This compilation allows readers to adjust their thinking to appreciate the full impact certain select technologies will make on the industry by 2026.

Six Approaches Making the Most Significant Impact in the Future

The testing of new convecdiff membranes shows this material to be well suited for lab- and commercial-scale bind-and-elute applications.

Purification of Antibodies Using Novel Convecdiff Membranes Part 1

Cautiously setting aside pandemic practices, pharma workers appear ready for flux, change, evolution, and expanding molecular diversity.

Crossing the Same River Multiple Times

Biologic drug development requires relevant bioassays to measure and help predict cellular response.

Complex Analytical Workflows Increasingly Require Robust Bioassays

Affinity chromatography resins must perform well under mild elution conditions yet withstand robust cleaning and sanitization protocols.

Choosing the Right Resins for Viral Vector Affinity Chromatography

Efforts to optimize the ideal blend of technology and best practices that are needed to protect and deliver time- and temperature-sensitive biologic therapies, vaccines, and cell and gene therapies continue to evolve.

Safeguarding Biologics— Blending Engineering Ingenuity and Managerial Excellence

Health crises, political tension, and budget concerns were major challenges.

Pandemic and Politics Shaped Pharma and FDA in 2022

Chris Spivey is the editorial director of 

Devoting time to track what developments will impact bio/pharmaceutical manufacturing isn’t easy, unless (like an editor of this publication) it’s your primary task. In a framework of descending order of impact, the first trend discussed in this article is messenger (mRNA) applications beyond vaccines. At the end of this list is bringing pharmaceutical manufacture right to the patient’s bedside. For near-patient and distributed manufacturing, FDA calls for not only fresh approaches but the willingness to use new ways of thinking to achieve this goal. Being focused on the year 2026, we allow the reader time and space to better reset, and prepare for only the most seismic events.

“The very essence of what makes mRNA a great way of delivering vaccines is the very real challenge of making them anything other than fit for that purpose, namely their inherent ability to cause activation and alarm within out highly sophisticated adaptive immune systems,” says Stephen Rapecki, director, Experimental Therapeutics, UCB. “We need to devise improved means to disguise and deliver both mRNA itself and also it’s delivery packaging, if that can be accomplished,” continues Rapecki. “The second challenge is delivering mRNA to its chosen cell or organ. mRNA vaccines administered subcutaneously most likely deliver their immunogenic payload to antigen presenting cells at the site of injection and to draining lymph nodes. This allows small and targeted doses of vaccine to be amplified as the immune reaction is the intended outcome not the production of the protein per se. To deliver a protein to correct a condition or replace a defective version of a protein will require much larger amounts than for immunization, perhaps by factors of up to a thousand. Such manufacturing challenges though are not insurmountable given the exciting opportunities mRNA offers drug hunters,” he contends.

The next hurdle, common to any drug therapy, is liver metabolism and toxicity. An approach here, Rapecki continues, “is to attach a targeting portion to your LNP [lipid nanoparticle], which typically could be a peptide, antibody, or antibody fragment. This doesn’t avoid the liver but can potentially swing the selectivity in favor of your cell type of interest. The final challenge to expanding mRNA beyond vaccines could be a strength or weakness depending on your point of view. This is the transient nature of mRNA expression which can vary from hours to many days but not the months or years that might unlock applications which currently are the domain of viral delivery. The iterative development of non-natural mRNA sequences, self-amplifying mRNA and now circular mRNA are beginning to extend the length of protein expression delivered by mRNA, but it is still envisaged that mRNA therapies outside the vaccine field will need repeat dosing to be truly effective. This leads to which applications will come after infectious disease vaccines. The low hanging fruit will be not to avoid an immune response, but to rely on it and deliver cancer vaccines, many of which could be personalized through sequencing tumour antigens to discover which give the best anti-tumor responses ... Beyond vaccines lies the non-immunogenic applications already mentioned. Assuming, and it’s a very big if, immunogenicity is greatly reduced, the next application is likely protein delivery to enclosed organs such as the eye, brain, etc. These will need larger doses and repeat administration so the durability of these responses will be key. In the periphery non-immunogenic targeted LNPs, which have the most scientific hurdles to cross, also have the potential to open the largest therapeutic space. Here you can envisage altering your own T cells to temporarily become CAR-T [chimeric antigen receptor T cell] cells circumventing the need for expensive cell therapy and with a safety profile that could work outside of oncology. Delivering a protein to cells in the blood altering their sensitivity in the case of autoimmunity should also be a possibility giving dosing regimens similar to current biologic drugs.”

Donald Ingber, founding director, Wyss Institute for Biologically Inspired Engineering at Harvard University, believes Organ Chip technology is at the tipping point when it comes to drug discovery and personalized medicine. He points to a study where scientists performed a comparison between animal models and human Liver Chips that shows these chips offer a way to predict drug-induced liver toxicities (1).

“Perhaps even more important for their acceptance by regulatory agencies and the pharma world, this study included an economic analysis that estimated drug developers would save about $3 billion per year if this one animal model were replaced by Organ Chip technology, given the huge costs of drugs failing once they get into clinical trials,” says Ingber. “My hope is that this will catch the eye of those in C-suites, which would ensure this transition towards a faster and less expensive way of developing safer and more effective drugs. At the same time, the ability to create Organ Chips lined by patient-derived cells, which we do standardly, opens the possibility of an approach to personalized therapeutics in which not only are better drug choices made, but the administration regimens—how frequently the drug is administered, by what route, and at what dose—may be optimized as well.”

Tissue Dynamic, an emerging organoid company, estimates (in a dramatic claim) that the company could cut drug development costs by 40–80%, and time required by 30–50% overall. Their approach is to ab initio embed sensors into the organoid while its being grown, which allows AI-driven computation to directly interrogate biology every step along the development process. “This allows the robot to start screening drugs against different models of disease. It can perform, by itself, safety assessments in the microtissues and identify the drug that works best and causes the least damage to human organs, and it does this extremely fast. We can do it in 19,000 tissue samples at once. It is the equivalent of [testing on] 5000 patients,” said Yaakov Nahmias, founder and chief scientific officer of Tissue Dynamics LTS (2).

Artificial intelligence (AI) and machine learning (ML)

In a presentation at the 2022 PDA-FDA Joint Regulatory conference, Martin Van Trieste spoke about quality 4:0, six sigma, and the date deluge, saying, “We’re now using machine learning and AI, and that will really help eliminate failures, eliminate deviations, eliminate non conformances, and get past what I call blind compliance.”

