Both demand for and investment in fill/finish capacity continue to rise.

Focus on Fill and Finish

There are many benefits of employing a reformulation strategy, but companies must also overcome a variety of challenges too.

Reformulating Success

The industry revisits the pros and cons of microbial fermentation at scale for biotherapeutics.

Weighing the Benefits of Fermentation for New Biotherapies

BFS technology can help maintain sterility during the biologics manufacturing process.

Improving Sterility Using Blow-Fill-Seal Technology

A simplified downstream process can save time and costs but requires enabling technologies.

Considerations for Simplifying Downstream Processes

Using a minimum valuable product and process approach would make it is possible to discipline and structure the development of biopharmaceuticals in the fastest way possible.

Introducing a New Concept for Value-Driven Acceleration in Biopharma Development

Awareness of recently implemented—or ongoing—advances by the pharmacopoeias can help biotherapeutic manufacturers remain compliant with current requirements.

Biologic Standards in the Pharmacopoeias: An Update

Cue Biopharma, a clinical-stage biopharmaceutical company focused on injectable biologics designed to selectively target tumor-specific T cells directly within a patient’s body, announced on Oct. 4, 2022 that FDA has granted Fast Track designation to CUE-101 for the treatment of patients with human papilloma virus (HPV16+) recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) as a monotherapy and in combination with KEYTRUDA (pembrolizumab).

Fast Track is a process designed to facilitate the development and expedite the review of drug candidates to treat serious conditions and fulfill an unmet medical need. Therapeutic candidates with Fast Track designation may be eligible for accelerated approval and priority review if supported by clinical data.

CUE-101 is currently being evaluated in a Phase Ib trial as a monotherapy for the treatment of second line and beyond patients with HPV16+ R/M HNSCC and as a first-line treatment in a Phase I dose escalation and expansion trial in combination with pembrolizumab for the same patient population.

“We are very pleased to have received Fast Track designation from the FDA for CUE-101. This designation not only underscores the large unmet need for patients with R/M head and neck cancer who currently rely on available non-targeted therapies, but also highlights the potential of CUE-101 to provide a significant clinical benefit,” said Matteo Levisetti, senior vice-president, clinical development of Cue Biopharma, in a company press release. “To date in its Phase Ib clinical trials, CUE-101 has demonstrated a favorable tolerability profile and single-agent anti-tumor activity in monotherapy as well as encouraging anti-tumor clinical activity in combination with pembrolizumab, supporting the potential to improve overall survival for these patients. We look forward to providing periodic updates and remain committed to advancing the development of CUE-101 to provide patients with a potentially more effective and better tolerated treatment option. We anticipate initiating a registrational trial for CUE-101 monotherapy by mid-2023.”

Articles

FDA has granted Fast Track designation for CUE-101, a treatment of recurrent/metastatic head and neck squamous cell carcinoma. 

FDA Grants Fast Track Designation to Cue Biopharma

Pfizer announced on Oct. 3, 2022 that it has completed its acquisition of Biohaven Pharmaceuticals, the maker of NURTEC ODT (rimegepant), a migraine therapy approved for both acute treatment and prevention of episodic migraine in adults.

The acquisition adds a calcitonin gene-related peptide (CGRP) portfolio to Pfizer, including rimegepant, zavegepant, and a portfolio of pre-clinical CGRP assets. Pfizer has acquired all outstanding shares of Biohaven not already owned by Pfizer for $149.50 per share, for a total cost of approximately $11.6 billion. Biohaven is now a wholly-owned subsidiary of Pfizer.

Immediately prior to the closing of the acquisition Biohaven completed the spin-off of a new Biohaven company that retained the company’s non-CGRP development stage pipeline compounds, Kv7 ion channel activators, glutamate modulation, myostatin inhibition platforms, preclinical product candidates, and certain corporate infrastructure assets excluded from the Pfizer acquisition. Pfizer owns approximately 3% of the new Biohaven company.

"We are proud to build on Pfizer’s legacy of delivering breakthrough medicines for patients living with complex pain disorders,” said Aamir Malik, executive vice-president, chief business innovation officer, Pfizer, in a company press release. “The success of NURTEC ODT coupled with Biohaven’s CGRP pipeline will strengthen Pfizer’s innovative Internal Medicine pipeline through 2030, and beyond. Combined with Pfizer’s global reach, this acquisition increases our potential to bring new treatment options to patients with migraine – a disease which affects over 1 billion people worldwide.”

Pfizer has completed its acquisition of Biohaven Pharmaceuticals for approximately $11.6 billion.

Pfizer Completes Acquisition of Biohaven Pharmaceuticals

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

The biopharmaceutical pipeline is changing with respect to the diversity of modalities and delivery technologies while it is also expanding. This evolution has placed pressure on fill/finish capacity and capabilities across the sector. These challenges continue to be exacerbated by the COVID-19 pandemic, which has also highlighted supply-chain and cold-chain issues. Investments in both additional capacity and new equipment are improving the situation, but demand growth is expected to outpace these activities, at least into the near future.

The number of conventional monoclonal antibodies in the clinical pipeline remains high, even at a time when many new modalities—multispecifics, antibody conjugates, fusion proteins, and other next-generation antibody-based products; cell and gene therapies; nucleic acid-based treatments—and other novel entities are progressing from early to later development stages. There are also well more than 100 COVID-19 vaccines in clinical development, the vast majority of which are administered via injection and thus require aseptic fill/finish processing.

“Continued innovation in both conventional and next-generation protein therapeutics, cell and gene therapies, RNA- and DNA-based treatments, and vaccine technologies is driving demand for fill/finish capacity,” says Ping-Yang Yeh, president of AltruBio Taiwan, a subsidiary of AltruBio, Inc. He notes that the increase in demand for fill/finish capabilities just to meet the production needs for COVID-19 vaccines alone could account for the majority of existing capacity and thus potentially render a slowdown of clinical development and commercialization for other biotherapeutic candidates.

The increased demand for fill/finish operations is presenting scheduling challenges and requiring the need for better planning and more accurate demand forecasting, agrees Fred Fleitz, group vice president, chemistry, manufacturing and controls at Arrowhead Pharmaceuticals

The greater diversity of biologic modalities is creating some challenges with respect to fill/finish processes, according to Yeh. “Many of these biotherapeutics are unstable at room temperature and therefore require rapid fill/finish processing and delivery to the clinic. They also often are targeted therapies and thus more potent and produced in smaller batch sizes. Addressing both of these issues requires high agility and speed in fill/finish operations,” he observes.

Changes in efficiency and productivity during manufacturing operations are, agrees Kelly Christiansen, vice president and general manager of Emergent CDMO’s Rockville manufacturing facility, being largely driven by the growth of novel therapeutics and vaccines for rare and orphan indications, as well as new drug formulations that require technological advancements and flexible solutions for manufacturing.

