Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

Pressure is mounting on FDA to step up the pace of on-site inspections that were postponed due to COVID-19 safety issues and restrictions. An open question is whether the agency will use new remote auditing technologies to improve its ability to inspect facilities during the COVID-19 pandemic. 

Pharmaceutical Technology's Regulatory Sourcebook 


eBook: Regulatory Sourcebook, March 2021
March 2021
Pages: 4-5

When referring to this article, please cite it as A. Shanley, “Can FDA Reinvent Inspections,” 

Pharmaceutical Technology Regulatory Sourcebook eBook 

Articles

A plant inspection backlog caused by COVID-19 restrictions threatens innovation and public health.  Now pressured to step up on-site inspections, will FDA embrace new methods?

Can FDA Reinvent Inspections

Despite the limitations set by the COVID-19 pandemic, bio/pharmaceutical manufacturers achieved unprecedented speed in developing new products in 2020. This was evident with the first two COVID-19 vaccines, which reached the public under Emergency Use Authorization in December 2020. Where developing a vaccine has traditionally required 10 years, Pfizer-BioNTech and Moderna Therapeutics cut that time to less than a year (1,2) with their messenger RNA (mRNA) vaccines.

Developers attribute this speed to their willingness to assume more risk from the start, and to leverage years of past research and clinical experience with the platforms themselves (e.g., mRNA or, in the case of Johnson & Johnson’s (J&J’s) COVID-19 vaccine candidate, with human adenoviral vector [Ad26]). With J&J’s vaccine, cell-line optimization was also crucial, not only for speeding the vaccine’s development but for optimizing its manufacturability and stability, as Paul Stoffels, executive vice president and chief scientific officer told attendees at the 2020 Galien Forum (3). Stability was optimized to levels of 2-8 °C, simplifying global distribution to developing nations.

However, with COVID-19 vaccines and therapies, the greatest increases in developmental speed and agility were achieved on the clinical side. New adaptive clinical study models were used; some early testing in humans was done concurrently with animal testing; some safety tests were run simultaneously with efficacy tests, and elements of Phase II and Phase III trials were combined.

Even on the preclinical side, work on Moderna’s COVID-19 vaccine was accomplished within a few months, CEO Stéphane Bancel explained at the 2020 Galien Foundation Forum (3). Scientists had sketched the experimental design in January 2020; the first test product was sent to the US National Institutes of Health in February; and Phase I testing started in early March. By the autumn of 2020, chemistry, manufacturing, and control (CMC) documentation had been submitted to FDA while safety testing was still going on.

Clearly, achievements in time reduction for COVID-19 therapies and vaccines have proven what is possible and set the bar high. One question is whether achievements made during a time of crisis can be sustained after the pandemic and move into mainstream bio/pharmaceutical development. New approaches, and the use of innovative technology, promises to enable additional gains in speed and efficiency.

A number of trends have already been in place to speed new drug development, including increased use of biomarkers and better patient targeting during clinical stage planning. In addition, more bio/pharma companies are using data analytics. One platform that is seeing increased adoption is artificial intelligence/machine learning (AIML), which can be applied to real-world data, including such diverse data sources as electronic health records, lab test results, and insurance claims, to ensure that trial design and patient recruitment reflect actual conditions.

Efforts by FDA and other regulatory agencies to speed review of important new drugs have also helped shrink development timeframes. Where the first decade of the 2000s saw slower development times and higher attrition rates for new drug candidates, notable increases in efficiency were made between 2010 and 2020, according to a recent study (4).

In a speech on June 1, 2020 (5), former FDA Commissioner Stephen Hahn pledged to make permanent some innovations that the industry and agency made to increase agility during the pandemic. He emphasized FDA’s interest in advancing practices such as decentralized clinical trials and increased use of real-world evidence in clinical trials. Technology is becoming increasingly important in optimizing study design, site selection, and patient recruitment, and also in predicting R&D and clinical outcomes, to help prioritize, early on, the most promising candidates, says Natalia Kotchie, vice president of R&DS Applied Data Science Center at the contract research organization, IQVIA.

