Every year, new and innovative drug products and technologies emerge, changing the landscape of biopharma and the treatments that are possible. This can be credited—in part—to the capabilities and flexibility provided by outsourcing.

“Drug developers are reshaping modern medicine by bringing possibility to reality. They are transforming how diseases are combated by bringing new curative treatments to the forefront. Emerging and virtual companies that are driving the future pipeline heavily rely on external development partners—but not just for hard-to-make products. Even more established companies are contracting with CDMOs [contract development and manufacturing organizations] to gain access to capacity and specific capabilities,” says Dirk Lange, head of life science services, MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany.

As the biopharma industry continues to outsource tasks within analytics, development, and manufacturing, one question continues to arise: what should be outsourced vs. performed in-house? Moreover, should the industry outsource more and, if so, where? Prior to establishing what should or shouldn’t be outsourced, it should first be determined exactly what is being outsourced.

“In cell and gene therapy [CGT], many of the CMC [chemistry, manufacturing, and control] tasks are outsourced including process development, analytical development, testing, manufacturing, and fill/finish. Outsourcing can occur really at any point in a therapy’s life cycle up and through commercial production,” says Audrey Greenberg, co-founder and chief business officer, Center for Breakthrough Medicines.

CGTs, specifically, have challenges that require costly and difficult-to-procure consumables, equipment, space, and talent, explains Greenberg, which might further encourage a company to consider outsourcing clinical through commercial manufacturing processes. Hanna Lesch, PhD, chief technology officer, Exothera, adds that the level of outsourcing will depend on the size and type of biopharma company.

“Big companies have the resources to perform development and manufacturing, but they might need support with specific tasks, like dedicated analytical assays or process optimization studies,” says Lesch. “Small companies—which represent the majority of the advanced biotherapeutic developers right now—have very limited internal development and manufacturing capacity and expertise; so, they tend to outsource process development, process scale-up, and manufacturing (including analytics).”

Similarly, Sigma Mostafa, senior vice president and site head, KBI Biopharma, expresses that what is outsourced usually depends on the size of a given company, adding that the overall level of outsourcing has recently increased.

“The smaller biopharma companies usually outsource most of their activities from early development to manufacturing and rely on partners for early and late phase activities,” says Mostafa. “Larger pharmaceutical companies tend to manage their early development work in-house and then ‘tech transfer’ the process to a CDMO for manufacturing.”

According to Hanns-Christian Mahler, chief enablement officer and board member, ten23 health, outsourcing has been traditionally more focused on manufacturing. Mahler adds that development is increasingly being outsourced as well.

Early-stage candidate selection, scaled-down, and at-scale process characterization studies, according to Mostafa, should be outsourced more. Candidate selection is when it’s determined which molecule best matches the target profile for efficacy, pharmacology, and manufacturability. Mostafa explains that biopharma companies usually consider three to six molecules at this stage with a focus on predicting clinical outcomes—regardless of the manufacturability of a molecule.

“Typically, this early-stage candidate selection process is not outsourced but doing so can bring benefits, such as offering a broader set of analytics and a more representative cell line and process,” says Mostafa. “By using a stably transfected cell line instead of a transiently transfected one, we can identify potential productivity and product quality challenges. An extensive array of analytical methods can be utilized to determine whether any candidates have aggregation, deamidation, oxidation, isomerization, or peptide bond cleavage issues. Surface hydrophobicity and conformational stability evaluation are the other services that CDMOs can provide.”

Meanwhile, scaled-down and at-scale process characterization studies, according to Mostafa, are rarely outsourced. These studies require nine to 12 months to complete and are resource intensive, and CDMOs can potentially perform these studies with greater efficiency.

Other internal tasks to consider outsourcing, according to Lesch, are CMC studies and regulatory review.

“CMC is a particularly complex area, and the increasing regulatory requirements placed upon advanced therapy medicinal products makes this an area where service providers can provide the latest expertise,” says Lesch.

Greenberg, on the other hand, points out that recent market movements have resulted in finances as another deciding factor for what to outsource.

“Customers strapped for capital should consider outsourcing activities from process development, manufacturing, fill/finish, primary and secondary packaging, analytical development, testing, and regulatory support during IND [investigational new drug application]/BLA [biologics license application] filings,” says Greenberg—adding that it will come down to what is best for the process, and where some companies might benefit from an entirely outsourced approach, others may only require 50% outsourced efforts.

“Overall, outsourcing is a much more efficient use of capital for the industry, as it prevents building something from scratch that involves learning curves, which can create a backlog inventory of products, materials, and consumables as well as underutilized space and talent,” says Greenberg.

Meanwhile, Lange emphasizes the advantages of outsourcing to a CDMO, which offers end-to-end services, as this can help to integrate activities, reduce interfaces, and create better alignment between teams. For sterile manufacturing, for example, companies should consider working with a CDMO that is already equipped with formulation development, primary packaging selection, and manufacturing process design space, rather than working with various partners, according to Mahler.

There are a lot of differing opinions regarding which analytical, development, and/or manufacturing tasks—if any—should be performed in-house instead of outsourcing. What it often comes down to is existing capabilities in a company’s facility/facilities, whether the maintenance is sustainable, in-house talent, and bandwidth (among other reasons). According to Mahler, it’s all about balancing risk and cost.

Mostafa adds: “Any analytical methods that are subject to interpretation, such as specific cell-based assays, are not ideal activities for outsourcing. Any activity that would be significantly more efficient in-house, such as narrowing down the candidate pool from hundreds to <10, should also be done in-house. If the process is extremely long compared to standard process duration, then considering the cost of the additional suite time, manufacturing in-house may make the most sense.”

Greenberg further points out that biopharma companies, especially those in the CGT space, should consider outsourcing as soon as possible in a drug’s life cycle to adhere to GMP-grade materials, methods, processes, and testing as part of forward process integration activities. This avoids delays and regulatory issues down the road that may further delay approval.


Potential pain points for frequent outsourcing

When selecting and working with partners, one fact many companies drive home is the importance of good communication and trust. However, after having worked on a given biomolecule or product for many years, it can be difficult for a company to bring in a third party and hand over the reins.

“Innovator companies are rightly concerned with maintaining not only the intellectual property, but also clarity and control in their process,” says Greenberg. “These products are the result of years, if not decades, of work, and it can be hard to trust and share with a new party. This is what makes choosing the right outsourcing partner so critical.”

Lange also highlights the importance of trust. CDMOs should be transparent and engage with the client in decision-making, which builds trust in the partnership.

“Clients need to be engaged in decision-making to ensure the CDMO’s programs meet the client’s scientific and regulatory goals, timelines, and budgets. Therefore, engaging in co-development with a flexible, collaborative, and client-centric CDMO is key to ensuring success,” says Lange.