Christiansen points specifically to the need for expertise in complex molecule formulation to help overcome challenges with stability and efficacy, including experience working with traditional liquid and lyophilized formulations as well as more complex bioconjugates, liposomes, and nanoparticle formulations. He adds that having the right equipment in place to ensure manufacturing needs are met for these novel modalities can be challenging.

One example highlighted by Yeh is the growing need for lyophilization capabilities, given the potential for freeze-drying to help overcome stability issues while enabling storage within the conventional cold-chain infrastructure (e.g., 2–8 

C). “An increase in capacity for lyophilization fill/finish manufacturing and greater versatility in pharmaceutical container selection are needed,” he says.

The need to manage complex formulations and particularly high-viscosity products is another growing issue that is affecting fill/finish operations. High-concentration protein formulation has become a key enabler for patient self-administration for chronic disease indications. However, efforts to develop highly concentrated biologics for subcutaneous delivery can often result in viscosities at the edge of what peristaltic pumps can manage, according to Christy Eatmon, an R&D staff scientist in the Pharma Services group of Thermo Fisher Scientific.

“Care needs to be taken to handle these highly concentrated antibodies so that aggregation does not occur,” Eatmon comments. Yeh also remarks that fill/finish manufacturers should focus on the design of processes and equipment specifically for viscous biologics solutions so that line wastage can be reduced and recovery improved for these often-expensive drug substances.

Special handling or filling modifications may also be required for suspensions and dispersions to ensure homogeneity, Eatmon comments. Yeh agrees that the nature of vaccine and therapeutic modalities will determine facility design needs, including processes and components of choice.

As an example, Yeh mentions messenger RNA (mRNA) vaccines formulated as lipid nanoparticles (LNPs), which are unlike standard protein therapeutics that are typically soluble in aqueous formulations. In addition to continued need around the world for mRNA vaccines and boosters against the initial and newer variants of the SARS-CoV-2 virus, the success of the first two COVID-19 mRNA vaccines has driven interest in the use of these platforms for additional indications, observes Eatmon.

The discrepancy between mRNA and protein therapeutic formulations could impact the design of processing steps and the choice of equipment for manufacturing, while the greater instability of mRNA vaccines may reduce the time allowable for fill/finish operations to minimize room temperature exposure, according to Yeh. In fact, as more complex processes become the standard, process design and development of suites that allow for emulsion/dispersion technology will be required, according to Eatmon.

The constraints associated with mRNA products and other similar types of formulations, therefore, pose additional operational complexities in facility and logistics design and require additional resources compared to those needed for the standard processing of protein therapeutics, Yeh concludes.

In a similar vein, Eatmon notes that with the emergence of more intravitreal products, development of solutions for the delivery of small fill volumes in the range of 0.15–0.25 mL will be increasingly important.

Finally, with such a growing diversity of biologic modalities, manufacturers are faced with a shortage of qualified technical experts to support fill/finish operations from the process engineering, quality assurance and quality control, and regulatory perspective, according to Yeh. “Talent recruitment and retention, including rigorous training programs, will become crucial for fill/finish manufacturers that wish to stay competitive,” he contends.

The wider range of modalities is not the only change affecting fill/finish operations. There is also a shift in the industry towards single-use delivery systems (also considered ready-to-use containers) such as pre-filled syringes (PFS) and single-dose vials (SDVs), according to Sophia Percival, director of drug product manufacturing for Catalent.

For COVID-19 vaccines, multi-dose vials were used so that more people could be treated in the shortest amount of time. At this later point in the pandemic, however, companies are now considering ways to optimize resources and make delivery of treatments more patient- and carer-friendly. “PFSs and SDVs help ensure the correct dosing of patients and can also significantly reduce drug product waste,” Percival says. Patient and caregiver safety, including avoiding needlestick injury to those administering vaccines and treatments and disposing of spent needles, remain key drivers, she adds. Direct-to-patient delivery and home care are also made easier with PFSs and SDVs.

Eatmon agrees: “One of the biggest drivers in the movement to pre-filled syringes is the desire to make products easier to use. Whether that’s in
emergency medicine or at home by patients, there is an increasing desire
for efficiency and ease in delivery of parenteral medicines.”

Of course, as more products move from vials to syringes (and cartridges), the need for syringe capacity is growing.

The COVID-19 pandemic affected all business around the world, including the biopharmaceutical industry and fill/finish activities. It had, says Belinda Holdsworth, senior director, strategic growth project lead, Lonza Drug Product Services, a dramatic impact across the globe with almost no region left unaffected, and magnified the challenges of unpredictable demand and demand fluctuations. Specifically, it triggered the rapid development of vaccines, antivirals, antibody therapies, and diagnostic products, which in turn resulted in significant and rapid capacity ramp-up and, in the fill/finish sector, technological growth to support analytics and agile fill/finish capabilities.

At the same time, Holdsworth believes the pandemic drove biopharma companies to assess their manufacturing networks and supply chains, particularly in the scope of resilience. “This includes securing supply chains through dual source manufacturing and raw material suppliers, on-shoring of manufacturing, and response to personnel disruptions,” she explains.

Indeed, according to Percival, the COVID-19 pandemic brought about a significant and permanent change in the way that the pharmaceutical industry approaches the supply chain. “We are now more attuned to how materials are sourced globally, and how small changes to production in one part of the world can significantly limit the supply of critical materials,” she says.

In fact, Fleitz notes that the COVID-19 pandemic continues to present supply-chain issues, particularly for the supply of glass vials, caps, and seals, as well as with respect to the ability to achieve reliable, timely shipping of goods.

Percival also observes that the pandemic reminded manufacturers about the benefits of more traditional production methods, including reusable tanks and equipment that allow for more internal control and less reliance on the global supply chain for materials consumed during processing.

Impacts of the pandemic continue even though the virus is slowly becoming endemic. “I believe the COVID-19 pandemic will continue to apply stress to the fill/finish sector due to the high demand for manufacturing capacity and raw material supply,” Yeh comments.

Shortages do still continue to plague manufactures and range for single-use components such as bags and filters to primary packaging components, including vials, PFSs, and cartridges. Access to dependable shipping remains an issue as well.

“To address these challenges,” says Eatmon, “efforts are ongoing with suppliers and customers to account for long lead times and also look for alternatives that can be considered equivalent and will have minimal impact to the product validation and regulatory strategy.”