At the conference, Van Trieste spoke about saving an in-process batch of protein product at Amgen as a case example, before proclaiming that because of AI, “the future looks really bright for patients with improved safety, reliability, and quality, and all at a lower cost, some of which will be passed on to the consumer. Now if the future is bright for this group of people, it must be bleak for somebody else. And it’s going to be bleak for the dinosaurs of the industry, for the large quality organization that have been built around testing and inspecting the product, because if you are doing AI, you don’t need large testing organizations. The computer will not allow a mistake to happen, and it will safety check everything at the end … It’s really good for the patients. It’s not good for the quality unit, so I suggest that you really learn data analytics, you really learn AI‚ become that resource in the company, because that’s how you’re going to keep your job in the future.”

In concrete terms, Nicholas A. Geisse, CSO of Curi Bio, explains, “Where we’ve been using AI at Curi is to unbias the observer. We routinely use AI/ML routines to analyze our imaging data in an unbiased way and use it to find the unquantifiable subtle idiosyncrasies that are within the data. One thing that always frustrated me was that for certain procedures, for example stem cell differentiation, we’d have to grab one specific expert to look down the microscope and give a thumbs up or a thumbs down for our go/no go criteria.” That was the past.

According to a press release, PictorLabs (3) uses deep learning algorithms to stain tissues 

, producing near-instantaneous virtual stains, claiming, “From a single unstained tissue sample, PictorLabs’ proprietary platform can produce an unlimited number of virtual stains that are indistinguishable from analogous chemical stains.” To even imagine this requires a robust adjustment of our preconceptions.

Drug recalls, warning letters, and persistent repeated drug shortages have been a drag on both the bottom line and the perception of the pharmaceutical industry for many years. FDA has now moved ahead in its plans to push for higher corporate quality culture through its QMM assessment program. In an article published in 

 (4), the authors state their experiences running the overseas pilot program. The program assessed eight overseas excipient companies’ quality culture and business process performances. “While FDA provides oversight of the site quality management processes and product quality via CGMP [current good manufacturing practice] inspections, and other surveillance methods, there are currently no comparable regulatory tools that examine a site’s business processes and how well they are integrated with quality objectives. QMM fills that much needed gap.”

, Somnath Mishra of Shabas Solutions pointed to senior management’s role in controlling aspects of quality (5). “They’re the ones that control the purse strings and the decisions that are made that actually breathe life into a quality system ... Those people can better solve some of the pernicious intractable problems that exist … Pharmaceuticals are simply recognizing the initiatives and successes that these other industries have achieved, and realizing these only so much that can be done at the technical level, …. you can train technicians, provide SOPs [standard operating procedures], specifications … You can oversee with managers, supervisors, even director level personnel, and still there are problems. So, it was these other industries that solved that. They illuminated the source of some of the pernicious problems, and it pointed back to senior management … [who] had underappreciated the quality aspects of corporate culture.”

To clarify the reasoning to include QMM in this list of trends, QMM won’t promote pharmaceuticals to make a bigger impact on patients directly, but it will make a very big impact on how the industry conducts itself internally, in particular, at C suite levels, and how better outcomes and efficiencies cascade outwards.

Improving yield and standardizing manufacturing for viral vectors

One of the constraints to cell and gene technology (CGT) growth is to scale vector production. “By its very nature, transient transfection is an inconsistent process and really limits the ability of the field to make significant yield improvements,” says Clive Glover, general manager, gene therapy, Pall Corporation. Comparatively monoclonal antibodies (mAbs), “are three to five orders of magnitude greater than when the field started out. We are aiming to reproduce this in the viral vector field, but it turns out to be significantly more difficult to make a stable producer cell line for viral vectors due to the inherent toxicity of some of the proteins to the producing cell,” Glover observes.

Optimally, we might have producer cell lines that can produce vectors without the need of transient transfection, but creating high-titer stable producer cell lines is difficult. “In time, researchers rediscovered the potential for gammaretrovirus in CGT, focusing where oncogene promoter-adjacent insertion is less of a concern, including CAR-T therapies—and this is where the industry stands now, at an exciting nexus point where potential is becoming reality,” Bill Vincent, founder and executive chairman, Genezen remarked (6).

Glover elaborates on his earlier point saying, “CEVEC, a Germany company, recently acquired by Cytiva, has figured out how to solve this problem by putting the genes required for viral vector production behind an inducible switch that can be turned on once the producer cells have been grown up to their final production volume.”

Adam Fisher, director, Science Staff, Office of Pharmaceutical Quality, Center of Drug Evaluation and Research (CDER), FDA, rhetorically asked (7), “If a future with distributed and point-of-care manufacturing doesn’t look like traditional brick-and-mortar manufacturing, what might it look like? Prefabricated, mobile, modular manufacturing units might move frequently between different geographical locations. Manufacturing units at multiple locations, perhaps even 3D [three-dimensional] printers at patients’ bedsides may operate under a single remote quality management system. This is no longer science fiction. FDA has seen some of these technologies from developers of distributed manufacturing processes.” While FDA’s CDER does not have any approved drugs in its current purview made with distributed or point-of-care technology, experts know they are coming.

CDER’s outreach is asking input by Dec 13, 2022 to: “How can manufacturers ensure location changes do not impact product quality?” The article ends by quoting FDA’s Larry Lee, “I think pharmaceutical manufacturing is on the verge of reconstruction; we have reached the point where change is necessary to improve quality and access” (7). A sentiment echoed by the 

(8), “…cryopreservation has become a critical area of interest in cell-therapy manufacturing, as issues of cell viability, functionality, and patient safety become increasingly important to resolve as more therapies reach the market. For autologous cell-based applications, many have argued that the best place for cell production is the ‘bedside’.”

1. Ewart. L.; Apostolou, A. et al. Performance Assessment and Economic Analysis of a Human Liver-Chip for Predictive Toxicology. 

2. Nahmias Y. Biologic Drug Development and Manufacturing.

3. PictoriLabs. PictorLabs Launches with More Than $18.8 Million to Advance Transformative Virtual Staining. Press Release. Dec 1. 2022.

4. Mishra, S.; Hauck, W.; Royal Z.; and Michalik R., Introduction to Pharmaceutical QMM Model: QMM Assessment to Promote Pharmaceutical Operational Excellence, 

5. FDA Quality Management Maturity (QMM) Overseas Pilot Progran Findings: Going Beyond the Regulations, 

6. Mirasol F. Driving Manufacturing Improvements Through Viral Vector Advances. 

7. Fisher, A. Nurturing Manufacturing Agility,

8. Kaiser A.; Assenmacher, M. Towards a Commercial Process for the Manufacture of Genetically Modified T Cells for Therapy. 