Similarly, Mahler believes a fear of a loss of control can be a challenge for certain companies. Though this will depend on the collaboration model.

There are other potential challenges, one of those is being reliant on another party’s capacity and timelines, adds Lesch. Another is the potential time investment during the tech transfer phase of the in-house process to the service providers platform, which might take more time than expected.

“[Biopharma companies] may have developed a platform process with a standard set of assays since they have a molecular structure that can use the same analytics across their pipeline and feel those processes and analytics cannot be replicated in a CDMO,” says Mostafa.


The most popular tasks to outsource in biopharma

Depending on where a company sits in the supply chain (upstream through downstream), different tasks will, of course, be more top-of-mind for outsourcing. The experts interviewed by 

share the following as some of the most popular tasks to outsource:

. “The activities outsourced are dependent on different factors, such as modality, capabilities of the customers, and phase of the molecule,” says Lange. “In general, we do see more outsourcing in the early phases. This is mainly driven by the rise of emerging biotechs since they are predominantly driving the development of new molecules.”

“It’s quite common to outsource process development if the outsourcer is looking for the right technology for manufacturing. It is usually prompted by a need to improve upstream unit operations, like the selection of transfection/infection strategy or the type of bioreactor,” says Lesch. “During manufacturing, it’s common to outsource specific release assays; for example, assays to detect adventitious viruses or sequencing undesired DNA/RNA portions which can be complex to establish and are thus outsourced.”

Viral vector manufacturing, testing, and analytics. 

“Viral vector manufacturing seems to be the most outsourced task,” says Greenberg. “Testing and analytics remain strong outsourced activities. And we are also seeing a growing interest in newer or re-emerging modalities, such as mRNA, exosomes, and plasmids.”

. “As a general approach, anything closer to manufacturing, anything that's just replicating something done in-house, is more frequently outsourced,” says Mostafa. “For instance, in case of a re-supply run: a clinical trial has already started, and a process is in place. Outsourcing involves transferring the process to another site (CDMO) and having the CDMO be responsible for the manufacturing.”

Large molecules are no longer limited to monoclonal antibodies (mAbs) and have become more diverse, says Mahler, adding that this encompasses therapeutic proteins, oligonucleotides, and CGTs. More expertise is required for increasingly diverse molecules.

Thus, with more biomolecules to pursue, it would be no surprise to learn that outsourcing in general is a trend, specifically for complex molecules and recombinant proteins (not just novel modalities), according to Lange.

“The next generation of mAbs or fusion proteins are more complex, and we see the share of projects in this space increasing,” says Lange. “This is not limited to the development and manufacturing space, since these complex constructs require extensive analytical characterization and advanced formulation capabilities in order to navigate their way to treat patients safely.”

Other trends, according to Lange, include a larger number of smaller, refined indications, and not only in the rare disease arena—courtesy of increased capabilities, specifically in diagnostics. Furthermore, single-use technologies continue to gain traction.

“[T]he technology landscape keeps evolving, since manufacturing templates are driving efficiency in the manufacturing process,” says Lange. “For example, today’s cell culture titers allow for smaller manufacturing scales. This creates a shift towards single-use manufacturing services. Today, single-use manufacturing trains can support the entire life cycle from clinical to commercial volumes of many assets.”

Yet another trend that has formed roots is outsourcing at a “one-stop-shop” provider.

“[S]mall companies are looking for a CDMO that can provide end-to-end services, from plasmid constructs to fill/finish within quality and regulatory standards,” says Lesch. “This allows them to reduce the number of interactions with external partners and optimize costs while saving time.”

What does this look like going forward? Like most industries, the pandemic has made lasting effects in biopharma, including the need (and, therefore, trend) to outsource. This is often due to resources, capital, expertise, and time constraints, according to Greenberg.

“Outsourcing is here to stay,” says Mostafa. “The CDMO industry has been flourishing over the past decade.”

“We are still navigating a pandemic where supply chain constraints have challenged business models. There does not seem to be any easing up of current market landscape; so, I believe we will see the outsourcing trend continue because of cash, time, and resource constraints,” says Greenberg. “It is critical to have partners you can trust and who provide the transparency and the flexibility to work with you based on the program needs. In the end it is about doing whatever it takes to bring these innovative therapies to the patients who need them the most—and we have all acknowledged, you cannot do this alone.”

“Biopharma is an exciting space to be in,” says Lange. “The rise of novel modalities and the second generation of biologics will open endless opportunities to improve the life of patients. We as a CDMO/CTO [contract testing organization] have a crucial role to play on this quest, as we can help accelerate the time to market and bring therapies to patients faster.”

Whatever a company chooses to outsource, evaluate whether that potential partner has the proper experience, capabilities, and lead times to determine whether it’s a good fit all around. Be clear in your needs and expectations and find a partner you can trust.


Vol. 35, No. 8
August 2022
Pages: 10–14

When referring to this article, please cite it as M. Rivers, "Deciding Where to Outsource in Biopharma Development and Manufacturing," 

Articles

Cover Story

Experts divulge where the industry is outsourcing most frequently, when companies should outsource more, and when performing tasks in-house might be best.

Deciding Where to Outsource in Biopharma Development and Manufacturing

Improving viral vector manufacturing for gene therapy applications is an important step in developing effective end product. In recent years, the biopharmaceutical industry has seen a flurry of activity in which service providers, such as contract development and manufacturing organizations, have invested in expansions of viral vector manufacturing capacity or in enhancements to viral vector development technologies. But why has it quickly become so important to improve manufacturing and development processes for viral vectors?

For one, there have been significant advancements made over the past 10 years in the use of viral vectors within the gene therapy and gene-modified cell therapy fields, explains Arvind Srivastava, PhD, technical fellow, Avantor. For instance, eight therapies using viral vectors have been recently approved by FDA in that timeframe. “Although the early approvals of viral vector-based therapies were for the treatment of rare diseases, more recent approvals have been therapies for cancers of the blood. This shift requires the expansion of global viral vector manufacturing to meet the demands of a larger patient population. For this reason, improvements in the efficiency of viral vector production, as well as refinement of complex production processes, are required to support this growing market,” Srivastava points out.

The ultimate goal of the cell and gene therapy (CGT) field is to deliver new therapies to patients who have few or no other options, continues James Cody, associate director technical sales and evaluations, Charles River Laboratories. Manufacturing is one of the key bottlenecks for these products, both in terms of the time required and the cost, which can be prohibitive in some cases. By improving manufacturing processes, however, the industry can increase overall yields. “This could potentially allow for lower costs and/or smaller batches with more rapid turnaround times. By saving time and cost, we can deliver more therapies to more patients and can do so more rapidly,” Cody emphasizes.

