For a biotherapeutic to be effective at treating disease, the manner in which the therapeutic is delivered in vivo plays a significant role. The need for new, and oftentimes innovative, drug delivery systems is related to the drug substance, which informs the final formulation that the end product must use for optimal therapeutic effect as well as shelf-life stability. As such, the biopharma industry is exploring next-generation drug delivery approaches to meet the needs of new and increasingly complex biotherapeutics.

The current challenges to biologic drug formulation center around antibodies, which make up the majority of biologics under clinical development and that are licensed for use, says David Bunka, PhD, chief technical officer, Aptamer Group, a company specializing in the development of next-generation aptamer molecules, which are derived from oligonucleotides and function as an antibody alternative. Bunka explains that the specific targeting ability of antibodies has allowed leaps in therapeutic innovation and the ability to treat diseases in new ways.

“Antibodies can be conjugated to a variety of payloads, such as small-molecule drugs for chemotherapy, radionuclides for radiotherapy or imaging, and oligonucleotides for gene therapy. However, as application of this technology has increased within the therapeutic pipeline, the significance of some of the limitations of antibodies has been highlighted,” Bunka says.

Biologics are typically administered via intravenous injection (IV), which allows for maximum efficacy; however, many of these molecules are highly sensitive to their environment and can be rapidly denatured or can aggregate in vivo, Bunka explains. These events can reduce the effective therapeutic dose that reaches the target tissue and give rise to unwanted toxic side effects within the patient.

Size is a major limiting factor in biologics formulation, making delivery challenging. Bunka notes that there is a move in drug development towards “subcutaneous injection as a preferred and more patient-tolerable approach.” A key issue, he says, is balancing the small injection volume with the necessary high concentration of API. “As you increase the therapeutic concentration, the viscosity of the dose increases, which can cause problems with isotonicity of liquid formulations and make it both difficult and painful to administer,” Bunka says. Using large molecules, such as antibodies, reduces the potential acceptable dose for subcutaneous injection.

The large molecular size of biologics also poses another issue: access to the site of action in vivo. “For therapeutics, such as immuno-oncology targeted biologics, the large size of antibodies often prevents them from penetrating solid tumors, precluding targeted treatment and leaving the therapeutic antibody in the surrounding tissues or blood for extended periods,” explains Bunka, adding that this extended residence time in tissue or blood can lead to further off-target or toxicity effects.

Another key challenge in current biologic formulations is their structural complexity, says Bunka. Biologics are far more complex than traditional small-molecule drugs, which gives rise to difficulties in processing, logistics, and long-term storage. “This can create problems with stability during processing and has the potential to result in a loss of activity and increased immunogenicity for the biologic product following patient administration,” Bunka states.

To tackle the issues encountered in formulating large complex molecules such as antibodies, work is being done to develop nanoparticle drug delivery systems that can incorporate specific biologics for targeted delivery to the site of action, says Bunka. “Incorporation of biologics or therapeutic payloads into these nanoparticles enables specific targeted delivery whilst forming a protective barrier around the specific payload to reduce the potential for denaturation or aggregation,” he says.

Bunka also states that, in order to deliver new treatments to help a wider population of patients, improve current treatments, and make treatments more “patient friendly”, the biologics industry must continue to innovate. The industry must also be driven by new biomarkers and a more detailed understanding of disease. “This includes enabling the gaps where antibody-based drug delivery systems have not been effective to be filled,” he says.

“Despite numerous new and improved drugs and gene therapies being developed, the delivery of these molecules to specific cells and tissues remains a major translational challenge. Enabling targeted delivery of therapeutic molecules to the proposed site of action could offer better patient treatment across numerous indications,” Bunka states.

He explains that targeted delivery to specific organs or cells, rather than systemic administration of the drug, is more effective and can come with less patient side-effects as well as offering the benefits of increased potency, flexibility in dosing, increased patient safety and tolerability, and the potential to address new tissues and diseases with these systems.

In addition, targeted delivery systems are tuned to the specific requirements of the disease target and delivery mode. “Numerous strategies are being explored: from extending half-life through methods such as binding human albumin, to delivering chemotherapeutics into the tumor microenvironment of difficult to penetrate solid tumors, and targeting gene therapies to new tissues, such as kidney or the brain, to generating new medicines with the potential to treat previously intractable conditions, such as Alzheimer’s disease or multiple sclerosis,” says Bunka.

Among the next-generation drug delivery technologies in development today are lower molecular weight affinity ligands for targeted delivery of conjugated payloads. Bunka states that these novel delivery vehicles include antibody fragments—such as Fab fragments—camelid antibodies, nanobodies, andoligonucleotide affinity ligands (aptamers, e.g., Optimers). Many of these smaller biologics (aptamers, camelids, and nanobodies) are now progressing through the clinic as alternatives to standard antibodies, Bunka notes.

These alternatives aim to increase access to the in vivo site of action to address new targets and improve therapeutic efficacy. The use of smaller biologics will be coupled with the ability to develop superior subcutaneous formulations, containing increased dose-per-injection volume, compared to standard antibody formats, explains Bunka.

In particular, Optimers (Aptamer Group) area next-generation aptamer developed for the delivery of a wide range of therapeutic cargo. They deliver high-specificity target binding in the same manner as antibodies, says Bunka. “They can be targeted to specific proteins, cells, or tissues for precise delivery of the intended therapeutic. For example, it is well recognized that antisense oligonucleotides (ASOs) are difficult to target to specific tissues, such as muscles. Conjugation of a therapeutic ASO to a muscle-cell targeted Optimer could increase the proportion of the ASO that effectively reaches and penetrates the muscle,” Bunka explains. He says that this conjugation can be used to target diseases such as Duchenne’s muscular dystrophy or spinal muscular atrophy.

Bunka also explains that rapid Optimer discovery enables the acceleration of pipeline progress, with the anticipated benefit of significantly reducing time to clinic while at the same time mitigating development risk and cost through early indications of success.

“The wider target range of the Optimer platform, compared to protein-based affinity ligands, such as antibodies, allows new targets and therapeutic strategies to be pursued,” Bunka says. As these ligands are approximately 10 times smaller than antibodies, they can yield both improved tissue penetration and uptake for inhalation therapy and subcutaneous injections.

Beyond targeting single molecules as direct conjugates to affinity ligands for targeted drug delivery, additional developments in next-generation drug delivery technologies include the targeting of nanoparticles bearing encapsulated payloads. Encapsulation protects non-target tissues from potentially toxic effects, while ensuring that the intended site of action receives the full therapeutic dose. “We are experienced in working with a variety of nanoparticle types to conjugate Optimer ligands to the nanoparticle as a strategy to promote in-vivo targeting to the site of action, such as a solid tumor,” says Bunka.

Many next-generation drug delivery technologies are approaching the clinic, but new demands such as alternative cargo and increased tissue targeting are pushing this field to innovate further. For example, as new gene editing technologies, such as CRISPR, approach the clinic, there will be a need for delivery of large multi-macromolecular payloads, and the delivery technology for these payloads is still at research phase. Such delivery technologies could include novel delivery vesicles or nanoparticles with appropriate in-vivo targeting, says Bunka.

