Eighteen months ago, Leslie B. Vosshall, PhD, a leading neuroscientist at the Rockefeller University and a Howard Hughes Medical Institute investigator, took to Twitter to voice her frustrations with a mundane yet critical piece of lab equipment.
“Does anybody make a RELIABLE freezer for scientists?” she pleaded, after trashing her existing malfunctioning equipment. Vosshall’s timeline briefly turned into a Consumer Reports column on lab equipment, as researchers echoed her sentiments while endorsing products, notably from Stirling Ultra and Panasonic.
Vosshall recently reiterated her recommendations as the topic of reliable ultra-cold storage solutions suddenly became headline news. With the first COVID-19 vaccines due to reach patients in a matter of weeks—including some that require cold storage down to -80º C (-112º F)—companies that manufacture freezers are scrambling to keep up with surging customer demand.
The demand led Stirling Ultracold this year to expand its staff by 30%, to roughly 150 people, while business has grown about 150% from the first quarter to the current quarter, CEO Dusty Tenney told GEN. Plans to introduce several new products this year have been shelved as COVID-19 refocused priorities. Stirling Ultracold has shifted its business entirely toward serving customers scrambling to procure its freezers.
“We put a lot of our development on hold. We understand the importance of this mission globally, to really help and support the world in its mission to get past this pandemic,” Tenney said. “This mission is way too important for us, at least in the short term.”
Stirling Ultracold markets three ultra-low temperature freezers: the upright SU780XLE, the portable ULT25NEU, and the undercounter SU105UE, at prices ranging from $7,000 to $15,000.
Among Stirling Ultracold’s customers is Infinity BiologiX (IBX), a Piscataway, NJ-based central lab that maintains one of the world’s largest academic biorepositories and also serves researchers with biological sample processing and cell line services.
“We’re trying to take the headache away from the end users,” said Robin Grimwood, IBX’s president and COO. “The freezer farms can hold bulk vaccine storage. Then we come as the next step, where we’re holding it locally for our clients, and then helping them with the distribution strategy.”
IBX’s COVID testing site is one of the largest in the New York area. In choosing freezers, Grimwood said, IBX considers power consumption, heat load, storage capacity, noise, and especially reliability: “You don’t want your freezers to be going wrong. But if they do go wrong, you’ve got a limited time to get the samples from one freezer into the next freezer before the samples degrade.”
Grimwood said IBX’s range of cold storage environments attracted one recent customer, New York-Presbyterian Hospital, as it prepares for the arrival of COVID-19 vaccines: “They obviously know that they need to be prepared. They have been told to prepare. But they don’t know what to prepare for.”
Currently, there are no recommended storage guidance or standards for ultra-low temperature vaccine handling. Each leading COVID-19 vaccine comes with different storage requirements. Messenger RNA (mRNA) vaccines are particularly vulnerable to degradation by enzymes, hence vaccine developers modify their mRNAs to enhance stability, contain the mRNA in lipid nanoparticles—differences between which can explain why some vaccines require colder storage than others—and ultimately freeze the mRNA.
Two leading COVID-19 vaccine candidates poised for release are mRNA-based. Pfizer and BioNTech’s BNT162b2, the leading candidate in the companies’ BNT162 vaccine program, requires shipping and storage at -70º C. Pfizer and BioNTech—which on Friday requested authorization of BNT162b2 for emergency use—say they have developed temperature-controlled thermal shippers using dry ice to maintain temperature conditions of between -70º C and +10º C.
The shippers can be used as temporary storage units for 15 days by refilling with dry ice. Once thawed, the vaccine can be refrigerated for five days. Each shipper contains a GPS-enabled thermal sensor to track the location and temperature of each vaccine shipment across their pre-set routes leveraging Pfizer’s broad distribution network.
By contrast, Moderna says its mRNA-based vaccine mRNA-1273—which showed 94.5% effectiveness in early Phase III data—“must be stored at 2º to 8º C in a secure area with limited access (unblinded personnel only) and protected from moisture and light until it is prepared for administration,” according to the protocol for its 30,000+ patient Phase III COVE trial (NCT04470427).