Chris Spivey is the editorial director for 


Vol. 36, No. 1
January 2023
Pages: 10-13

When referring to this article, please cite it as C. Spivey. Six Approaches Making the Most Significant Impact in the Future. 

Articles

Six Approaches Making  the Most Significant  Impact in the Future

Grant Playter is the Assistant Editor for 

 conduct a survey (1) designed to measure the state of the bio/pharma industry. More specifically, the survey assesses various employment metrics, thoughts on ongoing trends, and predictions for the future of the industry. The intent is to not only create a snapshot of the bio/pharma industry as it exists in 2022, but to also encapsulate the thoughts and feelings of those within.

In recent years, this has been dominated by the specter of a generational pandemic. While most are reluctant to declare the end to COVID-19—the continual discovery of new variants would stay the hand of even the boldest of public health officials—its influence has nonetheless diminished, even in an industry that has become inextricably tied to the virus.

However, in this year’s survey, consisting of 296 respondents in the bio/pharmaceutical industry, almost all key metrics that concern COVID-19’s importance to daily operations (

) decreased. One of the largest practices, social distancing, dropped to 28.2%, less than half of the percentage in last year’s survey (2). And while remote work remained prominent, with approximately 58% still engaging in the practice—especially notable given that many pharmaceutical positions require working on-site—it still had an approximate 10% drop from last year’s sample. Of the eight measures, the only pandemic-related metric that saw a rise in use was “assuming additional responsibilities,” which saw a modest increase of approximately three percentage points.

While the reticence to banish COVID-19 will continue to permeate through society, it is clear that the pharmaceutical industry is de-escalating many of the practices associated with it. Setting aside the validity of this approach, this shifts industry discussion to other aspects of the pharmaceutical market and what the future may hold.

Among survey respondents, wage growth appeared to stagnate relative to last year’s survey. As seen in 

, 72.8% of respondents indicated that their salary remained “approximately” the same, almost twice as much as last year’s 39.0%. Similarly, just 22.1% of respondents indicated a significant increase in salary, less than half of last year’s 55.4% number. Salary decreases also had a modest reduction, as they did in 2021, dropping from 8.1% to 5.1%.

Approximately 24.3% of respondents felt some increase in job security, a slight dip from the 30.4% number observed in 2021; the percentage of those who felt no change in job security dropped just three tenths of a percentage from 52.6% to 52.3%. As seen in 

, these modest reductions appear to have funneled into a slight increase in those who felt less secure, from 17.0% to 21.3%. As it pertains to job satisfaction, while those who felt somewhat satisfied or unsatisfied with their jobs remained similar to 2021’s numbers, those who felt fully satisfied dropped from 23.7% to 14.5% and those who felt mostly satisfied increased from 39.2% to 51.4%, resulting in a slight drop to the weighted average.

Interestingly, this only appears to have corresponded with a slight decrease in overall salary satisfaction. While those who were fully satisfied with their salary did drop from 18.8% to 14.9%, there was an increase from 37.7% to 41.9% in those who were mostly satisfied; this means the total number of those who responded positively to the question (i.e., fully or mostly satisfied) actually increased slightly. It is worth noting that the survey slightly changed the wording of the pay assessment question to include the word “significantly” to prevent raises designed to keep pace with inflation from being considered a metric of real wage growth. This change could result in some degree of variance among responses in the survey population, especially given the otherwise bullish market for employees in the greater economic landscape.

However, in tandem with work wages, job security, and overall job satisfaction metrics dropping, concerns of the survey population (

) revolved around finding proper staff. More specifically, over half of the respondents indicated that either an insufficient number of staff with specialized training (35.0%) or number of staff in general (22.8%) were their biggest concerns. Taken together, this could suggest that the pharmaceutical industry is struggling between attracting skilled talent and raising compensation for existing workers, an especially difficult task with inflation in countries like the United States outpacing many company’s
standard annual raises.

Alternatively, given decreases in job security metrics and the fact that just 26.4% of the respondents have changed jobs in the past two years, this could perhaps indicate a reluctance to re-enter the job hunting market. While it is generally understood that pay bumps from job to job will be, on average, higher than those within the same company, the uncertain state of the market could be staying the hands of those who would otherwise pursue new opportunities. In conjunction with high inflation and the perceived need for spending on additional staff, this could result in fewer raises and lower wages.

While wages and employment remain in a murky place, the other questions on the survey—those concerning past trends, future trends, and how they might intersect—painted a clearer picture of where the future of the industry might be headed.

In last year’s survey, the pharma industry had begun its recovery from the lows of COVID-19 and responses corresponded with that. Approximately 53.2% of respondents felt the industry had performed better than anticipated, while 47.4% thought the same about their company’s performance. As one would expect, those numbers both dropped significantly this year, as seen on 

However, there were only modest increases in those who felt it did worse than expected, an especially notable statistic in light of the fact that over half of the 2021 respondents expected increases in the industry. This affirmation of last year’s inclinations toward continued growth in the industry could perhaps explain the continued optimism in this year’s sample. As shown in 

, nearly half of respondents believe their individual company’s and the industry itself will continue to improve in the following year, while only a small fraction of the sample (10.9% and 11.5%, respectively) believe that things will get worse.

This, however, begs the question of where this growth may occur. The editors selected several intriguing areas of opportunities for participants to choose between, and as shown in 

, just under half (47.3%) chose cell and gene therapies. While chimeric antigen receptor-t cell therapies have been drawing increased interest from companies since tisagenlecleucel’s approval in 2017, this interest can also be explained by the rise of mRNA vaccines. Following their accelerated development in wake of the COVID-19 pandemics, there have been many vocal proponents for their use in personalized vaccines, in particular for conditions like cancer. In addition to cell and gene therapies, machine learning and artificial intelligence (22.3%) also drew significant interest from the survey population.

In total, while this year’s employment survey did shine a light on some intriguing trends throughout the industry, it has also reiterated, as it almost always does, that the industry continues to be in a state of flux. While there is continued optimism and hope for promising technologies, struggles among employees and business could easily boil to the surface. Employees may continue to face wage stagnation, while businesses may face struggles to maintain proper staffing for current operations, let alone branch out into new technologies of interest.

