OR WAIT null SECS
Jennifer Markarian is manufacturing editor of BioPharm International.
Outsourcing partners provide capacity and tech transfer expertise in the pharmaceutical industry response to the COVID-19 pandemic.
As the biopharmaceutical industry races ahead with development of vaccines and therapeutics to address the COVID-19 pandemic, experts have acknowledged that building up adequate capacity for fill/finish and ensuring the supply of materials for primary packaging containers are crucial requirements. In an unprecedented compression of manufacturing timelines and with significant investment from government and non-profit sources, commercial fill/finish manufacturing capacity is being built at-risk, while drug development and clinical trials are ongoing.
“A vaccine will only be effective if we can make and distribute adequate supply,” John Shiver, senior vice-president of Vaccines Global R&D at Sanofi pointed out in a March 23, 2020 post (1). He expressed confidence that industry is up to the task, saying, “If we can develop a safe and effective vaccine, the global pharmaceutical industry has the capacity to make and deliver it. [Sanofi] has the established capacity and infrastructure to make up to 600 million doses in two existing facilities based in New York and Pennsylvania, without compromising the supply of vaccines for other illnesses, including influenza. Other companies have similar capacity.” Furthermore, he noted, “Fighting an emerging pandemic is an enormous undertaking requiring the entire pharmaceutical ‘ecosystem’ to come together at pace and at a scale that are both extraordinary.”
Contract development and manufacturing organizations (CDMOs) are crucial components of this ecosystem for handling the expected surge of capacity needed for vaccines and therapeutics to treat COVID-19.
Over the past few months, CDMO Catalent, for example, has announced manufacturing agreements with COVID-19 vaccine candidate developers including Johnson & Johnson’s Janssen (2), Moderna (3), and AstraZeneca (4) to provide fill/finish capabilities. Catalent says it is working with more than 40 customers on COVID-related antivirals, vaccines, diagnostics, and treatments for symptoms and effects of COVID-19 (5). At the Catalent Biologics business unit’s facility in Bloomington, IN, the company reported that the scale-up in production would include the use of two new high-speed machines, including an Optima vial filling line and a Dividella NeoTOP 1604 top-load cartoner (2). The company is rapidly scaling segregated manufacturing capacity at the Bloomington facility to support dedicated production of Johnson & Johnson’s investigational vaccine candidate and plans to hire approximately 300 additional employees “to meet operational readiness and 24x7 manufacturing schedules by January 2021” (2).
The Bloomington facility is also being prepared to provide vial filling and packaging capacity for Moderna’s mRNA-based COVID-19 vaccine candidate (mRNA-1273). Barrier isolator technology will be used for filling. The capacity and the staff for commercial-scale production expect to produce an initial 100 million doses of the vaccine candidate for the US market starting in the third quarter of 2020, and the companies are discussing fill/finish capacity for continued production of hundreds of millions of additional doses (3).
Catalent Biologics facility in Anagni, Italy is being prepared for commercial-scale vial filling and packaging for AstraZeneca and the University of Oxford’s adenovirus vector based COVID-19 vaccine candidate, AZD1222. The facility will be able to supply hundreds of millions of doses of the vaccine candidate from August 2020, and potentially through to March 2022 should the product be approved by regulatory agencies, Catalent reported (4).
One of the funding sources for COVID-19 countermeasures is the US government, which is building a network of manufacturing partnerships through programs including Operation Warp Speed, which is a partnership among components of the Department of Defense (DoD) and the Department of Health and Human Services (HHS), including the Centers for Disease Control and Prevention (CDC), FDA, the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA) (6). BARDA, for example, awarded more than $49 million to ThermoFisher Scientific to expand its sterile injectables capacity for fill/finish of vaccines in vials (7). HHS, in addition to contracts with Johnson & Johnson, AstraZeneca, and Moderna, in June 2020 contracted with Emergent BioSolutions for manufacturing capacity, including an investment of approximately $85.5 million for the rapid expansion of the company’s viral and non-viral CDMO fill/finish capacity for vaccine and therapeutic manufacturing (8).
“Emergent has a long, successful history of working with the US government to develop, manufacture, and deliver safe and effective medical countermeasures for public health. BARDA has been an excellent partner, across all levels from leadership to the project and technical teams with whom we work closely,” says Dino Muzzin, senior vice-president of manufacturing operations at Emergent BioSolutions. “As partners on a team, we work collaboratively to monitor, evaluate, and progress projects and help remove barriers that slow down the directive of Operation Warp Speed.” Muzzin notes that BARDA has worked to secure the supply of primary packaging components, including vials.
