Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

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 

Articles

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.

COVID-19 Vaccine Distribution: Preparing for the Unexpected

Despite limitations posed by the COVID-19 pandemic, FDA has continued to oversee bio/pharma operations, issuing warning letters and, occasionally, 483s, and performing plant inspections prioritized based on risk. In March 2020, the agency had postponed routine site surveillance inspections, resuming them four months later for “mission-critical inspections” (e.g., those required to approve potential COVID-19 therapies or vaccines, critical drugs that are in short supply, and novel drugs developed for serious conditions on fast-track approval), and issued guidance (1) on the subject.

Between March and October 2020, the agency conducted more than 200 such inspections, Judith A. McMeekin, associate commissioner for regulatory affairs with FDA’s Office of Regulatory Affairs, told attendees at the Food and Drug Law Institute’s (FDLI’s) annual conference on October 6, 2020 (2).

However, based on FDA 483 inspection data for the fiscal year, between Oct. 1, 2019 and Sept. 30, 2020, FDA conducted only 28 biologics plant inspections in 2020, compared with 116 the year before, and 349 drug facility inspections vs. 779 in 2019 (3,4). The lower inspection numbers in 2020 also reflect five months before COVID-19 travel restrictions prevented the agency from conducting inspections.

In lieu of onsite inspections, FDA is taking a number of different approaches, including document review (permitted under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act), before or in place of onsite inspections, McMeekin said. The agency is also leveraging inspection reports from other global regulatory authorities, under the Pharmaceutical Annex to the US/EU Mutual Recognition Agreement.

Well before the pandemic—in fact, for decades now—FDA has emphasized the importance of drug developers communicating with reviewers and inspectors at the agency. “Clearly, if one is a sponsor in need of a pre-approval or pre-license inspection, being in regular contact with the people at FDA who will be making decisions on your application is key, and should extend all the way up the chain of command if necessary,” says Mark I. Schwartz, director at the Washington, D.C.-based law firm, Hyman, Phelps, & McNamara, P.C. Schwartz spent 13 years at FDA, and left five years ago as deputy director of the agency’s Office of Compliance and Biologics Quality.

FDA’s new remote document review process has underscored the need for sponsor outreach and communication with the agency. Recent examples have shown what can happen when FDA reviews documents remotely, without sufficient context. “The biggest mistake a company can make is throwing things over the wall to FDA. It’s up to the owners of the documentation to put it into context for the regulators, requesting a meeting to discuss issues with them,” says Peter Miller, President/CEO of Dynamic Compliance Solutions (DCS), which offers a platform designed to help pharma companies handle remote audits.

In October, for example, Alkermes received a complete response letter (CRL) from FDA due to tablet coating issues with its new schizophrenia treatment ALKS 3831. Only after the company received the CRL did it discover that FDA was concerned about the tablet coating process that had been used to make development batches. The firm had reportedly resolved these issues for manufacturing-scale batches (5).

“In instances where FDA requests documents, it is very important to suggest a call with FDA prior to sending the documents, to at least give an overview of any nuances within the documents that exist,” says Schwartz. Recalling working on the “other side” on inspections while at FDA, he says, “One is constantly seeking input from subject matter experts at the facility regarding arcane issues in the company’s records. That connection is completely lacking if the firm just dumps the documents on FDA, and it can lead to misunderstandings with tragic consequences for the firm,” he says.

So far, FDA has been reluctant to approve use of technologies such as 360-degree video (6) to perform remote site tours and inspections. However, regulators—including the European Medicines Agency (EMA), the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), Health Canada, the Therapeutic Goods Administration (TGA) of Australia, Japan’s Pharmaceutical and Medical Devices Agency, and the Russian Ministry of Health—are all using some forms of remote technology for remote inspections (7).

McMeekin reported in October 2020 (2) that the agency had begun to pilot the use of new technologies such as live or recorded video in food-related investigations. “As we learn more from the pilot and decide how and when we might use these and other technologies, we commit to having transparent dialogues with regulated industry as to how this may affect our procedures in the future,” she said (2). However, FDA remains cautious about their use in pharmaceutical inspections. “The agency is exploring all options for evaluating facilities when a physical inspection is not feasible, [and] is assessing the potential use of other tools to serve as supplements to FDA inspections, including remotely evaluating pharmaceutical manufacturing operations, using remote live-streamed video and other remote and live interactions with facility operators and records,” Charles Kohler, press officer with FDA’s Center for Drug Evaluation and Research (CDER) stated in a written response to 

Some question whether the agency is moving quickly enough to approve the use of supplemental technology for drug and biologics inspections. In the title of an op-ed that was published in December 2020 (8), Schwartz accused FDA of ‘fiddling while pharma burns.’ “It’s difficult to understand the agency’s position, but it’s certainly not helpful,” he says. Schwartz argues that FDA’s stance against using new technologies for remote inspections has left patients without access to potentially life-saving therapies in 2020. As an example, he cites the agency’s failure to approve Bristol Myers Squibb’s (BMS) lymphoma treatment, the chimeric antigen receptor T cell (CAR-T) therapy, liso-cel. This approval delay, the second so far for the drug, happened in November 2020, when a local flare-up of COVID-19 in Texas prevented FDA investigators from traveling safely to BMS’s contract manufacturing partner’s (Lonza’s) facility for an on-site inspection. The postponement occurred, even though liso-cel met FDA’s criteria of a ‘mission critical’ inspection, in that the therapy had been granted breakthrough therapy and regenerative medicine advanced therapy designations, he says.