To get a coda on this from the survey respondents, we asked every respondent to submit one word that they felt best described the industry as it currently stands. While there were a variety of responses, two words kept popping up: “Challenging” and “Evolving.”

Will this prove true? Only time will tell—see you next year.

. Employment and Trends in the Pharma Industry Survey 

2. G. Playter, “The Long Path to Normal,” 


Vol. 36, No. 1
January 2023
Pages: 14-18

When referring to this article, please cite it as G. Playter. Crossing the Same River Multiple Times. 

Katrin Töppner, Katrin.Toeppner@Sartorius.com, is Product Development (PD) scientist at Sartorius Stedim Biotech.

Patrick Adametz, Patrick.Adametz@Sartorius.com, is process engineer at Sartorius Stedim Biotech.

Chaz Goodwine is lead downstream scientist at AGC Biologics.

Ricarda A. Busse is product manager for Membrane Chromatography Consumables at Sartorius Stedim Biotech.

Volkmar Thom is head of PD Purification Materials at Sartorius Stedim Biotech.

 membranes, a new type of chromatographic material that combines high protein-binding capacity with high productivity while providing scalability, are introduced. The 

 membrane prototypes presented in this study reach a dynamic binding capacity of approximately 40 g/L at residence times in the seconds range while pressure drop is below 2.5 bar at a bed height of several millimeters. The robustness of the new material is proven up to 200 cycles. The material performance regarding yield, impurity reduction, and other results observed during cycling is comparable to the performance of established materials, and no performance decline occurred during cycling. With all these characteristics, the material is well suited for protein bind-and-elute applications ranging from laboratory to production scale.

Submitted: March 2, 2022
Accepted: July 21, 2022

Katrin Töppner*, Katrin.Toeppner@Sartorius.com, is Product Development (PD) scientist; Patrick Adametz*, Patrick.Adametz@Sartorius.com, is process engineer; Ricarda A. Busse is product manager for Membrane Chromatography Consumables; and Volkmar Thom is head of PD Purification Materials; all at Sartorius Stedim Biotech. Chaz Goodwine is lead downstream scientist at AGC Biologics.

*To whom all correspondence should be addressed.


Vol. 36, No. 1
January 2023
Pages: 22–27

When referring to this article, please cite it as Töppner, K; Adametz, P.; Goodwine, C.; Busse, R.A.; Thom, V. Complex Analytical Workflows Increasingly Require Robust Bioassays. 

Purification of Antibodies Using Novel Convecdiff Membranes Part 1: Providing High Binding Capacity at Short Residence Time and Low Pressure Drops

Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.

Affinity chromatography is a powerful separation technique employed to capture targets from complex and challenging feed streams, which makes it ideal for use in the purification of viral vectors. Most viral-vector harvest fluids, however, contain low titers of viral vectors and comparatively high impurity levels, and that places significant demands on affinity-resin performance. The sensitivity of viral vectors and their variability with respect to size and other characteristics adds to the challenges associated with affinity chromatography process development, including selection of the right chromatography matrices (resin/monoliths/membranes/fibers) and ligands.

Unlike traditional biologic drug substances, including recombinant proteins and antibodies, viral vectors can be highly sensitive to high- and low-pH levels, high- and low-salt concentrations, and high-shear environments.

“This instability is a big differentiator for viral vectors and presents some challenges when it comes to developing effective affinity ligands for use in the production of affinity-chromatography resins,” observes Ian Scanlon, a subject matter expert for cell and gene therapy at Astrea Bioseparations. More specifically, affinity ligands are required to have a good binding behavior toward the target viral vector, and at the same time, have relatively mild elution conditions to avoid a pH shift that could result in loss of infectivity of the viral particles during the process, according to Piergiuseppe Nestola, manager of process technology consultants with Sartorius.

In addition, different types of viral vectors have different sizes spanning from 20 to 200 nm and even higher for some oncolytic viral vectors, according to Nestola. “Viral particle size affects the dynamic binding capacity (DBC) of an affinity resin in an inverse relationship. Thus, for larger viral vectors, larger-column affinity-chromatography systems are needed, leading to an increase in the overall cost of the unit operation,” he says.

Some viral vectors, particularly adeno-associated viral (AAV) vectors, are generally formed as mixtures, with some containing the full genetic material and others containing none, partial or even incorrect (e.g., host-cell) DNA, according to Laurens Sierkstra, business segment leader in the BioProduction Group at Thermo Fisher Scientific.

The size and sensitivity of some viral vectors also creates issues for bioburden removal, particularly viral clearance, as typically 0.22 µM filtration cannot always be employed, adds Scanlon. “As a result, the importance of cleaning and sanitization of adsorbents used for affinity capture increases,” he notes. That can be problematic, as some of the proteins and peptides used as affinity ligands are not compatible with sanitization-in-place (SIP) protocols.

Generally, affinity chromatography for viral vectors can only be performed when commercially viable ligands are available, Nestola comments. Until recently, only ligands designed for use in affinity-chromatography resins for adeno-associated viral (AAV)-vector purification have been available. New resins for purification of lentiviral (LV) vectors are now on the market (vide infra).

One challenge to commercialization of affinity-chromatography resins relates to the size of viral vectors relative to the pore sizes of commercially available adsorbents, according to Scanlon. “Current offerings are often designed for optimal processing of antibodies—usually around 10–15nm. Many viral vectors are larger (adenovirus at ~90–100nm, gamma retrovirus and lentivirus at ~80–100nm) and thus excluded from accessing binding surfaces within pores. As a result, implementing bead-based approaches for these larger targets may yield lower capacities,” he explains.

Another difficulty is that affinity resins often must be specific for a given viral vector (LV vs. AAV vectors, for instance), and in the case of AAV, specific serotypes (AAV2, AAV8, AAV9, etc.). LV vectors are enveloped viruses, while AAV vectors are non-enveloped viruses. “In general, non-enveloped viruses are more stable and resistant than enveloped viruses, which means that from a chromatography condition point of view, elution conditions and shear stress for LV vectors are a much bigger issue than AAV,” Sierkstra notes. In addition, while empty/full capsid ratios are an issue with AAV vectors, for enveloped viruses like LV vectors, the production of a plethora of non-infective lenti resembling particles (e.g., exosomes) presents purification difficulties, she adds.

“That means the application of such resins is less flexible, and it is difficult for viral vector manufacturers to build platform-purification processes for a range of vectors using a single affinity-chromatography resin,” Nestola says.