“The COVID-19 pandemic demonstrated the impressive ability of the pharmaceutical industry to rapidly innovate and deliver new therapeutic modalities and vaccines. These new innovations could hold huge promise for many fields of medicine, but may need to be supported by the development of novel drug delivery systems to ensure applicability to some harder to reach tissues and targets,” Bunka says.

Many affinity ligands such as protein scaffolds in development for drug delivery face issues, such as immunogenicity, that yet prevent them from being feasible commerically. The use of these affinity ligands (as antibody alternatives) has the same potential for immunogenic responses as seen for many therapeutic antibodies, Bunka says. “These are issues that have even appeared during the latter stages of development at Phase III, resulting in significant loss of time and [greater] costs to the developers,” he cautions.

According to Bunka, protein-based affinity ligands face the obstable of taking a long time to develop and bring to market. Bunka notes that, following initial discovery of the appropriate protein ligand, there are many additional production and scale up processes and costs that must be undertaken develop a high-performance molecule.

Newer drug delivery vehicles, such as Optimer ligands, have been engineered to overcome these potential development issues. “Oligonucleotide therapeutics have shown significantly reduced immunogenicity compared to protein-based molecules. This reduces the potential risk in development while delivering equivalent or improved performance in drug delivery,” says Bunka.

Because new drug delivery systems are offering the potential to target new tissues and therapeutic targets, they present a possible future where new diseases can be treated and where patient care can be improved.

“Many drug developers are now focusing on methods to deliver drugs across the blood-brain barrier,” says Bunka. Overcoming the blood-brain barrier has proven particularly intractable for antibodies because of their large size, but has been shown to be possible with oligonucleotide affinity ligands, according to Bunka.

“The ability to deliver therapeutics across the blood-brain barrier creates new potential to treat a range of neurological conditions, from neurodegenerative diseases to epilepsy or brain cancers. Similarly, the potential to improve access to solid tumors with improved drug delivery could increase treatment efficacy and patient outcomes across a range of cancers,” states Bunka. These conditions have previously been difficult to precisely target, which has driven the development of solutions via an improved drug delivery system approach.

With the important potential posed by nucleotide-based drug formulations, it is not surprising that much work is being done by researchers to overcome challenges in their development, says Nigel Theobald, CEO of N4 Pharma. Challenges to nucleotide-based formulations include achieving successful delivery to the target cells; protecting any nucleic acid from early or rapid degradation in the body; reaching the desired combination of high loading, controlled release with extended half-life, no leakage, and no interference with the biological functionality of the attached nucleic acid payload; and ensuring stability, good shelf life, and easy storage of the formulated product.

Furthermore, good biocompatibility, low toxicity, and a clear understanding of the mode of action of the delivery system are also important factors, says Theobald. “To achieve this, many believe that nanoparticle delivery is critical to enabling effective use in a therapeutic setting,” he states.

Theobald explains that, following early experiments using simple, direct delivery methodologies, encapsulating the nucleic acid in lipid nanoparticles (LNPs) emerged as the standard first-line approach to achieving the in-vivo performance required for nucleic acid molecules, RNA in particular (with electroporation for DNA). Challenges remain, however, and issues such as the propensity for LNPs to accumulate in the liver, which leads to unwanted toxicity, and the complexities of developing optimal formulations, have driven researchers further into finding improved or alternative delivery technologies.

Administration of nucleotide-based drugs is largely limited to the parenteral route, moreover, and with the biopharmaceutical industry increasingly considering patient-centric medicines, new technologies are being investigated to deliver biological molecules by alternative routes. The “holy grail” of drug delivery remains the use of inhalation or oral delivery, Theobald says. Next-generation drug delivery systems could, therefore, help to overcome the hurdles attached to formulating for these routes of administration.

Because of the ongoing challenges with delivering effective biotherapeutics in vivo, the targeted delivery approach has risen to the forefront of the drug delivery technologies in development currently. Whether that be through the use of ligands and/or nanoparticle systems, this targeted delivery approach is designed to maximize the efficiency of cellular uptake following administration, says Theobald.

“At N4 Pharma, we have been developing a novel silica nanoparticle technology for the delivery of vaccines and drugs, with a particular focus on supporting the commercialization of cancer treatments and viral vaccines based on RNA and pDNA,” Theobald says. He explains that the company’s technology, Nuvec, which are silica nanoparticles, have a unique spiky surface structure, coupled with polyethyleneimine (PEI). This design simply and effectively traps and protects nucleic acid as it travels to the cells.

“The cationic nature of the surface on the nanoparticle ensures effective initial contact and subsequent uptake by the cell. In the case of RNA, the load is delivered to the cytoplasm, and for DNA, the nanoparticle facilitates delivery directly to the nucleus. Nuvec can also easily be functionalized with the addition of ligands,” Theobald further explains.

Theobald points out that particle engineering is another area of rapid development for alternative drug delivery technologies. With particle engineering, researchers are looking to improve the delivery of drugs to the lung—spray-drying and super-critical carbon dioxide (CO2) fluid technologies are examples of the techniques being employed. For oral delivery formulations, enzymatic protection and permeation enhancing techniques are increasingly being investigated to effectively deliver biologics, he says.

In the case of nucleotide-based therapeutics, having a drug delivery vehicle, especially a viral vector, in the manufacturing process adds an additional layer of complexity to the process, Theobald emphasizes. “Scientists must ensure that the vector is of good quality and also focus on its mechanism for release, which can be both costly and time consuming—as well as adding additional risk to what is already a challenging process. Any improvement to that process could result in nucleotide-based therapeutics being available more quickly,” he states.

“A big challenge for many of these new technologies is creating solutions that can be easily scaled up. We saw throughout the COVID-19 pandemic the issues faced by RNA/DNA vaccines using lipid nanoparticles, where the sub-zero storage requirements limited their rollout significantly. In addition, supply has been restricted due to shortage in both lipid components and assembly technology at scale,” Theobald continues.

The importance of nucleotide-based therapeutics, including vaccines and genetic modification, has grown more evident as they have begun to make a large impact in treating viral and bacterial outbreaks and rare and difficult-to-treat genetic diseases. “In the case of cancer, they look likely to take the lead, particularly with vaccine based immune-oncology approaches and direct alteration in cellular systems using SiRNA [small interfering RNA]. There is also CAR [chimeric antigen receptor] T cell therapy, which has been on the market since 2017. They too are genetically manipulated, and there is a large market for using nucleic acids to introduce the CAR,” says Theobald.

He notes, however, that there is an important difference between efficacy and effectiveness of the therapeutics that are available and being developed. As such, more work still needs to be done on drug delivery systems. “The development of smart drug delivery systems (nanocarriers) will improve drug efficacy, reduce costs, and improve storage, and ultimately lead to better treatments for the patient,” Theobald asserts.

Furthermore, the biopharma industry is also reflecting the drive toward a more precision approach to medicine, he concludes. By using relevant data to inform clinical decisions, clinicians have the capability to tailor a patient’s care based on their perceived risk and/or response to certain diseases. Theobald says this will lead to a truly personal, targeted treatment plan.