Schwartz also notes that there is a “real need” for timely pre-approval and pre-license inspections (PAIs and PLIs). “Companies’ livelihoods—and in some cases, their very survival—depend on it,” he says. It’s also crucial that FDA find a solution for non-mission-critical inspections, he says, since only a tiny fraction of the inspections that need to be performed have been deemed mission critical by FDA. “While the agency has been performing some record reviews, FDA is unwilling to overturn a facility’s Official Action Indicated (OAI) status based on a record review, so even if a firm’s records demonstrate full CGMP [current good manufacturing practice] compliance, it won’t overturn a previous problematic finding. FDA has also been ambiguous as to whether foreign regulatory reports can overturn a previous problematic FDA finding,” he says, leaving pharmaceutical firms with few good options.

The vast majority of facilities are still waiting for FDA to explain how the agency will determine their CGMP compliance status, Schwartz says. "The situation is bad enough for companies submitting new drug applications (NDAs) and biologics license applications (BLAs), but it’s horrific for companies with OAI status," he says. 

“FDA is basically telling firms that they cannot improve their regulatory status until the pandemic ends. This essentially means that OAI facilities cannot be listed as API or finished dosage form manufacturers in new NDAs, ANDAs [abbreviated new drug applications], or BLAs,” Schwartz says, “so they cannot get these applications approved for the foreseeable future.”

Schwartz has asked FDA for a breakdown of how the agency is performing inspections but hasn’t received a response so far. He senses that the agency’s leaders are concerned that the technology won’t offer a complete view of what’s going on in a facility. As a result, he says,“They have failed to heed the truism of not letting the perfect be the enemy of the good, or the good enough, as the case may be.”

No inspection, even when it’s onsite, can really offer a complete view of what’s going on, Schwartz explains. “All inspections, whether remote or on-site, are only a snapshot into the firms’ CGMP compliance status. In a one-week onsite inspection, investigators can only really see certain portions of the facility, certain activities and manufacturing practices, and review a finite number of records. In practice, you’re limited to a set amount of time which limits what you can discover about the CGMP practices at the facility,” Schwartz says. It’s crucial for both regulators and companies to know that using technology in remote inspections can work, but won’t be perfectly equivalent to an on-site visit, Anne Miller, senior counsel for Medtronic said during a panel discussion on remote inspections at FDLI’s December meeting (7). “Regardless of the purpose of the remote audit, as an inspection by a regulator or a proactive site visit as a part of a sponsor’s compliance program, it’s not just about accepting the latest technology, but how effective the audits are in the end, which is based on completeness and consistency,” says Miller of DCS. His company is working with the Parenteral Drug Association (PDA) to help establish best practices for auditors and auditees during remote audits.

The fact that US legislation has often been interpreted as requiring that agency inspectors be physically present on site may be slowing FDA’s use of remote technologies for inspections. A simple solution is broadening or redefining what “on site” means, says Miller. Coming up with the best definition will likely require working with industry partners, through groups such as PDA and the International Society of Pharmaceutical Engineering (ISPE). “Guidance from FDA on the use of these technologies isn’t likely to come any time soon. It would likely be more productive to have industry stakeholders identify requirements,” he says, noting that PDA is hosting a virtual conference in January 2021 to define some of these issues.

There are also some pre-requisites for any kind of remote inspection process to be considered effective. First, the facility tour must be interactive in real time and the auditor needs to be in control of what he or she is looking at, says Miller. In addition, no modifications or augmentations to the environment can be allowed, he says, and most companies don’t want anything to be recorded in video or photos.

At a special panel on remote inspections at FDLI’s December 2020 conference, Stephanie Haggerty, senior counsel at Pfizer, discussed the company’s experience with remote inspections during the COVID-19 pandemic (7). “There are growing pains on both sides,” she acknowledged, although she expects new technology to play a greater role in the future. The company had anticipated more than 20 FDA GMP inspections in 2020, she said, but did not have any onsite inspections from February through December, and all good clinical practice (GCP) inspections were in person in the US in 2020, she said.

Haggerty discussed FDA’s requirements for documentation using FDA’s Inspection Records Request Form 4003, which requires that inspected companies provide extensive lists of deviations, recalls, and lab events. “Pfizer sites have had to make over 30 submissions in order to complete each request,” she said, and translations can double the volume of submissions.

In addition, there are size limits to what FDA can receive, requiring that responses be broken down into as many as 30 to 50 pieces, she said. Pfizer has not received requests from FDA for virtual inspections, but has had a number of them with other global agencies, Haggerty said, emphasizing that pre-inspection discussions must carefully consider such details as time zone differences when coordinating the timing of reviews and interviews.