Moderna used predictive models in the earliest phases of its COVID-19 vaccine development planning (3). As a CRO, IQVIA has been developing AIML-based tools and systems for the past five years to optimize clinical trials, for example prioritizing the highest potential sites. During the pandemic, IQVIA-developed COVID-19 models informed trial operational planning choices depending on areas where COVID-19 outbreaks were most likely to occur, says Kotchie.

For bio/pharma companies, one fundamental change that is speeding drug development has been increased collaboration and cross-learning through partnerships, says Lance Minor, national co-leader of life sciences practice for the management consultant, BDO USA LLP. The industry has engaged in collaborative research for decades, but during the current pandemic, the level of collaboration intensified, bringing together competitors such as Roche and Regeneron, Gilead and Roche, Gilead and Pfizer, Sanofi and GlaxoSmithKline (GSK), as well as companies working in incubators set up by the World Health Organization, the Global Alliance for Vaccines and Immunizations, the Coalition for Epidemic Preparedness Innovation, and the Gates Foundation (6).

Close work involving bio/pharma companies, CROs, and healthcare organizations has added another dimension to collaboration, Kotchie says. Another important factor speeding development of COVID-19 treatments and vaccines has been drug developers’ increased tolerance for risk, not only on the capital and financial side, but in the clinic, Minor says. Pfizer-BioNTech and Moderna spent billions of dollars on development for COVID-19 vaccines, but they also took risks by changing the traditional sequential approach to clinical testing, Minor says. In 2020 assuming these risks, and managing them, paid off in shortened development times. In 2021, novel approaches to enrolling patients and use of remote patient monitoring should also have an impact, he says.

Although efforts in 2020 focused on therapies and vaccines for COVID-19, the pace of development projects outside that area will pick up again in 2021, says Minor. Success in a very challenging year has led to optimism for 2021. In BDO’s 2021 survey, 100 chief financial officers (CFOs) at medium-to-large life sciences companies, the company found that 69% plan to increase spending on R&D, most of them singling out three or four promising products as commercialization targets. Pharma companies are still planning to increase investment in the development of new COVID-19 treatments, but a larger number also plan to invest in other therapeutic areas, with 57% mentioning cell therapies (up from 41% in 2020) and 56% targeting immunotherapies (up from 32% in 2020) (7).

Significantly, many respondents to the 2021 survey see digitalization as important to achieving their goals, with 63% responding that digital transformation would be their leading growth strategy in 2021.

One innovation that has helped shorten drug development timeframes has been use of biomarkers, indicators of a patient’s medical state that can be readily measured that have become a mainstay for clinical trials. Biomarkers were used in 55% of oncology clinical trials alone in 2018, up from 15% 20 years ago (8). FDA has recognized biomarkers’ importance since the agency first established its Critical Path initiative in 2004. More recently, however, FDA has begun to recognize other innovative drug development tools that are expected to help shorten drug development times, a mandate of FDA’s 21st Century Cures Act. On Nov. 30, 2020, FDA established a new pilot program, the Innovative Science and Technology Approaches for New Drugs (ISTAND) (9).

The effort could break through some of the industry’s reluctance to use technologies that have not first been applied in approved new drug applications. Through ISTAND, technology developers can apply to FDA for qualification of a novel technology for a specific use. The pilot would cover new, nontraditional data collection or analysis methods; technologies such as tissue chips that serve as micromodels of specific organ systems for drug safety assessments; and use of artificial intelligence and wearable sensors, which could be used during clinical trials.

To strengthen its foundation for data analytics, FDA has been working on initiatives in food import screening and medical devices. For pharma, key targets are drug safety testing and development of real-world data approaches.

In December 2020, FDA signed contracts with Palantir and SAS to build the database foundation required (10,11). Bio/pharma companies, including Novartis, Roche, Merck, Pfizer, AstraZeneca, and GSK, have also been actively working in this area, with more firms using AI for clinical trial optimization (12).

Among the challenges for pharma companies that have already embraced new technology is finding, cleaning, and reorganizing data to be research-ready so that AIML platforms can yield useful results, says Kotchie. Another new capability that will be required, she says, is the ability to translate business problems to how users make decisions, and ensure that the user experience of new systems is able to maximize the application of the models developed. “This is an area that the new discipline of ‘decision intelligence’ is helping us to address,” Kotchie says.