In addition, while both AAV serotype-specific and non-specific affinity-chromatography products are available on the market, not all serotypes bind well to affinity ligands. “For each serotype, therefore, optimization and screening should be performed to find the best affinity ligand/resin for the specific serotype,” Nestola notes.

Complicating the picture is the constant evolution of the viral-vector field, according to Nestola. For instance, he points to the ongoing development of new AAV serotypes, or chimera serotypes, that do not bind to existing off-the-shelf affinity ligands. For this reason, Scanlon observes that manufacturers are moving away from the current affinity approaches and returning to a platform charge-based approach (as outlined in reference 1). “Although more polish steps may be required to reduce process-related impurities, this platform approach has the advantages of compatibility with SIP and clean-in-place (CIP) processes, flexibility across serotype variants, and reduced cost,” he says.

Several important affinity resin attributes

As with any other affinity-chromatography resin, those for use with viral vectors should allow for clearance of impurities with high flow rates for reduced purification times to reduce costs and, in this case, also avoid loss of infectivity. These goals must be achieved, reiterates Nestola, under mild elution conditions. Affinity resins for viral vectors must also be readily scalable and have the correct build-in attributes for the viral vector of choice, according to Sierkstra.

Major impurities that must be removed include host-cell DNA and other nucleic acids, according to Scanlon. Adventitious and process-related viruses must also be cleared, which requires that helper viruses (such as adenoviruses in AAV processes) not be bound by the affinity ligand employed.

Robust separation of the target virus from impurities at high supernatant loading volumes is also essential given the often quite low titers of viral vector products, Scanlon stresses. He adds that affinity resins must also be designed to withstand strong SIP and CIP processes without compromising their performance because of the crucial role they play in bioburden removal.

High-throughput screening is the best approach to both the development of novel ligands for affinity chromatography of viral vectors and for development of optimal affinity-chromatography purification processes for a given vector product.

“Phage-display- and library-based approaches with high-throughput process-development tools such as liquid handling and plate-based screens allow for the screening of large numbers of constructs and conditions to develop novel ligands,” Scanlon states. Thermo Fisher Scientific uses the specific attributes of a viral vector as the starting point for high-throughput development employing a quality-by-design approach. “In the initial screening phase, this technology ensures that the ligand being developed has the ability to elute at the conditions and with the specificity needed,” says Sierkstra.

Meanwhile, optimization of affinity chromatography process conditions should start with small-scale screening, normally using 96-well plates, according to Nestola, to examine different ligands/matrices and buffer systems. “Developing good buffer strategies that allow good binding of the viral vector product to the affinity resin with minimal virus aggregation is critical,” he observes. Screening is then typically validated on small-scale devices (1–5 mL) to confirm the screening results.

Further advances needed to address scalability

The need for vector—and serotype-specific affinity resins—creates an opportunity for chromatography-technology suppliers to offer a greater variety of ligand/matrix solutions. “Having a selection of off-the-shelf ligands for several viral vectors including but not limited to AAV would provide good benefit to the industry,” Nestola
contends. “Such matrices could be based on various types of ligands from antibodies to antibody fragments to synthetic peptides and thus provide options for achieving enhanced purity and selectivity for any given viral vector,” he adds.

In particular, Nestola notes that the need for caustic-stable ligands will only rise as more gene and gene-modified-cell therapies that leverage viral vectors reach commercialization, and as a result, the number of batches produced increases exponentially. He also observes that the use of different formats (e.g., membrane, monolith) for immobilization of affinity ligands other than beads/resins should be explored to achieve more rapid purification of labile viral-vector products.

Scanlon agrees that current processing times when using affinity resins for large viral-vector purification are long due to low volumetric flow rates, which directly impacts cost of goods. “Any reduction in processing time results in lowering this cost and increasing the speed of delivery to market of new therapies,” he states.

Based on the specific needs of each viral vector, Sierkstra believes that improvements in these products will require continued R&D investment regarding all aspects of their manufacturing processes. As an example, she points to the pretreatment steps often needed for AAV vectors prior to the affinity capture step. “Thermo Fisher Scientific has developed a purification solution leveraging magnetic beads that for small-scale processes offers a simpler approach,” she comments.

A few new solutions have reached the market

Two companies have recently introduced new affinity resins to the market—one set for AAV vectors and another solution focused on LV vectors. Avitide, a Repligen company, has developed three ligands specific to the major AAV gene therapy vectors used today (AAV2, AAV8, and AAV9). The AVIPure affinity chromatography resins have increased caustic stability without sacrificing high dynamic binding capacity, according to the company (2).

The latter comes from Thermo Fisher Scientific. CaptureSelect Lenti VSVG Affinity Matrix has been designed specifically for the purification of VSV-G pseudotyped lentivirus particles under mild elution conditions (3).The company also offers Poros CaptureSelect AAVX, a resin for all serotypes of AAV. “These products were developed to address the specific need for platform purification processes and the rapid growing clinical pipeline. Previous technologies and solutions lacked specificity and resulted often in purification processes that involved multiple, sometimes complex, steps, increasing the clean-room and manufacturing time as well affording low yields,” Sierkstra comments.

Heparin affinity chromatography has also been proposed by bluebird bio and collaborators as an effective method for the purification of retroviral vectors used for gene-therapy applications (4).

Astrea Bioseparations, meanwhile, has targeted its efforts at the development of a novel bioseparation material for viral-vector affinity chromatography. AstreAdept is an electrospun composite nanofiber chromatography membrane with a large open structure that provides virtually instantaneous binding of large targets, including viral vectors, to significantly larger binding surface areas, according to Scanlon. “Importantly,” he emphasizes, “this increased capacity is not compromised by the high flow rates enabled by the nanofiber’s open structure and operates without the pressure drops observed with other convective chromatography media.”

Nereus LentiHERO, the first commercial product to incorporate the AstreAdept technology, was launched in September 2022 and is optimized for primary capture of LV particles at lab scale (5). “This new non-pseudotype-specific affinity chromatography solution specifically addresses the issues of capacity and process times seen with legacy bio separation tools. Operating at physiological pH and salt concentration, it preserves the integrity and quality of the LV particles and delivers a high binding capacity and high recovery for higher yields from feedstock volumes,” Scanlon says. Scalable solutions to bring this technology to process scale are under development.

Rieser, R.; Koch, J.; Faccioli, G.;et al., Comparison of Different Liquid Chromatography-Based Purification Strategies for Adeno-Associated Virus Vectors, 

Repligen. Repligen Launches AAV Affinity Resins for Gene Therapy Purification. Press Release, Feb. 15, 2022.

