Having a clear clinical strategy early on can shave time off overall development projects.

Early Strategizing Tightens Development Timelines

With recent approvals of bispecific antibodies, these complex molecules are fast moving out of the research box and into clinical pipelines.

Bispecific Antibodies are Moving from Research to Clinical Development

Extensive work has greatly expanded the possibilities for fetal bovine serum sourcing.

Considerations for US Fetal Bovine Serum Sourcing

Thanks to technological advances, process chromatography challenges are surmountable, but increasingly complex therapies in the pipeline will demand more efficient processes in the future.

Advancing Process Chromatography in DSP

The complex nature of biologics creates challenges for GMPs in sterile manufacturing, and the EU’s Annex 1 is making an impact.

GMPs for Sterile Manufacturing of Biologics

Precompetitive consortiums seek solutions to industry-wide challenges.

Coming Together to Enable Cell and Gene Therapy Manufacturing

When considering whether to outsource work to a CRO, there are a number of factors to assess, including the type of work that may be outsourced, regulatory considerations, and needs for the study.

When Is It Appropriate to Outsource Bioanalysis Work to a CRO?

On Aug. 4, 2022, Amgen announced a definitive agreement to acquire ChemoCentryx, a biopharmaceutical company specializing in therapeutics to treat autoimmune diseases, inflammatory disorders, and cancer, for $52 per share in cash, which represents an enterprise value of approximately $3.7 billion. Each company’s board of directors has approved the transaction, which is expected to close in the fourth quarter of 2022.

The acquisition includes Tavneos (avacopan), an orally administered selective complement component 5a receptor inhibitor. The drug was approved by FDA in October 2021 as an adjunctive treatment in combination with standard therapy for adult patients with severe active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two main forms of ANCA-associated vasculitis.

ANCA-associated vasculitis is a group of multi-system autoimmune diseases with small vessel inflammation. With these diseases, inflamed vessels may rupture or become occluded, which gives rise to a broad array of clinical symptoms and signs related to a systemic inflammatory response. This may result in profound injury and dysfunction in the kidneys, lungs, and other organs.

Outside the United States, Tavneos is also approved in the European Union and Japan. Under the acquisition agreement, Vifor Fresenius Medical Care Renal Pharma will retain exclusive rights to commercialize the drug outside the US, except in Japan and Canada. In Japan, Kissei Pharmaceutical holds commercialization rights, and in Canada, Otsuka Canada Pharmaceutical holds commercialization rights.

ChemoCentryx also has three early-stage drug candidates that target chemoattractant receptors in other inflammatory diseases and an oral checkpoint inhibitor for cancer in its pipeline.

"We are excited to join in the T[avneos] launch and help many more patients with this serious and sometimes life-threatening disease for which there remains significant unmet medical need. We also look forward to welcoming the… team from ChemoCentryx that shares our passion for serving patients suffering from serious diseases," said Robert A. Bradway, chairman and CEO at Amgen, in a company press release.

"Last year, after 25 years of proud history, we at [ChemoCentryx ] delivered on our founding promise with the approval of T[avneos] for patients with [ANCA-associated vasculitis]. It is an honor to now join Amgen's great mission, and together begin a bright new era bringing landscape-shaping medicines [such as] T[avneos] to those who will benefit most," said Thomas J. Schall, president and CEO of ChemoCentryx, in the press release.

Articles

Amgen’s acquisition of Chemocentryx includes the autoimmune disease drug Tavneos (avacopan).

Amgen Will Acquire Chemocentryx in $4 Billion Deal

AES Clean Technology, a cleanroom facilities provider, launched its OMNI Electric Utility Raceway smart cable management system in July 2022. An expansion on the OMNI Gas Utility Raceway, the new cable management system was created to reduce the cost and time needed to provide electrical utility integration, while also minimizing the risk of creating dust particles and contaminants in cleanroom environments.

According to a July 27, 2022 company press release, the raceway comes with up to six pre-wired ports based on customer preference. The product allows users to customize their optimal data, power options of up to 300V, circuiting, and outlet heights.

“We strongly believe [the raceway] is the cleanest approach to electrical utility access in the industry and look forward to hearing more from our partners on the success of the product within their facilities,” said Grant Merrill, CEO, AES Clean Technology, in the press release. “Ensuring a seamless cleanroom delivery is important to AES because it means our customers can focus on their life saving sciences.”

The OMNI Electric Utility Raceway power and data management system is designed to reduce risk and accelerate cleanroom delivery.