But even without the advantage of new technology, clinical trial flexibility has had to be balanced by strict risk evaluation and management. Business continuity programs have been crucial, says Teresa Lamentia, senior vice-president of operational transformation and performance at IQVIA, who also leads the company’s COVID-19 task force for R&D.

IQVIA’s clients range from small innovators to large pharma companies, and although some firms had to halt projects in 2020, most have restarted efforts, she says. “We’re not back to previous levels, but recruitment is definitely increasing and this trend should continue in 2021,” she says.

Lamentia and her team take a three-pronged approach, examining every trial protocol from the standpoints of patient safety, data integrity and robustness, and day-to-day realities affecting site visits (e.g., to ensure that subjects receive trial drugs and have necessary tests performed when COVID restrictions cause a site to be shut down).

Detailed reports were then developed to ensure that risks would not affect pharma clients or patients. As she notes, the company had to adopt remote approaches, for dosing or for patient testing, and wound up taking a hybrid approach combining on-site and remote elements.

This method demanded that both the CRO and pharma company pay close attention to supply chain issues. For IQVIA, an especially challenging problem was the sourcing of personal protective equipment and ancillary products for technical and business staff. Outside the United States, particularly in the United Kingdom and European Union, conformance with patient data protection regulations was another challenge.

In general, clinical trials are being run to optimize flexibility. “Taking an ‘umbrella’ approach to protocols allowed us to be able to perform more tests concurrently,” Lamentia notes.

It is not yet clear which new methods adopted during the pandemic’s first year will become permanent best practices, she says, but she expects to see more remote study approaches and more flexible clinical trial designs dominating drug development in the future. Based on regulatory and corporate plans, data monitoring and analytics promise to play an increasingly important role as well.

1. J. Hopkins, “How Pfizer Delivered a COVID Vaccine in Record Time,” 

, Dec. 11, 2020.
2. S. Mukherjee, moderator, “Can a Vaccine for COVID-19 Be Developed in Pandemic Time”, 

 June 9, 2020.
3. A. Shanley, “The Last Mile: COVID-19 Vaccine Developers Prepare to File for Emergency Use Applications,” 

18 (162) (2020).
5. S. Hahn, “Remarks by Commissioner Stephen Hahn MD on the COVID-19 Pandemic—Finding Solutions and Applying Lessons Learned,”

 June 1, 2020.
6. C. Leaf, “The Whole World is Coming Together: How the Race for a COVID Vaccine is Revolutionizing Big Pharma,”

, Sept. 21, 2020.
7. BDO Life Sciences, “2021 BDO Life Sciences CFO Survey,” Report, January 2021.
8. A. Vadas, T.J. Bilodeaux, C. Oza, “Special Report: The Evolution of Biomarker Use in Clinical Trials of Cancer Therapies,” 

, 2019.
9. FDA, “Innovative Science and Technology Approaches for New Drugs (I-Stand)”

, Nov. 30, 2020.
10. C. O’Donnell, “Palantir Wins $44 million FDA Contract,” 

 Dec. 7, 2020. 
11. SAS, “FDA Inks $49.9-Million Dollar Deal with SAS”, 

, Jan. 11, 2020.
12. Novartis, “AI at Novartis,” 


Vol. 45, No. 2
February 2021
Pages: 16-18

When referring to this article, please cite it as A. Shanley ,“Drug Developers Put Pedal to the Metal,” 

New approaches to clinical trials, spurred by the COVID-19 pandemic, have dramatically shortened development timeframes. Can these gains be sustained once conditions return to normal?










Drug Developers Put Pedal to the Metal

Cell and gene therapies (C&GTs) have made huge advances in a few short decades. By February 2020, five therapies were on the market and FDA had approved nine more, while 362 treatments were in the US pipeline, up 25% from the previous year, according to the Pharmaceutical Research and Manufacturers of America’s latest survey (1). 