Though relatively new, the CGT space has expanded rapidly since the first human gene therapy trial—using gammaretrovirus—occurred in 1990 for treating severe combined immunodeficiency (SCID). With advancements in molecular biology and biotechnologies enhancing their safety, the massive potential of CGTs to improve patients’ lives has been realized by the biopharma industry, adds Bill Vincent, founder and executive chairman, Genezen. Reflecting this, Vincent points out that the global CGT market was valued at $4.99 billion in 2021 and is expected to grow to $36.92 billion by 2027, at a compound annual growth rate (CAGR) of 39.62% (1).

“The surge in both growth and demand in the CGT space has necessitated rapid improvements in viral vector manufacturing processes—a decade or so ago, the industry was still in its infancy. But, as critical tools in gene delivery, viral vectors need to be produced while balancing quality and speed in order for essential therapies to be delivered to patients quickly,” Vincent says, reinforcing Cody’s sentiment.

In addition to manufacturing processes, regulations surrounding viral vector manufacturing for CGTs have been under pressure to evolve just as rapidly. “But this naturally takes time as the therapeutic area is relatively new. With expertise and experience in the area, it’s fallen to viral vector manufacturers to ensure processes are optimized for safety, speed, and quality. Applying their understanding and knowledge to continually improve processes will mean that they are prepared for future changes to regulatory requirements,” Vincent explains.

Megan Hardy, senior staff scientist, research and development, viral vector services, pharma services, Thermo Fisher Scientific, adds that continuous improvement of viral vector manufacturing processes is necessary as the industry continues to grow and apply lessons learned from the vectors currently being produced. Increased yields and scalability allow for more patients to be treated from a single batch, thereby reaching more of these (often rare-disease) patients sooner.

Hardy’s colleague, Samira Shore, director, research and development, viral vector services, pharma services, Thermo Fisher Scientific, states that improvement of viral vector manufacturing process means not only improving the chance at curing life-threatening diseases, but doing so while minimizing the risk of experiencing off-target responses. “This improvement is focused on maximizing yield of target therapeutic per batch, while maintaining high quality standards and target key characteristics of the product,” Shore says.

Limitations to viral vector manufacturing have included the finite amount of manufacturing space available, says Cody. Many manufacturers have responded to this issue by expanding capacity. Another issue is that many of the key raw materials used for vector manufacturing have lead times measured in months. “These long lead times were an issue prior to the COVID-19 pandemic and have worsened due to increased (and reprioritized) demand as many resources have been diverted to vaccine manufacturing,” Cody says.

“The most difficult challenges in viral vector manufacturing originate in the fine-tuning of complex processes to optimize yield and recovery of vectors,” says Srivastava. In the upstream, processes must be optimized to produce high yields of vectors because it is these processes that define the quality of the end product, he points out. Vector titer can be impacted by plasmid design, cell culture conditions, and key reagents, such as transfection reagents and cell lysis solutions, in upstream processing.

In the downstream process, Srivastava continues, a key challenge lies due to the formation of empty and “false full” vectors in the upstream process that require separation from the full capsids used in the therapeutic end-product. “Separation can be improved using anion exchange chromatography, although the exact operating conditions require significant optimization,” he suggests.

Shore explains that, during the infancy stages of gene therapy, the majority of innovators were developing processes capable of supporting the product yields associated with the target diseases and dosing regimens. Since then, however, the use of viral vectors has expanded for various indications and, lately, viral vectors have been applied to vaccine candidates. The latter brings viral vectors into the arena of high dose, high patient population indications, according to Shore.

This move into a high dose, high patient application (i.e., vaccines) requires, in return, manufacturing processes that can be executed at large scale and yield significant viral vector product to support the therapy treatment needs. “Process scale-up and/or evaluations of suspension-based systems has been a key driver toward overcoming those challenges. Some of the processes, for example, transient transfection or adherent-based systems, are still facing challenges with scale-up and the ability to maintain process control and consistency while expanding to larger scale,” Shore says.

Shore also points out that yield differences are observed when switching from one platform to another. Even if the process is scalable and producing consistently, some innovators are still faced with the regulatory filing challenges of introducing significant process changes post-early phase clinical trials. In addition, there certainly has been much more focus on improving and enhancing analytical methods available to support product characterization, especially with a focus on more quantitative methods, according to Shore.

“There have been several challenges in the past that have hindered the use of viral vectors, the impact of which we are still seeing today,” Vincent says. Notably, safety concerns surrounding the use of gammaretrovirus in CGTs were a considerable obstacle to the expansion of this therapy space. Vincent explains that gammaretroviruses are an attractive CGT tool because of their ability to carry a large cassette, enable the production of stable producer cell lines, and offer high rates of transduction (2). However, these viruses also have an inherent preference for integration near oncogene promoters, increasing the risk of cancer in patients receiving the CGT.

“With this risk in mind, developers moved away from therapies using gammaretrovirus, opting for alternative, safer vectors such as lentivirus. In time, researchers rediscovered the potential for gammaretrovirus in CGT, focusing on other uses where oncogene promoter-adjacent insertion is less of a concern, including CAR-T [chimeric antigen receptor T cell) therapies—and this is where the industry stands now, at an exciting nexus point where potential is becoming reality,” Vincent remarks.

CAR-T therapies are now the most common technology in genetically modified cell therapies, representing 50% of those in the development pipeline (3), according to Vincent; however, the previous safety concerns have meant that expertise in the development and manufacturing of gammaretroviruses is limited. Thus, those organizations offering these capabilities are set to experience a period of significant demand.

In the past five years, the expansive potential of viral vectors as tools for gene transfer in CGT has stepped further into the spotlight. Vincent points to the fact that, currently, five of the 14 FDA-approved CGTs use gammaretroviral vectors (3). “The biopharma industry’s growing interest in this sector has resulted in the global viral vector market being predicted to grow at a CAGR of 18.5% between 2020 and 2026, from a value of $450.5 million to $1.2 billion, respectively,” (4) he cites.

As increasing numbers of CGTs relying on viral vector technologies enter the development pipeline, process development, analytical development, quality control, good manufacturing practice (GMP) cell banking, and GMP vector manufacturing requirements also continue to expand. “It is no surprise that we are seeing a wave of facility expansions and enhancements across the industry in response to this surge in demand,” Vincent says.

Genezen, for example, recently completed construction in April 2022 at its site in Indianapolis, Ind., of an early phase clinical current good manufacturing practice (CGMP) manufacturing facility. The completed facility is just one part of a planned 75,000-ft2 lentiviral and retroviral process development and CGMP vector production facility, Vincent specifies. In addition, the company has announced a next stage of expansion to support the increased demand for GMP viral vectors (5).