For audits of suppliers and contract partners, smaller companies are becoming more comfortable with the remote approach, although many professionals recognize that it may not be the best way long term and its use will depend on the situation involved. “A big part of any audit, whether remote or onsite, is document reviews, and as long as there is a way to share document securely, remote audits work well for now” says Joelle Yang, head of HBT Labs’ quality group. “When the pandemic is over, I am still planning to focus on onsite audits, because it is not clear how FDA will respond to remote audits for critical suppliers (e.g., for contract development and manufacturing organizations and API suppliers). But, for non-critical suppliers, remote audits work well,” she says.

As for compliance issues found during plant inspections, the same problems tend to be recurring. Between Oct. 1, 2019 and Sept. 30, 2020, FDA issued 28 warning letters to biologics manufacturers and 349 to drug manufacturers (2). Echoing past years, the top four problem areas, according to FDA, included inadequacies in the following areas: defining quality unit responsibilities; reviewing batch failures; implementing and following lab and sampling procedures and written procedures; determining the root cause of out-of-specification (OOS) events; and establishing process and cleaning validation practices.

Water system and other maintenance problems figured in a number of inspection reports. One Canadian manufacturer of over-the-counter medications was cited for many of these problems, including lack of process validation or cleaning validation procedures; lack of stability data; failure to test incoming raw materials; inadequately outlined quality unit responsibilities; and water systems issues.

Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers Guidance for Industry,

Remarks at the Food and Drug Law Institute Annual Conference

, December 2020.
5. B. Cox, “Can We Talk? US FDA Remote Records Review Missteps Worry Industry,” 

(December 2020).
7. FDLI Institute, “FDA Inspections in the Age of COVID-19, a Panel Discussion,” The Food and Drug Law Institute Conference, Dec. 15, 2020.
8. M. Schwartz, “FDA Fiddles with Remote Inspection While Pharma Burns," 


Vol. 45, No. 1
January 2021
Pages: 46-49

When citing this article, please refer to it as: A. Shanley, "FDA Inspections Remain Stalled During the COVID-19 Pandemic," 

During the COVID-19 pandemic, when inspectors cannot visit sites directly, FDA is relying on other global inspection reports and remote document review, yet does not consider them equivalent to on-site inspections. Manufacturers await more clarity. 

FDA Inspections Remain Stalled During the COVID-19 Pandemic

Disclaimer: This article reflects an editor's views based on interviews and a review of documents. It in no way represents the official opinion of our magazine or company.

Like any organization, FDA has been criticized for political divisions and resistance to change.

In the late 2000s, the agency launched initiatives designed to hire more technical people with engineering backgrounds and better understanding of the scientific principles behind genomics and concepts such as biomarkers. Efforts were made to recruit more inspectors, improve inspector training, and to harmonize requirements and expectations. As Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research (CDER) noted in testimony to Congress in December 2019, inspector training and support remains a key area of focus for CDER and the agency.

But questions may remain about how well inspectors outside of CDER are keeping up with the quick pace of scientific and industry change. Team Biologics, a core group of 14 inspectors and managers, is responsible for ensuring the safety of vaccines, plasma derivatives, and other biologics. 

Part of FDA’s Office of Regulatory Affairs’ Office of Biological Products Operations, the team faces a daunting task, at a time when technologies are constantly changing. In addition, their inspection activities can range widely. One day, a team inspector may be called upon to visit an advanced personalized medicine facility and the next a commodity vaccine plant, the type of installation that does not typically receive much in the way of upgrades or capital investment. Balancing responses so that they are not overly punitive, yet protect the public, is not easy.

On December 18, FDA Press Officer Jeremy Kahn issued the following statement affirming the agency’s commitment to its inspectors, and to supporting and continuing to build on the expertise of Team Biologics.

“…The agency’s investigators are essential to the FDA’s ability to help ensure the quality and safety of medical products. FDA’s investigators are experienced and trained professionals, and the agency provides its investigators with numerous resources to support inspections and investigations, including continuous advanced instruction and training… The Team Biologics Staff (TBS) currently has 14 investigators. The FDA plans to increase the number of investigators assigned to conducting surveillance inspections of biological products regulated as drugs (e.g., vaccines, recombinant therapeutic proteins and cellular and genetic therapies),” he wrote.

However, in early December, reports of a former FDA inspector’s whistleblower complaint in 

(1) focused attention on the timelines, training, and support given to inspectors on Team Biologics. 

The report focused on vaccine manufacturing, but when examined more broadly, the complaint also raises some fundamental questions about the benchmarks that are used to determine compliance with current good manufacturing practices (CGMPs) at biologics facilities, and whether there are unwavering standards for judging data integrity and aseptic conditions, overall manufacturing safety, and product quality. 

On the corporate level, it also provokes questions of whether industry operators are receiving the basic respect required for them to solve problems and do their jobs properly, and whether changes in shift scheduling and better approaches to gowning and error prevention are needed. This is particularly important at commodity vaccine facilities, some of which are older and whose products may be essential for the public, but are not financially profitable to their manufacturers.