Through Operation Warp Speed, the US government has invested in US domestic capacity for glass vials, with $204 million going to Corning to expand capacity for its Valor Glass vials, and for two more unconventional container types—$143 million to SiO2 Materials Science to increase capacity to produce the company’s glass-coated plastic containers and a $138 million contract with ApiJect to produce prefilled syringes using the blow-fill-seal process for plastic containers (6).
In addition to planning for vaccine production, fill/finish capacity is being built up for therapeutics, and CDMOs again play a key role. Ajinomoto Bio-Pharma Services, for example, signed a manufacturing agreement with Humanigen for fill/finish of lenzilumab, which is in Phase III clinical trials in adult, hospitalized patients with COVID-19 to prevent or treat cytokine storms (9). Aji Bio-Pharma will perform fill/finish of the monoclonal antibody at its San Diego, CA facility. Programs related to the pandemic are currently being prioritized over other programs, with appropriate consideration to existing commercial supply agreements, notes Dustin Campbell, associate director of commercial operations at Ajinomoto Bio-Pharma Services.
As development speeds ahead, CDMOs are working to ensure quality by considering how to work within the shortened timelines, ensure the most efficient tech transfers, train staff, and source raw materials and single-use components.
“The most significant challenge in responding to the pandemic is making sure we’re proactive with how we plan, resource, and execute programs with our customers, rather than reactive to the larger challenges they are facing with supply chain and general development,” says Campbell. “From a business perspective, our customers are expecting quick turnaround times to shorten the CDMO selection process in order to advance COVID specific therapies, but also to make up for lost time being seen in supply chain delays. Similarly, the tech-transfer and preparation process for fills is being tightened with customers racing to get treatments into the clinic. Clinical timelines in general are usually very fast, and the expectation is the CDMO can adjust to meet the changing demands of the customer’s program.”
Campbell notes that a unique aspect of the pandemic is that the influx of government funding for sponsored programs is increasing the overall demand for capacity, which increases the pressure on CDMOs to provide a flexible service that can meet the expectations of customers and the public. In response to this changing landscape, he says, the company introduced its new Ajility platform to minimize the time to clinic. Launched on June 30, 2020, the platform is designed for novel therapeutics or vaccines and existing drug products with a new indication that can be used in COVID-19 trials, FDA Emergency Use Authorizations (EUA), or other programs (10). The company explained that the platform’s goal is to guide clients through decisions, such as choosing components, excipients, and method qualifications, with the aim of minimizing variables during tech transfer, manufacturing, and shipping processes (10).
“The team worked through every step of the manufacturing process in defining this service offering,” says Campbell. He does not currently see any supply problems for fill/finish and packaging, noting that the company already had a strong vendor supply chain in place. Flexible production is key. “The main change we have made to our operations to support the AJILITY program have allowed flexible capacity to meet demand. With increased business coming as programs increase in number, we expect these changes can support the demand that may be placed on these pieces of equipment,” says Campbell.
Planning ahead for fill/finish includes having options for filling formats and considering primary packaging supply.
“Emergent is currently working with four innovators for their COVID-19 vaccine candidates, and each client has a slightly different filling format. We continue to evaluate options as the clients’ process information is defined,” says Muzzin. “Worldwide shortages can create long lead times on single-use materials and containers like glass vials, which make the logistical planning difficult and very important. While we need to leave enough time to source these materials, deciding too early may require us to make significant assumptions of what a product will need. Alternatively, decisions that are delayed until there is enough information to be sure about what materials are needed may result in extra costs associated with expedited delivery. COVID-19 may be a new indication, but material sourcing is a universal complication of the manufacturing process, and we continue to work with our sourcing and industry partners to plan ahead and prepare appropriately to minimize the risk of delays associated with container sourcing.”
Given the fast pace of development and the expected speed of scale up, tech transfer—from innovator to the CDMO and from smaller to larger scale—is a particularly critical step. An added challenge is that processes are still being developed while manufacturing capacity is being prepared.