The most prominent and most recent enhancement that the viral vector manufacturing industry has implemented is the development of standardized platform processes, observes Hardy. She explains that these platforms aim to shorten process development timelines by leveraging standardized, scalable processes, which have been proven across multiple scales and serotypes, such as in the case of adeno-associated virus (AAV).

“Customers can expect a more ‘plug-and-play’ approach with little, if any, process optimization prior to CGMP manufacture, thus reducing time to clinic and often cost. This approach is especially attractive to early phase customers,” Hardy says. “The industry has also seen tremendous investment in expanding manufacturing capacity, with several key players adding new or expanding existing facilities to meet capacity demands.”

Shore adds that, in addition to process improvements and capacity expansion, significant progress has been made on product purification technologies as well as increased focused analytical methods and instruments.

Outside of new product introductions, Avantor is investing considerably in capabilities that support its viral vector customers, according to Srivastava. This includes expanding internal CGT expertise within the company’s product R&D teams as well as the company’s commercial teams and leadership. “Additionally, we are investing in our global facilities, having recently announced a new distribution center in Dublin, Ireland, as well as a new manufacturing and distribution center in Singapore to support the ever-growing European and Asia-Pacific viral vector markets,” says Srivastava.

With strong demand forecasted over the next several years for viral vector-based CGT’s, it is not surprising that the biopharma industry is continuously seeking ways to improve viral vector manufacturing. As part of the industry’s continuous efforts at improvement, vendors have brought innovation to available technologies to better support the unique requirements of viral vector manufacture, remarks Hardy. These innovations include the advent of the iCELLis technology for adherent cell culture and chromatography resins specifically designed for viral vector manufacture. “Additionally, next-generation analytics such as ddPCR [droplet digital polymerase chain reaction], AUC [analytical ultracentrifugation], SEC–MALS [size-exclusion chromatography–multi-angle light scattering], and CE–SDS [capillary electrophoresis–sodium dodecyl sulfate] allow for more accurate and precise absolute quantification,” Hardy states.

Srivastava emphasizes the point that improvement of viral vector processes requires the fine-tuning of what has traditionally been mAb manufacturing processes. “While some parts of the process are innovative, others are iterative of other bioprocess workflows. In both cases, improvements in manufacturing are being found through the appropriate design of processes with cost efficiency, process efficiency, quality, and compliance in mind,” Srivastava says.

Furthermore, end-to-end planning also mitigates risk across the whole development and manufacturing workflow, Srivastava adds. Such planning enables the identification of strategies to improve process efficiency and vector yield.

“In my opinion, there may not be one single technology that will be the ‘best’ way to improve manufacturing,” says Cody. “Rather, it might be a synergistic combination of improvements across multiple fronts: improved upstream processes with higher cell densities, higher per-cell vector productivity, and improved chromatography materials and methods with higher recovery, etc.”

Meanwhile, Vincent points out that bioreactors—particularly single-use fixed-bed bioreactors—have revolutionized scalable viral vector production. He explains that lentivirus production predominantly relies on adherent producer cell cultures, which are traditionally grown in 2D systems such as cell-culture chambers. Scaling would then involve using this cell-culture chamber setup in multitudes (i.e., scaling-out). “This not only requires huge amounts of incubator space but also extensive manual procedures, increasing the risk of contamination,” Vincent says.

Fixed-bed bioreactors, in comparison, offer a high surface-area-to-volume ratio for adherent cell growth within a compact space. “Their automation and single-use properties also alleviate the need for delicate and time-consuming manual operations, thereby reducing contamination risk. This innovative technology has effectively solved many of the issues associated with scaling lentivirus manufacturing to commercial levels,” Vincent explains.

The development of single-use technologies, overall, has been particularly enabling for viral vector manufacturing processes. Besides fixed-bed bioreactors, other single-use technologies that have been essential in viral vector manufacturing include bag filling and draining systems. “As viral vectors are inherently unstable from a pharmaceutical perspective, exposure to adsorptive containers like glass vials that are often used in fill/finish processes can result in vector loss. Using single-use bag filling and draining systems reduces this potential loss while offering the advantage of continuous filling and high filling volumes for increased speed,” Vincent adds.

Cell & Gene Therapy Market—Global Outlook & Forecast 2022–2027

, Market Report (January 2022).
2. X. Wu, et al., 

 300, 1749–1751 (2003).
3. American Society of Gene + Cell Therapy, 

Gene, Cell, & RNA Therapy Landscape: Q3 2021 Quarterly Data Report

Viral Vector Manufacturing - Global Market Trajectory & Analytics, Market Report

 (February 2022).
5. Genezen, “Genezen Completes CGMP-Lentiviral and Retroviral Vector Clinical Production Facility Buildout,” Press Release, April 26, 2022.

Feliza Mirasol is the science editor for 


Vol. 35, No. 8
August 2022
Pages: 18–21

When referring to this article, please cite it as F. Mirasol, “Driving Manufacturing Improvements Through Viral Vector Advances,” 

Development

The growth in demand of viral-vector-based gene therapies drives continuous efforts to improve viral vector manufacturing.

Driving Manufacturing Improvements Through Viral Vector Advances

Biopharmaceutical manufacturers are looking for ways to run downstream processes more efficiently, so that higher volumes can be made in a shorter time without adding more or larger processing equipment. Intensified and continuous methods are needed to keep up with the increased volume from upstream processing, as well as improve cost, time to process, and the area of floorspace needed to operate, says Martin Lobedann, Process Technology consultant at Sartorius. Intensified processes rely on process analytical technology (PAT) to collect real-time data used for automated process control. “Higher automation per unit operation and orchestration across multiple unit operations enable continuous and closed processing,” says Lobedann.

“In processes that are more intense, where variables are changing at a faster rate, the margin for error is decreased,” says Alexei Voloshin, global application development manager for 3M Separation and Purification Sciences Division. “A machine can analyze and adjust much faster than a person can. The ability to control systems, which may be inherently unstable, is better left to automation technologies.”

Automation can enhance the operation of downstream processes, such as purification and filtration.

Downstream processing of monoclonal antibodies (mAbs) traditionally uses chromatography capture followed by viral inactivation and two other chromatography polishing steps, with a batch going through each unit operation in sequence. This method of processing one after the other is “costly, non-optimized production,” says Jérôme Chevalier, manager of Product Management, Chromatography Systems at Sartorius. One way to optimize and speed up production is to use several chromatography columns in parallel. A second strategy, says Chevalier, is to use automation to interconnect all the downstream unit operations. This continuous processing method avoids manual intervention and dead time, he explains.