Feliza Mirasol is the science editor for 


Vol. 34, No. 10
October 2021
Pages: 12–16

When referring to this article, please cite it as F. Mirasol, “Next-Gen Technologies Tackle Drug Delivery Challenges,” 

Articles

Cover Story

The complexity of newer biotherapeutic molecules calls for alternative drug delivery strategies.

Next-Gen Technologies Tackle Drug Delivery Challenges

The development of biologic drugs continues to increase at a rapid pace. Growing numbers of conventional recombinant proteins and monoclonal antibodies, as well as next-generation molecules such as multispecifics, antibody-drug conjugates, and cell and gene therapies, are advancing through the clinic. Many of the biopharma companies behind these drugs are seeking assistance with bioprocess development from outsourcing partners with platform solutions and specialized knowledge, expertise, and technologies.

The increased level of bioprocess development outsourcing can be attributed to several macro- and micro-level drivers.

On the macro level, there is significant growth in the biologics development and manufacturing pipeline worldwide due to increased treatment successes, according to Judy Chou, CEO and president of AltruBio. She highlights the development of advanced cell and gene therapies and gene editing as being particularly important.

Growth of COVID-19 related projects, biosimilars, and the burgeoning Chinese market is further increasing demand, adds Jeetendra Vaghjiani, senior director of clinical development and strategic marketing at Lonza. “With most of the drug development pipeline being held by emerging and small biotechs, the support of contract development and manufacturing organizations (CDMOs) is gaining even more importance,” Vaghjiani says.

Creative approaches recognized by regulatory agencies to address unmet medical needs are another factor noted by both Chou and Vaghjiani. “New challenges have brought accelerated approval pathways such as FastTrack and Priority Review,” Vaghjiani says. That opportunity places increased pressure on biopharmaceutical companies to deliver therapies quickly for patients with commercially ready products, which puts pressure on process development.

Changes in the industry ecosystem have also favored increased investment in biotech and biopharmaceuticals, according to Chou. This trend is attributed by Vaghjiani to the COVID-19 pandemic, which has generated greater interest and awareness in the biotech sector.

All of this growth, however, has also resulted in a general trend of biopharmaceutical capacity shortage, Vaghjiani observes. He does note, though, that many companies are announcing expansions to ensure flexibility with respect to project needs.

CDMOs like Lonza, for instance, have responded by investing heavily in shortening development timelines. This achievement has come through the introduction of new expression technologies, use of parallel workflows for activities not on a critical path, and implementation of high-throughput, scale-down modeling systems. “These improvements have resulted in a significant reduction in process development timelines and therefore are having a positive impact on upstream capacity,” comments Vaghjiani.

The micro trends driving bioprocess development outsourcing are also related to technology development. Identifying technologies that improve stability and distribution as a way to improve access to medicines and to manage cold-chain limitations while reducing costs, is one example noted by John Koleng, vice-president of product development and manufacturing at TFF Pharmaceuticals, which develops dry-powder formulations of biologics using proprietary Thin-Film-Freezing technology.

Biologics developers are also, according to Koleng, looking for technologies that allow biologics to be administered through alternative routes to injection and platform technologies that can be applicable to a variety of biologic products to facilitate rapid scale-up and rollout.

The COVID-19 pandemic is impacting the outsourcing of bioprocess development activities and often magnifying previously existing trends. “The rapid development of COVID-19 vaccines has put a spotlight on biologics and has shed light on limitations that have historically not been appreciated, as technologies were not available to address them,” states Koleng.

The COVID-19 vaccines from Pfizer and Moderna are a case in point, according to Koleng. They remain dependent on extreme cold-chain storage-distribution and injectable administration, both of which limit access to broad patient populations.

“These problems existed prior to the COVID-19 pandemic, but were limited to much smaller scales. The COVID-19 pandemic has emphasized a need for technologies that allow for biologics to be provided as stable compositions that do not require extreme cold-chain storage-distribution; to be administered by noninvasive routes of administration, such as inhalation; and to be scaled up rapidly to support global rollout of essential medicines,” Koleng asserts.

The COVID-19 pandemic has also focused emphasis on speed to market, says Vaghjiani. Additionally, he observes, it is leading to increased demand for single-use equipment used for biologics manufacturing.

Awareness of the healthcare system and the lack of investment resources funneled to the sector has also been raised during the COVID-19 pandemic, according to Chou. “Recent investment in novel therapies and technologies in biotech has created opportunities not only to respond to the needs of the COVID-19 pandemic, but also to introduce more molecules into development that can be applied to other diseases,” she explains. This increased investment and development of biologics has elevated the outsourcing needs in bioprocess development.

In addition, Chou believes the continuation of remote working will make it harder for start-up companies to build up their internal bioprocess development capacity quickly, thus increasing their need to establish CDMO partnerships too.

Combined, these trends will likely result in more entities offering bioprocess development services, Chou says. It could also, she remarks, lead to continued innovation in optimizing and improving supply chains in case of future external disruptions.

With many of the biopharmaceutical pipeline candidates being developed by emerging and small biotechs, often with next-generation biologics, the need for outsourcing early on in the drug development cycle has become clear.

“Small and emerging biotech companies typically rely on the development and manufacturing capacity, expertise, and flexibility of CDMOs to bring their candidates to the clinic, and thus services for bringing potential drug candidates from gene to investigative new drug (IND) [are] gaining importance,” Vaghjiani explains.

The shift to next-generation biologics also leads to the need for deeper understanding of the biological mode of action early on, according to Vaghjiani. “This understanding is strengthened by advances in science and access to data and sequencing capabilities, and will increase demand for bespoke and flexible development strategies and new technologies to handle unique product features,” he says.

In addition to good manufacturing practice capacity for product launches, early development for IND enabling studies is one of the most in-demand outsourcing services today, Chou agrees. “New advances in science will continue to drive the increasing bioprocess/biologics development needs,” she states. She elaborates that the need to develop and produce novel COVID vaccines/therapeutics has created a capacity crunch in biologics development that must be addressed in the upcoming years, given that further increases in demand for biologics development services are expected.

Regardless of the shift to new modalities, the overall goals for bioprocess development across the development lifecycle, including process and product development, remain the same. “Drug companies want help finding solutions that improve the stability of biologics, provide alternative routes of administration, improve therapeutic outcomes, and manage manufacturing costs,” Koleng comments, “Historically,” he adds, “biologics have been extremely expensive to develop, so pricing has an important role to play—the priority will be to reduce costs while also increasing therapeutic outcomes and access.”

As demand for bioprocess development services expands and the specialized nature of those services increases, the need for CDMOs to invest in additional capacity, both equipment and capabilities, is growing.

“The goal is to help new medicines reach patients faster and give customers the flexibility to manage supply, addressing drug development uncertainty and market demand changes,” Vaghjiani says.

Indeed, a CDMO has to keep up with advancing technology to best serve customers and ultimately patients, stresses Casey Franklin, vice-president of business development at Alcami. To do so requires upgrades over time. “An example would be the shift from traditional restricted access barrier systems (RABS) to isolator technology for increased sterility assurance during the fill/finish of biopharmaceutical products,” she observes.

When presented with an unexpected project, Lonza performs an assessment to determine what changes are needed in the process or facility to accommodate the project. Usually processes can be adapted to fit its current facilities, which according to Vaghjiani, highlights the advantage of operating a plug-and-play concept, such as Lonza’s Ibex. If capital investments are deemed necessary, the strategy is scenario-specific.