It is also imperative that fill/finish manufacturers keep a close watch on the quality of incoming raw materials. “Proactive raw-material-supplier management is imperative, particularly when a raw-material supplier makes changes to a process that may have inadvertent negative impacts on product quality,” Yeh states. “A thorough risk assessment on the adjacency of the raw material to the safety and efficacy of the product can help to manage the priority,” he adds. “In the meantime,” Yeh continues, “capability in forensic sciences and analysis should be established via the science-based approach to defend the decision on the disposition of batches, particularly when it comes to raw-material impacts.”

Yeh in particular points to issues with the supply of single-use system (SUS) components, for which lead times can be as long as 12 months. He does note that suppliers have been ramping up production through scale-up of existing processes and the building of additional manufacturing plants. However, he cautions that rapid expansion has in some cases resulted in compromised quality for some components depending on the process used to produce them and the particular manufacturing sites where they are made. These issues have, in turn, led to a higher incidence rate for manufacturing deviations and product lot rejections, according to Yeh.

Although there has been some recognition of the value that permanent stainless-steel manufacturing equipment can provide in times of supply shortages, the interest in disposable technologies for biologics manufacturing at commercial scale, including fill/finish operations, continues to grow.

“Industry competition continues to drive the need for improved efficiencies, lower costs, higher quality, safety, and regulatory compliance, and greater manufacturing agility. In response to these demands, the use of [SUS] continues to grow, as single-use technologies have proven to reduce overall facility costs while providing faster changeover times and lowering cross-contamination risk,” explains Holdsworth. The COVID-19 pandemic accelerated this trend.

Another related trend in biomanufacturing, according to Yeh, is the shift towards agile, modular design. “This new approach enables the reduction of facility footprints, speeds of the design-build-validation process, supports smaller batch sizes, and like SUS, reduced change-over times. All of these features are advantageous for novel biologic modalities, such as antibody-drug conjugates, bispecific antibodies, mRNA vaccines and therapeutics, and personalize medicines,” he comments.

More emphasis on closed and automated processing

Given the need for aseptic processing, the industry has been moving towards the use of closed processing solutions for many fill/finish operations. This trend is in alignment with the greater adoption of single-use technologies, and these systems provide better control over aseptic filling and thus greater sterility assurance, according to Fleitz.

“Gloveless, closed systems with robotic handling, filling, and closure processes provide a high level of sterility and fill accuracy and are ideal for supporting high-value, small-batch-size drug products such as next-generation therapies,” observes Christiansen.

Christiansen has seen the shift away from restricted access barrier systems (RABS) toward isolator systems in combination with increasing use of automation to streamline fill/finish operations. Isolator lines provide the flexibility for both large-scale therapeutic filling and enable smaller fill quantities for more targeted and potent products. Certain products (e.g., viral therapies), he notes, require the use of isolator technology.

“Isolators represent the superior choice in terms of sterility and eliminate more contamination risks, especially when combined with room controls such as biosafety
level 2 environments,” Christiansen states. In addition, such fill lines with integrated lyophilization capabilities minimize operator interventions and ensure aseptic conditions from fill to freeze drying.

Furthermore, isolators allow campaign filling, in which manufacturers fill one batch after the next without any intervening vaporous hydrogen peroxide cleaning cycles, which is an optimal approach for late-phase and commercial products that are produced in larger volumes.

One of the most significant trends in the fill/finish sector is the rapid growth of the contract development and manufacturing organization (CDMO) market, according to Holdsworth. Grand View Research predicts the sector will expand at a compound annual growth rate of 6.1% to reach $14.0 billion by 2030 (1). “An increasing number of new drug approvals are being filed by small and medium-sized pharma and biotech companies with no in-house manufacturing capabilities. CDMOs are strengthening their services across the full lifecycle, including product development, clinical testing, commercial manufacturing, and regulatory expertise, supporting this industry segment,” she says.

The COVID-19 pandemic only reinforced the pre-existing trend toward outsourcing. One fundamental change has been a shift to engagement by drug makers in strategic partnerships with the contract manufacturers they include in their established manufacturing networks. “Fill/finish vendors are becoming more of an integrated partner with our operations team, increasing the level of communication between us and vendors,” Fleitz notes.

Eatmon agrees that the role of the CDMO is changing. Rather than just provide one or two services that are predefined, partnerships are being formed in which both the CDMO and customer work together to come up with creative solutions for quality products. She points to the increased demand for pre-filled syringes as an important driver. “For PFSs, there is not only a need to fill the drug product, there is an increased demand for devices such as autoinjectors, necessitating engineering teams on both sides to come together and work on selecting the best device for the application.”

This more strategic approach, says Holdsworth, will facilitate regionalization, with manufacturing capabilities established around the world in countries where manufacturing was traditionally not strong. “This CDMO growth will bring much sought-after resilience to the market, facilitating expedited time-to-market and improving cost efficiencies,” she contends.

It is also helping some drug makers better manage the currently heavily constrained pharmaceutical supply chain, according to Percival. “Sponsor companies are relying more heavily on their outsourcing partners, requiring them to diversify their supply chains and assure reliable supply,” she notes.

Finding good-fit CDMOs is essential, though, Yeh emphasizes, particularly for small and virtual biotech companies, which constitute a significant segment of the biopharma industry. “While the general considerations of a competitive cost-structure and capacity are important, smaller companies also tend to value other differentiation factors too, including skill set, regulatory experiences, proven regulatory inspection record, operational agility, technical innovation, and ability to support projects from start to finish,” he says.

In fact, Yeh believes it is becoming increasingly important and highly desirable for CDMOs to provide support for development and manufacturing of both biologic drug substances and drug products through fill/finish, product inspection, labeling, and packaging “under the same roof”. “The fill/finish service can then be offered as a
continuation of the drug substance manufacturing service and be subjected to the same quality framework. Logistics, planning and procurement can also be streamlined to gain consistency and efficiency,” he explains.

With more combination products moving through the pipeline, such as PFSs that require autoinjectors, Yeh adds that the ability to streamline operations and logistics will become a key differentiating factor. Fleitz notes, too, that “end-to-end” CDMOs with the flexibility to support filling of both small batches for early-phase clinical programs and larger-volume filling within to meet Phase III and commercial needs will be in demand.

Manufacturers are not completely alone as they work to meet evolving fill/finish needs. Equipment vendors are aware of the key shifts in the sector, and some have already expended significant effort to introduce new solutions. Yeh points to new types of aseptic filling systems that integrate technologies applicable for ready-to-use pharmaceutical glass containers and isolator systems that comprise modular processing units with built-in robotic capabilities. “Such new equipment offers the advantages of a smaller manufacturing footprint, shorter design-build-validation times, and minimization of human interventions during operations. They also provide the flexibility needed to manage the ever-increasing demand for fill/finish capacity and provide an effective way to generate process insights through efficient data collection and analysis,” he believes.