Near the end of 2018, former Team Biologics staffer Arie Menachem filed a complaint with the Office of Special Counsel (OSC), an independent agency established to address federal employee whistleblower complaints. He alleged that his supervisors had downplayed serious concerns that he had noted during facility inspections. 

Plant inspection is by definition subjective, and results will vary depending on the training, background, and interests of the individual inspector. However, Menachem’s complaint would seem to demand clarification of the following questions:

Are there unwavering definitions (transcending subjectivity) of what constitutes a serious versus a routine instance of noncompliance (or, using the language of FDA 483 Letters, what should merit an official action indicated [OAI] vs. a voluntary action indicated [VAI] citation)? 

Are sufficient resources and time being allocated to facility inspections and their analysis and followup, by inspectors and their supervisors?

Can there be room for internal dispute resolution within the agency when disagreements come up between field inspectors and management?

Is the agency taking sufficient care and responding quickly when confidential informants at manufacturing facilities risk their livelihoods to present documentation of chronic compliance problems?

The following is a brief summary of the story behind the complaint, without company names.

 that he found a number of serious CGMP compliance problems during routine biopharma facility inspections in 2017 and 2018, a year that started off with furloughs at FDA and the US Health and Human Services and a government shutdown. In these cases, Menachem says, he had issued 483s with “official action indicated,” requiring that FDA take administrative action and suggesting that recipients address problems before a followup inspection could trigger a Warning Letter.

He says that he began to notice a trend of managers systematically downgrading OAIs to VAIs, even though the problems that he had seen could compromise fundamental aseptic quality and data integrity, and result in adverse effects in patients.

He began to correspond with an OSC attorney in late 2018. OSC requires that departments cited in the complaints resolve them independently, instead of sending them to a neutral third party, so Menachem’s complaints were returned to FDA, and Team Biologics leadership officially dismissed them and closed out their investigation of the matter in June 2019.

Knowing that his dismissal was imminent and that, if he withdrew his complaints, he would be banned from government service for “only” seven years instead of for life, Menachem chose instead to resign from a job that he had embraced with enthusiasm and energy, and now works in the private sector. He had joined Team Biologics after 2.5 years at FDA. “I was excited to join, because of the intellectual challenge, but also the motivation to protect and promote public health,” he says. 

As he noted, the short deadlines for filing detailed reports posed significant challenges for field and team managers alike. For inspectors, an OAI designation requires that a full report be filed 10 days after the site inspection. “If we found something to be OAI, we had to tell our supervisor about it ahead of time, in order to write the report within the 10-day deadline. That was difficult, in and of itself, because it required coordinating with the different people involved in the inspection,” he says. Supervisors then had 30 days to review the report, discuss findings with the inspectors involved, and begin to prepare a response to the manufacturer.

Perhaps the most dramatic examples of noncompliance were seen at a vaccine manufacturing facility in North Carolina. Menachem was assigned to inspect the 450,000 square foot factory, which manufactures both API and finished drug product, by himself, a task that would normally be assigned to two people. “We’d never done a solo inspection of this facility, which makes both API and finished product. It was like doing two inspections in one, using half the resources and in less time,” he said. Then, at 3 PM on the first day of the inspection, he received an unexpected email with a 20-page long document, a confidential informant’s (CI’s) complaint about ongoing CGMP problems at the site, he said.

Menachem asked his supervisor for help, but was refused. When he contacted the informant, Menachem found that the employee was concerned about conditions at the facility and anxious for FDA to use the information he had reported, in order to perform a more comprehensive inspection.

As it turns out, a compliance officer at FDA had received the CI’s report 11 days before Menachem’s inspection started, but had not shared it with Team Biologics. In addition, the same informant had sent a similar complaint to FDA in 2016, before the agency was scheduled to inspect the facility that year, and yet the agency did not share the letter with the Investigators that performed the 2016 inspection.

While Menachem’s supervisor focused on the late transmittal of the informant’s report and procedural issues, he grappled with the content of the letter. “I was in the middle of an inspection, and now I had to follow up on this CI complaint and do a GMP inspection, which was inadequately staffed to begin with, all while protecting the informant and not revealing any hints that could clue the manufacturer to the fact that an informant had complained.”

According to the CI’s account, staffers were forced to remain in place for long shifts, foregoing bathroom breaks that would require their degowning and regowning, a process that can take more than 30 minutes, because there were no staffers to cover them while they were away from their stations.

The CI had included in his complaint a photo of a biohazards bin right in the middle of a gowning area, which he said had been removed before FDA inspectors arrived. In documentation, Menachem soon found the smoking gun that proved it had existed. “A deviation report referred to a technician who had cut himself but didn’t report it, and then threw a bloody glove in a regular waste bin. The report noted that the glove should have been put “in the ‘biohazards bin’“ he says, into which operators were also alleged to have deposited gowning soiled by urine and fecal matter.