When a CDMO takes on a specialized project, such as one involving an innovative product with special and sometimes complex requirements that creates a need for investment in additional equipment or capabilities, the investment can be fully funded by the CDMO or the customer, or a shared investment.

“There are many considerations here, including the footprint of the equipment or facility modification, the capacity required for the customer, the market demand or potential to serve other customers, the necessary expertise and staffing implications, and the stage of the program and expected long-term requirements,” says Franklin.

Whichever party is responsible for the equipment depends on what is right at any given point in time for the arrangement, adds Koleng. “In general, the investment equation typically varies and depends on the volume of work and stage of development. At TFF, we’ve found CDMOs to be particularly receptive to customizing their facilities and maintaining a variety of arrangements,” he remarks.

Chou agrees that there are different business models that can be established to address the mutual interests of CDMOs and the sponsors. “We have found that most CDMOs try to fit development projects into their existing equipment and systems, but it is not unusual for a CDMO to customize a bit to meet the need if the modifications are minor. If substantial revisions are required in the facility, usually a cost-sharing model is built,” she observes.

CDMOs always aim to maximize utilization of their facilities and equipment to stay profitable and grow, but this optimization becomes even more crucial with capacity shortages across the industry, according to Franklin. Some facilities may be able to increase capacity by implementing an extra shift or purchasing additional equipment, she notes.

Biopharma companies need to take action as well. “One way to help alleviate the capacity shortage is for sponsors to be more proactive in scheduling, and some are beginning to identify key players much earlier. Consolidating work with fewer CDMOs so that a sponsor can be a more substantial customer or client, and garner greater resources for their projects is another strategy,” Koleng explains.

CDMOs already near full utilization have to focus on effective project management and transparent communication with customers to ensure manufacturing readiness and minimize dead time due to project delays, Franklin says.

“With the supply-chain challenges and the general element of unpredictability that has come with the COVID-19 pandemic, it also helps for the CDMO and the customer to be as flexible as possible. CDMOs must keep in constant communication with customers around these challenges and work creatively to find alternate solutions when needed to keep project timelines on track,” Franklin asserts.

To address capacity shortages for development projects in particular, Chou notes that on the technical front, companies are improving bioprocess development efficiency by introducing advanced platform technologies. Development is also being accelerated through the application of automation, modularization, and digitalization solutions. On the business front, she points to improvements in the partnership model to ensure that business processes do not get in the way of development.

Partnerships make “end-to-end” support possible

Strong partnerships are, in fact, the key to successful provision of services across the entire development cycle. To accelerate the progress of development, the “one-stop-shop” or “end-to-end” CDMO model would be more attractive, in general, according to Chou, and she believes most CDMOs are moving in this direction.

“The technical challenges in bioprocess development, however, often require specific expertise, and therefore in some cases, a development-driven company is needed to address these challenging issues,” Chou states. Both types of CDMOs are needed as a result.

In fact, the sheer volume of work in outsourcing right now is being appreciated by all CDMOs, whether they are a one-stop shop or handling only one piece of the process, Koleng observes. He also believes that true one-stop shops are rare, since usually there is at least some project component that requires a third party or subcontractor to meet the demand for capacity or production.

It is, adds Franklin, actually difficult to find “end-to-end” CDMOs that truly function as a single provider, since so many of these organizations are born from mergers and acquisitions. “We find that many biopharma companies are more interested in forming a lasting partnership and prefer the customer focus that you more often find at smaller, more specialized firms,” she notes.

Franklin also points out that small and mid-sized CDMOs can offer the advantages of a “one-stop-shop” by teaming up with synergistic organizations. For instance, as a fill/finish provider, Alcami focuses on drug product and analytical services, forming strong relationships with its customers and supporting them long-term in those areas. “But we also work with biologics drug substance manufacturers to understand complementary operations and processes and offer customers an efficient, streamlined approach that saves time and gets products to patients faster,” she comments.

“Ultimately,” stresses Vaghjiani, “to address increasing cost pressures, it is critical for pharma and biotech companies to partner with CDMOs that have the right manufacturing scale at the right time in the lifecycle of their products in order to optimize the cost of goods and meet market demand. He believes that end-to-end CDMOs like Lonza, which operates across nine global sites, three continents, and a spectrum of scales in single-use and stainless-steel bioreactors, help address demand uncertainty and fluctuations.

Leveraging innovative solutions for the future

The COVID-19 pandemic has emphasized the need for innovative drug products and technologies, according to Koleng. TFF Pharmaceuticals is striving to develop such impactful solutions. “With the support of our CDMO partners, we continue to prioritize improving therapeutic outcomes and access, reducing cost of goods and enabling faster rollout of breakthrough medications,” Koleng states.

Chou adds that although the bioprocess development of proteins and antibodies is becoming a commodity, there is still work to do to bring it to the next phase: Industry 4.0 and leveraging big data and the Internet of Things. “Bioprocess developers should push boundaries to ultimately benefit patients with cost-effective medicines,” Chou asserts.

The alternative regulatory approaches established to enable the introduction of COVID-19 vaccines should also continue to be applied going forward to accelerate novel drug development, according to Chou. “Adjustment of the bioprocess development mindset may be needed to fully realize the value of innovative treatment,” she concludes.

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


	Vol. 34, No. 10
	October 2021
	Page: 18–23

	When referring to this article, please cite it as C. Challener, “Trends in Outsourcing of Bioprocess Development" 

Development

Speed-to-market, capacity, technology development, and increased investment top the list.

Trends in Outsourcing of Bioprocess Development

The SARS-CoV-2 outbreak, which started late in 2019, has demonstrated how devastating novel infections can be for the global population. In response to the infectious threat posed by the novel coronavirus, the pharmaceutical industry rallied and managed to develop effective parenteral vaccines in record breaking speeds. However, the COVID-19 pandemic has also brought to the fore the development and distribution challenges associated with mass vaccination programs as well as difficulties ensuring equitable access to vaccines—a particular challenge for low-income countries.

Mucosal pathogens, such as SARS-CoV-2, are a major cause of infectious diseases across the world, and the mucosal route of vaccination has been of interest for some time, primarily due to the induction of immune response that is achievable with this form of delivery (1).

Although there are numerous avenues available for mucosal vaccination, the most commonly employed routes are via the mouth and nose. However, the number of licensed mucosal vaccine formulations is limited, and the available formulations tend to use attenuated strains of pathogenic bacteria or viruses, which carry specific risks such as reactogenicity and post-vaccination reversion of the pathogen to a virulent form (1).

Nevertheless, mucosal vaccines provide a strong immune response in patients, both in mucosal sites and systemic circulation (2). Additionally, these types of vaccines also offer cost and administration benefits over the traditional injectable forms (2).

Nasally administered vaccines are widely accepted and easily accessible, and have reportedly achieved a better systemic bioavailability and protection from gastric enzymes when compared with orally or parenterally administered vaccines (3). Yet, there are multiple hurdles that can hamper development of nasal vaccines.