The need to produce millions of doses of COVID-19 vaccines led to a huge surge in fill/finish infrastructure investment, according to Holdsworth. She stresses that this high level of capacity expansion remains strong and sustained. “Even so,” she adds, “global capacity remains insufficient, and ongoing infrastructure investment, particularly by CDMOs, is needed to ease this gap.”

Christiansen notes that the continuing significant investment is largely in isolator-based technology “because of the flexibility it offers for aseptic filling, processing both vials and syringes, and the enhanced sterility assurance made possible through minimized operator interventions and automation.” Emergent CDMO has, for instance, proactively invested more than $150 million in capability expansions across multiple sites to provide additional drug-product manufacturing automation and capacity, including isolator technology, inspection, and packaging and labeling lines.

Eatmon, meanwhile, underscores the fact that investments are not just needed to expand fill/finish capacity. “Significant funding also must be directed towards increasing the capacity for inspection, packaging, and other supporting activities,” she states.

Despite the challenges posed in recent years for fill/finish operations, there are high expectations that investments in innovation and capacity will help move the field forward significantly. “Aseptic fill/finish continues to be a dynamic and exciting area of the pharmaceutical industry,” avers Eatmon. Yeh adds that although the focus in the biopharma industry has traditionally been on drug substance manufacturing, the sector has matured to the point where platform technologies are now widely used. He believes that “the time has come for the focus to shift to drug product manufacturing, with an emphasis on fill/finish, as it is a key enabler for product differentiation.”

Research and Markets, “Global Fill-finish Pharmaceutical Contract Manufacturing Market Report to 2030–Size, Share & Trends Analysis Report,” Press Release, July 18, 2022.

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


Volume 35, Number 10
October 2022
Pages: 10–15

When referring to this article, please cite it as C.A. Challener, “Focus on Fill and Finish,” 

Matthew Sanders is vice-president, head of Global Drug Substance at GSK, Rixensart, Belgium.

Roland Mainil is director, Technical Development Lead at GSK, Rixensart, Belgium.

Wael Chahim is associate director, Development Unit Head at GSK, Rixensart, Belgium.

This opinion paper seeks to introduce a disruptive model to accelerate product and process development in the biopharmaceutical industry, especially for vaccines. This model is based on the minimum valuable product and process (MVaP&P), a new concept that allows for adaptation and acceleration, which would enable agility in the way biopharmaceuticals are developed. This article discusses how the MVaP&P approach would make it is possible to discipline and structure biopharmaceutical development to achieve a phase-appropriate and strategy-aligned product in the fastest time possible.

Submitted: May 12, 2022
Article accepted: June 28, 2022

Matthew Sanders* is vice-president, head of Global Drug Substance; Roland Mainil is director, Technical Development Lead; and Wael Chahim* is associate director, Development Unit Head; all at GSK, Rixensart, Belgium.

*Both authors contributed equally to this paper.


Vol. 35, No. 10
October 2022
Pages: 34–41

When referring to this article, please cite it as M. Sanders, R. Mainil, and W. Chahim, “Introducing a New Concept for Value-Driven Acceleration in Biopharma Development,” 

Editor of Pharmaceutical Technology Europe

Traditional drug development is costly and time-consuming, with many hours, days, and years spent researching and developing novel chemical entities that, for the most part, will likely fail to get to the commercial finishing line. Repurposing a drug can offer companies an approach to drug development that is much more time- and cost-efficient and offers a higher chance of success. According to research, 30% of repurposed drugs gain approval, which is three times higher than the rate for new drugs (1).

There are three main strategies to repurposing a drug product: determining a novel therapeutic indication for an already known drug (repositioning); developing a new formulation of a drug product (reformulation); and combining two or more drugs that were already being used as single drug products (combination) (2). Despite the various benefits of repurposing existing drug products can offer, each strategy also has certain challenges to overcome that can act as a deterrent to developers.

“Reformulation can be used very effectively to develop improved medicines and treatment options for patients,” confirms Jan Jezek, chief scientific officer of Arecor. “For example, creative formulation can be used to improve the pharmacodynamics and pharmacokinetics of a drug.” Highlighting a specific case of creative formulation, Jezek points to the development of a novel formulation of insulin that has is being developed by Arecor, which accelerates the drug’s absorption post-injection, leading to improved glycemic control.

“Another example benefit of reformulation is to convert a lyophilized powder medicine to stable liquid ready-to-use (RTU) product formats, which are becoming increasingly important to enable fast, safe, and effective treatment of patients,” Jezek continues. “Innovative formulation approaches can also lead to improvement in stability of small- and large-molecule products and enable their use outside the cold chain, which can significantly improve convenience of use.”

Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm, emphasizes that reformulation can be performed for several key reasons. “[Reformulation] can allow developers to improve the performance and patient centricity of an existing drug. For example, it may be done to create a version of an existing drug that is more convenient and easier to use for the patient, increasing quality of life or boosting adherence and, in turn, therapy success,” he says.

Additionally, Jagdish remarks that reformulation can be used to enhance solubility, to improve absorption, or to boost the stability of a drug product formulation. “In all cases, reformulation can save a considerable amount of time and financial resource compared with the discovery and development of an entirely new chemical entity,” he states.

Moreover, it is possible to use reformulation as a way of extending the line of an older drug product, Jagdish points out. “[Reformulation] offers an opportunity to change an excipient or evolve the manufacturing process to deliver marginal gains in performance or ensure compliance with new regulatory requirements,” he says. “Regardless of the reasons for the reformulation, assessment of the regulatory implications of reformulation is essential.”

First and foremost, Jagdish stresses that it is critical for companies to be aware of the regulatory requirements of the target geography of the reformulated drug product. “There is considerable variation in the regimes in each country, so pharmaceutical companies should evaluate their compliance needs on a case-by-case basis,” he says. “For example, the US Food and Drug Administration (FDA) has published its guidance for industry on Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route, which can help companies understand the regulatory requirements in the [United States]” (3).

For Jezek, considering the formulation excipients and whether those being used in the reformulated product are indeed approved for the intended use—administration route and desired dosage regimen—is critical. “[Whether or not the excipients are considered novel] impacts the complexity of development as it is necessary to justify the use of the excipients and to demonstrate the safety of the excipients required. Novel excipients will carry a higher regulatory and development burden,” he specifies.

When approaching a reformulation strategy for a drug product, developers should define the target product profile at the outset, Jezek continues. “In other words, the formulation scientist needs to understand the desired stability and other requirements that the products must meet, such as specific impurity levels, to be approved by the regulatory authorities,” he says.