Chevalier says that Sartorius implemented automation strategies to intensify downstream processing at Phase II/III clinical-scale for a major biopharmaceutical manufacturer. “The BioSC hardware concept linked with an automation platform allowed us to reduce processing time from six days to one day; reduce the footprint by approximately 15-fold; and save up to 42% of the cost of goods,” he reports.

A key to user acceptance is ease of programming and flexibility of the recipe editor, Chevalier adds. A possible future step is to integrate other unit operations, such as filtration, concentration, and diafiltration into the continuous, automated workflow.

Intensification of the capture step would have a significant impact on process economics, suggests Lobedann. “Application of current affinity-based resins in the market make this step the most expensive due to a lower productivity (<20 g/L/h) caused by a combination of low binding capacities and linear flow velocities due to diffusion limitations,” he explains.

Automation systems can be further optimized by incorporating process data, collected using PAT sensors and analyzed with a data analytics platform. These technologies can result in better process control and cost reductions, says Artur Arsenio, head of product management for PAT and Automation at Sartorius. For example, a biosimilars manufacturer is using PAT, data analytics tools, and bioprocessing software to enable a platform with continuous upstream and continuous downstream processing. The upstream process uses Sartorius’ intensified seedtrain, and the downstream process uses Sartorius’ multi-column chromatography combined with flow-through filtration.

Researchers in the lab of Professor Anurag S. Rathore at the Indian Institute of Technology Delhi have developed a method for automating a dead-end filtration skid for continuous depth-filtration, used for clarification of microbial and mammalian cell-based biopharmaceuticals (1). One of the challenges for continuous filtration is that the feedstream characteristics, such as turbidity or host cell protein content, can vary over the weeks or months of the continuous process, which affects the size of the filters needed, they explain. The researchers proposed a filtration skid with multiple, small-sized filters, with pressure and turbidity sensors that enable the process to automatically switch to a new filter when the sensors indicate a limit has been reached.

Automating filter switching also saves cost because smaller-sized filters can be used. In batch processing, filters are typically sized up by 1.5 to 2 times the calculated size. With an automated system, the filters do not have to be over-sized because the filters will be switched as needed. This method should result in more consistent filtrate quality (1).

The skid has been successfully tested in the lab and is being considered by major manufacturers, says Rathore, who is coordinator of the Center of Excellence for Biopharmaceutical Technology and professor in the department of Chemical Engineering at the Indian Institute of Technology Delhi. He notes that the skid is available to manufacturers as open-source technology and is part of the continuous process technology being developed at the Center.

In addition to capture and filtration, polishing and buffer exchange steps can benefit from intensification. “Buffer management—preparation, distribution, and hold—is often overlooked,” says Lobedann. “Intensifying here would greatly reduce the auxiliary footprint, because one would need smaller storage tanks with concentrated buffers, which can then be diluted at point of use.”

In-line dilution of concentrated buffer solutions or in-line blending and conditioning of component stock solutions has been demonstrated to reduce footprint and cost, and automated systems for “on demand” buffers are commercially available; there is some hesitancy by processors, however, to implement this new concept (2). There is room for new technology and methods that could ease implementation.

An open-source system being developed by two precompetitive consortiums, the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and BioPhorum, is the NIIMBL-BioPhorum Buffer Stock Blending (BSB) System, which was described in a December 2019 report (3). The prototype was displayed at INTERPHEX in October 2021, and more details on the concept are planned for publication in 2022. The consortiums’ vision for the open-source system is to accelerate adoption; allow companies to evaluate the technology and dataset; and allow companies to leverage the approach to deliver buffer preparation with a reduced footprint, in less time, with reduced labor (4).

Interoperability between different systems in a manufacturing facility is crucial. One challenge in downstream processing is that different pieces of equipment often come from different vendors; each skid from a different supplier may use a different control system platform, resulting in a higher level of complexity required to integrate the skids, explains Yvonne Duckworth, director of Digital Technology and senior automation engineer at CRB. “Making data available via communication protocols can be complex with multiple control system platforms, but [it] is crucial to provide the level of data connectivity that is key to smart manufacturing and digitalization in accordance with Pharma 4.0,” she explains. “A vendor-neutral protocol that has been gaining popularity is the OPC Foundation’s OPC Unified Architecture (UA). OPC UA is an easy way for third-party platforms to communicate, providing enhanced interoperability, while adding more robust security for access control, authentication, and encryption.”

Integration and standardization are important for control systems to handle the growing need for flexible production systems used to make multiple products. “This shift towards a more flexible but also more integrated approach has generated a desire for technologies that make it fast and easy to transfer recipes and integrate new equipment into the control system,” says Michalle Adkins, director of Life Sciences Consulting at Emerson. “If you need to switch to a new
product quickly, you can’t get caught up spending weeks or months updating recipes, writing custom code to integrate essential equipment, and testing these changes. To meet this need, the most flexible control systems are incorporating integration of skids with both tighter native controller
integration and standardized integration of the equipment controls and graphics using NAMUR’s [User Association of Automation Technology in Process Industries] Module Type Package (MTP). MTP provides a framework for standardized connectivity between equipment to streamline interoperability, making equipment nearly plug and play.”

Standardizing interfaces for technology transfer

Technology transfer is another area that benefits from standardized, automated tools. “To break down the silos that create tech transfer delays and inhibit speed to market, manufacturers are leveraging process knowledge management (PKM) software to build a bridge between development and manufacturing,” says Adkins. “PKM solutions are becoming more important for process knowledge capture and transfer.” She explains that these tools can be used both for developing new products and for managing changeover from one product to another. “Parameter-driven recipe management and the ability to transfer recipe parameters from a higher-level system to the production execution systems has become a focus,” Adkins explains. “By standardizing data, interfaces, and usability across the entire production pipeline, PKM tools make it easier to evaluate sites against a master recipe, transfer master recipes with process details, and push parameters to downstream systems to determine which sites are the best fit and [to] transfer the details for how to manufacture specific products. Emerson has found that under the right circumstances, a more automated technology transfer process can help reduce time to market from 10 years to less than three years.”

Automation technologies that minimize human involvement inside upstream, downstream, and fill/finish manufacturing suites provide the dual benefits of reducing contamination risk and helping address personnel shortages. “The ultimate long-term vision [for many life sciences organizations] is to enable lights-out manufacturing, creating continuous production and packaging lines that operate with minimal human intervention,” says Adkins. “Automation technologies [such as] simulation and predictive modeling, remote monitoring, and even artificial intelligence and machine learning will be key to the success of a future with lights-out
manufacturing initiatives.”

 online, DOI:10.3389/fbioe.2020.00758 (July 3, 2020).