Thermo Fisher Scientific. Cell and Gene Therapy Purification Solutions. Resource page [accessed Nov. 21, 2022].

Mercedes Segura, M.; Kamen, A.; Trudel, P.; Garnier, A., A Novel Purification Strategy for Retrovirus Gene Therapy Vectors Using Heparin Affinity Chromatography, 

Astrea Bioseparations. Astrea Bioseparations Introduces Nereus LentiHERO, A Fit-for-Purpose Solution for Lentiviral Vector Purification Nereus LentiHERO. Press Release, Sept. 29, 2022.

Cynthia A. Challener, PhD has been a freelance technical writer for over 20 years, leveraging her education from Stanford University (BS) and University of Chicago (PhD) and 10+ years of industry experience. She currently focuses on pharma/biopharma topics, writing technical articles, white papers, blogs, and other content for a variety of clients in addition to contributing regularly to 


Volume 36, Number 1
January 2023
Pages: 19-21

When referring to this article, please cite it as Challener, C.A.. Choosing the Right Resins for Viral Vector Affinity Chromatography. 

Suzanne Shelley is a contributing editor to 

The coordinated steps required to safeguard biologic medications, vaccines, and personalized cell and gene therapies (CGTs) from the moment they begin the journey from origin to destination are notoriously complex. Many best practices and lessons learned have emerged in recent years as pharma/life sciences companies, along with their third-party logistics partners and vendors that supply specialized packaging and monitoring solutions, have all weathered the COVID-19 pandemic together and continued to support ongoing growth in the pipeline of therapeutic products that must be continuously maintained at refrigerated, frozen, or ultra-frozen temperatures.

There is no room for failure if any of these high-value—and increasingly one-of-a-kind—therapy options are allowed to experience temperature excursions. “Especially when it comes to autologous CGT products, the need to track the shipment from the donor patient to the processing center (laboratory or manufacturing location) and back to the patient is of
paramount importance,” says John Bermudez, vice president, product marketing, TraceLink.

“What really complicates CGT shipping in particular is that these high-stakes shipments must be customized for smaller-sized, highly individualized parcels,” notes Shea Vincent, senior marketing director of BioLife Solutions. “With some of today’s gene therapies priced at $1, $2, or even $3 million, failure is not an option during distribution.”

While the industry has learned a lot during the steep and fast learning curve imposed by the pandemic, and many of the lessons learned are now routinely being applied to optimize the shipment of both larger-volume biologic products and vaccines and smaller-volume CGTs, “the reality is that the tactical implementation of these specialized supply chains for CGT products has yet to be fully established on an industry-wide scale,” says Vivian Berni, director of product management and strategic marketing for Sonoco ThermoSafe. “This leaves a significant burden on manufacturers of today’s cell-based products to distribute their products reliably. Unknowns cause doubt, uncertainty, and risk—and these are not friendly ingredients in a discipline that strives for repetition and predictability.”

“There are already a lot of capabilities in place—experienced cold-chain couriers, state-of-the-art insulated containers, the ability to track and monitor with reliable, cost-effective sensors—so it’s more about pulling the right mix of the elements together in the most strategic and effective way to maximize visibility and minimize the risk,” says Bermudez.

Cold chain planning and execution “… continues to be impacted by not only the pandemic but by other factors, such as air cargo capacity being down, instability related to inflation, the Russia/Ukraine conflict, and more, but despite it all, you still have patients depending on what you’re delivering,” notes Rob Coyle, senior vice president, healthcare strategy, Kuehne+Nagel. As such, he says that stakeholders handling high-end CGT products “need to be really honest about the risks and plan for them ahead of time. Developing a robust backup plan (and having all parties agree to it) ahead of time allows for seamless pivot and rapid response should any delay arise en route.”

For many routes, it makes sense to use passive shipping containers, as they require no power infrastructure, have a more favorable carbon footprint, and can often provide a lower-cost option if appropriate. “With careful planning, we’re often able to replace active shippers with passive units by leveraging existing infrastructure, ongoing advances in insulation materials, phase-change materials (PCM), and container designs, using advanced GPS and other monitoring devices to ensure continuous access to real-time location, temperature, and other data,” adds Scott Ohanesian, senior vice president, commercial operations, QuickStat, a Kuehne+Nagel company.

“Those handling temperature-sensitive pharma products and biologics have experienced a lot of frustration over the past few years due to strategic shortages and supply-chain issues related to dry ice, liquid nitrogen, and the types of specialized packaging that is needed,” says Vincent. “Fortunately, newer materials such as advanced insulation materials and PCMs that continue to come to market are setting up the industry for a better, more reliable future.”

PCMs are engineered materials—based on paraffins, fatty acids, alcohols, hydrated salts, and more—that are conditioned to the refrigerated or frozen setpoint temperature at the outset and placed inside the specialized transportation container. They are able to store and release energy (undergoing a change in phase as they are warmed and cooled) as needed to maintain the critical setpoint temperatures inside the passive thermal containers throughout the trip.

Meanwhile, to ensure dock-to-dock shipping integrity, Vincent says it’s important “to develop a backup plan and to ensure that all stops on the trip have sufficient ultra-low-temperature (ULT) storage capacity, or the ability to access more dry ice or recondition the PCM.” She notes that the planning gets more complicated when the customer will be shipping product by the pallet but then dividing the pallet to repackage smaller volumes to ultimately reach many different destinations.

“The Holy Grail for the pharma cold chain is ‘how do I get perfect service at a more economical price?’” says Dan Gagnon, vice president of global strategy for UPS Healthcare. Economies of scale and tighter overall integration can help to coax out some unnecessary expenditures.

A particular challenge is that the end-to-end distribution of biologics often requires handoffs among multiple partners using disparate systems, and this creates unnecessary complexity. “Today, existing tools can be used to reliably track individual shipments, but the challenge is that it has to be coordinated with actual patients and the labs that process the cells,” notes Bermudez. “The ability to closely coordinate all handoffs improves visibility and gives timely alerts when a shipment has gone out of temperature range or needs intervention.”

In other cases, pharma/life sciences stakeholders producing biologics and CGT products enlist multiple vendors and partners to create complex end-to-end distribution routes. “Stakeholders should choose partners who take a consultative approach,” says Amy DuRoss, president, cell and gene therapies, CSafe Global. “They can help to identify the challenges ahead of time and address them effectively when they do arise.”

