Jennifer Markarian is a contributing editor for 

Jennifer Markarian

Automation—using machines rather than people to perform tasks—offers benefits to biopharmaceutical manufacturers in multiple facets of plant operation, such as transporting materials, taking samples, and controlling the process. Digitalization—replacing manual records with digital ones and using data in a variety of digital tools and connected systems—works synergistically with automated processes. Data collected from equipment that is connected via the industrial Internet of things (IIoT) and analyzed with artificial intelligence (AI), for example, allow the control system to know when a process is trending out of specification, or when a piece of equipment needs maintenance. The digital or “intelligent” plant makes use of both automation and digitalization.

“With the advance of data science enabling factors such as easy access to scalable memory and computing resources; our growing competence in collecting, storing, and contextualizing data; advances in robotics; [and] the quickly evolving method landscape driven by the open-source community, the benefits of automation and simulation are becoming accessible in the notoriously complicated realm of biopharma manufacturing,” says Marcel von der Haar, head of product strategy data analytics at Sartorius.

Business benefits of the digital plant include getting new products to market faster; faster changeover of products, which enables flexible and multi-product manufacturing; improved operational integrity, which includes predicting and correcting potential problems before they occur; and real-time release, which makes production faster and minimizes inventory, says Nathan Pettus, president of process systems and solutions at Emerson. Digital tools accelerate the pipeline and help commercialize products faster by easing technology transfer. “For example, cloud-enabled knowledge management software that manages product and process specifications through the entire drug development lifecycle is enabling biopharma manufacturers to minimize errors in the tech transfer process,” says Pettus.

Automation leads to improved product quality and compliance, reduced risk, and improved productivity, says Heather Coglaiti, global industry strategy and marketing lead for life sciences, Rockwell Automation. An increase in right-first-time occurrences leads to fewer deviations and investigations. Predictive or adaptive mechanisms to prevent equipment failure, as well as real-time asset management, help reduce operational risk, she explains.

“Automation, even partially digitized, reduces the human errors associated with batch-to-batch variability,” adds Dennis Brandl, BRL Consulting. For example, automated dispensing systems have less variability than manual dispensing. Automation also eliminates human error associated with manual data entry.

Automation provides consistency in performance, quality, and process, agrees Dushyant Arora, life sciences industry manager for Siemens Pharma USA. He explains that automation and digitalization enable online quality testing and review-by-exception, which can enable real-time release.

Automating flexible and intensified processes

Adoption of these technologies in biopharma is driven in part by the ongoing push for speed-to-market and the trend to flexible and multi-product manufacturing. Digital technologies are also a crucial part of continuous processing.

“As life sciences plants have moved away from manufacturing a single product and are focused more on developing a wider range of specialized treatments, the importance of flexible manufacturing has taken center stage,” explains Pettus. “Plug-and-play” capabilities of automation systems, which enable flexible manufacturing and faster technology transfer, are more important than ever, he says.

For scaled-down and distributed systems that use multiple, identical manufacturing lines located in one facility or at multiple sites, the ability to collect and share information across the enterprise is crucial, adds Pettus. “Today’s automation platforms leverage scalable ‘data aggregators,’ often based on software-as-a-service models and cloud-architectures. [This ability to scale allows] companies to use automation from the beginning, develop the right process, and then scale the solution as they build their business and infrastructure globally,” he explains. Pettus concludes, “At any scale, there is too much at stake to dismiss automation and digitalization, as they are truly critical pieces of the quality puzzle.”

Intensified and continuous processes rely on real-time testing for process control. “We are focusing our efforts for the ‘factory of the future’ on process intensification and connecting unit operations together, which is enabled by single-use technology, automation, and process analytical technology (PAT),” says Darren Verlenden, head of bioprocessing at MilliporeSigma, the US and Canada life science business of Merck KGaA.

MilliporeSigma’s good manufacturing practice (GMP) PAT platform for bioprocessing includes a Raman spectroscopy analyzer and software that can achieve in-line, real-time monitoring of process parameters and quality attributes. These data can be used to automate control of the bioreactor. In April 2022, the company acquired Lonza’s MAST platform, an automated, sterile bioreactor sampling system; upon closing, it will become part of MilliporeSigma’s BioContinuum platform. The GMP MAST system will help processors evolve from manual sampling to automated sampling, says Verlenden.