In September 2020, the first patient was dosed with autologous chimeric antigen receptor (CAR-T) lymphoma treatment using an automated closed system. “Despite complex and mainly manual processes, we can produce these therapies. Now we must work on making processes reproducible,” says Joerg Ahlgrimm, president and chief operating officer at The Discovery Labs, who was previously head of global C&GT operations at Lonza Pharma & Biotech.

Significant progress has already been made, he notes. “The fact that we can routinely upscale a viral vector to 200–500 L standard represents a huge accomplishment. Years ago, we could not even have imagined reaching this point. And now, we are approaching 2000-L batch sizes,” he adds. The Discovery Labs is building a Center for Breakthrough Medicines to accommodate 80 to 120 C&GT customer development programs at any point in time. 

For now, the goals are clear, Ahlgrimm says: stable cell lines, better scalability, smaller footprints, and better automation. He sees autologous therapies dominating with adeno-associated virus (AAV) and lentivirus vectors the dominant vehicles for manufacturing.

Both autologous and allogeneic therapies face steep hurdles to commercialization. Where allogeneic therapies are a bit more similar to traditional biopharmaceuticals, autologous therapies change the manufacturing paradigm completely, adding the extra steps of cell collection from patients and transport to and from patients to manufacturing, necessitating a just-in-time approach that is new to the industry. “On the autologous side, most processes are still extremely manual, and they are still coming into the manufacturing space as laboratory type setups, so they’re really going fresh from the bench to the GMP suite,” says Ahlgrimm, who sees the solution in closed equipment systems that remove human beings from the process as much as possible. Additional challenges include the need to coordinate manufacturing activities to optimize scheduling, and the flexibility to accommodate changes in protocols that can be expected in brand-new manufacturing processes.

Progress is clearly being made. At the end of 2020, Discovery was in final negotiations with potential clients, more than half of which are focusing on AAV with an emphasis on mid-range to high-volume vector manufacturing, Emily Moran senior director for viral vector manufacturing at Discovery Labs told Pharmaceutical Technology in December 2020. “We’re definitely seeing a progression in industrialization as we know it, and are working to ensure diverse offerings to clients. We don’t want to limit what needs we are able to meet,” she says.

While Discovery is starting to move into lentivirus processing, Moran says that most gene therapy projects currently underway are processing AAV vectors. The CDMO/incubator is working with both triple transfection, which is feasible up to 500 L, and virus-mediated processes, both of which may be better suited to a scale-out, rather than a scale-up strategy. Standard suspension-based bioreactors also continue to be important, Moran adds, since they offer high yield and can also improve scaleability downstream, for viral vector as well as cell therapy development. Discovery has designed its suites to be able to accommodate both allogeneic and autologous processes. “Allogeneic is where a lot of cell therapy should be heading, and process development in that field is similar to that for vector manufacturing,” Moran says.

The past few years have seen closer partnership between developers and CDMOs and technology vendors, including smaller, specialized equipment companies, some of which are new to this corner of the industry. CDMOs provide a showcase and reference and show how their technologies can be used. “Upstream, many of our suites feature automated equipment, including new bioreactor technologies,” says Moran. One new presence upstream has been Distek, which has introduced bench-scale bioreactors designed to make scale-up or scale-down more efficient, she says.

Downstream, Moran notes, the focus is on recovering the maximum amount of full vector particles by optimizing chromatography resins, materials, and charges. Discovery is also planning to have capabilities in ultracentrifugation, which can lead to a more manufacturable process, Moran says. Refractive index is being evaluated as a way to improve extraction of the material. “It’s a bit less manual and can improve recovery,” she explains. In formulation, she notes, Discovery’s scientists are not only focusing on final formulation parameters, but also on improving buffers. “By optimizing the best salt concentration, we can make our own buffers rather than buying them.”

January 2021 brought a major vendor-CDMO collaboration, when Cytiva and Lonza completed work on a new 17,000 m2 modular KuBio plant based in Guanzshou, China. The facility, which includes both process development and manufacturing capacity and employs single-use technology, can be used for AAV production as well as for more traditional monoclonal antibody production, and has been designed to optimize quick scaleup or scaleout. Partners say the project took two years, from site selection to completion.