In recent years, UPS Healthcare “has made its mission to streamline and integrate the pharma cold chain as much as possible, bringing as much of the end-to-end capabilities—in terms of storage capacity, ocean, ground, and airline networks—in house as possible to maximize quality and visibility,” says Gagnon. “Any time you can remove a handoff between two parties it dramatically reduces the risk of excursion, and our singular, unified system uses the same systems and similar training for all personnel, which provides a complete end-to-end cold chain under one roof.”

In November, UPS Healthcare acquired global healthcare logistics provider Bomi Group, helping to expand its footprint across Europe and Latin America. UPS Healthcare customers now have access to 216 facilities with 17 million square feet of current good manufacturing practice and good distribution practice-compliant healthcare distribution space in 37 countries and territories.

“Scientific advances are always ahead of the regulatory frameworks, so logistics providers need to work closely with regulatory authorities when it comes to CGT distribution,” notes Ohanesian. For example, delays in Customs vary from country to country and can chip away at the limited window for which packages transporting biologics and CGT products is guaranteed to remain at its setpoint temperature. “Customers often make a packaging choice and get locked in, so they don’t really consider qualifying newer packaging options—we see that a lot,” adds Coyle.

For instance, Ohanesian says, “If your quality team has already qualified a particular technology that can ensure the setpoint temperature is maintained for three days, but there exists an option that can maintain it for eight days, you need to consider making the switch.”

“One of the challenges associated with competing technology options is that you need to keep investing in new technology, but you can’t just get distracted by every shiny new technology solution,” adds Gagnon. “You have to critically evaluate which technology advances will bring significant value to customers and focus on which offerings are likely to still be around in the years to come.”

Despite ongoing innovation in supply chain traceability, real-time tracking, and enhanced visibility, DuRoss says, “we urgently need solutions that simplify and standardize CGT operations so that this field can scale. High complexity often translates to higher-than-necessary costs, which results in fewer patients being treated.” To achieve mass adoption within the CGT space, “we need to both industrialize and personalize in parallel,” she continues.

“Having a comprehensive commitment to quality is a winning strategy and putting the systems in place now can save you a lot of headaches later,” says Gagnon.Meanwhile, in all partnerships, specific elements (such as hardware, software, service, and more) must go through consistent qualification and validation processes and be demonstrated as suitable for use in the regulated environment, notes Emanuel Schäpper, head of global business management for ELPRO. Coyle adds, “If you don’t have detailed standard operating procedures (SOP) and quality systems in place, and enforce that each of your partners implement them, too, it will open you up to human and process error.”

“Not all technology, tracking devices, and packaging options work across all networks, locations, or applications,” adds Berni. “Understanding the constraints of each option helps all parties to manage expectations and set things up for success.”

“In response to the COVID pandemic, we developed a passive parcel ULT shipper that can transport and store mRNA [messenger RNA] vaccines at a range of -60 °C to -90 °C for up to 30 days, and it has been used to reliably ship COVID-19 vaccines to 180 countries,” says DuRoss of CSafe Global. “We must leverage all of the global COVID-19 learnings and solutions to enable scaleup in CGT.”

When it comes to container designs, insulation, and PCM materials, monitoring, and control systems and versatile cloud-based solutions to enable greater visibility, stakeholders should keep up with ongoing advances and be willing to embrace best-in-class solutions, rather than becoming locked into a particular solution. “The entire chain is only as strong as its weakest link,” says Schäpper.

Choose monitoring and tracking devices carefully

“From the perspective of a suitable monitoring solution, care must be taken to ensure that the operability of monitoring devices [is] user-friendly and easy to understand, especially in the case of extensive, global distribution networks,” says Schäpper. “The operating elements must be clear, and the display must provide unambiguous information about the status of the product or the measurement parameters.”

Engage logistics partners and vendors as early as possible

“The more we can get critical information earlier in the product lifecycle, the better we can design systems to optimize each of the steps. This has been one of the biggest learnings in recent years,” says Coyle. Similarly, Berni adds, “Involving packaging providers and logistics partners in the discussions early on enables a more cohesive overall strategy. I cannot emphasize this enough; start the conversation early with all of your partners—don’t wait.”

“You can’t adequately support CGT patients worldwide when you have cold chain service centers in just a few locations—for instance, you can’t support and service the distributed global CGT infrastructure if you operate just a few locations in North America and Europe,” says DuRoss.

“More than ever, these two teams—which formerly functioned largely independently of one another—are working hand-in-glove from the earliest phases of drug development, and that’s the way it should be,” says Coyle. “We’re still in the infancy of the era of high-end biopharma and personalized medicine, and while we’re already learned so much, there’s still so much more room for ongoing improvement to minimize the risk of product damage and ensure patient access to these high-value, lifesaving therapies,” says Coyle. As the pharma/life sciences pipeline of biologic therapies, vaccines, state-of-the-art CGTs, and other gene therapies continues to grow, so does the need to push for ongoing innovation in the technologies and practices needed to safeguard them during shipping and storage. 

Suzanne Shelley is contributinng editor for 


Vol. 36, No. 1
January 2023
Pages: 28-30

When referring to this article, please cite it as S. Shelley. Safeguarding Biologics— Blending Engineering Ingenuity and Managerial Excellence. 

Efforts to optimize the ideal blend of technology and best practices that are needed to protect and deliver time- and temperature-sensitive biologic therapies, vaccines, and cell and gene therapies continue to evolve. 

Safeguarding Biologics— Blending Engineering Ingenuity  and Managerial Excellence

Feliza Mirasol is the science editor for 

Bioassays play a crucial role in biologic drug development as a means to determine potency, toxicity effects, pharmacological activity, stability, purity, and other product qualities. The complexity of biological molecules, however, requires a wide range of analytical procedures to adequately characterize the product. In particular, the concern over immunogenicity in the use of biologics is driving the need to develop more highly sensitive assays. Because of this concern, there is a continual need to refine biological assays to increase accuracy and reproducibility. There is a specific need to replace 

 bioassays are important tools employed during drug discovery/drug development, according to Weihong Wang, PhD, director of Technology Development, Eurofins BioPharma Product Testing. 

 bioassays use cell culture and offer the benefit of low cost and high throughput, both of which are essential during early development. An 

 bioassay also has the necessary robustness needed for use as a lot-release assay for product quality control later in the drug development life cycle, Wang explains.

 bioassay is a more efficient method that allows researchers to clearly characterize product mechanism of action in a controlled environment, says Catherine Liloia, director, Cell & Microbiology, PPD clinical research, Thermo Fisher Scientific. “This approach is scalable and reproducible across production and can assess product stability,” she states.

 bioassays (non-clinical) use animal models and are considered more relevant to potential clinical outcome, says Wang. 

 bioassays are often costly, however, and are less robust and subjected to strict regulations and compliance standards. “Regulatory agencies across the world have been encouraging sponsors to replace, reduce, and refine (the three Rs) dependence on animal studies by advancing development of, and evaluating new, fit-for-purpose methodologies,” Wang explains.

 bioassays are more representative of the full biological complexity and pharmacokinetics of the human body; they can, therefore, more broadly assess potential patient safety impacts stemming from metabolic changes and other side effects. The downside, however, is that 

 bioassays require high investment, strict animal care protocols, and are not as conducive to high-level analytics, according to Liloia.