Digital transformation is an ongoing journey, says Verlenden. He adds that some customers may want to run a fully continuous, automated process, while others want to intensify and automate certain unit operations.

The digital biopharmaceutical manufacturing plant is the “facility of the future,” but it is also a reality today. Sanofi’s digital and paperless facility in Framingham, Mass., for example, won the 2020 overall Facility of the Year Award (FOYA) from the International Society for Pharmaceutical Engineering (ISPE). The company says that the manufacturing facility is 80 times more productive than a traditional facility and has a smaller environmental footprint (1). ISPE’s 2022 FOYA category award for innovation went to another digital plant located in Framingham, Mass.: CRISPR Therapeutics’ facility, which uses digital systems and automation for production and filling operations (2). Digital tools allow this facility to manage multiple production suites and products at different stages of development (2). Takeda Pharmaceuticals International’s vaccine facility in Singen, Germany won ISPE’s 2022 Pharma 4.0 category award for its use of digital technologies, which include an electronic batch record system, an embedded warehouse management system, and autonomous mobile robots to transport materials (3). ISPE’s Honorable Mention-award winner, Iovance Biotherapeutics’ autologous cell therapy facility in Philadelphia, uses digital tools, including electronic batch records and centralized equipment monitoring (4).

Walvax Biotech’s new COVID-19 messenger RNA (mRNA) vaccine plant in China is another example of an intelligent and digital plant; it uses Honeywell’s batch process control, building and energy management solution systems, and digital twins to monitor assets (5).

“As the need for speed and agility increases, biopharma production facilities need some way to better visualize and integrate batch processing across various equipment and systems,” says Shawn Opatka, vice-president and general manager, life sciences at Honeywell. He explains that the data capture, recording, and reporting systems used by Walvax will help maintain auditability as well as optimize production. Opatka says that data from the live process will be sent to the digital twin, where operators can proactively watch for problems and fix them before they occur.

“The application of AI is paramount and will continue to grow as many organizations progress in their digitalization journey,” says Opatka. “We see more biopharma customers interested in having plants with planning and production executed automatically and using advanced analytics.”

Using AI in predictive analytics to anticipate manufacturing problems—the predictive plant—is the next level of digital maturity after a connected plant, says Yvonne Duckworth, Industry 4.0 specialist, director of digital technology, and senior automation engineer at CRB. “Predictive analytics can reduce downtime and promote quality,” says Duckworth. She points to a real-life example of a vibrating agitator that unthreaded itself before the operators noticed; if a vibration sensor had been attached to the agitator, the control system would have flagged the vibration as a concern before it could have been seen by a human eye. “Some equipment vendors don’t yet offer this capability; some have vibration or temperature sensors available as options, and others offer a fully integrated predictive analytics platform,” says Duckworth. “Vendors have been challenged over the past year to have an answer to the question of predictive analytics capability.”

Another step forward on the digital journey is the use of digital twins, which are digital models of a physical system. Brandl says that digital twins have been used for the past 30 years in process industries where the chemistry of the processes is well understood. Only recently, however, enabled by AI and data availability, have digital twins been developed for biological processes, where there is no ‘first principle’ development possible, he says. “Automation brings in the data for machine learning to model the dynamic processes of cell growth and map it against the multiple dimensions provided by advanced sensors,” explains Brandl.

Digital twins are being used today in biopharma process development to optimize the process in a simulated environment. They can also be used for collaborating in real-time across the value chain and validating new lines and processes virtually, says Coglaiti.

“We will likely see biopharma manufacturers moving from using the digital twin primarily as a simulation and training component to making it a key part of the overall dynamic control of the process,” suggests Pettus. “Manufacturing models are becoming more well defined and well understood, and measurements that were virtually impossible to understand in the past are now enabled with various technologies such as spectral-based techniques. As the industry becomes more comfortable with this more complex, closed-loop control and includes the digital process response predictions with advanced control techniques, we will see the digital twin become even more relevant than it already is today.”

“Today, digital process twins based on statistical models, such as multivariate statistical process control, are increasingly widely applied to obtain predictive and even prescriptive insights into biological process development as well as GMP manufacturing,” adds Mark Demesmaeker, head of data analytics at Sartorius. “We are now moving toward the next step, which will combine data-driven methods and mechanistic concepts—such as growth kinetics and specific metabolite consumption rates in upstream processing, and fluid dynamics or neural networks in downstream processing—to obtain enhanced observability of highly complex cell culture processes or separation and purification steps. This will allow the industry to advance to a closed-loop model predictive control strategy in the coming years.”