Challenges to the formulation of nasal vaccines include, but are not limited to, the size of the dose required, limited efficacy of the vaccine due to mucociliary clearance, the necessity for adjuvants to enhance immunogenicity, restricted delivery volume in the nasal cavity, and normal human defense mechanisms (3). According to expert opinion, the incorporation of effective adjuvants that can trigger both mucosal and systemic immune responses are necessary for noninvasive vaccine delivery, and a more extensive understanding of mucosal immunity is required (4).

Currently, the commercially available intranasal vaccines are FluMist/Fluenz Tetra (AstraZeneca) and Nasovac (Serum Institute of India), which are both liquid, live-attenuated vaccines for influenza administered via a nasal spray (5). Other formulations for nasal vaccines include solutions administered via drops, powders, gels, and solid inserts, although there are no other nasally administered vaccines approved for marketing authorization globally.

Spraying a solution into the nasal cavity is simple for administration purposes; however, some of the formulation may leak from the nasal cavity or into the oral cavity, which would reduce potential therapeutic effect and dose. To overcome these potential issues, it has been suggested by some experts that gelling agents, such as polymers, included in the formulation could increase the residence time of the vaccine in the nasal passage (5).

Solid formats for nasal vaccines can offer the advantage of being more stable than liquid formulations but may have disadvantages in terms of cost and ease of administration due to the potential requirement of specialist applicators. Additionally, there has been interest in the development of particulate carrier systems, such as liposomes, for vaccine products (5). To achieve success, however, vaccine formulations that are designed for intranasal administration must maintain the antigen stability, provide sufficient residence time in the nasal mucosa, and should be compatible with other components, such as adjuvants (6).

For COVID-19, it has been specified that the intranasal route of administration for a vaccine is promising due to the fact that the normal route of infection for the SARS-CoV-2 virus is also via the nose (6). Furthermore, it is widely reported that vaccines administered intramuscularly are less likely to provide immunity protection in the upper respiratory tract—the area of primary attack from SARS-CoV-2.

At the time of writing, the World Health Organization (WHO) has reported that there are 112 vaccines in clinical development and 184 in pre-clinical development for COVID-19 (7). Of those candidates in clinical phase, only eight vaccines are formulated for intranasal administration (7).

The furthest along the clinical lifecycle, according to WHO, are a viral vector (replicating) vaccine being developed by the University of Hong Kong, Xiamen University, and Beijing Wantai Biological Pharmacy, and a protein subunit vaccine being developed by the Center for Genetic Engineering and Biotechnology (7). Another potential intranasal candidate from Altimmune is no longer in development as a result of inadequate immune response in healthy volunteers (8).

Of the vaccines that currently have authorization from regulatory bodies to treat COVID-19, only one is in clinical development as an intranasal formulation (7). The University of Oxford announced the launch of a study investigating the efficacy of nasal administration of the ChAdOx1 nCoV-19 vaccine, which was originally co-developed for intramuscular administration with AstraZeneca, earlier in 2021 (9). The trial will assess the efficacy and immune response of either one dose or two doses of the intranasal vaccine in healthy participants and is expected to take four months (10).

Regarding the other potential intranasal COVID-19 vaccines in clinical development: two are live attenuated virus vaccines—COVI-VAC from Codagenix and Serum Institute of India, and MV-014-212 from Meissa Vaccines; two are non-replicating viral vector vaccines—BBV154 from Bharat Biotech International and PIV5-vectored vaccine from CyanVac; and one is an inactivated virus for intramuscular or intranasal administration from Laboratorio Avi-Mex. There is an additional protein subunit vaccine listed in WHO’s COVID‑19 vaccine candidate tracker, which is administered intramuscularly for the first two doses and then intranasally for a third dose, from Razi Vaccine and Serum Research Institute (7).

Another potential intranasal candidate that is currently in the pre-clinical stage is a vaccine that uses a common poultry virus, the Newcastle Disease Virus, to produce spike proteins of SARS-CoV-2 (11). The collaborative effort from the University of Lancaster (United Kingdom) and the Texas Biomedical Research Institute has garnered positive results with reductions in both disease impact and transmission in animals (12).

Rokote Laboratories Finland—an academic spin-out company from the University of Eastern Finland and the University of Helsinki—has secured funding that will help it push forward with clinical development of its intranasal COVID-19 vaccine candidate, FINCoVac (13). The vaccine is based on gene transfer technology that has proven successful in other fields.

A further intranasal candidate is in development by Dutch company Intravacc (14). The SARS-CoV-2 Outer Membrane Vesicle based recombinant spike protein candidate has delivered positive pre-clinical results in mice and hamsters, and the company hopes to move forward to in-human trials quickly. And, researchers from TheraVectys—a spin-out from Institut Pasteur—have been developing a lentiviral vector vaccine candidate, which it reports would represent “a second generation vaccine that could generate a durable cellular response against the original SARS-CoV-2 strain, existing, and future variants” (15).

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Micro and Nanotechnology in Vaccine Development

, M. Skwarczynski and I. Toth, Eds., pp. 279–301 (Elsevier, Amsterdam, The Netherlands, 1st ed., 2016).
4. M. Skwarczynski and I. Toth, 

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6. V.P. Chavda, et al., 

, In Press, Corrected Proof, doi.org/10.1016/j.drudis.2021.07.021 (July 29, 2021).
7. WHO, COVID-19—Landscape of Novel Coronavirus Candidate Vaccine Development Worldwide [Accessed Aug. 24, 2021].
8. Altimmune, “Altimmune Announces Update on AdCOVID Phase I Clinical Trial,” Press Release, June 29, 2021.
9. University of Oxford, “University of Oxford to Study Nasal Administration of COVID-19 Vaccine,” Press Release, March 25, 2021.
10. The Jenner Institute, “COVID-19 Vaccine Intranasal Study (COV008),” Trial Information, 

 [Accessed Aug. 24, 2021].
11. Lancaster University, “Lancaster University Intranasal Vaccine Offers Promise to Block COVID-19 Where it Starts,” Press Release, Aug. 10, 2021.
12. J.-G. Park, et al., 

, 24 (9) 102941 (2021).
13. University of Eastern Finland, “Finnish Coronavirus Vaccine Developer Rokote Laboratories Finland Secures Significant Funding,” Press Release, July 7, 2021.
14. Intravacc, “Intravacc Announces Positive Pre-Clinical Data for its SARS-CoV-2 Nose Spray Vaccine,” Press Release, April 7, 2021.
15. TheraVectys, “Lenti-Covid: Robust Answer Addressing Long-Term Immunity and Emerging Variants,” Press Release, May 30, 2021.

Felicity Thomas is European Editor for BioPharm International.


Volume 34, Number 10
October 2021
Pages: 48-51

When referring to this article, please cite it as F. Thomas, “Getting a Nose for Vaccines,” 

Pandemic Response

The intranasal route of administration is showing clinical promise, particularly for COVID-19, but there are multiple hurdles to overcome to ensure successful formulation.

Getting a Nose for Vaccines

The need for large-scale single-use bioreactors (SUBs) may grow more urgent as biologics manufacturers aim to meet the growing market demand for biologics, especially monoclonal antibodies (mAbs). The 2000-L scale SUBs have become an industry standard, and these SUBs have proven their mettle amid growing demand for biologics. The question on whether size increases in SUBs may be necessary rests in both the successes and limits of single-use technology (SUT) moving forward.