The informant had also reported that staffers moved to differently graded classified areas in the facility, contrary to the required directional flow. They all wore the same color uniforms (contrary to best practices, in which staffers’ uniforms are color-coded or differentiated based on the level of classification of the area they work in) and one couldn’t tell where they had been, where they were going, or where they were supposed to be at any given time, Menachem recalls. He verified this, he says, by noting the way handles were installed on facility doors, which would allow staff to move in a direction opposite to the required flow. The company claimed that state building code required the handles to be installed that way.

He says that he looked into environmental monitoring and glove checks, but found multiple instances in which no indentation in the plates that would have suggested that staff fingertips were being checked for contamination. When he asked that plant employees save and show him plates that had actually recovered microbes, he was told that the plates had been thrown out, against his express request. Other problems included deleting footage from a cleanroom video and removal of documents from a shredder. Are these problems substantially different from the stonewalling tactics that some facilities in China have used when dealing with FDA inspectors?

But noting the problems was only the first hurdle. Menachem saw the key problem as adulteration of evidence, most flagrantly demonstrated by removal of the biohazards bin before the inspection. However, his supervisor wanted him to zero in on individual technicians and how well they followed gowning procedures. Doing this would be impossible, Menachem said, given the way that gowning procedures are set up. “It became clear that [my supervisor] had never performed a inspection of an aseptic manufacturing facility,” he says. 

Fudging potency and averaging OOS results

That was not the only problem noted in his complaint to the OSC. In another instance, Menachem noted that a facility that manufactured a treatment for hemophilia was fudging potency results, taking vials from various batches to achieve desired results. They were also averaging out-of-specification (OOS) results in stability testing. “Averaging OOS results meant that you had no idea when the product would expire,” he said. That OAI recommendation was also downgraded.

Another writeup was for tests that were licensed by FDA’s Center for Biologics Evaluation and Research and used to fractionate plasma to ensure that donors did not have diseases such as HIV or hepatitis. Menachem found data integrity problems, including one login for all analysts, preventing traceability, as well as the fact that alarm and other data could be easily deleted or changed without detection.



Menachem believes that time pressure and workload contributed to some problems that occurred during his tenure with Team Biologics. “Supervisors had to downgrade inspection findings, in part, because they didn’t react in time,” he says. “But whenever an inspector describes something as OAI, people’s lives are at stake.” Training was another problem, Menachem said. Few people on the supervisory chain of Team Biologics had been specifically trained in drug inspection, and a number of team members came from food and devices, he says, despite the fact that they are overseeing complex therapeutics, such as cell and gene therapies. The one time three-hour training program given in gene and cell therapy was not enough, he says.

Before taking his complaints to OSC, Menachem says, he had contacted everyone along the supervisory chain, even going to the head of operations, to alert them to potential dangers to patients. Even in his initial letter to OSC, he insisted that he had no personal grudges but was genuinely concerned about patients. FDA received the report in February and his computer was taken away from him, and from that point on, Menachem’s story follows the traditional whistleblower path. 

One quirky note in the CI’s message to FDA noted that staff members at the vaccine manufacturing facility mentioned in Menachem’s complaint would sometimes dance during longer breaks, occasionally videotaping these activities. Strange behavior for people at a pharma plant. Definitely not regulated by CGMPs.

But is that behavior common in hospitals? In the Spring of 2020, when makeshift morgues were set up throughout New York City, households opened their windows every evening at 7 PM to make noise to recognize the heroism of healthcare workers treating patients with COVID-19. Physicians and nurses at hospitals around the world were videotaped dancing. One can only assume they did that to maintain spirit, despite few resources and unbelievable stress.

Not that pharma workers’ situations are in any way comparable to those of healthcare workers during this second, terrible COVID-19 surge. But nobody is making noise for, or can attest to the stress that some bio pharma operators (or regulatory agency inspectors) may be experiencing. That’s what makes accounts like Menachem’s important.

One former operator at the vaccine plant emailed Menachem after the 

 article came out in December, a note that Menachem shared with 

, corroborating shift, gowning, and other problems and a grueling, exhausting job. Despite his respect for what the industry does, he has left pharma and is now working in a different industry.

There are no villains in this story. But whether or not FDA agreed with Menachem’s version of the truth, allegations in his complaint suggest problems that require communication and collaboration to resolve, and may be driving idealistic people out of bio/pharma. What are your thoughts?

1. K. Eban, “The COVID-19 Vaccines are Approaching: Is FDA Ready to Inspect the Plants Where They’re Made?” 

A whistleblower’s complaint raises questions about FDA inspector training and support, as well as CGMP noncompliance patterns at biologics facilities.

Whistleblower Complaint Raises Questions About FDA Inspector Training and Support

The late US President John F. Kennedy once remarked that any crisis represents both a danger and an opportunity (1). He had illustrated the point with Chinese characters, in an analogy that, like his famous Berliner quote, was found to be wrong. But the observation that good things can come out of a crisis holds true. As the COVID-19 pandemic continues to disrupt lives and business operations around the world, some drug companies are achieving unprecedented efficiency improvements. Despite travel restrictions and other limitations, a few have stepped up collaboration and slashed development times by 80%.