Experts agree that there are some regulatory challenges to the concept of applying AI-based models to closed-loop controls. “The use of AI, or even machine learning in a regulated environment, still needs a more elaborated validation framework to manifest [the] great promise [of these technologies],” says Dirk Wollaert, digitalization lead at Siemens Pharma headquarters.

Pettus says that Emerson and others are working together in the BioPhorum consortium to develop strategies
to meet this challenge. “We are optimistic that a path forward for these remaining regulatory hurdles is already underway, particularly as we continue to work with BioPhorum, other similar organizations, and companies that are already engaging regulatory bodies around the world,” he explains.

Despite these many potential benefits, one of the obstacles to automation is the difficulty of calculating the return on investment of a project. Identifying the value is key, says Verlenden.

Duckworth agrees that cost can be a barrier. “Identifying the problem you’re trying to solve makes it easier to identify the savings,” she explains. Some are concerned about the cost and effort of revalidating an existing process, she adds.

“It is important for companies putting in a new facility to think about what approach they want to take from a digital technologies perspective,” adds Duckworth. “A lighthouse approach incorporates all the new technologies at the start. A phased approach, however, can be more beneficial if there are limited resources or a need for speed to market. In this case, we can design a robust network infrastructure which will allow for more advanced digital technologies to be added in later phases.”

Development-stage biotech companies that are moving to commercial manufacturing may not be as familiar with automation and the requirements for using computer systems in GMP environments, such as computer system validation, says Michel Claes, biopharma portfolio lead at Siemens. System integrators can provide guidance, he suggests.

In the past, connecting different types of equipment was a big challenge for automating bioprocesses, but this difficulty has begun to be addressed by modular systems and open-source module type package (MTP) communication protocols that standardize the connections.

“With MTP, organizations can easily add new equipment without having to worry about compatibility and need not spend weeks or months integrating equipment when moving from bench-scale to production-scale,” says Pettus.

Standard interfaces make it easier to integrate PAT sensors into automation systems, says Brandl. “Adding a new sensor for pH, oxygen, or carbon dioxide, for example, can be done at 10% of the cost that it was a few years ago,” he says. Another key development provides the ability to port automation logic across platforms, which is important for biopharma companies that have production in different parts of the world, says Brandl. “PLCOpen has provided the ability to use the same machine control strategies in different facilities using locally supported automation systems,” he explains.

Industry members have been working with the BioPhorum consortium to further pave the way for plug-and-play automation. A current issue is a lack of standardization for data integrity requirements, such as audit trails. In a 2021 paper, BioPhorum proposed a harmonized audit trail model, which is intended to stimulate development of a formal international standard (6).

Maintaining data integrity faces multiple challenges. “Organizations must centralize their data because traditional on-premises historians often lack the metadata and contextualization required to uphold data integrity,” suggests Petter Mörée, managing director for EMEA, Seeq. In addition, he says, data must be reliably stored and managed and available throughout its lifecycle.

Having the right workforce with the suitable skills necessary to incorporate and maintain digital technologies can be another challenge, says Duckworth. Recognition of the need for workers to have digital skills is part of the European Commission’s “Industry 5.0” vision, which seeks a human-centric approach to digital technologies (7) and incorporates sustainability into the way industries are moving forward.

Technology is driving rapid and significant change in biopharmaceutical manufacturing, with more to come, experts suggest.

“Most industry players have merely scratched the surface of what could become a fully automated and digitally twinned manufacturing process,” says von der Haar. “At Sartorius, we are convinced that the companies that adopt and master these methods will disrupt and guide the biopharmaceutical industry in the coming years, generating benefits ranging from drastically reduced time-to-market, lower process variability and failure rates, [and] resource efficiency gains.”

“Real time release, one-click tech transfer, autonomous plants, and self-adjusting processes are going to be important in our future,” says Pettus. “I would be very surprised if these four areas are not significantly developed and advanced in the coming three to five years. The life science industry is going to impact all of humankind over the coming two decades in ways similar to how the semiconductor industry has over the past 50 years.”