Reformulating an existing drug product can be a time- and cost-effective way of rejuvenating a product line while also making a therapeutic more patient-friendly. To find out more about how external expertise can help sponsor companies achieve success in reformulation strategies, 

 spoke with Jan Jezek, chief scientific officer of Arecor, and Balasubramaniam Jagdish, assistant vice-president, Formulation Development, Bengaluru Site, Recipharm.

 How might companies benefit from using a partner for reformulation tasks?

 An innovative formulation technology company, such as Arecor, can use its expertise, know-how, and technology to develop novel formulations of therapeutic medicines with enhanced properties, enabled by the formulation, which would otherwise not be possible. These enhancements can improve treatment options and outcomes for patients. The technology can be applied to a variety of new products in development to maximize their benefit for patients. However, the reformulation technology can also be applied to existing marketed products as part of life cycle management.

 Reformulations are often considered by big-brand pharmaceutical companies as a strategy for enhancing the lifecycle management of their patented product and to delay generic entry as far as possible. These companies often have many lead molecules to work upon, meaning it can be hard to find the capacity required for reformulation in-house. Working with a contract development and manufacturing organization (CDMO) partner can help them find that additional resource, enabling them to manage multiple reformulations simultaneously while freeing in-house capacity to focus on innovation.

For generic companies, reformulation gives them an advantage in terms of 505 b(2) filing. [FDA] 505 b2 approvals give additional exclusivity to a product. When applied to a reformulated drug, it can help to prevent generic entry until the expiry of the filing. As such, they keep development in-house, provided they have the internal capacity and infrastructure. However, if the generic company is reformulating to change excipient or manufacturing process, they may well prefer to outsource to a CDMO to provide the necessary expertise and infrastructure so they can concentrate on other projects.

After defining the target product profile, the developer needs to understand the degradation pathways that can potentially impact the stability of the drug product during storage, Jezek adds. Appropriate methods must be established so that any degradation pathways can be measured and understood. “Such methods are often referred to as stability‑indicating methods,” he notes.

“The last challenge, which is most critical for successful reformulation, is to be able to select the right combination of inactive ingredients that will collectively interact with the small- or large-molecule drug in a way that reduces the degradation rate and thus enables the desired product profile,” Jezek confirms.

According to Jagdish, the challenges that pharmaceutical companies need to overcome when approaching a reformulation project depend upon the type of reformulation they are undertaking. “For example, when developing a new formulation of a drug for the same indication, achieving bioequivalence for the new formulation with the existing one poses a significant challenge, because it is no longer a like-for-like comparison,” he asserts.

“Reformulation can also be considered to reduce the size of the dose of a medication, to improve safety profile and patient compliance,” Jagdish continues. “Again, in this case, there is a need to demonstrate that the efficacy of the lower dose is equivalent to that of the already clinically proven and approved higher dose.”

Providing another example, Jagdish points out that when developing a fixed-dose combination therapy from two independently approved drugs, demonstration of the bioequivalence can also be tricky. “Here, in addition to maintaining bioequivalence with the two existing single-dose products, companies have to ensure the compatibility of the two drugs when in the same formulation,” he says.

When reformulating large molecules, Jagdish emphasizes that additional challenges—when compared with those facing small-molecule formulators—need to be addressed. Challenges such as solubility, absorption, and stability, he specifies.

Because large molecules are commonly administered via intravenous injection, it can be desirable and more patient-friendly to reformulate a drug product to be administered in an alternative way. “Often the focus of a change in the route of administration for a biological medicine is to enable a change from a time-intensive intravenous administration to a single subcutaneous injection,” Jezek confirms. “This [change] requires developing a highly concentrated formulation of the product that can be delivered via a small volume in a single injection.”

However, by reducing the volume of injectable product, the viscosity can become problematic. “Challenges that need to be overcome in developing these high concentration formulations is high viscosity (which can make the product too difficult to inject) as well as the propensity of proteins to aggregate (resulting in the formation of particles, which are unacceptable in pharmaceutical compositions),” Jezek explains. “In addition, proteins are subject to chemical degradation such as hydrolytic cleavage or oxidation. Innovative approaches to formulation design are often required to overcome these challenges.”

Yet, there are relatively easier reformulation routes, such as updating the excipients or the manufacturing process to extend the product’s line, Jagdish states. “Reformulation in these cases often simply involve step changes in the production process or the preparation of ingredients to enhance product quality or to improve manufacturing efficiency,” he specifies. “New ingredients are not generally involved, reducing the number of challenges that need to be overcome.”

1. N. Sommerford, “Drug Repurposing Basics,” Blog, IQVIA, May 12, 2022.
2. S. Murteira, et al., 

Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

Felicity Thomas is the senior editor for 


Vol. 35, No. 10
October 2022
Pages: 16–17, 48

When referring to this article, please cite it as F. Thomas, “Adopting Smart Development Strategies,” 

Feliza Mirasol is the science editor for 

Microbial fermentation has its place in the biomanufacturing industry, despite the prevalence of mammalian-based cell culture processes for the production of biologics. However, despite the lower costs and potential for substantial product yield with microbial fermentation, this process has challenges. This article discusses the advantages and challenges of microbial fermentation and looks ahead at what place fermentation may hold in the biomanufacturing industry moving forward.

Industry sources note that fermentation has played a role in manufacturing biologics for quite some time. “The first biopharmaceutical, insulin, was produced in the early days via microbial fermentation in 

), and is now also produced in yeast,” says Gregor Awang, PhD, director, Biologics Process Development, BioVectra, a contract development and manufacturing organization (CDMO).

In addition to insulin, many other biologic drug substances are now made via fermentation, including human growth hormone (HGH), enzymes, cytokines, monoclonal antibodies, antibody fragments, and bioconjugates, Awang enumerates. Furthermore, plasmid DNA, which is the intermediate needed to make messenger RNA (mRNA) for vaccines and therapeutics, is also produced in bacteria, and some bacteria have been modified as a product themselves to be used in nutritional supplements, Awang states.

“Fermentation is a key technology at the core of all biologics, whether it is antibodies, complex proteins, or genetic medicines,” says Jess Tytell, director of Technical Business Development, Ginkgo Bioworks, a US-based biotechnology company specializing in bioengineering microorganisms. Tytell explains that cell lines that have historically been employed for biologics production have been mammalian in origin, but with advances in cell engineering and development of new formats of biologics, microbial platforms will start to become more relevant.

In the meantime, more biosimilar products are expected to come onto the market in the next decade, so the question is whether fermentation will hold a place in the manufacture of these biosimilars. Tytell believes that fermentation will continue to remain a fundamental technology enabling the manufacturing of biosimilars as much as they have been for novel biologics. In the context of biosimilars, microbial platforms can enable the improvement of access to much-needed therapies because these platforms can help make the manufacturing of biologics much more cost effective, she notes.