Moderna recently announced a longer shelf life for mRNA-1273, saying the vaccine remained stable at 2º to 8º C for 30 days (up from an earlier estimate of just seven days). Moderna added that mRNA-1273 remains stable at -20º C for up to six months, “and at room temperature for up to 12 hours.”
AstraZeneca’s vaccine candidate AZD1222, which is being co-developed with the University of Oxford and a spinout, also allows for storage and shipping at -20º C. AstraZeneca said today that AZD1222 generated positive Phase III efficacy ranging from 62% when given to 2,741 participants as two full doses at least one month apart—to 90% when given to 8,895 participants as a half dose, followed by a full dose at least one month apart. A total of 131 COVID-19 cases were reported in the interim analysis.
Novavax’s NVX-CoV2373 requires shipping and storage at 2º to 8º C.
“We expect the product to be viable a minimum of six months at 2º to 8º C, and at least 24 hours at room temperature,” Novavax spokesperson Edna Kaplan said. Novavax plans to distribute NVX-CoV2373 in multidose vials, with each vial containing ten doses. “The vaccine is ready-to-use and does not require admixing or reconstitution. It can be delivered using any standard needle and syringe, including those routinely used in vaccination programs,” she said.
Speaking at the virtual HLTH 2020 conference in October, FDA Commissioner Stephen M. Hahn, MD, said cold storage requirements will not be a deciding factor as his agency decides on approvals for COVID-19 vaccine candidates. However, Hahn said that cold chain requirements will be evaluated when it is shown to affect the safety or effectiveness of those vaccines.
Translate Bio, which is developing MRT5500 through an up-to-$2.3 billion collaboration with Sanofi, said its mRNA-based COVID-19 vaccine originally required storage at -80º C.
“We already have generated data and formulations showing stability at -20º C and we hope to implement this for an anticipated Phase III trial for MRT5500,” said Frank DeRosa, PhD, Translate Bio’s chief technology officer.
“We have been working diligently on formulations that would allow for storage and transport at higher temperatures for longer amounts of times,” DeRosa said. “This will be a critical component of distributing our vaccine at a large-scale level, and we are committed to working with Sanofi, experts in global vaccine distribution, on this important issue. Sanofi will be responsible for distribution and they have the global infrastructure in place to manage this process.”
In the longer term, Translate Bio hopes to apply to its COVID-19 program a lyophilized formulation that would allow for extended refrigeration at 2º to 8º C. That formulation has generated encouraging stability data in other pipeline programs.
Non-RNA vaccines, as with therapeutics, do not require ultra-low temperatures. Janssen Pharmaceutical Cos. says its JNJ-78436735, an adenovirus vaccine based on the company’s using Janssen’s AdVac® and PER.C6® vaccine technology platforms, can be stored at standard refrigerator temperatures.
“We currently expect to store then transport our vaccine to customer warehouses at 2º to 8º C, based on available stability data using this vaccine platform,” said Craig Stoltz, a spokesman for Janssen Manufacturing & Technical Operations. “We will use the same cold chain technologies we use today to transport treatments for cancer, immunological disorders, and other medicines. We anticipate our vaccine candidate to be compatible with standard distribution channels without the need for new distribution infrastructure,” Stoltz added.
Sanofi is also partnering with GlaxoSmithKline (GSK) on another COVID-19 vaccine in development, a vaccine incorporating Sanofi’s S-protein COVID-19 antigen, which is based on recombinant DNA technology; and GSK’s pandemic AS03 adjuvant. That vaccine can be stored at 2º to 8º C.
However, Russia’s approved COVID-19 vaccine Sputnik V, developed by the Gamaleya Research Institute of Epidemiology and Microbiology, requires storage at -20º C (-4º F). Sputnik V consisting of two components, administered 21 days apart: A recombinant adenovirus vector based on the human adenovirus type 26, containing the SARS-CoV-2 S protein gene, and a vector based on the human adenovirus type 5, containing the SARS-CoV-2 S protein gene.
Faster timeline, more customers
The scale and level of collaboration required to develop and ramp up distribution of COVID-19 vaccines from production to distribution to point of care injection is unprecedented, said Alex Esmon, PhD, senior director and general manager for the strategic business segment, that includes ultra-low temperature freezers at Thermo Fisher Scientific: “The industry has been making progress with mRNA-based vaccines, but the COVID-19 pandemic has dramatically accelerated the timeline.”