“Many activities, from development to tech transfer, are being done in parallel, which takes significantly more coordination and communication to ensure that both the innovator and CDMO can stay in lock-step,” notes Muzzin. “Processes for the drug product are still being developed, so as they become more defined, we need to shift our resources to adapt. A significantly positive outcome from this approach is how this leads to a higher degree of transparency and willingness to assume ‘positive intent’ in all interactions, which builds and improves trust faster, and drives us toward the desired successful outcome. At each stage there is a high degree of collaboration and coordination. We are doing this in new ways—from acquiring and delivering the equipment, to configuring and testing the equipment, and helping ensure processes will be ready for CGMP [current good manufacturing practice] manufacture all while working in new ways and at an unprecedented, accelerated pace. We maintain the same level of safety and attention to detail in these processes as always.”
The Operation Warp Speed plan calls for manufacturing and fill/finish to be prepared to be used “for whatever vaccine is eventually successful, if possible” (6). Potential shifts as development progresses will pose challenges for tech transfer.
“When we talk about switching lines, we have to remember this is not only about changing hardware. It is about the transfer of process know-how to ensure that the process runs effectively and in a repeatable fashion. The ability to do more parallel technical transfer activities is the key to rapidly moving through different vaccines and being ready to meet each client’s needs,” notes Muzzin.
Emergent’s Baltimore Bayview facility is designated as a Center for Innovation in Advanced Development and Manufacturing (CIADM) by HHS, is designed to be flexible to be able to manufacture product in large quantities during public health emergencies, explains Muzzin. The CIADM has four independent suites, and each allows products or customers to move in and out quickly, he notes.
“As with any tech transfer and scale-up, a thorough assessment by pharmaceutical development experts is required, including a comparison of equipment, related process adaptions, gap assessment, and overall risk assessment,” adds Hanns-Christian Mahler, head of Drug Product Services at Lonza, which is producing the active ingredient for Moderna’s COVID-19 vaccine. “Depending on the level of change, it may be required to elaborate further on testing [critical] quality attributes to ensure there is no relevant change in the product quality, safety, and efficacy profile due to this change.”
Analytical method transfers are typically rate-limiting steps for tech transfer when bringing a new product or process into a facility, notes Campbell. “Especially with early-stage, novel therapeutics, there are often gaps between the state of the methods for in-process control and product analysis and what is suitable for CGMP operations. Likewise, with the formulation details, often these early programs have been performed on a benchtop with inadequate attention having been paid to the scale and process characterization needed to ensure a successful CGMP operation. A clinical to commercial program typically involves fewer unknowns but includes long lead-time activities that may or may not propose a risk to a customer’s timeline depending on the quality of the process characterization activities that the customer and CDMO-focused on during clinical development.”
Designing early-stage programs appropriately can reduce problems in late-stage development and facilitate getting from clinical to commercial scale, concludes Campbell.
1. Sanofi, “Sanofi Mobilizes to Develop a Vaccine against COVID-19,” Sanofi.com, March 23, 2020.
2. Catalent, “Catalent Signs Agreement with Johnson & Johnson to be US Manufacturing Partner for Lead COVID-19 Vaccine Candidate,” Press Release, April 29, 2020.
3. Catalent, “Moderna and Catalent Announce Collaboration for Fill-Finish Manufacturing of Moderna’s COVID-19 Vaccine Candidate,” Press Release, June 25, 2020.
4. Catalent, “Catalent Signs Agreement with AstraZeneca to Manufacture COVID-19 Vaccine Candidate,” Press Release, June 15, 2020.
5. Catalent, “Catalent COVID-19 Response,” Catalent.com, accessed July 9, 2020.
6. HHS, “Fact Sheet: Explaining Operation Warp Speed,” hhs.gov, June 16, 2020.
7. HHS, “Pharmaceutical Manufacturing in America,” medicalcountermeasures.gov, June 12, 2020.
8. HHS, “HHS Adds $628 Million to Contract with Emergent BioSolutions to Secure CDMO Manufacturing Capacity for Operation Warp Speed,” Press Release, June 1, 2020.
9. Aji Bio-Pharma, “Ajinomoto Bio-Pharma Services Signs Manufacturing Agreement with Humanigen for Lenzilumab, Currently in FDA-Approved Phase III Study for COVID-19,” Press Release, May 27, 2020.
10. Aji Bio-Pharma, “Ajinomoto Bio-Pharma Services Introduces AJILITY Fast Track Platform for Drug Product Manufacturing,” Press Release, June 30, 2020.
Supplement: Outsourcing Resources
When referring to this article, please cite it as J. Markarian, “All Hands on Deck for Fill/Finish of Vaccines and Therapeutics," Pharmaceutical Technology Outsourcing Resources Supplement (August 2020).