AES Clean Technology Launches OMNI Electric Utility Raceway

Carterra, a provider of technologies enabling high-throughput biology, and the La Jolla Institute for Immunology (LJI), a non-profit entity focused on immunology studies, announced that LSJ acquired Cartera’s LSA antibody discovery and characterization platform on Aug. 1, 2022. LJI first worked with Carterra and the LSA platform on the Coronavirus Immunotherapy Consortium (CoVIC), a project that attempted to find the most potent antibodies against COVID-19.

The LSA platform is designed to enable rapid characterization of hundreds of antibodies in the early stages, then provide in-depth analysis of leads during later stages of discovery. According to a company press release, relative to traditional methods, the LSA generates results 100 times faster while using 99% less sample. In addition to autoimmune and cancer targets, it is also designed to enable rapid characterization of sera samples from vaccine studies.

“The LSA was key to mapping the epitope landscape of the SARS-CoV2 spike, using the 400 antibodies in the consortium. That information was instrumental to understanding which target sites are still effective against emerging variants of concern,” said Erica Ollmann Saphire, professor at La Jolla Institute for Immunology, director of the CoVIC consortium, in the release. “Having seen what the LSA can do first-hand through our collaboration with Carterra as part of the CoVIC, we now look forward to using this instrument to propel our own discovery efforts.”

“We’re proud to see the benefit of Carterra’s LSA platform being brought to bear for global good,” says Tim Germann, chief commercial officer, Carterra, in the release. “Working with Erica and her team at LJI has been truly enlightening—they understand the importance of breaking down the old paradigm of slow and inefficient biologics discovery. Bringing the LSA to LJI represents their commitment to leading the effort to end the suffering from pandemics like Ebola and COVID-19.”

La Jolla’s acquisition of Carterra’s LSA Platform is designed to advance their immunological and infectious disease research.

La Jolla Institute for Immunology Acquires Carterra LSA Platform

Synthego, a US-based genome engineering company, announced on Aug. 2, 2022 that it has launched engineered cell libraries that further enable access to clustered regularly interspaced short palindromic repeats (CRISPR). These libraries, based on Synthego’s Eclipse Platform, provide arrayed CRISPR-edited cells that can be directly used in functional screening assays.

The new offering is a high-throughput cell engineering platform that delivers cell-based models for disease research. The platform provides highly predictable CRISPR-engineered cells at scale via the integration of engineering, bioinformatics, and proprietary science and aims to enhance the speed, scalability, and efficiency of the drug discovery process by optimizing the path between experimental design and execution.

This platform, the newest addition to Synthego's engineered cells product line, offers a custom-arrayed library of multi-guide knockout cell pools (immortalized or induced pluripotent stem cells [iPSC]). These libraries are delivered ready-made to researchers and enable them to bypass the need for equipment and reagent sourcing, transfection, generation of an extensive CRISPR library, and hiring and training of staff. This advantage, in turn, allows researchers to overcome common hurdles associated with CRISPR-based target discovery and instead focus specifically on the science, according to Synthego in a company press release.

With engineered cell libraries, scientists can specify the human or mouse cell type (immortalized or iPSC available at launch) and gene targets they want to knockout to generate a custom “Knockout Cell Library.” The cells are then edited on Synthego’s Eclipse Platform, which handles guide design, cell line optimization, editing through transfection, and assessment of editing efficiencies. This results in cells that are ready to screen upon arrival.

Benefits of the engineered cell libraries on the Eclipse Platform include:

Scalability and flexibility—engineered cell libraries allow researchers to maximize their screening power, which allows them to identify more targets earlier in the screening process.

Predictability and transparency—Synthego’s multi-guide technology can achieve reliably high knockout efficiencies, which offers researchers confidence in their screening process.

Cell engineering expertise and support—Synthego offers its expertise in automation innovation to provide greater consistency in outcomes and scalability.

Both the Eclipse Platform and the engineered cell libraries enable a wide range of applications in research and development across various disease areas and research disciplines, including oncology and neurology.

“Arrayed screening approaches are more sensitive, compatible with a broader assortment of downstream assays, and can yield data that is more readily interpretable than the more commonly used pooled approach but are underutilized due to lack of infrastructure and limited bandwidth,” said Travis Maures, chief technology officer, Synthego, in the release.