Awang points out that, since most of the non-glycosylated biosimilars on the market—such as HGH and insulin—are made in either 

 or yeast, fermentation will continue to be important in the manufacture of biosimilars. However, one limitation of fermentation for biosimilars is the proteins needing glycosylation, which adds polysaccharides to the protein to improve stability and potency. “Protein glycosylation is specific to mammalian cells, and microbes, as a rule, don’t add polysaccharides to proteins. If a product requires glycosylation, you would use mammalian cells. Specifically, you need to ensure human or human-like glycosylation to avoid an adverse immune response,” Awang explains.

Traditionally, biosimilars have been cultured in Chinese hamster ovary (CHO) cells, and, even when glycosylated, these protein products tend to be compatible with the human system—though there are human cell lines now available that provide fully human glycosylation.

“It is sometimes possible to make the protein with 

, then chemically add a carbohydrate moiety 

. This has the benefit of reducing costs of protein production as fermentation is less costly than mammalian cell culture. It depends on whether the protein is amenable to this approach, depending on the complexity of the required glycan. For example, some proteins can be PEGylated, which adds a relatively less complex carbohydrate,” Awang says.

) is a yeast that combines high-yield production and is capable of some post-translational modifications, including glycosylation, Awang adds, noting that companies have engineered 

—and many other yeasts—to mimic the human glycosylation pathway.

As with most manufacturing processes, a particular process will have both its pros and cons when it comes to scale up, and microbial fermentation is no exception. When comparing fermentation to mammalian cell production, Cameron Graham, senior manufacturing and science technology (MST) process engineer, BioVectra says that scale up of a microbial process benefits from the fact that microbes are usually more resistant to shear than mammalian cells; however, microbial fermentation has the challenges of needing adequate oxygen transfer and mixing as well as the removal of excess metabolic heat.

“Typically, for microbial scale up, we’ll pursue a more robust scale up strategy in terms of the power per unit volume input and kLa (volumetric oxygen transfer coefficient), to maximize the efficiency of oxygen transfer into the fermentation broth. Particularly at larger scales (>1000 L) of high-growth cultures, the amount of heat can be more than what jacket cooling can handle since single-use bags don’t have the same conductivity as a stainless-steel surface. This can also be challenge in traditional stainless-steel vessels,” explains Graham.

Graham notes that there are options to lower the jacket coolant temperature, but the ratio of jacket heat transfer area to fermenter volume typically becomes more unfavorable as vessel volume increases. “In those cases, you have to explore internal surface area additions to the vessel itself. For example, we are exploring an upgrade to our 17,000-L stainless steel fermenter to include internal baffles that will allow us to achieve about 300 mmol/L/hour OTR [oxygen transer rate] at 30 °C broth temperature, and up to 450 mmol/L/hour OTR at 37 °C. Such an upgrade will allow us to maximize the microbial process while reducing the risk to product quality due to uncontrolled temperature rise,” Graham states.

Awang observes that media costs are lower for microbial fermentation, making scale up less expensive than with mammalian cultures, which can have up to 20 different ingredients—a few of which are extremely expensive and sensitive to certain conditions.

“Yields tend to be much better with mammalian cell cultures (up to 10 g/L), than for fermentation (1–3 g/L). However, fermentation process development is faster and less technically challenging since there are a lot of tried-and-true methods for optimizing the process in 

Awang continues that the key for both microbial fermentation and mammalian cell culture is getting the correct type of DNA inserted into the cells to ensure a high titer and yield of product. For example, transferring DNA into 

 and selecting a suitable clone with the intact DNA is much simpler than transfecting mammalian cells. In the latter case, it is necessary to screen thousands of mammalian cell clones to get one that has the desirable combination of traits, depending on where in the cell genome the inserted DNA (transgene) has located, and how many copies. “In the past decade, DNA editing using CRISPR [clustered regularly interspaced short palindromic repeats] and other techniques has made inserting DNA precisely into stable ‘hot spots’ in mammalian cells much more precise, resulting in higher stability and product yield,” says Awang.

Fermentation, however, has shorter processing times. According to Awang, a good microbial process can take as little as one to three days, as opposed to the weeks necessary for mammalian cell culture. “This faster process has the added benefit of reducing the risks associated with contamination. Not only is the risk lower with fermentations, but if you do have a contaminated fermentation, the loss of worker hours is a lot less. A contamination two weeks into a mammalian culture can be a massive financial loss,” Awang emphasizes.

Tytell concurs that microbial fermentation advantages include significantly lower costs for microbial hosts, less expensive media, and fewer issues with contamination. The latter can mean less downtime and higher productivity. In addition, optimizing microbial hosts is faster, leading to a shorter turnaround time to develop the final production strain, which can decrease overall production timelines, she adds. In comparison, mammalian hosts require more screening (e.g., for viral infections).

The disadvantages of microbial fermentation that Tytell sees include the fact that post-translational modifications are different, and this difference is relevant for more complex biologics. In addition, there are fewer approved biologics from non-Chinese hamster ovary hosts, so there may be higher regulatory hurdles for newer biologics produced via microbial fermentation; however, these hurdles are expected to go away quickly after the first few approvals, says Tytell.

With a rich pipeline of emerging therapy drug candidates, what place will fermentation-based processes hold in the biomanufacturing industry as these more highly complex biomolecules move towards commercialization?

“Fermentation has a place in a range of therapeutics in development. For example, plasmid DNA produced in 

 can be used as both a therapeutic or an intermediate to make mRNA vaccines, gene therapies, and for gene editing,” says Awang.

Conjugated protein therapeutics, in which a protein and another chemical entity, such as polyethylene glycol, are linked to improve the function of a biologic, is another area in which microbial fermentation has application, says Awang. “Bioconjugation had died out around the turn of the century but is coming back with a bang. Products in development include PEGylated hormones, such as GM-CSF [granulocyte-macrophage colony-stimulating factor], which can be made in bacteria or yeast, and is then PEGylated to improve its stability. Or mAb protein fragments made in E.coli, which can be conjugated to therapeutic payloads to direct the payload to specific disease cells,” Awang explains.

Tytell says that many current biologics do not require post translational modifications. For those biologics, and because of cost of goods and development timelines, microbial fermentation is poised to become a workhorse (e.g., nanobodies, aglycosylated antibodies, other protein based biologics, etc.). As microbial hosts continue to develop, they will become more valuable for complex biologics, she anticipates.

“As microbial engineering continues to develop and microbial strains can be produced that can mimic key mammalian features, such as glycosylation, these fermentation-based processes will become extremely valuable in more complex biologics. The faster turnaround to testing and higher titers will be especially valuable for the discovery and validation phases, which become more critical as molecules get more complex,” Tytell states.