Many companies have started to use, or have increased their use of novel technologies—not only standard web video-conferencing tools, but platforms that incorporate video, augmented and/or virtual reality, and features such as borescopes and secondary cameras — to allow partners and regulators remote access to facilities, equipment, and documentation. For some companies, these tools had already been in use on a limited basis to audit suppliers, troubleshoot technical problems with vendors and consultants, and improve collaboration with customers. Using them for interactions with regulators represented a whole new use case.

For an industry known for its aversion to risk and new technology, the move to virtual technology was driven by necessity. Challenges had reached a high point in March 2020, when the FDA commissioner said the agency would be postponing routine on-site surveillance inspections (2). At the time, shortages were developing for commodity drugs, including some that were being used to treat COVID-19 and its associated problems.

Companies that had spent millions to develop new, non-COVID treatments could not have post-approval inspections performed, delaying progress. “Some customers were on hold and losing millions of dollars each day,” says Devon Copley, CEO and cofounder of Avatour, whose remote inspection platform focuses on immersive 360-degree video.

“The whole industry went through massive shock. Senior managers were concerned about supply chain preservation and how to even conduct normal daily operations,” says Angelo Stracquantanio, CEO and cofounder of Apprentice.io, whose remote inspection platform is centered around augmented reality and works with smartphones and other mobile devices. “There were questions of how to handle tech transfer, factory and site acceptance tests, and regulatory inspections when the world was no longer travelling,” he says. Apprentice responded in March by releasing rapid deployment kits, “do-it-yourself” packages that would allow companies to set up the technology required for remote inspections, themselves. Since July 2020, Stracquantanio says, usage of the platform has expanded by a factor of 17, and new site deployments by a factor of ten. On November 17, 2020, he says, the company received $24 million in venture-capital funding, bringing its total to $40 million in 2020. During the pandemic, the company has worked with clients to improve its Tandem platform, and recently introduced a Tandem Smart Hub specifically designed for use in cleanrooms, adds Stracquantanio.

Taking a different approach to virtual inspections is Avatour, which was established in 2017, and offers a remote inspection platform designed for location-immersed collaboration and 360-degree video. The technology, which was prototyped and beta-tested in 2019, works with smartphones, and can be used with a browser or virtual reality goggles for full immersion, says Copley.

Avatour’s cofounders are experts in this technology, having helped lead the Nokia team that invented and integrated the 360-degree video camera. Demand for the platform has been growing briskly, Copley says. Avatour has seen 25% growth per month, and roughly 12 pharma companies and consultants have deployed or are deploying the system, he says. This year, the company has released regular updates, increasing the number of people who can take part in a tour from five to nine, adding a secondary camera source, and integrating a microscope, Copley says.

Using Avatour’s platform is Lachman Consultant Services, which established a formal practice devoted to remote inspections and audits in October 2020. What began as a response to an overall top-down leadership commitment to find new ways to work, became more focused in March and April 2020, says compliance director Scott Deckebach. By the summer, Lachman had begun to engage more with the technologies and encouraged clients to do the same. Pharma companies are adopting these technologies because they find it easier to do this remotely than to let people into their facilities, Deckebach says. So far, Lachman has worked on fully, or highly, remote projects, even in China, which is one of the more difficult regions in which to do this, due to government restrictions on communications, as well as technology, time zone, and language differences.

Two parallel technology tracks are important in any remote audit, Deckebach says. The first is a more general 360-degree view. “Auditors need to be immersed in the environment in order to get an overall sense of facility flow and cleanliness. You cannot get that with a traditional camera-based technology, where the host can decide what you see,” he says. The other essential requirement is the ability to perform focused interrogations (e.g., to watch an analyst perform a method in some detail, or to zero in on a computer system or a label). Lachman establishes both tracks for its remote audits.

Pharmaceutical contract development and manufacturing organizations (CDMOs) have been enthusiastic adopters of virtual audits and inspection. Catalent Pharma Solutions, for instance, has used remote technologies since 2015, to give clients easier access to its facilities, says Joe Montano, director of customer experience, who calls remote inspections a core competency for the company. Currently, the company is working with Apprentice.io, mainly using its Tandem platform, but it is also using 360-degree video to give clients virtual tours of facilities.

Remote inspection technology was first piloted at Catalent’s Kansas City, MO facility, and has extended use of the technology since the COVID-19 pandemic began. “We were able to expand its use from a few pilot sites to more than 40 sites around the world,” Montano says. The company is now using the remote approach with all major global regulatory agencies. Since Catalent hosts or performs more than 500 audits each year, new technology has allowed the company to keep pace, while observing social distancing requirements, Montano adds. At this point, Montano says, regulators are taking a hybrid approach, sending one or two dedicated team members onsite and bringing additional inspectors in virtually. “We’ve only done a handful of audits that were fully remote, but we expect that number to increase over time,” he says.