Hurdles in data and supply-chain management

Additional challenges for cell and gene therapy developers include the need to coordinate manufacturing activities to optimize scheduling, and the flexibility to accommodate changes in protocols that can be expected in brand-new manufacturing processes. The manufacturing setup for autologous therapies is different from anything that has existed in the past, says Alberto Santagostino, senior vice president and head of cell and gene therapy manufacturing at Lonza Pharma & Biotech, who spoke about these issues in a BioPharm International webcast (2). “It is important to integrate data management, chain of compliance, and chain of custody, by tracking every single unit operation, every activity, every piece of equipment, and every operator back to every batch, and connecting that data to the external supply chain,” he said.

The company has partnered with the software specialist, Vineti, to integrate Lonza’s manufacturing execution systems and electronic batch recordkeeping software with Vineti’s supply chain orchestration platform, using application programming interfaces to feed chain of identity and chain of custody data to Lonza’s manufacturing floor. From a supply-chain standpoint, autologous treatments pose inherent risk since both supply and distribution are traced to a single source. “Anything as simple as needing to change a time or day for cell collection when a patient is ill can interrupt cycle times and deliveries,” says Mark Sawicki, CEO of Cryoport Services, a logistics specialist that is working with Lonza and Vineti.However, allogeneic therapies pose problems of their own, particularly on the distribution side, notes Sawicki, including a host of shipping and distribution issues. An example would be performing a drug product label verification on a cryogenic product. “You can’t pull product out of a cryogenic shipping environment to verify the label,” he says, noting that most third-party logistics providers do not currently have the ability to support these products to any scale.

Automation and digitization will be key to improving autologous manufacturing, reducing error and cost. On a fundamental level, Santogostino explained, they will ensure patient safety, but they also promise to reduce costs by eliminating the errors caused by manual processes. “Robotics is likely to be more dominant in autologous C&GT than it might have been for biologics or traditional biopharmaceutical manufacturing,” says Ahlgrimm.

In September 2020, the first patient was dosed with autologous CAR-T therapy using the Cocoon platform, a closed and automated system developed by Octane Biotech, which Lonza acquired an 80% share of in 2018 and has helped develop. The device features a single-use cassette, including process operations, media, and consumables. The work took place at the Sheba Medical Center in Israel, which boasts an experienced cell therapy team and had an ongoing CAR-T clinical trial underway, explains Matt Hewitt, head of R&D and Clinical Development at Lonza.

Hewitt says similar projects are being considered in other parts of the world, including the United States and European Union over the next 12 to 18 months. He sees the project proving that onsite, decentralized manufacturing at the point of care will be possible. “It won’t be the only way to do things in the future, but will be an option for some facilities,” he says. 

The study also proved the technology’s potential effectiveness in reducing the cost of goods required to manufacture the therapies, Hewitt says, by addressing two main cost drivers: cleanroom space and skilled labor. “A traditional open manual process uses Class B cleanroom space, where the closed system with integrated culturing can run in Class C space. Even a back-of-the-napkin calculation suggests a 40% reduction in costs,” he says. Lonza is now looking at ways to integrate manufacturing execution systems and electronic batch record keeping functionality and logistics tracking into the software. The company is also exploring the addition of beads that would allow for magnetic separation as well as the incorporation of new sensors (e.g., for glucose) and process analytical technology (PAT) that would enable setpoint-based control, Hewitt says.

More “forward facing” approaches to process development and scale-up, with Phase III and commercial stages firmly in sight, are also boosting manufacturing improvements, says Thomas VanCott, PhD, global head of product development at Catalent Cell & Gene Therapy. For example, he says, pre-process performance qualification activities (e.g., designing target product profiles, identifying critical quality attributes [CQAs] and critical process parameters [CPPs], and considering optimal scale-down models) are being done earlier in the cycle.

Before any process-development effort begins, or any external customer process is transferred to the company, initial gap analyses and risk assessments are done for both the process and raw materials to determine whether the process can be scaled to meet the product’s long-term clinical production needs, VanCott says. Analytical needs must also be determined, to assess whether the desired quality attributes are being achieved and in evaluating any critical raw materials.