“We were able to quickly combine our proteomic expertise with Synthego's genome engineering capabilities in a matter of weeks,” said Nevan J. Krogan, director, Quantitative Biosciences Institute, University of California, San Francisco, in the release. “Normally, work such as this would take many years. We were able to quickly pinpoint which human genes are important for infection, and that allowed us to jump to which ones if we were able to drug them, could have a positive pharmacological effect on SARS-CoV-2 infection. That whole pipeline allowed us to identify several potential drug candidates, several of which we're still looking at.”

Synthego has launched new engineered cell libraries to validate targets for quicker drug discovery timelines.

Synthego Aims to Accelerate Drug Discovery with New Engineered Cell Libraries

 Washington Editor, jillwechsler7@gmail.com.

Amidst a host of serious challenges for maintaining FDA operations and programs, FDA Commissioner Robert Califf is most determined to combat erroneous reports about medical treatments and clinical practice. “Misinformation is the leading cause of death in the United States today,” Califf stated at a online briefing sponsored by the Alliance for Health Policy on July 28, 2022. He noted that a poor understanding of the effects of medical treatments “leads people to make decisions that are harmful to health.”

Unfortunately, Califf fears that FDA is “actually losing the battle on misinformation” related to COVID, as seen in the large number of Americans who have not been vaccinated, he observed in a conversation with the editor of 

 on August 3, 2022. Millions of people are refusing vaccines and therapies despite evidence that such treatments can reduce the risk of dying from the disease by 90%. “Vaccines are basically working,” Califf stated, yet he sees many people who won’t take a treatment that’s free and highly effective.

Califf hopes to address this conundrum with a strategy for dealing with the “avalanche of differing opinions” that is confusing and difficult for Americans to navigate. This cardiologist recalls such problems throughout his career, as experts failed to reach agreement on treatment strategies for critical conditions. And today, when FDA makes a regulatory decision, it draws comments from all corners of the world, he notes, which ends up providing the public with a “sea of information” that’s difficult to navigate.

Califf’s response is to establish a “better evidence generation system” in the United States, with expert networks devoted to developing reliable information and to checking facts to overcome misleading statements. He recognizes that there is a highly effective clinical trial system in the US, where pre-approval studies produce needed data on product safety and effectiveness. But problems arise in postapproval confirmatory studies, where answers can take years, even decades, to emerge. To gain needed evidence, Califf would like to see clinical trials embedded in care and utilizing information systems that can tap larger samples of patients to answer questions very quickly.

Clinical research has experienced some success is becoming more diverse in several ways, Califf believes, as seen in “tremendous progress” in including children in research, a group that he saw completely left out of clinical trials in the past. He would like to see similar gains in bringing research to rural America, where inadequate health care has reduced life expectancy notably. Califf would like clinical research to address disparities between urban and rural areas, as well as differing treatment responses of ethnic and racial populations.

A continuing challenge for FDA is the use of expedited clinical research approaches to accelerate the development and approval of treatments for lethal and rare diseases. The agency’s accelerated approval pathway has raised questions about abbreviated testing methods and chronic delays in follow-on trials. Califf indicated that while abbreviated, single-arm trials may be appropriate for testing new therapies for untreated cancers and rare diseases, randomized trials with proper controls may be more acceptable in providing evidence for treating conditions with approved therapies.

In addition to addressing the harmful effects of medical misinformation, Califf faces a host of regulatory and policy crises across the board. Not the least is the looming loss of funding due to delays in Congress reauthorizing user fees and a new budget for 2023.

In addition, a broad overhaul of the agency’s oversight of tobacco and related products is a top priority. With 30 million Americans still using tobacco, plus a rise in vaping products, Califf sees FDA entering a new era in tobacco product oversight, with key decisions looming on menthol cigarettes and reduced-nicotine products. Califf anticipates “major disagreements” no matter what FDA does but hopes that transparent communications will build support.

Opioid addiction remains a critical challenge. Califf seeks new strategies for providing education and oversight of prescribing and access to regulated opioids, while also dealing with a huge increase in illegal high-dose fentanyl pills sent through the mail. FDA is preparing a plan for more collaborative approaches to address these issues, but Califf recognizes there is “no magic bullet” for dealing with this ongoing national crisis.

Califf also has launched a broad review of food oversight and regulation by the agency, spurred in part by the recent infant formula crisis. FDA seeks better funding and improved hiring authority for its food programs, as well as a broader assessment of the impact of changes in how food is grown and distributed in the US. And the sudden drop in infant formula supplies has highlighted the need to diversify sources and increase US production of such critical products.