Also going remote for inspections and audits is Thermo Fisher Scientific’s Pharma Services. The company is currently working with a number of technologies, focusing on Microsoft HoloLens and Microsoft Teams, and the use of virtual tour software. Live facility tours are filmed with a 360-degree camera, and 3-D tours with a 3-D mapping camera, says Sandy Immerman, vice president of Information Technology (IT), Pharma Services. The company began to move in this direction during the fourth quarter of 2019 and stepped up efforts during the COVID-19 pandemic. So far this year, Immerman says, Thermo Fisher has hosted multiple regulatory inspections and more than 125 client audits, focusing efforts on current good manufacturing practice (CGMP) activities in work that has involved FDA, the European Medicines Agency, which issued formal guidance on the use of this technology last May (3), the Russian Ministry of Health (MoH), and the Swedish Medical Products Agency. Russia’s MoH has conducted the most remote/virtual inspections, she says.

Before a remote audit or inspection begins, it’s important to establish a strong partnership with clients, says Deckebach. “You can’t just pull these technologies in on day one. Use of the technology requires coordination and ensuring that the client has the right hardware and knows how to use it.” In addition, a remote audit needs to be more scripted than a standard audit if it is to succeed, he says. Tech experts will be needed on both sides to ensure that the technology is incorporated, connected, and built into their systems, says Deckebach. “They need to be confident and to break down any connection or communication barriers ahead to time to make sure things are working (e.g., firewalls, connections into networks, and general network flow). A back-end IT person is required to ensure that these networks are opened appropriately to allow information to flow,” he adds.

The extra coordination and care these remote technologies require may be a reason why regulators have been so cautious about adopting their use, says Deckebach. “These newer technologies need a bit more care and handling,” he says. “It’s not like you can simply click on a Zoom link to activate them.”

IT infrastructure is a primary challenge. “Not all facilities have installed solid wireless Internet capabilities throughout their manufacturing areas. We ask clients for layout drawings and make decisions on where we want to tour facilities. Once agreed upon, we have them complete a bandwidth survey confirming that minimal bandwidths are met,” says Deckebach.

Problems will invariably come up, but persistence and flexibility are key. “We can get into a dark spot in a warehouse and lose communication, for example, or a user may not know how to get on the system, resulting in 10–15 minute delay. These are typical things that can happen, which is why you need good plans, contingency plans, and backup systems,” says Deckebach.

A week before any audit or inspection begins, Catalent’s team holds a pre-briefing exercise with clients, to familiarize them with the technology platform and give them a high-level view of what to expect, says Hasan Daniel, Catalent Cell and Gene Therapies’ associate director of quality assurance. Through November 2020, he says, the company’s site in Gaithersburg, MD, has performed six virtual audits, the first of which took place in May. “This pre-briefing process is extremely important,” Daniel says, and must involve all staff members that will be working on the audit. In addition, it must feature a secure mechanism for sharing files, and must ensure that everyone working on the audit has full access to all required technology platforms.

One detail that might seem minor but is actually quite important is ensuring that battery-powered devices are fully charged and that enough backup batteries are available. Auditors must also be given a map of the facility, with visual indicators that outline the sequence of the tour so they can see what they are viewing at any point, relative to the whole facility, Daniel explains. Ensuring data integrity and security is of paramount importance, he says, and it usually requires two days to ensure that all documents and proprietary documentation are secure, and cannot be downloaded, printed, or corrupted in any way.

Catalent is not using virtual reality, but sees tremendous potential value in augmented reality using technology such as HoloLens, which allows text, graphics, or video to be overlaid on the user’s view. The benefits should trickle down into employee training and onboarding, says Montano, who says that Catalent is starting to explore its use in training for some standard operating procedures (SOPs) that involve high-risk processes.

While WiFi and other infrastructural issues pose some limitations to implementing remote technology, most of them can be overcome, says Immerman. Montano expects these problems to dissipate as the industry moves to 5G, Starlink, and other new communications platforms. “Training is another limitation, although it can be positioned as an opportunity if you’re willing to invest in it,” Immerman says. “Because the technology is evolving at such a rapid pace, it can also be difficult to gain visibility into the latest capabilities as well as vendor stability,” she says.

On Catalent’s wish list for the technologies would be extending battery life. Currently, says Montano, devices can run up to eight hours (in 2015 the limit was 30 minutes), yet that figure could stand to be improved. Another advantage would be allowing clients to be able to observe operations for their projects reotely, since some of the unit operatiohs are very lengthy and can take a whole day to complete, says Daniel.

However, users note considerable benefits from the technology, saving travel time and cost, and even costs for gowning supplies and consumables. “Having just one person gown in leaves much more time for Q&A and document review,” says Montano. Both Catalent and Thermo Fisher have realized significant gains from using the technology and plan to continue to expand and invest in it. Even if this technology does not replace on-site audits and inspections completely, users don’t see the industry going back to the old ways of doing these things. Deckebach sees the hybrid model, with one or two local staffers onsite and the rest of the team connected virtually, as minimizng risk yet enabling savings and other benefits.