3. BioPhorum Operations Group, “NIIMBL-BioPhorum Buffer Stock Blending Systems: A More Advanced Concept for Buffer Manufacturing,” December 2019.

4. BioPhorum Operations Group, “Showcasing the NIIMBL-BioPhorum Buffer Stock Blending System,” Press Release, Nov. 30, 2021. 

Jennifer Markarian is manufacturing reporter for 

When referring to this article, please cite it as J. Markarian, “Developing Automation Downstream,” 

Downstream Processing

Automation enables intensification of downstream processes.

Developing Automation Downstream

In the high-stakes world of microbial biomanufacturing, there are dozens of critical moments and crucial decisions to be made on the path from clinical trials to regulatory approval to commercial manufacturing. Planning and executing both scale-up and a successful biologic licensing application (BLA), however, may be two of the most significant moments in the regulatory pathway.

First and foremost, the financial, intellectual, and time investment in developing a biopharmaceutical product through microbial fermentation is high. Tens and even hundreds of millions of dollars are at stake. Errors, lack of knowledge, and poor planning can have catastrophic effects on a project, leading to tens of millions of dollars lost or even projects being discontinued for budgetary reasons.

But a well-planned scale-up and soundly executed BLA, implemented with an experienced contract development and manufacturing organization (CDMO), can save pharmaceutical companies months of wasted time and money. When development timelines are measured in years and investments are measured in eight and 10 figures, planning and execution are of the highest importance.

When moving from early stage proof-of-concept to clinical and then commercial stages, the crucial steps of scaling up a microbial product and garnering regulatory approval both become significant steps. Both these undertakings require a full understanding of the goals, the process, the facilities, the safety, and the demand for the bio/pharmaceutical by the manufacturer or CDMO and its partners. Scale-up planning and the development of the BLA work in concert to help all of the collaborators define, plan, forecast and execute the development of the product and reach its market potential (see 

Once the proof-of-concept has been achieved, a manufacturer must develop a full understanding and plan for scale-up. All partners, which could include biotechs, bio/pharma companies, and CDMOs, must understand and agree on the goal, the process, the development plan (including potential deviations), production, and manufacturing. In addition, all partners should also be addressing questions about demand, scale, budget, and details of the supply chain.

Preparing to scale up and file for a BLA requires that the manufacturer answer these questions so they can test and understand the boundaries of their project’s parameters: process design, plant fit, process robustness parameter characterizations, and design space, to name a few. If the project isn’t properly planned, one might not be able to ramp up supply quickly enough due to a lack of capacity and/or throughput. If the manufacturer scales too high, then it will build up inventory, and the shelf-life or stability of the product may be at risk. That product may need to be scrapped, which is an expensive error. Conversely, if the scale is too low, the manufacturer might not be able to produce enough product or substance, which results in a loss of market opportunity.

With an increased focus on smaller next-generation biologics, such as antibody mimetics and novel scaffolds as well as vaccines (e.g., subunit vaccines, plasmid DNA, and messenger RNA), interest is shifting back toward microbial biomanufacturing. There is also an increase in microbial biologics as the method of choice in both fighting infectious diseases as well as in oncology, which contribute to the rising use of microbial biomanufacturing as an effective and cost-efficient manufacturing platform.

Microbial biomanufacturing can reduce development timelines and costs. Starting a project with microbial fermentation is quicker and easier than using mammalian cells because microbial cells are easier and more convenient to access. Because a plasmid is used in these situations, there is no need to select a particular clonal line; thus, the upstream function is easier and quicker when working with bacteria.

Microbial biomanufacturing’s technical requirements, however, increase the already inherent complexity of biologic drug development. Unlike mammalian cell culture, where platform processes are routinely used, microbial manufacturing requires customized processes tailored to the characteristics of each specific molecule, leading to variations in product titer, yield, and process approach. These variations have a broad impact on several elements of development and manufacturing, from analytics to a regulatory filing as well as on the facility and the manufacturing process itself (1).

Additionally, microbial processes include the fermentation of microbes in bioreactors to produce enough product for each stage of development, from early to later stages, including clinical trials and commercial manufacturing. Each scale-up must be executed in consecutively larger bioreactors (e.g., 0.5 L–10 L for early stages up to 15,000 L for later stages and commercial) with scale factors ranging from thousands to millions.

Scale-up of the process to accommodate larger batch sizes brings a host of additional variables that must be taken into account. One example is the use of buffers. Corrosive buffers can be prepared and used in single-use plastic bags for small batch production at an early stage, but, when it is time to move to larger stainless-steel equipment, single-use bags cannot be used. This is just one of the dozens of elements that must be considered as the product moves through each stage of development that demands ever-increasing batch sizes. It is critically important for a biotech company to focus both on the early planning of process scale-up and BLA activities to maximize its chances of success. Approaching the project with a view of the entire process will decrease the potential for costly setbacks and secure a right first time (RFT) approach.

Ideally, a biotech company will choose an experienced and high-quality CDMO that will work as a partner/advisor throughout the project’s entire scope—with the end goal as its primary focus. A detailed and accurate plan can only be developed when the entire process and the final goal are considered when planning its lifecycle.

Approaching the development of a microbial biopharmaceutical by focusing only on individual phases or stages will often lead a manufacturer down the path of delays, setbacks, rework, and millions of dollars wasted or lost in potential sales. A common fundamental error is to select the microbial host strain and develop it without regard for its suitability for large-scale production. Often, new opportunities are conceived by professionals who don’t have relevant technology commercialization experience. They may realize that commercial engineering input is needed but don’t realize that the input is best when given at the earliest point possible (1). This serial approach can lead to costly mistakes and delays, whereas an experienced CDMO will have the entire project in mind when making major decisions, such as which microbial strain to employ.

Whichever partner a biotech chooses, that partner should understand and advise on the entire product lifecycle: assessment, development, process, analytics, production, the regulatory landscape, validation, manufacturing, and optimization (see 

). Often, CDMOs are the partners that have insight into the entire lifecycle. They can build a detailed vision of the early-, mid-, and late-stage process development. They can also plan out the BLA and manufacturing process. The initial investment is negligible compared to the total project cost and the potential losses that poor or narrow planning can cost.

Unfortunately, there are myriad opportunities in the development of a microbial product for oversights and shortcuts as the result of working with multiple partners rather than an integrated one. The consequences of this can range from inconvenient to catastrophic.