Thermo Fisher Scientific markets 198 freezers of varying sizes and temperatures, the coldest ones operating as low as -86º C. The company’s three largest freezers have capacities of 33.5 cu. ft. (949 L) and 700 2-inch cryoboxes, but only one operates on U.S. voltage of 115 volts—the TSX70086A, which sells for almost $30,000.
According to Esmon, Thermo is increasing production of ultra-low temperature freezers, -20º C freezers and refrigerators “to manage demand and ensure availability and we’re confident we have the capacity to meet the needs of our customers.”
The cold-storage requirements of leading COVID-19 vaccines is changing the types of customers reaching out to freezer manufacturers.
“It’s a multifaceted increase in demand. I’d say the big drivers have been smaller clinics, state health, as well as logistic and shipping companies,” said Carl Radosevich, senior manager, scientific applications & collaborations with PHC Corp. of North America. PHC is the former biomedical division of Panasonic Healthcare, which markets freezers for life sciences uses under the PhCbi brand.
“The demand has certainly increased especially for -80º C freezers,” Radosevich said. “The last three months, especially once the various state health departments started submitting their vaccine preparation plans, that’s where we really started to see this demand.”
Hospitals have also expanded their freezer demand, as smaller facilities may not have previously needed -80º C units. Larger hospitals need freezers beyond those in diagnostic or research lab settings, including sites where vaccines will be administered.
“Some customers to which we were selling high volumes of vaccine storage refrigerators now need minus 80s [freezers]… We’ve had to try to understand where the vaccines are going, so we can advise correctly as to which unit they need to store those vaccines,” Radosevich added.
PHC markets its PHCbi-branded, -86º C ultra-low temperature freezers based on two types of refrigeration systems. The company’s flagship PHCbi VIP ECO Series, which operates on natural refrigerants, offers five models in three sizes from 18.6 cu. ft. (528L) to 29.8 cu. ft (845 L). The PHCbi TwinGuard Series, which uses two independent refrigeration systems, offers a 25.7 cu. ft. (729 L) chest freezer and three upright freezers, the largest being 25.3 cu. ft. (715 L).
Esmon of Thermo Fisher Scientific identified the toughest challenges associated with COVID-19 vaccines. One is managing temperature throughout their distribution, achievable with temperature tracking devices and digital solutions. This is especially critical for mRNA vaccines, for which temperature maintenance represents a new challenge from standard vaccine delivery. Manufacturers also must ensure they can provide mRNA vaccines requiring -70º C temperature protection from the site of manufacture to their final destination.
There, the vaccines may be held in the original manufacturer’s shipper, which needs recharging after 10 days. Or they may be transferred to an ultra-low temperature freezer for storage or moved to a refrigerator if used within five days, in preparation for vaccination.
Esmon also identified gaps in the existing cold chain for vaccine distribution. The distribution process isn’t set up for large-scale transport of products that must be kept at ultra-low temperatures. Some manufacturers, he said, have responded by creating low-temperature storage containers for their vaccines that maintain a temperature of -70º C through transportation and up to 10 days with the aid of dry ice.
“We’re actively collaborating with FedEx, UPS, and large pharma manufacturers,” Esmon said. The logistics giants have established freezer farms enabling storage of large vaccine quantities. UPS’ farms are being built in Venlo, the Netherlands, and Louisville, KY. FedEx operates a Cold Chain Center in Memphis, TN, capable of storing frozen goods at -25º to -10º C. FedEx also added ten freezer facilities over the past three years, and plans to build more.
But very few pharmacies and clinics have equipment for storing and dispensing mRNA vaccines and other vaccines requiring very low temperature storage and for extended periods, Esmon said.
“These sites will need to have vaccination plans in place to manage these vaccines depending on the number of vaccines they receive and plan to distribute and in accordance with the parameters of the life of that vaccine,” Esmon said. “In many cases, because these vaccines are meant to be delivered quickly to patients and not stored, using the original shipping container or a 2º to 8º C refrigerator may be sufficient for the short time that vaccine is onsite prior to delivery to a patient.”