Meanwhile, another current popular trend in biomanufacturing, single-use technologies, may have a place in fermentation processes, but stainless-steel systems will likely remain the core setup for microbial fermentation. Single-use microbial technologies can be conducive to fermentation-based biomanufacturing if certain criteria are met, Jeremy Kerrick, head of Process Development and Engineering at Ginkgo Bioworks emphasizes.

For instance, scale matters. If the output of a process is a commodity, then scaling up is often the approach that drives down cost of manufacturing and the final product. This typically means that the best option is stainless-steel, since there are currently no single-use fermentation options beyond 50 L, and these are only just now showing up on the market, says Kerrick. Thus, scaling up into a single use microbial fermentation-based platform to drive down cost is not currently possible.

The availability of single-use platforms is also a factor. High-value mammalian-based therapeutics such as CGTs rely heavily on single-use reactors. Yet, these single-use reactors typically scale to up to 2000 L. “While they may incrementally increase in size in the future and perhaps marginally drive down the cost of manufacturing, it seems unlikely that they can get much larger than what is on the market now. It seems logical that once single-use technology reaches this scale for microbial fermentation, it will also be limited, and then the economics of scaling will again steer one toward stainless steel,” says Kerrick.

In terms of titer, novel approaches to increasing the expression of the modality of interest could swing the pendulum back to smaller-sized fermenters and, thus, to single-use technology. According to Kerrick, superior producer cell lines, induction or transfection advances, and genetically modified organisms are all means being explored across industries to increase titers. He explains that, if a process currently provides 2 g/L of product and is produced in a 20,000-L reactor, which suddenly sees an increase of 10 fold titer, then 1000-L or 2000-L single-use fermenters are a viable option. Further, single-use technology has some advantages over stainless-steel at this scale, which could make single-use the superior choice.

Meanwhile, development at the bench and pilot scale needs to be taken into consideration. Until recently, mammalian and microbial development laboratories were dominated by glass and stainless-steel reactors, Kerrick points out. With the introduction of high throughput bioreactor systems many mammalian development teams have made the move from stainless-steel to single-use technologies.

“Breaking down a dirty reactor, autoclaving, reassembly, cleaning in place (CIP), and steaming in place (SIP) are required [with stainless-steel bioreactors], which are time consuming and lead to downtime. Systems are often contaminated because a single step in the cleaning process was not done perfectly, leading to more downtime. Single use systems are typically provided in gamma-irradiated bags and arrive sterile. Single use systems greatly reduce the need for laborious cleaning and downtime. As more and larger single use microbial fermentation technologies are introduced onto the market, more microbial teams will follow the trend of their mammalian counterparts,” Kerrick states.

Meanwhile, Awang notes that single-use fermenters have many benefits, including the rapid changeovers between batches (which can occur within one day) as well as the previously mentioned decreased risk of contamination and the elimination of costly and time-consuming cleaning and sterilization between batches that is essential with stainless-steel equipment. “Single-use processes can also be large enough for a client that wants to do some fast clinical runs, since it will be much less expensive, and there are efficiencies with single-use up to 2000 L that aren’t available with stainless-steel systems,” Awang says. One caveat being, however, that for biologics produced in the range of tons per year, stainless steel remains the preferred option.

Graham points out that biopharmaceuticals made by single-use fermentation units require purpose-built fermenters with a bottom radial impeller for adequate mixing/power per unit volume input. These fermenters must also be capable of one to two vessel volumes per minute at commercial scale. “It is also advised that single-use fermenters have oxygen supplementation available for increased driving force in lieu of the lack of head pressure capability for single-use fermenters to optimize microbial growth and, ultimately, yield of drug substance,” he states.

Choosing the best equipment will depend on scale and the type of product being manufactured, Awang continues. “A good example is the autologous therapeutics used in personalized medicine. These require small-scale runs of 50 L or less with batch segregation. For these, single-use fermentation is great because one vessel is dedicated for each patient. There is no need to clean it, leading to faster turnarounds. This increases speed, reduces costs, and, most importantly, prevents cross-contamination,” empasizes Awang.

In addressing the current viability of microbial fermentation for the anticipated influx of new emerging therapies, Graham points to work BioVectra has been doing. The company has been testing a new 100-L single-use fermenter to verify their ability to deliver suitable power per volume and mixing. “In our experience, we can increase oxygen supplementation, but, without sufficient mixing to properly disperse the oxygen and achieve the desired transfer rate, oxygen supplementation can have limitations. Recently, we were excited to test a 400 mmol/L/hour process and completed the run while maintaining fermentation broth temperature within the expected specification. This is an important consideration for our clients in terms of the feasibility of single-use fermenters for use in high growth microbial processes,” Graham explains.

A final selling point for using single-use systems is that they also tend to have lower utility needs, and single-use has faster equipment qualification than stainless-steel bioreactors, Graham concludes.

While fermentation has roots in ancient history, it has a bright future in the world of emerging therapeutics. Depending on the product being considered, the scale required and the need to speed a process to market, fermentation-based manufacturing—when reconfigured for nuanced requirements—holds a valuable and flexible position within the manufacturers toolbox.


Vol. 35, No. 10
October 2022
Pages: 18–22

When referring to this article, please cite it as F. Mirasol, “Weighing the Benefits of Fermentation for New Biotherapies,” 

Blow-fill-seal (BFS) technology presents several advantages over other aseptic techniques, such as flexibility in packaging design, the ability to ensure a high level of sterility assurance, and maintaining low costs (1). In addition, the use of BFS technology limits human involvement, which further improves the level of sterility assurance by removing a significant contamination factor from the process entirely. The technology enhances the ability to form the container and closure during the packaging process, which allows for a more custom design of the container. BFS technology can thus be used to meet specific needs and improve container ease-of-use (1). In order to learn more on the logistics, benefits, and potential drawbacks of BFS technology, 

 spoke with Waiken Wong, PhD, manager of development engineering at Woodstock Sterile Solutions, an Illinois-based provider of sterile development and commercial solutions.

Can you please explain what BFS packaging technology is and how it applies to bio/pharmaceutical manufacturing?

 Blow-fill-seal packaging technology is a method where the container is formed, filled with product, and then sealed in a sterile environment. What comes out is a fully sterile finished product. It’s a good presentation for many drugs, including biopharmaceuticals. Sterility is critical for biologics and many other drugs because it prevents microbial contaminants in products.

 What benefits does BFS packaging technology offer, compared to traditional glass vial manufacturing?