For example, a biotech can engage with one CDMO to get a product to Phase I or II and then work with another to scale up for the next phase or the BLA. Since the biotech company partnered with two different CDMOs that may have different manufacturing processes, revisions may be needed and, sometimes, complete redevelopment. In addition, microbial manufacturing requires customized processes for each specific molecule, and, therefore, working with multiple partners can lead to potentially unwanted surprises, such as additional plant adaption, a higher level of capital expenditure, longer batch and cycle times, and a resultant higher cost of goods. These circumstances can happen at every stage of development, but its impact is highest at the later stages of development.

The financial investment to scale up a microbial process to manufacturing scale can be greater than the cost to develop the production microbe and lab-scale process. This can be $100 million to $1 billion, including intermediate process validation (pilot and demo scales) and construction and start-up of the manufacturing plant (1). The annual operating cost of the manufacturing plant is in the same order of magnitude. The time required to transition from lab-scale to manufacturing is typically three to 10 years. Under these circumstances, the financial risk is high, so a deterioration in process performance during scale-up will be costly and disruptive, potentially leading to project failure. Short of failure, even incremental (5–10%) under-performance and/or delays (three to 12 months) during scale-up will substantially reduce financial returns and undermine stakeholder and customer confidence. So, when scaling up microbial processes, it is imperative to get it right and to get it right the first time (1).

During the manufacturing process, it is imperative for biotech companies to work alongside the appropriate strategic partner in order to help prevent any surprises and deviations and get the product ready for the commercial phase.

There is some flexibility in time and budget for scale-up, but there is little flexibility or negotiation in a regulatory filing.

For a BLA, a highly defined approach to determine the parameters, scientific method, the development and manufacturing spaces, and equipment for the product is important. In a BLA application, there is a focus on the process and the scale-up, but the analytics are equally, or more so, important because the analytics validate the quality and attributes of the product. Because a large percentage of delays in BLA approvals is due to chemistry, manufacturing, and controls (CMC), which can be as much as 18 months, it is important for biomanufacturers to devote time to ensuring that the methodology for safety and consistency is laid out in addition to the process details. A focus on RFT is crucial to avoiding significant costs associated with rework as well as loss of opportunity (see 

A quality CDMO is also aware that a successful BLA application or approval is not the finish line. Post BLA filing, manufacturers may undergo on-site audits from regulators while running the first commercial batches. A quality CDMO is prepared for those audits, making them a critical part of the preparation and approval plan.

Once a BLA is approved and the product is moved to commercial-scale manufacturing, processes must be maintained within regulatory boundaries but must also be optimized for efficiency. If manufacturing is built out correctly, a CDMO can continually optimize post-launch to improve efficiency in yield, batch time, cycle time, and other key performance indicators. Manufacturing build-out must be done correctly, however, within regulatory boundaries and built into the BLA. If the BLA boundaries are set too narrow, there is almost no chance of improving the process. Designing the right space, equipment, and regulatory strategy is not only part of a successful filing but also gives companies the “license” to continually optimize manufacturing.

Developing and manufacturing microbial biopharmaceuticals demands high financial and long-term investments, making a RFT approach a priority for most bio/pharmaceutical and biotech companies. Two elements in the lifecycle of a biopharmaceutical—scale-up and the BLA—are particularly vulnerable to mistakes due to poor planning or inexperience. Those mistakes, which can cost a drug developer months or years and millions of dollars, can be mitigated or avoided with detailed planning, experience, and a holistic view of all phases (rather than just each phase one at a time). Mistakes made in early phases can become catastrophic at scale-up and during the BLA. Working with a CDMO that has a complete line of service from strain development through manufacturing, however, will not only help a bio/pharmaceutical or biotech company avoid costly missteps but will also facilitate the saving of time and money.

Stéphane Varray, PhD, is senior director, head of Commercial Development, Microbial Business Unit, at Lonza.


Vol. 35, No. 8
August 2022
Pages: 22–26

When referring to this article, please cite it as S. Varray, “Outlining Successful Steps for Scale-Up and BLA Filings,” 

Upstream Processing

Successful scale-up and BLA filings for products manufactured by microbial biomanufacturing require strategic planning.

Outlining Successful Steps for Scale-Up and BLA Filings

Messenger RNA (mRNA) is an ingenious natural molecule involved in the creation of proteins, which are essential to biological processes. This same molecule is the basis of a new breed of mRNA vaccines, which were adapted in a matter of months to combat the SARS-CoV-2 pandemic (1).

Rapidly evolving mRNA technology will be key to addressing many unmet needs in vaccines and oncology, as well as supporting a more rapid, global response to future pandemic threats. The mRNA process offers the potential to rapidly produce more vaccine doses compared to conventional vaccines that use cell-culture based production routes, which are often more prone to failure (2).

Advances in mRNA, coupled with the need to ramp up production capacity to meet global demand (3), provide an opportunity to build flexible manufacturing capacity (4). However, larger-scale mRNA vaccine manufacturing poses challenges relating to facility design. As each project will have a unique set of requirements, it is important for solutions providers to address each consideration.

New mRNA good manufacturing practice (GMP) facility design must comply with strict regulatory and sustainability codes of practice, which vary globally. When it comes to delivering such projects, teams with expertise across a wide range of specialisms are needed to design, build, and operate this new class of therapeutics facility.

Production of mRNA-based vaccines differ from the approach used in conventional protein or viral vector-based vaccines as they are produced in cell-free systems. mRNA manufacturing involves the production of a DNA template, typically using linearized plasmids, followed by an 

 transcription (IVT) enzymatic capping reaction, which produces the mRNA 

Following purification using chromatography techniques, the mRNA drug substance is encapsulated with a selection of nanolipids to form lipid nanoparticles (LNP), before further purification and buffer exchange using chromatography coupled with tangential flow filtration (TFF) to make the bulk drug product (BDP) (5)

Low-temperature storage is needed until such time the BDP can be formulated, sterile filtered, filled or lyophilized in vials, labeled, and packed to make the vaccine. At present, multidose vials plus diluents comprise the pandemic vaccine product, but this is likely to change in the future (6).

The different process needs necessitate different facility design requirements. Examples are given in 

From a manufacturing perspective, mRNA’s potential lies in the capability of smaller-scale facilities to produce clinical trial materials as well as larger volumes of patient doses with the same equipment. The latter can be achieved via more intensive production schedules, or semi-continuous processing techniques.

As a rapidly evolving field using disruptive approaches and technology, mRNA requires a reset in terms of the thinking around facility design. In contrast to the conventional approach, each mRNA project needs solutions providers to provide a ‘bottom up’ strategy, which should emanate from teams on the ground who have the necessary insight into the specific design, equipment, and materials handling considerations.

Biopharma companies should provide their best forecasting estimates for future capacity, number of products, and various formats that mRNA vaccines can be formulated into (e.g., liquid vs. lyophilized, multi-dose vs. single dose vials, transdermal patches, or inhalants).