1. J. F. Kennedy, “Speech at the Convocation of the United Negro College Fund,” Indianapolis, IN, April 12, 1959, 

, accessed Nov. 10, 2020.
2. FDA Press Release, “FDA Focuses on the Safety of Drug Products While Scaling Back on Domestic and Foreign Inspections,” 

, March 18, 2020.
3. EMA, Guidance for Remote GCP Inspections During the Pandemic, 


Vol. 44, No. 12
December 2020
Pages: 17-19

When citing this article, please refer to it as A. Shanley, "Can Pharma Qiuality Go High Tech?" 

The COVID-19 pandemic has pushed more pharmaceutical companies and regulators to use new technologies for remote quality audits and inspections.


Can Pharma Quality Go High Tech? 

The COVID-19 pandemic, and the need to accelerate development and distribution of vaccines, has required companies and governments to take on considerable risk in the hope that vaccines now under development prove to be safe and effective. Currently, Pfizer and BioNTech’s, Moderna’s, and AstraZeneca’s vaccine candidates are in advanced stages, with more than 150 other COVID-19 vaccines in development. Developers are ramping up just-in-time manufacturing and distribution efforts for their candidate vaccines even before they know their relative effectiveness.

As analysts from Charles River Associates (CRA) point out, vaccines developed during other pandemics have shown what can go wrong with traditional supply agreements. During the 2009 H1N1 pandemic, for instance, proactive governments that had arranged early purchase agreements cornered the supply of vaccines, leaving out countries that were slower to act. However, once that pandemic proved to be milder than anticipated, the proactive buyers were left with excess supplies to sell, donate, or dispose of.

In response to COVID-19, the United States government established Operation Warp Speed, which, so far, has coordinated just-in-time distribution of Moderna’s vaccine to begin the minute FDA issues emergency use authorization. In the United Kingdom, the government has entered into supply agreements with individual companies, and launched such an agreement with Moderna on November 17, 2020 (1).

Meanwhile, in the European Union, the European Commission’s (EC) Joint Procurement Agreement (JPA) has been more conservative about entering into supply agreements with individual manufacturers. Only time will show which approach proves the better one.

However, for future vaccine supply arrangements during pandemics, both approaches will ultimately prove inadequate, CRA researchers suggest. Instead, risk-sharing contracts will offer the best opportunity for balancing risks and benefits for developers, governments, and patients. London-based Eva Marchese, PhD, vice-president, and Abhishek 

Kumar, associate principal with Charles River Associates, shared insights from current CRA research with 

What is the greatest weakness in traditional procurement and distribution agreements for vaccines?

: Looking beyond the US from a holistic point of view, we have seen two approaches to procuring vaccines:that of the US and UK, which have been keen to enter into agreements with manufacturers and developers, and have invested in companies and these programs. As a result, they have secured vaccine supply for their populations earlier in the delivery schedule.

On the other hand, the collective approach shown by [countries that signed] the EC’s Joint Procurement Agreement has been more circumspect. They may be engaging with a lot of manufacturers, but have been slow to sign actual supply agreements. This fact may not be too surprising, since the EC is made up of many countries. But, in general, this strategy reflects the fact that government authorities are in a tight spot. If they move quickly to make agreements and commit large sums of money to support the development of specific vaccines, they also have to go back to their citizens to justify that spending. There is always the risk that the agreements they have entered into may not bear fruit.

Neither approach is ideal. In a pandemic situation, you need a better model to assume risk for both buyers and developers. Vaccine manufacturers are making large investments in testing and ramping up production capacities and producing vaccines even before they know with full certainty that the vaccines will work.

It is important to emphasize that, during COVID-19, countries and governments reacted to a situation for which they were not prepared. Handling and managing procurement must be done by respecting differing regulations, and it takes negotiation and time to change those regulations.

Given the lack of time available, governments had to react, and their approach is still reactive. In the UK and the US, political and economic pressures have also been in play. The UK, for example, was in the middle of Brexit negotiations when COVID-19 hit.

 Are there any examples of how these risk-sharing agreements would work, and are there any precedents from areas outside of vaccines? What types of “go/no go” gates should be in place to trigger key decisions? 

 This type of agreement is being seen in oncology and innovative therapies (e.g., cell and gene therapies). The challenge in adapting such models for COVID-19 vaccines is the fact that the vaccine development timeframes are so short and steps have had to be vastly compressed. It isn’t possible to have a full and clear understanding of the vaccines’ clinical effects because data available will be limited. As a result, agreements would need to link the risk to specific efficacy outcomes that will be learned once the vaccines are on the market.They would have to be linked to real-world evidence since, at the time of launch, the full standard package of clinical data won’t be available.

 A good idea to consider would be staggered payments triggered by specific milestones (e.g., linking a portion of payment to post-approval, post-launch, and real-world data).Payments could also be linked to approvals at different time points (e.g., getting Emergency Use Authorization or conditional approval and even to positive Phase III data).

Charles River Associates analysts see risk-sharing as the key to improving vaccine availability and access.