2. ISPE, “2022 Category Winner for Innovation,” 

3. ISPE, “2022 Category Winner for Pharma 4.0,” 

4. ISPE, “2022 Honorable Mention Winner,”

5. Honeywell, “Honeywell Collaborates With Walvax Biotech To Automate China’s First Digital mRNA Covid-19 Vaccine Plant,” Press Release, Feb. 1, 2022.

6. Biophorum, “On the Plug-and-Play Audit Trail to Connect Intelligent Pieces of Equipment,” Press Release, July 22, 2021.

https://ec.europa.eu/info/research-and-innovation/research-area/industrial-research-and-innovation/industry-50

Jennifer Markarian is manufacturing reporter for

When referring to this article, please cite it as J. Markarian, “Automating Biopharma Manufacturing,” 

Articles

Automation and digitalization work together in the digital plant.

Automating Biopharma Manufacturing

Precompetitive consortiums create a space for both manufacturers and equipment and technology suppliers to find solutions to manufacturing challenges that affect the whole industry. By working together, they seek to create standardized tools—including software, hardware, and analytical methods—and to harmonize the technical language around these tools. One of the desired results is that vendors can then create products that all manufacturers can use, rather than designing bespoke solutions. Another way consortiums boost technology adoption is by bringing together different perspectives to identify industry challenges, broaden and clarify the definition of specific problems, and propose “roadmaps” that companies can then use in their own journeys.

“A consortia-based approach affords the opportunity to broadly advance capabilities that can be used by many—and do so more quickly—through more iterations being conducted and communicated in a more compressed timeframe,” explains Chris Yochim, business development director at the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) in the United States. “Individual companies must intensely focus on addressing the challenges of their respective product portfolios. They try to apply what they learn to the next product coming through, but they are limited by whatever experiences they did or didn’t happen to encounter.”

Consortiums are especially crucial for emerging therapy areas. As these therapies move through development toward commercialization, collaborative efforts can help speed the solution of problems that arise when trying to manufacture efficiently at commercial scale. The common goal is to bring solutions—quickly and cost-effectively—to patients. Many companies and organizations, including consortiums, are currently working on challenges related to improving the manufacturing processes of cell and gene therapies (CGTs) as well as those of viral vectors, which are crucial raw materials.

“[Cell and gene therapies] are incredibly complex by historical biopharma industry standards,” says Tim Charlebois, NIIMBL Senior Fellow. “While we have seen great promise with the early successes, there is still a lot we don’t understand about them—how to make them, how to analyze them, [and] how to ensure they can be produced with a reliability and quality that meet the standards that patients expect and deserve. At the same time, there is great urgency to develop products rapidly, because many of the therapies are intended to address acute unmet medical needs.”

Charlebois explains that one challenge is understanding the relationship of critical quality attributes to fundamental process and analytical technology. Other challenges involve workforce needs and manufacturing capacity, complexity, and cost. “Overall, these challenges are tied to the tremendous novelty and diversity of the candidate technologies and therapeutic approaches being undertaken,” he concludes.

BioPhorum’s Cell and Gene Therapy Phorum, formed in 2018, aims to facilitate development of CGTs and smooth the way to commercialization of CGT products (1). For example, detailed process maps for the manufacture of cell therapies (2) and gene therapies (3) explain the different modalities. A “toolkit” released by BioPhorum in April 2022 (4) defines and describes the complex ecosystems of CGT manufacturing and supply to “provide a common language and framework for collaboration,” (5) which is important for supply partnerships and, in particular, for developing information technology (IT) systems. BioPhorum says that the models, which map out six common types of CGTs, can be expanded to new modalities as needed. According to BioPhorum, “If IT solutions built today can support multiple therapy modalities, then future therapies can be brought to market more quickly and supported more easily” (6).

The Bio-Process Systems Alliance (BPSA), an industry association that facilitates biopharmaceutical manufacturing using single-use technologies (SUT), has a technical committee dedicated to CGT chaired by Brendan Lucey, who is also Cross Unit director of Marketing Strategy at Entegris.

“Due to the broad nature of our membership, we are able to understand what is going on across the industry and address the pain points that we are seeing globally,” says Lucey. He says that a key advantage of addressing these issues through the BPSA consortium is having input from both the end users (i.e., drug manufacturers) and the SUT suppliers to find solutions that will work for everyone. Having broad solutions, rather than a custom solution that works for just one user, has been crucial to meet production needs during times of tight global supply chains, such as those the industry has been experiencing in the past couple years.