, generate valuable data needed for regulatory filings, such as investigational new drug (IND) applications. 

 bioassays support determination of product potency, for instance, says Liloia. “When included in analytical panels during release and stability testing, potency data can demonstrate lot-to-lot consistency and long-term stability of the product,” she says.

In addition, bioassays provide data to better understand the impact of manufacturing process changes through process development. “Early 

 methods may be needed to help discern true product mechanism of action in biological pathways that are complex or not well characterized. These methods can sometimes be consolidated or replaced on a product release panel as data [are] collected to determine a single method’s capability to reliably determine product potency across production samples,” Liloia explains.

 method cannot by itself model the biological response in a reliable manner, as is the case with immunogenicity and other safety testing, Liloia adds.

IND-enabling studies, including pharmacology/pharmacodynamic, pharmacokinetics, and toxicology studies, are typically done through both 

 assays, states Wang. She adds that additional 

 assays to address product safety and quality, such as viral testing, and potency testing, are also necessary later on for product licensing.

Cell-based bioassays have also become an important tool in the analytics arsenal for biologics drug development. According to Wang, cell-based bioassays measure relevant physiological responses in cell cultures, but unlike 

 bioassays, cell-based bioassays do not involve the use of live animals and often have different types of assay readouts/endpoints. “Nevertheless, the physiological responses are reflective of mechanism of action, and, therefore, cell-based assays are considered necessary components of product characterization, in addition to other biophysical/physiochemical analytical methods,” she states.

Cell-based bioassays utilize biologically relevant cell lines to measure product potency, says Benjamin Ziehr, senior group leader, PPD clinical research, Thermo Fisher Scientific. He notes that there are several types of cell-based bioassays that vary depending on what is being measured. “The classic cell-based bioassay compares the response of cells treated with drug sample or reference standard. Typically, sample and standard are diluted in a manner suitable to produce a four-parameter response curve in the target cell line. Well-defined response curves are critical for maintaining and demonstrating control of the assay and drug product in these assays,” he explains.

Ziehr further explains that the relative activity of sample drug material to reference standard drug material is reported as the relative potency of the drug product. In comparing cell-based bioassays to other types of bioassays, the key distinction lays in the fact that cell-based bioassays allow mechanism-of-action-dependent measurements, whereas other bioassays measure physical characteristics of the drug product, such as epitope binding or receptor occupancy. “Therefore, cell-based bioassays allow measurement of the cellular processes responsible for a drug product’s effects on the patient,” says Ziehr.

Meanwhile, there are several other modes of cell-based bioassays that provide information about other attributes of the drug product. Ziehr points out two common examples of these other modes from cell and gene therapy product testing: infectivity and replication competency assays. “These assays measure the infectious potential of the drug product and the presence of replication-competent viral particles, respectively,” he states.

In other words, rather than measuring a cellular response, these infectivity and replication competency assays measure the accumulation of viral genetic material following infection of permissive cell lines. “While these assays don’t measure product potency, they do provide critical process and safety data and detect lot-to-lot variability of products,” says Ziehr.

Cell-based bioassays become a clear front runner in this movement, where applicable, remarks Wang, who points out that, in other circumstances, sponsors may be able to eliminate certain 

 assays based on risk analysis. For example, per the International Council for Harmonisation Q5A(R2) (2), 

 testing is no longer necessary for well-characterized cell lines such as Chinese hamster ovary, non-secreting murine myeloma, and SP2/0 (a standard mouse myeloma cell line), based on cell-line history, prior knowledge, and other risk-based considerations, notes Wang.

Despite their advantages, however, cell-based bioassays are limited in their ability to represent more complex, distal biological responses in a patient, cautions Liloia.

Meanwhile, the challenges in working with cell-based bioassays include not only the fickleness of working with certain cell lines, but also the fact that the day-to-day variability is much higher in terms of assay performance, observes Ziehr. The state in which cells enter the bioassay affects their response in the bioassay.

“Cellular state is dictated by many factors, notably metabolic stimuli, cellular density—both in culture leading up to a bioassay and in the bioassay itself—and cellular age. Stable transfections, optimized banking, and robust maintenance controls are needed to minimize cell variability,” Ziehr says.

Ziehr explains that, typically, robust maintenance controls involve the use of well-defined and controlled culture protocols, qualification of critical reagents, and substantial system suitability criteria in the bioassay. “Consistency of technique is challenging, even with clear procedure, so robust training with clear connection between biological processes and cell handling technique remains important,” he remarks.

Because cell-based assays utilize live cells, they are subjected to intrinsic assay variability that are often larger than that of physiochemical methods, says Wang. Thus, the selection of an appropriate cell line that is not only relevant to product mechanism of action, but also able to support a robust response in a dose dependent manner, is the single most critical factor for successful method development, she emphasizes.

“Many details need to be considered and optimized to produce a robust assay suitable for quality control. In addition, for products that may have multiple mechanisms of action, a carefully selected matrix containing multiple cell-based assays may be necessary to fully characterize the product,” Wang says.

Wang also points out, however, that it may yet be difficult to develop a cell-based bioassay for some products that either have not known defined mechanisms of action or have complex mechanisms of action. Furthermore, some cell-based assays still require extended testing time, which can be a cause for concern regarding products that require rapid factory-to-patient delivery. In such cases, Wang suggests that development of surrogate assays and/or orthogonal assays may be beneficial, though subject to discussions with the relevant regulatory agency.

In terms of advantages conferred, compared to 

 bioassays, cell-based bioassays often offer the advantages of a more streamlined testing procedure, higher assay throughput, quicker turnaround time, and less assay variability, according to Wang. “It is generally easier to develop a cell-based assay with an accurate quantitative endpoint than an 