The 2000-L-scale SUB has been the mainstay of large-scale SUBs since its introduction. Yasser Kehail, Biomanufacturing Business Development leader at Cytiva explains that 2000 L is the sweet spot for large-scale manufacturing. Among the reasons for this are, first, that recent technological advancements in cell-culture media and cell-line development have increased product titer and yield significantly. What was once produced at 15,000-L-scale in stainless-steel bioreactors 10–15 years ago can now be produced at smaller sizes, such as 2000 L, states Kehail. Second, current biological entities are designed for specific patient populations, which are smaller and based on specific biomarkers, such as a gene or specific protein. “Hence the clinical material needed for studies and clinical trials are lower in terms of scale,” Kehail says.

According to Nephi Jones, senior manager, Research and Development, BioProduction, Thermo Fisher Scientific, most of the established SUB manufacturers have had a 2000 L or larger product offering for many years. “Clearly most users see the benefit of single-use bioreactors and have been requesting more capacity (displacing 10,000–15,000 L stainless-steel bioreactors), but not at the cost of ease of use, reliability, or performance,” Jones states.

However, as the biopharmaceutical market continues to diversify and grow, future demand in biologics is expected to go far beyond current capabilities of established technologies, Alex Chatel, product manager at Univercells Technologies, cautions. Chatel notes that manufacturers are continuously searching for solutions to reach higher production capacities but must remain vigilant of large footprints and consequent costs. “Currently high-demand applications require scaling-out of production with several bioreactors (i.e., placing multiple bioreactors side by side) which can be sub-optimal,” he adds.

Chatel also points out that there is a demand for significantly high-volume SUBs, as demonstrated by the launch of larger bioreactors; however, there must be a balance between operational complexity, footprint, and batch failure risk and cost with the scaling-out option.

Market pressure pushing the drive toward further adoption of large-scale SUBs primarily centers around demand, according to Adrian Mazzone, director, Process Development, Pharma Services, Thermo Fisher Scientific. These bioreactors allow for more traditional scale-up (single-process stream) and, by utilizing high turn-down ratios, add flexibility. Importantly, large-scale SUBs allow contract development and manufacturing organizations (CDMOs) to retain existing clients with a “start here, stay here” strategy, Mazzone says. This strategy is meant to ensure that clients have an uninterrupted pathway from development through commercialization and don’t feel the need to transition to a CDMO with stainless-steel capacity, he asserts.

In addition, large-scale SUBs enable manufacturers to increase their production throughput at

limited capital expenditure (CapEx) compared to stainless-steel facilities, says Chatel. “The growth of the cell and gene therapy market as well as the phenomenal needs in cell-based vaccines that will be sustained in the years to come means that large scale-bioreactors will be in demand,” he states.

Chatel adds that manufacturers must always keep two important parameters in mind when assessing biomanufacturing needs: scalability of the technologies they use and the cost of goods related to the final product. In his opinion, current capabilities offered by established technologies will end up constraining the availability of affordable biologics. Although the biopharma industry is addressing this issue through solutions such as process intensification to reduce equipment and facility footprint while increasing throughput at considerably lowered operational costs and cost of goods. Maintaining quality and safety is also a requirement.

Another key driver in the growing use of large-scale SUBs is the growth of gene therapies that rely on adeno-associated virus (AAV) vectors to deliver therapeutic transgenes, specifies Laura Juckem, PhD, vice-president of Scientific Operations at Mirus Bio. The commercialization of gene therapies requires high-titer AAV vector preparations, but the large-scale manufacture of AAV in adherent human embryonic kidney (HEK) 293 cells is both costly and inefficient, she points out. “We can therefore expect to see further additions of large-scale single-use bioreactors as manufacturers transition to suspension HEK 293 platforms,” she states.

Juckem points out that one of the performance limitations of SUBs in gene therapy manufacturing is the inefficiency of polyethylenimine-based transient transfection methods. Novel transfection modalities, however, can lead to multi-fold increases in viral titers, which result in significant gains in process efficiency and a corresponding reduction in manufacturing cost, she states. Examples of some novel transfection modalities include reagents and enhancers found in Mirus Bio’s good manufacturing practice (GMP) platform (VirusGEN).

“Optimization of the transient transfection process will lead to higher success rates in single-use bioreactors as vector production is scaled from research to industrial-scale manufacturing,” Juckem emphasizes.

Kevin Mullen, director of Product Management, BioProduction, at Thermo Fisher Scientific states that SUT has been adopted in abundance to meet early- and late-stage clinical processes. Furthermore, as the molecules in development progress from clinical to commercial (larger) scale, Mullen notes that there is market preference to stay within single use rather than shifting to stainless-steel bioreactors. The market has therefore asked for large-scale SUBs that scale well from small-scale process design to large-scale commercial manufacturing, he states.

“Not only has the market been asking for large-scale SUBs; they have also been asking for large-scale SUBs with significantly improved mass transfer and mixing capabilities to support high-cell density cultures,” Mullen adds.

“The single use bioprocess industry has crossed the chasm where this technology can be used beyond its original uses of evaluation, early adoption, and bench marking against stainless-steel processes,” states Kehail, who points out that the biopharma industry is now seeing GMP implementation of SUT in approved clinical drugs, where the technology provides robust data, comparable product quality, and positive business outcomes. Kehail says that these results demonstrate that the industry has matured in regard to SUT utilization. “The current [market] pressure comes from having more and more clients transitioning from evaluation to GMP, which places further pressure on the supply chain,” he says.

However, Kevin Jose, senior group leader of Upstream Process Development at Catalent Biologics, Madison, takes a different view and remains unconvinced that demand would grow for large-scale SUBs in the long run. He observes that there already exists a variety of options for companies looking for large-scale single-use manufacturing. One approach involves running multiple small-scale bioreactors in tandem (for example, 2 x 2000 L) with a large-scale downstream set up. Another approach is to leverage end-stage perfusion (i.e., continuous manufacturing), which would allow for the production of larger amounts of drug substance in a smaller single-use vessel.

“[As] there are options to address large-scale manufacturing with smaller bioreactors, it remains to be seen whether there will be high demand for large-scale SUBs themselves. Additionally, as the market moves towards smaller patient population sizes (such as rare/orphan diseases and personalized therapies), and as technologies improve to increase cell/process productivity, there may be less demand for large-scale manufacturing in the future,” Jose states.

As large-scale SUBs establish a firmer foothold in commercial manufacturing, their continued performance will be further scrutinized. For instance, according to Kehail, it has not yet been determined how well single-use bags will withstand high pressure, temperature, and aeration at volumes greater than 4000 L. He stresses that the robustness of the bioreactor bag is essential. “Any leak, pin hole, or puncture could result in significant financial and product loss,” he states, adding, “we have only demonstrated and proven performance of single-use bags at 2000-L scale.”

Meanwhile, Jose notes that the introduction of high turndown ratio (i.e., ratio of total volume to working volume) SUBs has addressed logistical and technical/engineering issues with respect to seed train and production culture flexibility for large-scale single-use manufacturing. “The technological advances made in SUBs have led to the development of contact layer films with ‘low’ to ‘no’ extractables and leachables that could affect cell culture performance. Also, the shift from cylindrical to cuboidal design for SUBs has improved the efficiency of gas transfer and mixing to ensure optimum scalability up to 5000 L,” Jones says.

