time increase. But Miller said overall customer demand for new installations, travel restrictions, and cancelled flights can make it difficult to get a service engineer on site quickly.
“We had a delay in installation due to engineers being quarantined. This was something I hadn’t anticipated,” she said.
Getting a new instrument also strains already overworked staff, since all the tests and specimen types that will be run on that instrument need to be re-validated before it can be used on patient samples.
At the moment, lab staff is “constantly validating, training, and doing both COVID and routine testing,” Miller said. “The human toll [of the pandemic] in the laboratory has yet to be fully realized,” she said.
Gretchen Johns, the medical director of the department of laboratory medicine and pathology at the Mayo Clinic’s Florida site, is also seeing shortages. Johns is hoping that pooled testing will ultimately help offset supply chain disruptions, although she noted in an email that this technique still needs to be validated across all the different lab instrumentation and testing workflows.
“Pooling is not very well tested currently so you have to consider carefully before using precious reagents to try to validate pooled samples,” she said. “It could be great, or it could waste reagents and staff time.”
In Jacksonville, the lab has validated five different PCR workflows for COVID-19 of varying throughputs.
The lab relies on fully automated high-throughput systems, as well as an EUA LDT, Johns said.
Although supplies of actual instrumentation have not been an issue so far, Johns said the lab continues to experience the shortages in swabs, transport media, and PCR reagents that had plagued test rollout in the U.S.
It is also experiencing supply problems with plastic consumables, like processing tubes and pipette tips, as well as components for test systems such as processing plates, according to Jane Hata, director of the clinical microbiology laboratory at Mayo – Florida.
And, “It is getting very challenging to get reagents, especially the high-throughput reagents, right now,” Johns also said, noting that this seems to be the case for her colleagues in other parts of Florida as well.
“We like to help other local hospitals and organizations, as well as our own patients and our reference lab clients, but it is very challenging right now.”
Staffing shortages are also an issue for the Mayo – Florida lab. It is not so easy to find the people with the requisite PCR skills, and the lab staff has already “been working really hard with a long road ahead,” Johns said. The lab is currently borrowing technicians from other departments to help as much as possible with sample preparation.
So for the time being, keeping enough reagents and supplies, operational instruments, and skilled staff remains “a constant juggling act,” Johns said.
This story first appeared in our sister publication 360Dx, which provides in-depth coverage of in vitro diagnostics and the clinical lab market.