Califf observed during these briefings that when he decided to return to FDA for another stint as commissioner, he anticipated there would be very serious challenges, but not as many as have erupted. But he re-upped for the job because he also recognized that heading FDA would “take someone with not much at stake.” His long experience overseeing clinical trials has made clear to him the importance of good evidence and strong collaboration in organizing programs and making sound decisions, and he continues to work to apply such approaches to the complexities and diversity of FDA.

Better clinical data are needed, as well as strategies for tackling opioid abuse, tobacco use, and food safety. 

Top Priority for Califf Is Combatting Health Misinformation 

Marengo Therapeutics, a therapeutics company specializing in oncology medicines, announced a collaboration with Ipsen to advance two precision immuno-oncology candidates on August 1, 2022. Under the terms of the agreement, Ipsen will make an upfront payment of $45 million for the rights to develop and commercialize the medicines, with potential payments totaling $1.592 billion plus additional tiered sales royalty payments.

The two medicines are based on Marengo’s selective T-cell activation repertoire (STAR) platform, a multi-specific fusion protein library. It is designed to develop potent T cell activators by targeting specific TCR Vβ variants fused to different costimulatory moieties. According to a company press release, its unique feature is its ability to fine-tune the T cell response in selected T cell subsets to generate endogenous, highly functional cancer-killing T cells for solid tumors. Marengo’s lead candidate STAR0602 is the first T-cell activator generated by this platform and is slated to enter clinical trials following an investigational new drug application (IND) submission at the end of 2022.

“Marengo’s foundational discovery of activation of T cell subsets via TCR Vβ is unprecedented and highly differentiated from the current immuno-oncology technologies we have seen,” said Howard Mayer, executive vice-president and head of R&D, Ipsen, in the press release. “This partnership with Marengo provides a strong foundation for a productive and successful collaboration as we embark on a journey to develop novel and durable therapies that will strengthen our oncology pipeline and further enhance our commitment to people living with cancer.”

“Our strategic partnership with Ipsen underscores our shared ambition to develop transformative medicines for people fighting cancer,” said Zhen Su, CEO, Marengo Therapeutics, in the press release. “Marengo brings a precision medicine approach to the field of Immuno-oncology with a focus on T cell activation and this collaboration is an important validation of our STAR platform beyond our lead candidate. Together, this partnership is a demonstration of the strong progress and promise of our innovative scientific platform.”

Marengo will lead preclinical development efforts and related costs until an IND to FDA is made. Following this, Ipsen will assume development and commercialization responsibilities.

Ipsen and Marengo Therapeutics will collaborate to advance two precision immuno-oncology candidates.

Ipsen Strikes Deal Worth Up to $1.59 Billion With Marengo Therapeutics

France-based CRYOPDP, a Cryoport company, has acquired Spain-based Polar Expres, a company that provides temperature-controlled shipments for biological and pharmaceutical materials worldwide.

According to a company press release, CRYOPDP has been actively acquiring companies with interesting new technologies, competencies, and similar principles to enhance its global delivery capacity. Polar Expres has an established presence in Europe’s cell & gene clinical research industry.

"The acquisition of Polar Expres will expand our coverage in Europe and enable us to provide end-to-end solutions to both global and local customers in Spain,” said Jerrell Shelton, CEO of Cryoport, in the press release. “Spain is a highly strategic and key area for pharma/biopharma clinical trials and a growing number of cell & gene activities.This tactical acquisition will provide strategic impact for CRYOPDP as requests for local, on-the-ground operations in Spain continues from many of our clients, as well as from potential new clients. With Polar Expres now operating as part of our growing CRYOPDP operations, we are confident this acquisition will provide us with additional growth in the EMEA region.”

CRYOPDP is expanding its footprint to Spain with its acquisition of Polar Expres.

CRYOPDP Acquires Polar Expres

Bio-Rad Laboratories recently expanded its portfolio of recombinant monoclonal anti-idiotypic antibodies to include antibodies that are specific to Adcetris (brentuximab vedotin), Cosentyx (secukinumab), and the secukinumab-interleukin 17A (IL-17A) drug-target complex.

Brentuximab vedotin is an antibody drug conjugate used to treat Hodgkin lymphoma, while secukinumab is used to inhibit inflammatory response in several diseases, such as ankylosing spondylitis, psoriasis, and psoriatic arthritis.

According to a company press release from July 12, 2022, these antibodies can be used in the bioanalysis and drug monitoring of brentuximab vedotin, secukinumab, and their biosimilars.