Moreover, the use of real-time technology, in conjunction with SUT such as Raman spectroscopy, can improve processes even further to ensure optimum cell culture performance, Jones states.

“From a SUB performance standpoint, ease of use (set-up, installation, execution, tear-down) and reliability are key to the success of any large-scale SUB offering,” adds Mazzone.

Meanwhile, Mullen notes that SUT has become the standard over the past 15 years, in which the technology has proved its reliability throughout an everchanging world of new technology, supply chain challenges, and a global pandemic. “The market demand is to have improved power input per volume (PIV) and mass transfer (kLa) to support high cell densities and support high product quality. The performance in the large-scale reactors needs to be similar to the performance in PD [process development] small-scale reactors so that processes can be optimized at PD small scale and scale up to the larger-scaled reactors,” he says.

While SUBs are mainly stirred-tank vessels, fixed-bed bioreactors are another family of large-scale bioreactors, says Chatel. These fixed-bed bioreactors are much smaller than an equivalent stirred tank vessel for an equivalent throughput. Both SUBs and fixed-beds are fitted with technology to control the basic needs of cell culture (pH, dissolved oxygen, temperature), but beyond the basic bioreactor features, process analytical technology (PAT) is increasingly developed and used to provide automated measurement of advanced production parameters, such as product titer and metabolites concentration, Chatel explains.

In all cases, Chatel emphasizes, the operational environment allowing cell cultures at high densities requires sufficient gas supply and, as mentioned earlier, kLa, which must be enabled by either sparging or gas overlays. Meanwhile, control over foam formation and carbon dioxide stripping must be ensured to prevent cytotoxic effects. “Good mixing that ensures homogeneous availability of nutrients and gases is essential to successful [bioreactor] performance, and this must be ensured by a carefully studied mixing environment,” says Chatel.

Finally, manufacturers must ensure that future SUBs are designed as part of a family that enables smooth scale-up and scale-down. This holistic approach will enable end-users to successfully translate from development to commercial production, Chatel concludes.


Vol. 34, No. 10
October 2021
Pages: 24–28

When referring to this article, please cite it as F. Mirasol, “Large-Scale Single-Use Bioreactors Prove Mettle Amid Growing Demand,” 

Upstream Processing

Large-scale single-use bioreactors prove successful as limits are tested.

Large-Scale Single-Use Bioreactors Prove Mettle Amid Growing Demand

Successful performance of large-scale single-use bioreactors (SUBs) depends in part on defining their limitations and working around them or discovering solutions to overcome them. A main concern, for instance, centers around the increased separation of scale with respect to the scale-down models and large-scale reactors, says Brian Follstad, scientific fellow, Upstream Process Development, Catalent Biologics, Madison. This increased separation makes it more difficult to qualify scale-down models, which Follstad says are crucial to establishing and characterizing process design space and robustness. In Catalent’s case, the implementation of their Ambr high-throughput bioreactor systems closed this gap significantly. “They have been routinely used in the industry to qualify scale-down models, effectively making process characterization easier and improving throughput,” Follstad asserts.

Yasser Kehail, Biomanufacturing Business Development leader at Cytiva states that high pressure, increased agitation rates, and aeration requirements will continue to challenge single-use bags because these increased forces may cause leaks, pin holes, or defects. “This is one of the major engineering challenges for large-scale SUBs,” Kehail states.

“In addition, single use bags need to be transported using special packaging to reduce any sort of rubbing that could cause damage to the film, tubes, and chamber. Hence, when you scale to larger than 2000 L, the robustness of the bag becomes a huge risk, the packaging will be larger, and the risk of failure and damage increases,” Kehail cautions.

It is also technically important to ensure that the process can deliver the requisite mixing and gassing at 2000 L, providing a truly scalable process, states Adrian Mazzone, director, Process Development, Pharma Services, Thermo Fisher Scientific. He points out that, logistically, the SUB packing is significantly larger for single-use SUBs greater than 2000 L. As the whole package comes partially inflated, it must be de-boxed prior to entering the cleanroom and managed through wipe-down through to its final destination in the production suite, Mazzone explains. In addition, effective pre-use visual inspection is difficult for such a large SUB, so a robust leak test is required following installation. “Lastly, from an engineering perspective, the 5000 L bioreactor needs to be installed in a production suite with high ceilings and must be bolted to the floor,” he says.

Making a SUB very large is an engineering challenge, adds Alex Chatel, product manager at Univercells Technologies, partly because the surface area of the vessel does not increase linearly with its volume (m vs. m3). Because of this, efficient heat transfer, gas transfer, and mixing must be considered carefully. Chatel explains that there is a theoretical limit above which making large vessels results in difficult trade-off in terms of operation performance. “This can be highlighted by the difficulty in providing adequate mixing in large-scale bioreactors while limiting shear rates at the impeller tip, which can be damaging to cell health. In this light, process intensification, which instead reduces the volumes of bioreactors for an equivalent throughput, is an interesting approach as the low volumes mean that engineering challenges are more easily resolved and scale-up is made simpler,” Chatel states.

Jorge Garcia, senior manufacturing sciences engineer, Catalent Biologics, Bloomington, emphasizes that currently installed 1000-L SUBs have proven success in efficient gassing and carbon dioxide-stripping of mammalian cell cultures, which reduces the creation of foaming in the reactors. This is a significant benefit because excess foaming can cause operational issues and affect metabolism of the culture. “The successes in controlling foaming through efficient gassing/carbon dioxide-stripping at these smaller scales suggest that this challenge can be overcome in larger-scale single-use bioreactors as well,” Garcia points out.

Kehail affirms that the 2000-L size SUB has also demonstrated its success, namely as 2000-L SUBs have been used in multiple approved protein therapeutics, including COVID-19 vaccines. “Its value proposition of being first or fastest to market has been proven,” Kehail says. “In addition, more clinical trial materials are being produced at GMP scale for different phases; and finally, the low initial CapEx [capital expenditure] required has been a catalyst to constructing more and more green field facilities than ever before,” he states.

For its part, Thermo Fisher Scientific has been seeing significant interest from SUB users since the launch of its large SUBs in March 2021, says Kevin Mullen, director of Product Management, BioProduction, at Thermo Fisher Scientific. “Thermo Fisher has made a significant investment to acquire inventory of these units so that these large-scale SUBs can be delivered in short lead times. There is considerable interest in the high productivity, low-risk scalability, small footprint, attractive GMP price-point and short lead time of SUBs,” Mullen states.

When referring to this article, please cite it as F. Mirasol, “Limits and Successes Define Large-Scale SUBs Path,” 

SUB bioreactor performance has had seen its limits and successes.

Limits and Successes Define Large-Scale SUBs Path

For small- and mid-size biologic producers that are incorporating single-use systems in their manufacturing facility, choosing the right process control system is one of the most critical decisions they make when building a facility. Integrated production processes and information-driven operations are needed to ease compliance, reduce batch cycle times, and get to market faster.