Increasing the industry’s capacity to make and supply viral vectors has been of high importance, as demand for these starting materials in cell and gene therapy production has outpaced supply. The BPSA CGT Committee has been working on a technical guide for viral vector manufacturing, which is due to be published in June 2022.

“This paper was an 18-month project led by more than a dozen subject matter experts [who have] insights into the challenges and benefits of scalable cell and gene therapy processes,” says Kevin Ott, executive director of BPSA.

The report will discuss how SUT can meet both present and future challenges in viral vector manufacturing. It will address topics including scalability, standardization, change management, system robustness and integrity, and quality. The paper will also show how a completely closed system is designed to keep out any potential contaminants, says Lucey.

The committee has previously published technical guides detailing best practices for SUT in CGT manufacturing (7) and considerations for extractables and leachables (E&L) in CGT development (8).

“Each emerging biotherapeutic class comes with potentially unique process, regulatory, and commercial requirements that must be taken into account,” says Lucey. For example, E&L concerns in CGT differ from the historical concerns of other types of bioprocessing. “[The BPSA report on CGT E&L considerations] helps end users assess their risk and think about regulatory concerns before having that first meeting with regulatory agencies. It enables end users to make smart choices early in the process that reduce any E&L concerns,” he explains.

Advancing innovation in the US and globally

NIIMBL, a public-private partnership funded by the US federal government and consortium members, works to advance biopharmaceutical
manufacturing in the US through activities such as developing standards and workforce training. In the CGT area, NIIMBL is focusing on viral vector manufacturing and analytics.

“Limited availability of viral vectors, such as adeno-associated virus (AAV) and lentivirus, represent a major bottleneck, which is constraining the growth and successful development of both gene and cell therapies,” says Charlebois. “Enormous investments in facilities, equipment, technology, and staff have recently been undertaken, but there is a long way to go to meet the overall needs of the cell and gene therapy community. We are bringing together thought leaders and technical experts across industry to develop a program of collaborative, precompetitive work that can both advance and improve access to the critical process and analytical technologies in this space. We are also developing and supporting workforce programs to help address the rapidly growing need for expertise in technical development, manufacturing, quality, and regulatory disciplines for viral vector manufacturing.”

In one project, the United States Pharmacopeia and the US Department of Commerce’s National Institute of Standards and Technology are performing an interlaboratory study to measure critical quality attributes for AAV products, which can be used to deliver gene therapies, and NIIMBL is providing the collaborative platform (9).

In a project funded through the American Rescue Plan (10), Caring Cross is working with NIIMBL to develop open-source platform technologies and materials for AAV and lentivirus. “The intent is to make these broadly available for research purposes and enhance the ability of investigators and smaller, less-well funded entities to pursue therapies dependent on viral vectors,” explains Charlebois.

NIIMBL is also partnering with the international advocacy group Alliance for Regenerative Medicine (ARM). NIIMBL and ARM’s Project A-Gene is a case study-based approach to integrating quality-by-design (QbD) principles in gene therapy chemistry, manufacturing, and controls programs (11). The project brought together more than 50 industry experts from 20 therapeutic developers, as well as experts from FDA and the Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery to identify best practices for the manufacture of a viral vector for use in gene therapy. The results of the four-year project were shared in a report (12) and in a webinar series that will culminate with a workshop in June 2022. The project leaders hope that the study will help developers overcome barriers to moving from clinical trials to commercial production, similarly to how a 2009 case study on applying QbD to monoclonal antibody production lowered barriers in that area (11).

“The case study represents current thinking around best practices in advancing small-batch clinical trial manufacturing to commercial-scale production,” explains Gene Schaefer, NIIMBL Senior Fellow. “The output document is a valuable reference for both organizations that participated as well as other organizations working in this area. [The document] is not meant to be prescriptive, but rather a starting point for discussions and decisions within an organization about the best approach that aligns with an organization’s capabilities and priorities.”

Later in 2022, ARM and NIIMBL will be releasing project A-Cell, which takes a similar approach of applying QbD principles to the manufacture of a cell-based therapy.

Companies should get involved in consortia that are relevant to them, both to benefit themselves and the industry as a whole. “Progress is being made to advance the field, and that progress benefits from as broad a cross-section of stakeholders being engaged as possible,” concludes Yochim. “Organizations that actively engage in meetings, on project teams, in the governance of the institute, and in other ways generally have very deep and lasting interactions that provide technical and workforce-related benefits back to the member.”