The antibodies for antibrentuximab vedotin and antisecukinumab are approved for 

 testing services to support drug and biosimilar development, and patient monitoring.

Bio-Rad has expanded its range of recombinant monoclonal anti-idiotypic antibodies.

Bio-Rad Expands Portfolio of Anti-Idiotypic Antibodies

Oregon Freeze Dry (OFD), a lyophilization and freeze-drying company, opened a new biopharmaceutical development and clinical facility in Albany, Ore., on July 25, 2022. According to a company press release, the $7.5 million facility is designed to support the development of traditional pharmaceutical active ingredients, combination products, and medical devices, as well as support lyophilization process development.

The Albany facility will also host lyophilization process development and clinical trials, and features environmental controls that can support development of oral drugs. The Albany facility is OFD’s fifth facility in the United States and is set to add at least six new positions to a staff of more than 450.

“Our new facility supports the vision of a world where vaccines and medications can bypass a syringe and be administered orally, increasing access to life-changing medicine around the world,” said Joe Folds, president and CEO, OFD, in the release. “We’re ready and eager to collaborate with pharmaceutical companies and support advances in microbial therapeutics, immunotherapy, and cell and gene therapy.”

The new facility in Albany, Ore., will support biopharmaceutical development and lyophilization services.

Oregon Freeze Dry Opens $7.5 Million Biopharma Facility

Oversight of drug manufacturing and quality control will continue to utilize off-site reviews of documents and operations, as FDA moves to make permanent these approaches that proved efficient and effective during the COVID-19 pandemic. FDA says this hybrid inspection model will remain a regular means for supplementing onsite inspections and will be further integrated into the agency’s oversight operations as the agency endeavors to restore its field inspection program. That task faces added difficulties as a large number of vacancies in the agency’s field force has expanded the task of replacing and training more inspectors and compliance officials.

The importance of utilizing remote regulatory assessments (RRAs) was highlighted by Commissioner Robert Califf and Associate Commissioner for Regulatory Affairs Judith McMeekin in a 

 an “optimized approach” for overseeing manufacturers and supply chains “dispersed around the world” [see  RRAs won’t replace site inspections, but these top officials emphasize that they can serve as a practical way to ensure compliance, to verify information submitted to the agency, and to inform key regulatory decisions.

Earlier during the pandemic, FDA officials reported they were utilizing a “wide range of oversight tools” to extend the agency’s regulatory reach where on-site inspections were not feasible. In an 

, McMeekin and then-Acting Commissioner Janet Woodcock highlighted the value of alternative inspectional tools for verifying the quality and compliance of regulated products where on-site examination was not feasible. FDA provided added advice on utilizing this approach in a 

 on its use of remote interactive evaluations of drug manufacturing and bioresearch monitoring facilities during the pandemic.

now provides more specifics on how the agency will utilize RRAs and how these audits will coordinate with and supplement site inspections. In a question-and-answer advisory on 

 published July 22, 2022, the agency says that RRAs will be useful in seeking to confirm information more quickly and efficiently, particularly when FDA is unable to send in staff due to travel restrictions.

The draft guidance clarifies the scope and format of RRAs, the type of situations where they will be requested, and how these approaches will relate to and complement site inspections. The advisory explains how FDA will request an RRA and will carry out the process and notes that there are consequences for a manufacturer that declines to participate in an RRA, even when not mandated.

The guidance also informs stakeholders where compliance with RRA requests is voluntary or is required by statute, a policy that FDA would like to expand. Currently, FDA has stated authority to require compliance with RRA requests by certain food importers and by manufacturers of all human and animal drugs and biological products. Pending legislation, which FDA backs, would extend that policy to all regulated establishments, including food producers, clinical investigators, and manufacturers of medical devices and tobacco products.

Over the past two years, FDA reports that it has utilized RRAs in evaluating more than 1470 domestic and more than 600 foreign operations. These methods have identified unreported adverse events, provided information to support import alerts, evaluated how well companies are correcting issues raised in previous inspections, and assisted in making regulatory decisions on premarket submissions. As with other inspection activities, FDA will continue to utilize a risk-based approach to shape RRA requests, examining the location, inspection history, and complexity of products made at a facility.

FDA’s hybrid inspection model will remain a regular means for supplementing onsite inspections and will be further integrated into the agency’s oversight operations.

FDA Confirms Ongoing Reliance on Remote Inspection Methods FDA Confirms Ongoing Reliance on Remote Inspection Methods 

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," 

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

Feliza Mirasol is the science editor for 

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

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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.


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,” 

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