Where mRNA vaccines currently fall short versus their cell culture-based product competitors is their dependency on steady supplies from others of costly and scarce starting materials (plasmid DNA, enzymes, nanolipids), plus the need for lower temperature storage of intermediates and products.

The latter point provides a geographic constraint for manufacturing and distribution sites. Both have contributed to a higher cost of
goods, which may limit market penetration during non-pandemic times and affect the facility’s operational and environmental sustainability.

In the absence of such a capacity estimate, mRNA projects could be restricted when it comes to scale, and manufacturers may also face limitations in relation to handling and containment measures for the raw materials used to produce mRNA.

While each project has a unique set of manufacturing and facility design challenges, the key challenges facing mRNA facility projects are scalability, use of flammable materials, and equipment and manufacturing support.

Process scalability provides the potential to manufacture product in greater volumes. However, scaling out an mRNA process requires careful considerations and can introduce specific design requirements, which mean that it may not be possible to renovate a brownfield site or an existing facility.

The mRNA process can produce more doses than conventional biologics projects, so best practice involves estimating in advance the number of doses per batch that a project or facility will manufacture, establishing how many doses are required in what timeframe, and to evaluate the use of continuous processing strategies. This process will act as the starting point to guide each mRNA project and will determine the parameters for the design of a commercial facility.

To address this challenge, prefabricated modular facilities offer a solution for phased capacity expansion/scale out, while reducing interruption to existing operations.

The use of significant quantities of flammable materials that are central to the mRNA production process requires tailored containment, handling, and disposal measures. These measures vary from project to project and effectively necessitate solutions providers to deliver one-off, bespoke solutions. Wider regulatory and sustainability issues also need to be considered.

Increasing production capacity may necessitate the facility to cater for higher hazardous area category (e.g., H-Occupancy) design features, such as specialized building construction and potential blast zones. These are typically undesirable as they adds to the cost and complexity to the project, especially if the project is a retrofit.

Once the scale of operations is defined, it is necessary to determine flammable quantities and assess whether there is a need for hazardous area compliant construction. It is recommended to assess if the process can be scaled back or run differently (more batches per year) to avoid this specialized aspect by operating below the relevant maximum allowable quantities (MAQs).

Use of semi-continuous processing strategies can minimize solvent use. Such an assessment should cover:

Quantification of flammable material use for production steps, including buffer preparation and LNP storage

Equipment and facility cleaning strategies that contribute to the facility flammable materials inventory

Impact of HVAC design to avoid hazardous atmospheres (e.g., full fresh air), use of local exhaust ventilation (LEV) or fume hoods

Solvent distribution methods (e.g., closed solvent delivery and waste removal systems)

Location of solvent bulk storage outside of the processing area/facility, and piping in what is necessary plus removing spent solvent in a timely manner (e.g., piped transfer to a waste tank for removal by a specialist contractor).

Currently, there is limited commercial offering of dedicated, single-use, and/or explosion-proof equipment both for mRNA purification and LNP assembly at commercial scales (7).

Prompt equipment specification and procurement is needed to fix the facility design and ensure that their lead times are not on the critical path to plant start-up. At present, the process cannot be fully single-use, so thought needs to be put into the cleaning and sterilization processes, plus the analytical support infrastructure needed for reusable product-contact surfaces.

Therefore, it is recommended that for each mRNA project, consideration is given to the following aspects to determine the link between the equipment available and the facility design:

Independent production rooms with “through-wall” buffer transfer through iris ports in from logistics corridor (Buffer Prep/Hold)

Room electrical classification needs versus process step

Equipment selection versus electrical and fire code requirements

Benefits and limitations of implementing single-use technologies, given that the process will be hybrid (with stainless steel).

Operational capacity will be mainly dictated by the availability of a skilled workforce for GMP manufacturing. Thought should be given to staff welfare facilities, which are key to retain skilled workers. Onsite canteens, adequate spaces for parking, lockers, and shift handover meetings need to be considered as well as the manufacturing suites.

From an operational perspective, process and facility design should consider continuous processing and implementation of process analytical technologies (PAT) to automate selected process steps (8). Low-temperature storage capacity should be included to allow for processing breaks (e.g., freezing of intermediates) to enable day-shift production.

Finally, the limited capacity for outsourcing of supporting functions, such as facility environmental monitoring or product sterility testing, should be considered during concept design. Just because the process is cell-free, the analytical in-process testing and release methods needed may not be. Inclusion of fully-segregated microbiological testing laboratory suites in the scope of the project should be considered if outsourcing is not an option. Basing designs on the use of recent advances in microbiological testing such as enzymatic indicators and rapid sterility testing can reduce the footprint of these labs (9, 10). An example of an LNP manufacturing area is shown in 

Linking process engineering knowledge to facility design is critical for compliant and competitive manufacturing in the life sciences sectors.

Novel mRNA-based therapeutics are on the cusp of transforming product and project delivery and has the potential to revolutionize modern medicine. By overcoming challenges related to manufacturing and facility design, solutions providers can play an important role in helping mRNA to face down future pandemics and, more broadly, make these life-changing medicines accessible to a greater number of patients, faster.

1. Coalition for Epidemic Preparedness Innovations (CEPI), “How Rapid-Response Vaccine Technology can Combat Disease X,” 

online, DOI: 10.1038/s41541-022-00447-3 (March 2, 2022).

3. Pharmaceutical Technology Editors, “Moderna and Thermo Fisher Scientific Form Long-Term Strategic Manufacturing Collaboration,” 

4. Pharmaceutical Technology Editors,”BioNTech Plans to Build Modular mRNA Manufacturing Facilities in Africa,” 

 online, DOI: 10.1016/j.vaccine.2021.03.038 (March 24, 2021.)

7. Pharmaceutical Technology Editors, “Cytiva Provides Arranta Bio with Single-Use Manufacturing Platform for mRNA Products,” 

This article provides an overview of solutions to address key challenges facing vaccine developers or CDMOs wishing to build their own commercial-scale mRNA production facilities.

BioPharm International, August 2022 Issue

Deciding Where to Outsource in Biopharma Development and Manufacturing

Driving Manufacturing Improvements Through Viral Vector Advances

Developing Automation Downstream

Outlining Successful Steps for Scale-Up and BLA Filings

Overcoming Engineering Challenges to Enable Commercial Scale mRNA Vaccine Manufacturing

Continuous Processing for Viral Vectors

Accelerating Time-to-Insight Across the BioPharma Lifecycle

Automating Packaging of Bio/Pharmaceuticals

FDA Joins Effort to Curb Drug Patent Abuses

Navigating the Future

Regulatory Applications for Biologics

The Stick and Carrot of Quality Management