1. BioPhorum, “Cell and Gene Therapy,” 

2. BioPhorum, “Commercialization: Cell Therapy Process Map,” 

3. BioPhorum, “Commercialization: Gene Therapy Process Map,” 

4. BioPhorum, “IT for Cell and Gene Therapies,” 

5. BioPhorum, “Orchestrating the Supply of Different Cell and Gene Therapies,” 

6. BioPhorum, “CGT Actors and Process Maps: Who Does What in the Supply of Different Cell and Gene Therapies,” 

7. BPSA, “The Role of Single-Use Polymeric Solutions in Enabling Cell and Gene Therapy Production,” 

8. BPSA, “Extractables/Leachables Considerations for Cell & Gene Therapy Drug Product Development,” 

9. NIIMBL, “New Collaboration Aims to Improve Measurement of Viral Vectors,” Press Release, July 27, 2021

10. NIIMBL, “NIIMBL Announces 32 Projects Funded Under the American Rescue Plan,” Press Release, Dec. 20, 2021.

11. NIIMBL, “ARM and NIIMBL Release Project A-Gene,” Press Release, June 24, 2021.

12. ARM and NIIMBL, “Project A-Gene,” 

When referring to this article, please cite it as J. Markarian, “Coming Together to Enable Cell and Gene Therapy Manufacturing,” 

Precompetitive consortiums seek solutions to industry-wide challenges.


Coming Together to Enable Cell  and Gene Therapy Manufacturing

This discussion looks at some of the challenges facing broader industry adoption of continuous manufacturing, how process analytical technology data can be used for process control or for real-time release, and how implementation of continuous manufacturing approaches is evolving. Jennifer Markarian, manufacturing reporter, talks about continuous manufacturing of oral solid-dosage drugs with Lawrence De Belder, executive consultant at Pharmatech Associates, a USP company.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

In this episode of the Drug Solutions Podcast, Jennifer Markarian, manufacturing reporter, talks about continuous manufacturing of oral solid-dosage drugs with Lawrence De Belder, executive consultant at Pharmatech Associates, a USP company.

Drug Solutions Podcast: Drug Manufacturing Technology 

spoke with Colleen Floreck, vice president, Global Marketing and Strategy, Catalent Cell and Gene Therapy about the specific requirements and challenges for expanding production of viral vectors.

 What were the main drivers for the manufacturing expansion?

The gene therapy market has continued to grow at a high rate, with almost 100 new companies and over 900 assets in the pipeline in 2021.With this continued growth of gene and cell therapies, comes an increase in the demand for viral vectors and full-scale production capabilities so that companies can fast-track their molecule(s) to the clinic.

As viral vector-based therapies expand into indications with larger populations with higher incidence, for example hemophilia, and systemic administrations as opposed to localized (such as for the eye), the need for larger batch sizes is growing.Catalent has seen increased demand both from companies with no in-house manufacturing capacity, as well as Big Pharma and others that need back-up or secondary suppliers. To help address the increasing need for manufacturing capacity across the viral vector market, including viral vaccine and oncolytic virus assets, and to continue to grow with our customers’ futures in mind, Catalent has made strategic and aggressive investments in manufacturing technology and capacity.

In anticipation of market demand, Catalent secured extra space at its Harmans, Maryland commercial campus to add further suites to the network, while capitalizing on its local, established process development, quality, and regulatory teams. Additionally, learnings from previous production at the first commercial facility at the campus allowed the creation of an innovative layout to maximize and optimize the space. This new capacity will allow Catalent to be more flexible and able to rapidly pivot for customers.

Are there any other bottlenecks/supply-chain constraints affecting this part of manufacturing?

There are several bottlenecks that affect viral vector manufacturing, some of which are not exclusive to the cell and gene industry. For viral vector-based therapies, plasmid DNA (pDNA) is a critical raw material required for production, and often has long lead times (up to 12 months). With only a limited number of vendors offering GMP [good manufacturing practice]-grade material, this can affect their overall timeline.

Additionally, the single-use bioreactors used in the manufacturing process require consumables such as bags, which are used by more than just the cell and gene therapy industry. Each vendor’s bioreactor uses a specific bag configuration, so priority for the bags between viral vector manufacturers and those producing COVID vaccines can sometimes be challenging.