Quality problems can stem from manufacturing, when parts of the AAV’s native genetic material are removed and replaced by a transgene, the therapeutic gene and genetic elements that support the gene’s activity and expression, explains Stephen Gacheru, vice-president at PPD Laboratories GMP Lab. For recombinant AAV (rAAV) vectors, good quality equates with having a high level of capsids that contain the full transgene, Gacheru explains. Empty and partial capsids are considered product-related impurities, which can impact product efficacy and safety, posing risks of increased immunogenicity to the therapeutic vector and related immune responses, he says.

At Catalent, assessing the analytical requirements for rAVVs at the earliest developmental stages has led to significant improvements, says VanCott, allowing quality deviations to be found before scale-up, reducing the risk of cost overruns. In addition, there is an emphasis on scaling out, rather than simply scaling up, VanCott explains, and this is true for both suspension and adherent viral vector manufacturing processes, as well as autologous cell therapy production.

There may be an evolution in approaches to scaling up allogeneic therapies, he says. Currently, larger scaleup has been precluded by the absence of stable producer cell lines and transient transfection processes in viral vector manufacturing. “For gene therapies, scaling out and combining multiple upstream runs into downstream processes has been more common,” notes VanCott.

For the viral vectors used to make gene therapies, use of perfusion, seeding, and intensification has been less critical than it is for some traditional biologics because of unique processes associated with the transient transfection process used to produce viral vectors, VanCott says. However, perfusion is an advantage for other viral vectors such as the baculovirus/Sf9 platform, he says.

In addition, lyophilization strategies are being explored because liquid formulations require storage below -20 °C, posing challenges for formulation and vial composition. Formulation research projects are underway to address these challenges, VanCott says. Stable producer cell lines for AAV production will be key to reducing costs and improving scale-up (e.g., by obviating the need for clinical-grade plasmid DNA for transient transfection processes), he says.

New equipment designs are helping to advance scale-up goals. For example, Univercells Technologies recently commercialized a platform (NevoLine Upstream) that enables viral manufacturers to chain, integrate, and intensify processes, explains Mohammed Elfar, product innovation manager at the company, while the company’s fixed-bed bioreactors (scale-X) have been improved to enable linear scalability from the bench to the plant.

Similarly, Pall Corp.’s fixed-bed bioreactors (iCELLis) have been optimized to improve scale-up from the bench to the production floor. As Byron Rees, Pall’s senior manager of process development services notes, cell and gene therapy developers often choose to adapt adherent cells to suspension for viral vector manufacturing because they think this approach will speed scale-up. However, that approach can add months to process development time. As an alternative, he says, iCELLis can be used to scale up adherent cell-based processes to commercial scale while cutting process development timeframes down to three months.

Further upstream, the company’s nano bioreactor (iCELLis Nano) has been designed to optimize benchtop-scale (i.e., 0.53 m2– 4 m2) work and transfer to the large-scale manufacturing bioreactor (iCELLis 500). Using the larger bioreactor, customers can scale their production from 66 m2– 500 m2 within the same footprint, allowing more manufacturing flexibility with the ability to accommodate various molecules with different scales of demand, says Rachel Legmann, director of technical consultancy for gene therapy and viral vectors at Pall.

At Cytiva, equipment lines used for traditional biopharmaceutical manufacturing are also being optimized for use with cell and gene therapies. Not only single-use process equipment, but harvest clarification equipment, affinity resins, and low- shear pumps are areas of focus, says Joe Makowiecki, director of business development for FlexFactory and KuBio products.

Industry standards promise to clarify best practices and requirements, and help move more cell and gene therapies to market. The International Organization for Standardization’s (ISO’s) Standard 21973 (3) outlines best practices for manufacturing and distribution, Sawicki told webcast attendees (2).

Most notable have been its provisions for full traceability and the management of equipment used to ship the therapies, he said. “This equipment gets reused, so requalification processes are crucial to preventing product failures from occurring,” he told webcast attendees.

