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As the first wave of mRNA vaccines are distributed, efforts will be needed to protect data and prevent errors.
In December 2020, FDA agreed to Emergency Use Authorization (EUA) for Pfizer-BioNtech’s and Moderna’s COVID-19 vaccines, both based on messenger RNA (mRNA) technology. MRNA presents significant challenges to manufacturing, since the product is extremely unstable and requires minimal hold times. “You can’t just put it in ice overnight,” says Emily Moran, senior director of viral vector manufacturing with Discovery Labs, who formerly held that position at Lonza and Sanofi Pasteur.
“The level of excellence in execution required to be able to release the vaccines for shipment in the time they did speaks to a whole new level of manufacturing. This was also key in ensuring they had the required stability data for the shipments in just a short time,” says Moran. The work has required advancements in data processing and the monitoring of metabolites in bioreactors, and having a feedback loop in place so that any changes in key parameters could be detected and acted upon in real time, she says.
Complexity characterizes every stop along the COVID-19 vaccine supply chain. On Dec. 19, 2020, US General Gustav Perna, chief operating officer of Operation Warp Speed (OWS), which is coordinating efforts by the US Health and Human Services Department (HHS) and the Defense Department (DoD) to distribute COVID-19 vaccines, apologized for underestimating the number of vaccines that would be needed (1).
As he explained, he had misunderstood handoffs between manufacturing, fill/finish, and distribution, and the difference between product made and doses available for release after sterility testing (1). The first few weeks of COVID-19 vaccine distribution have brought questions about data and shipment security and avoidance of product waste. Technology promises to make the overall process safer and easier for all, and some companies are already using it proactively.
Cold-chain shipment has been an area of intense innovation (2), due to the fact that Pfizer-BioNTech’s vaccine must be shipped and stored at -70 °C (-94 °F). In December 2020, two shipments of the vaccine experienced temperature excursions in which product was actually kept at overly cold temperatures (3). They were pulled out of distribution, and subsequent testing at Pfizer showed that these events had no impact on product efficacy.
A number of new solutions center around remote temperature and condition monitoring using Industrial Internet of Things (IIoT) technology. In December, a report surfaced that Pfizer-BioNTech executives had decided to turn off the company’s temperature loggers once the product left its facilities, drawing a line in the sand regarding liability (4). OWS has since contracted with Controlant, which will use its remote IIoT temperature-monitoring platform throughout the vaccine’s distribution and at point of use (5).
The picture promises to become even more complex as more of the 165 COVID-19 vaccines now in the pipeline advance to Phase III and beyond. These vaccines are based on different platforms, from those using live, weakened virus (such as the vaccine being developed by Codagenix); to others based on live, inactived viruses (e.g., Sinovac’s); vaccines based on viral vectors (Oxford University/AstraZeneca’s, Johnson & Johnson’s [J&J’s] and Merck’s); protein vaccines (being developed by GlaxoSmithKline, Sanofi Pasteur, and Baylor College of Medicine), and nucleic acid vaccines based on RNA or DNA (such as Moderna’s and Pfizer-BioNTech’s mRNA vaccines, and a vaccine being developed by Inovio), according to a report by the Center for American Progress, a public policy research group (6). The Center’s report describes a tangle of contracts for fill/finish capacity. Pfizer-BioNTech, for example, has contracted with Catalent, Lonza, and Thermo Fisher Scientific to handle manufacturing; Moderna is working with Lonza and Catalent, and J&J, with Catalent. Capacity is also available via centers for innovation in advanced development manufacturing, which were funded by DoD’s Biomedical Research and Development Agency (7). They include Emergent Biosolutions, Seqiris’ Holly Springs facility (previously owned by Novartis), and Texas A&M’s facility, which is operated by Fujifilm Diosynth. Just-in-time manufacturing is needed to coordinate manufacturing and distribution efforts. In late October, Stéphane Bancel, CEO of Moderna, said that trucks were standing by, even before data were submitted for EUA from FDA, to begin shipment of vaccines (8).
One problem that vaccine developers and regulatory agencies need to address is the urgent need to protect data, says Nigel Thorpe, technology director with Secure Age, which specializes in enterprise data encryption using a public key infrastructure platform. “Unscrupulous organizations can easily get into unprotected networks and disrupt processes,” he says, which can result in counterfeit product distribution as well as supply-chain disruptions.
All too often, he says, pharmaceutical companies treat encryption as a routine “checkoff box,” activity and fail to realize that even documents that seem routine may pose risks if they fall into the wrong hands. Thorpe mentions a December 2020 IBM Security report that found COVID-19 vaccine distribution projects to be particularly vulnerable to cyberattacks and use of ransomware (9). He also points to a Dec. 10, 2020 incident in which hackers attacked the European Medicine Agency’s computer system to access COVID-19 vaccine approval and other data (10).