Traditional, large, and monolithic distributed control systems (DCS) can deliver these capabilities; however, they often aren’t flexible enough to meet production needs for smaller-volume processes using single-use equipment and systems.

Equipment-level automation is also not an ideal option. This approach, where each unit operation has a dedicated control system and user interface, creates challenges such as islands of automation that complicate centralized data collection and user account management for the system administrator.

A better approach to automation is to build for the future with a scalable and flexible system that allows producers to incorporate flexible “plug-and-play” equipment. A modern DCS uses modern technology (e.g., industrial ethernet, faster controllers, scalable distributed software) and practices (e.g., cyber-security standards) to make the system more scalable, flexible, and secure. Using flexible systems creates the ability to evolve operations over time, meet regulatory requirements, reduce validation effort, and lay the foundation for newer digital technologies and analytics—all of which can be accomplished with a lower total cost of ownership.

The challenge is making the right choices for this control system early in the process of building a new facility with single-use equipment, because those choices will reverberate and have consequences across the life of the facility. For this reason, producers should make sure to consider the following areas when designing a facility.

A good starting point for designing a control system is the network infrastructure. Producers should consider how a facility’s communications backbone will meet current needs with simplified connections and seamless data access, while providing the flexibility and scalability needed to accommodate future operational and technology changes.

Legacy fieldbus network protocols used in many pharmaceutical plants today can create challenges in a single-use facility. For example, data limitations can restrict a producer’s ability to get valuable diagnostic data from devices and instrumentation. Legacy fieldbus can also be harder to maintain and scale if the network infrastructure needs to change to support new technologies over time due to their inflexible nature.

A modern industrial network protocol, such as EtherNet/IP, does not have these limitations. On EtherNet/IP, single-use equipment and instrumentation can be easily configured to communicate with and publish rich diagnostic data to the process control system. This communication builds into scalable plant-wide ethernet architectures through switches and other network devices. This “plug-and-play” connectivity creates a simpler plant infrastructure, with only power and ethernet cabling required to connect unit operations, and allows for ease of expansion and easier equipment change-out.

Automation may not be on a producer’s mind when developing a new biologic or while in the early stages of clinical trials. It’s never too early to be thinking about automation, because the optimal automation set up can provide significant operational flexibility and greatly reduce the effort involved in tech transfer.

Take the example of a start-up biologic company that invests in single-use equipment with a modern DCS. The equipment can be flexibly assembled into a process train and run manually during early process development, which allows settings to be changed as the process is being fully developed.

Once the company is ready to produce at a commercial scale, the equipment can be easily configured to run repeatable recipes with no major software updates, because the recipe is assembled from the same manual phases run in development. The equipment can even revert to manual operation if an issue arises where intervention is required.

Additionally, equipment can be repurposed and used in a different process because each individual piece of equipment has a full set of functionalities, essentially making each component a replaceable part.

The more that customized technology and functionality is designed into a single-use facility, the more that specialized knowledge is required for design, operation, and maintenance activities. This requirement for specialized knowledge should prompt producers to establish and leverage standards as much as possible.

Standards such as the International Society of Automation’s (ISA) ISA-88 (1), ISA-18.2 (2), and ISA-101 (3) help create a consistent design approach across multiple pieces of equipment for functions, including procedural control, alarm management, and human-machine interface (HMI) style. These standards can be easily enabled when configuring modern control systems using commercial off-the-shelf software libraires. By using these class-based libraries, equipment vendors can create application-specific software with less time and development cost. These libraries also smooth the way for those who inherit equipment—such as validation teams, process engineers, and support technicians—because the software is lower risk, provides consistent information, and is easy to maintain.

The libraries also include standard data structures for specific classes of devices, such as pumps, valves, and others. These data structures provide the basis of constructing analytics for equipment, helping producers increase process performance or equipment uptime in the long run.

The user experience of operations staff is too often left out of automation projects. But producers should consider prioritizing the user experience of the control system if they want to create a more efficient workforce. Libraries of reusable class-based objects can be used to create a common user interface style for staff, for instance. For example, a valve will look and feel the same on a tangential flow filtration skid as it does a bioreactor.

Producers should also ensure their visualization system leverages industry standards, such as ISA 101 (3). The standard can help draw operators’ attention to adverse process conditions to help make sure these conditions are seen and dealt with quickly.

New technologies are changing how people work in a single-use facility—perhaps none more so than augmented reality (AR). How can producers apply technology such as AR in a meaningful way in facilities? The best way to find out is for automation engineers to meet with process engineering and operations teams to discuss needs and potential risks that the technology can address.

For example, single-use consumables can require operators to make hundreds of sanitary and aseptic connections during setup. One wrong connection can lead to a costly batch loss. By performing this work in an AR environment, an operator can confirm each connection and reduce the potential for mistakes.

In another scenario, production operators may not have a view of an HMI when they are performing activities such as pumping media, which can result in missing critical alarm notifications. It may be beneficial for operators to wear an AR headset while doing this work so they are more likely to see alarms as they happen.

Mitigating cybersecurity risks is a priority for most biologics producers today. A robust cybersecurity approach can help producers protect their sensitive regulatory and process data, while realizing the many benefits of digitalized operations.

Part of this approach involves designing a control system with standards like ISA/International Electrotechnical Commission (IEC) 62443 (4), which is a consensus-based cybersecurity standard for automation. The standard establishes that multiple layers of protection will provide the most redundancy in case a specific security layer fails. This concept is referred to as a defense-in-depth strategy and spans personnel knowledge and awareness, physical security, application, and device security. Some control systems are now certified to this standard.

Common Industrial Protocol (CIP) security-enabled control devices offer another layer of protection. CIP Security is an extension to the CIP from the automation industry association, ODVA. It uses data authenticity, integrity, and confidentiality to protect against attacks on industrial communications. Industrial asset-management software can also provide recovery and automatic back-up capabilities that are critical following a security incident.

Easing the journey to commercial production

A modern, scalable, and flexible control system offers a pragmatic approach to developing an automated single-use facility. With the right design choices, this architecture can help producers create a connected, information-driven facility that scales and evolves with their business.

ANSI/ISA-88.01-1995 Batch Control Models and Terminology

Management of Alarm Systems for the Process Industries

ANSI/ISA 101.01 Human-Machine Interfaces for Process Automation Systems

ISA, IEC 62443 Industrial communication networks–Network and system security series.

John Hatzis is a global Life Sciences industry consultant, at Rockwell Automation, and Peter Genest is a business development and strategic partnerships leader at Cytiva.

Early control architecture decisions can impact a facility’s long-term growth, flexibility, and efficiency.

BioPharm International, October 2021 Issue

Next-Gen Technologies Tackle Drug Delivery Challenges

Trends in Outsourcing of Bioprocess Development

Getting a Nose for Vaccines

Large-Scale Single-Use Bioreactors Prove Mettle Amid Growing Demand

Limits and Successes Define Large-Scale SUBs Path

Designing a Control Strategy for Facilities with Single-Use Systems

Increased Data Flow Demands Strategic Management

Public Trust in Medicine Quality as Public Health Challenges Emerge

Bioanalytical Studies Support Biosimilars Approval Pathway

FDA Moves to Advance Innovative Excipients

New Beginnings

The Basics of Aseptic Processing