Sawicki expects future work to focus on cleaning recommendations to reduce risk of cross contamination. One area that regulators may need to address is establishing universal conventions around label templates, said Vineti CEO Amy DuRoss. “Different labeling conventions in different markets introduce unnecessary risk,” she said on the

 webcast (2), noting a need to move to on-demand printing capability.

There will also be a need to optimize analytical testing to ensure quality control with cell and gene therapies. In January 2020, FDA released preliminary guidance clarifying some aspects of this problem. Various analytical methods have been developed to determine an rAAV product’s composition of full vs. empty/partial capsids, says Gacheru, including analytical ultracentrifuge, transmission electron microscopy, spectroscopy (A280/260 ratio), anion-exchange high-performance liquid chromatography, size-exclusion chromatography with multi-angle light scattering, and capillary isoelectric focusing assays. 

Efforts are underway to make these methods faster and easier to use for release testing, says Gacheru. Cleaning validation also needs to be optimized for cell and gene therapies. Based on traceability requirements mandated in Australia, Cryogen developed a specialized cleaning validation approach for cell and gene therapies, as well as a customized shipping container to move C&GT products.

New technologies promise to bring additional improvements to innovative therapy development and manufacturing. Ahlgrimm sees artificial intelligence playing a key role and notes that digital technologies, such as augmented and virtual reality, are already being used to help Discovery Labs improve employee onboarding.

The new industry faces a lot of questions. Will production become decentralized and move entirely to healthcare centers or points of treatment in the future? DuRoss doesn’t expect that shift to be possible for at least another 15 to 20 years. As the market grows, every new C&GT submission and product in development will continue to educate the industry and regulators. “We can only expect that more will be learned and that requirements will change as the field of C&GTs matures,” Ahlgrimm says.

1.  PhRMA, “Medicines in Development: Cell and Gene Therapy 2020,” 

 2020.
2.  PharmTech webcast, “Editors’ Series: Cell and Gene Therapies: Laying the Foundation for a New Supply Chain,”

, July 29, 2020.
3.  ISO, “Standard 21973:2929: General Requirements for Trasportation of Cells for Therapeutic Use,” 


Supplement: Partnering for Bio/Pharma Success
February 2021
Pages: s12–s15

When referring to this article, please cite it as A. Shanley, “Collaboration Takes Cell and Gene Therapies Closer to Their Full Potential,” 

Pharmaceutical Technology Partnering for Bio/Pharma Success Supplement 

From scale-up and tech transfer to analytical method development and quality testing, alliances between innovators and contract partners, and between CDMOs and technology vendors, are taking more therapies from lab to patient.



Collaboration Takes Cell and Gene Therapies Closer  to Their Full Potential

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 

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,” 

 34 (1), p. 37, January 2020.
3. US Dept. of Health and Human Services, “

OWS Briefing on COVID-19 Vaccine Distribution

, Dec. 16, 2020.
4. O. Goldshield, “Pfizer-BioNTech Decision to Turn Off Temperature Sensors Forced Scramble to Secure COVID-19 Vaccines,” 

, Dec. 17, 2020.
5. Controlant, “US Dept. of HHS and Controlant Enter Agreement,” 

, Press Release, Dec. 18, 2020.
6. T. Spiro and Z. Emanuel, "A Comprehensive COVID-19 Vaccine Plan," 

, 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

The Last Mile” COVID-19 Vaccine Developers Prepare to File for EUAs,

, Nov. 11, 2020.
9. J. Stubbs, “Hackers Steal Pfizer-BioNTech COVID-19 Vaccine Data from EMA,” 

, Dec. 9, 2020.
10. IBM, “COVID-19 Cyberwar: How to Protect Your Business,”

, Dec. 4, 2020.
11. C. O’Donnell, “Pfizer-BioNTech Says Supply Chain Challenges Created Slashed Target,” 

“Information for Healthcare Providers on PFizer-BioNTech’s COVID-19 Vaccine


Vol. 45, No. 1
January 2021
Pages: 34-35

When citing this article, please refer to it as: A. Shanley, "COVID-19 Vaccine Distribution: Preparing for the Unexpected," 

As the first wave of mRNA vaccines are distributed, efforts will be needed to protect data and prevent errors.