Another source of bottleneck can be analytical testing; as many analytical tests are outsourced to CROs [contract research organizations], some viral vector manufacturers are reliant on the timelines, and throughput of the CRO for their results and delays in results can impact manufacturing schedules.

What are the biggest challenges for this type of manufacturing?

 Adeno-associated virus (AAV) manufacturing faces many challenges including low vector yields, purification to separate empty and full capsids, and highly technical raw materials such as pDNA.

Catalent is committed to continuous improvement to help assure quality, de-risk processes and avoid CMC [chemistry, manufacturing, and controls] issues. This necessitates consistent incorporation of our learnings, combined with the latest developments in CGMP manufacturing into our new and existing facilities and operations. By applying the expertise we have gained from the past three years of operating our flagship gene therapy commercial facility, we are now able implement a design layout with state-of-the-art technologies and systems in our expansion that are innovative, efficient, and provide flexibility for our customers.

Seamlessly combining plasmid manufacturing with our cell and gene therapy services helps to remove waiting on third-party timelines, offers customers better control of raw material availability, and allows for simplified transfer into viral vector manufacturing, as well as easier/streamlined planning and control of manufacturing timelines.

: Are there any other key technologies/innovations for ‘state-of-the-art’ viral vector manufacturing (e.g., single use systems, automation)?

 The implementation of single-use systems in viral vector manufacturing provides many benefits including using lesser amounts of natural resources, such as water and power. Adherent and suspension-based systems are available and in use for viral vector manufacturing. Converting from adherent to suspension-based processes allows for scaling-up, rather than scaling-out, and removes the need for animal-based materials. Single-use systems can allow for standardization of manufacturing, which can, in turn, help meet aggressive and expedited timelines and potentially reduce manufacturing costs to better address the large therapy costs facing patients.

Innovative solutions to address purity, automate testing, or provide higher throughput can also help alleviate some of the manufacturing obstacles. Improvements in transfection reagents and the development of scalable, robust, easily transfected clonal cell lines can help produce high viral vector titers, while new affinity resins, especially those that are re-usable, can help address the empty versus full particle challenge. High-throughput analytical systems, including those that use new technologies to evaluate critical quality attributes, will again help to manufacture safer and more effective therapies.

Jennifer Markarian is manufacturing editor for 

When referring to this article, please cite it as J. Markarian, “Expanding Viral Vector Manufacturing,” Pharmaceutical Technology 46 (4) (2022).

Pharmaceutical Technology spoke with Colleen Floreck, vice president, Global Marketing and Strategy, Catalent Cell and Gene Therapy about the specific requirements and challenges for expanding production of viral vectors. 

Expanding Viral Vector Manufacturing

Manufacturers, regulators, and other industry organizations are aiming to advance biopharmaceutical continuous manufacturing and to connect upstream and downstream into fully continuous processes. The United States Pharmacopeial Convention (USP), a nonprofit organization known for developing standards for quality, is actively involved in facilitating implementation of continuous manufacturing in the bio/pharmaceutical industry. 

spoke with John Kokai-Kun, director, External Scientific Collaboration at USP about these efforts.

Facilitating Biopharma Continuous Manufacturing

Pharmaceutical Technology Quality and Regulatory Sourcebook Ebook

Read “Facilitating Biopharma Continuous Manufacturing” in 

Pharmaceutical Technology’s Quality and Regulatory Sourcebook Ebook.

When referring to this article, please cite it as J. Markarian, “Facilitating Biopharma Continuous Manufacturing,” 

Pharmaceutical Technology’s Quality and Regulatory Sourcebook

 USP is advancing understanding and developing guidance and standards to assist industry in implementing continuous manufacturing.

With the increase in drug products targeted to specific patient groups, including orphan drugs and even individualized medicine, manufacturers must consider how to optimize the manufacturing process for aseptic fill/finish of drugs in small batch sizes. 

 spoke with Joerg Zimmermann, vice-president of Development Service and External Affairs at Vetter, about these challenges and the equipment and facility options to consider.

Pharmaceutical Technology's Biologics and Sterile Drug Manufacturing

Jennifer Markarian is manufacturing editor of 


eBook: Biologics and Sterile Drug Manufacturing, May 2021
May 2021
Pages: 14–17

When referring to this article, please cite it as J. Markarian, “Filling Small Batches

" Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

Advances in automation and cleanroom technology improve efficiency for small commercial quantities of aseptically filled drug products.  