One problem with filling and transporting vials of vaccine is the need to maintain an accurate count. For operators on the plant floor, the efforts required are fraught with potential error, especially during shift changes, says Jim Evans, director of Verista, Inc.’s vision, connectivity, and automation division. “An inspection line for pharma runs about 300 vials per minute. With normal downtime, that is 100 million vials per year, not nearly enough to satisfy the requirements for a COVID-19 vaccine. Along the way, vials need to be counted, and counts need to be reconciled, and cracks and broken vials traced throughout the manufacturing process,” he says.
Both Pfizer-BioNTech and its contract manufacturing partner, Catalent, are using Verista’s COUNTQ technology, based on machine vision. The latest version of COUNTQ uses artificial intelligence, and a deep learning technology to count ampules. Pfizer-BioNTech and Catalent had each invested separately in the technology before the pandemic began. Since then, Pfizer-BioNTech has bought four machines for its COVID-19 vaccine lines, and has installed two so far, Evans says.
The speed with which vaccines have been developed and are being distributed pose important questions centered around variability. It will be essential to ensure that each person who receives the vaccines receives product of the same quality. Hedley Rees, pharma supply-chain expert and director of PharmaFlow Consulting in the United Kingdom, shared insights with Pharmaceutical Technology.
Rees projects shortages of raw materials for some COVID-19 vaccines and non-COVID-19-related manufacturing. “Everyone is pulling from the same pool of suppliers in biologics. If we’re having a raw materials shortage when the vaccines haven’t even been scaled up, what will happen when they get full approval?” he asks.
Several months ago, Pfizer-Bio-NTech acknowledged that it had underestimated raw material requirements, which significantly reduced the amount of vaccine that it could distribute (11). Finally, Rees observes that at the point of use, the scene differs significantly from what has been seen in the past. Healthcare facilities will receive boxes of 975 vials frozen to -70 °C. They will be placed in refrigerators validated to run from 2–8 °C, and then thawed for about three hours. Technicians must then inject saline solution into the vaccine concentrate and turn each vial over 10 times, as a machine would, separate the contents of each vial into five patient doses, and administer them. The vials will only have six hours of potential shelf life at room temperature (12).
Clearly COVID-19 has posed many “firsts” for the bio/pharmaceutical industry. We can expect to see greater leverage of new technologies as development of more new COVID-19 vaccines advances.
11. C-SPAN, “December 19 News Conference on COVID-19 Vaccine Distribution,” cspan.com, Dec. 19, 2020.
2. J. Markarian, BioPharm International, 34 (1), p. 37, January 2020.
3. US Dept. of Health and Human Services, “OWS Briefing on COVID-19 Vaccine Distribution,” hhs.gov, Dec. 16, 2020.
4. O. Goldshield, “Pfizer-BioNTech Decision to Turn Off Temperature Sensors Forced Scramble to Secure COVID-19 Vaccines,” statnews.com, Dec. 17, 2020.
5. Controlant, “US Dept. of HHS and Controlant Enter Agreement,” controlant.com, Press Release, Dec. 18, 2020.
6. T. Spiro and Z. Emanuel, "A Comprehensive COVID-19 Vaccine Plan," americanprogress.org, July 28, 2020.
7. US Government Accountability Office, “National Preparedness: HHS Has Funded Flexible Manufacturing Activities for Medical Countermeasures, but It Is Too Soon to Assess Their Effect,” gao.gov, 2014.
8. A. Shanley, “The Last Mile” COVID-19 Vaccine Developers Prepare to File for EUAs,” PharmTech.com, Nov. 11, 2020.
9. J. Stubbs, “Hackers Steal Pfizer-BioNTech COVID-19 Vaccine Data from EMA,” reuters.com, Dec. 9, 2020.
10. IBM, “COVID-19 Cyberwar: How to Protect Your Business,” ibm.com, Dec. 4, 2020.
11. C. O’Donnell, “Pfizer-BioNTech Says Supply Chain Challenges Created Slashed Target,” reuters.com, Dec. 3, 2020.
12. MHRA, “Information for Healthcare Providers on PFizer-BioNTech’s COVID-19 Vaccine,”uk.gov, December 2020.
Agnes Shanley is the senior editor of Pharmaceutical Technology.
Vol. 45, No. 1
When citing this article, please refer to it as: A. Shanley, "COVID-19 Vaccine Distribution: Preparing for the Unexpected," Pharmaceutical Technology 45 (1) (2021).