There is far less human intervention when BFS packaging [is employed], and humans are the biggest cause of contamination. Contamination can have a negative impact on microbial sterility. Because the BFS process happens completely inside the cabinet of the machine, there is little chance for external contamination and problems with sterility. With BFS, the environment inside the cabinet of the machine is continually monitored for viable and non-viable particulate, and there is a constant, positive pressure shower of high-efficiency particulate air (HEPA)-filtered air that covers the filling section of the BFS machine. With those controls in place, along with the automation of the BFS machine, the operator doesn’t have to be in the room. It is designed to operate on its own, without any human intervention. An additional benefit is that there are fewer components compared to glass vials, so you don’t have to deal with stoppers, crimp tops, and other closures. There are no equivalent cleaning steps to the ones glass vials need to go through. There are also no equivalent treatment steps to the ones glass vials need to go through, such as depyrogenation. Raw resin is used; it goes directly into the BFS machine and is molded directly. So, there are fewer components, fewer steps in the actual manufacturing process, and there is far less human interaction.

Can you explain cold temperature BFS and its benefits compared to regular BFS?

 Cold temperature BFS requires implementing a combination of techniques all together in one manufacturing process to help control the amount of heat that is imparted onto a drug product. During the typical BFS process, there is naturally quite a bit of heat, because raw resin is being melted to make bottles. The bottles themselves also need to be warm throughout the process so that the containers can be sealed shut in the final step. There is latent heat, but Woodstock Sterile Solutions has found ways to control that heat so that biomolecules can survive with no impact through the manufacturing process. With a cold BFS process, there are additional drug products that you can package, since you do not have to worry about drugs that are thermally sensitive. Many biomolecules are heat sensitive, and there are many proteins that can denature or degrade with heat, so traditionally, the biopharma industry has stayed away from BFS and stuck with glass—a tried-and-true option. Having this collection of manufacturing steps expands what is possible for drug products in blow-fill-seal.

What are some key considerations when implementing BFS technology?

One important consideration is understanding the drug product’s compatibility/interactions with plastic. Before opting for BFS, there needs to be an understanding of how the product interacts with plastic—if there are concerns about adsorption or absorption, for example. Additionally, plastic containers are permeable in a way that glass is not, and it is critical to understand if that will have an impact on the product throughout its shelf life. That being said, there are ways to counter permeation, whether it is water vapor moving out or oxygen moving in, in order to maintain the quality of the product inside. Lastly, although BFS can be used to fill liquids that are highly viscous, if the product is more ointment-like, then it will be difficult to fill using BFS. That makes it harder to push through the piping and other parts of the system, but the technology can handle a wide range of viscosities.

What are the drawbacks of using BFS technology, if any?

The permeability mentioned earlier is one challenge, as are the material interactions I noted. Also, there are challenges with heat and thermally sensitive products, but those can be addressed using cold BFS.

What are the regulatory and compliance considerations when using BFS, if any?

 FDA considers BFS as an advanced aseptic manufacturing technique, recognizing its ability to produce sterile drug products reliably while also ensuring a high level of quality for patients. The industry is held to the same standards, as all drug packaging technologies are, to ensure product safety and quality.

Pharmaceutical Technology, Pharmaceutical Technology Europe


Vol. 35, No. 10
October 2022
Pages: 28-29

When referring to this article, please cite it as A. Leon, "Improving Sterility Using Blow-Fill-Seal Technology," 

Bioprocessing operations have been growing more complex in response to the emergence of increasingly complex biomolecules in development. The biopharma industry continues to strive in optimizing downstream purification processes. In talking with 

, Jungmin Oh, PhD, manager, new product development, Avantor, and Jonathan Hester, PhD, division scientist for 3M Separation and Purification Sciences Division discussed the industry’s efforts to simplify purification processes while keeping them just as effective. Their discussion further explored whether simplified downstream purification can be applied to newer complex biotherapeutics.

 With the emergence of newer, more complex biomolecules moving through the clinical development pipeline, what have been the most challenging aspects of developing a downstream purification workflow?

 Many downstream processing steps for complex biomolecules iterate on steps for more established therapeutic products, such as monoclonal antibodies (mAbs)—steps whose capacity hasn’t kept up with advances in upstream production. These leave room for improvement, especially in chromatographic steps.

There are, however, innovative processing steps with unique challenges. For example, viral vectors used in cell and gene therapies can be difficult to purify thanks to the presence of empty or partial capsids that must be separated from full capsids before final formulation. This separation can be achieved through anion exchange chromatography, although process optimization is still needed.

 Newer modalities are posing challenges in the downstream purification workflow compared to protein products, such as mAbs, that have been the ‘bread and butter’ of the biologics industry up until now. For example, some of the most exciting cell and gene therapy therapeutics are based on viral vectors. In using therapeutics based on viruses, we must now answer the question, ‘How do you conduct viral clearance—removing potential impurity viruses—from a virus product?’ Instead of separating a virus from a protein as the industry had previously been conducting, we are now separating viruses from other viruses. This is a difficult fundamental challenge, but one we and many others are already working on, and one I am confident we can solve through innovative materials science.

 What technologies have so far been key at enabling optimization of downstream processing?

 The replacement of conventional, multi-use unit processes with single-use devices has been a huge driver enabling recent optimization of downstream processing. One example is conventional packed bed chromatography columns. A single column has conventionally been used over many cycles, requiring careful cleaning and validation procedures. These procedures use [a significant amount of] fluids in the form of buffers and cleaning fluids, are expensive, and require highly skilled operators to perform. A number of available single-use devices now enable replacement of multi-use columns, [such as] anion exchange columns, with a single-use capsule containing anion exchange filtration media that is operated much like a simple filter and replaced after each use. This eliminates all the wasteful, expensive, and time-consuming activities involved with cleaning and validating a multi-use column.

Additionally, the search for anion exchange filtration media with sufficient capacity to economically replace multi-use columns has resulted in exciting chemical innovations in ligand design. For example, new guanidinium and primary amine anion exchange ligands in these single-use devices often enable more robust operation of anion exchange polishing processes at fluid conditions under which conventional Q-functional anion exchange column resins fail to perform well. This can reduce the need to perform buffer exchange steps before polishing chromatography, leading to overall process simplification.

 One of the major issues biopharmaceutical manufacturers are facing at the moment is demand for speed. Optimizing buffers and buffer management has been helpful in alleviating that, as the use of single-use technology or hybrid approaches of outsourcing and in-house preparation allow buffer preparation to take place across a variety of scales. At the same time, improving buffer formulation with additives that increase binding capacity, stability, and separation dramatically can [significantly] increase the efficacy of chromatographic purification steps.

Quality support systems are also important in buffer optimization. Traditional sampling methods are destructive, risk contamination of buffer components, and waste time. With side sampling and non-destructive identification technologies such as Raman ID compatible packaging, however, there is no need for physical sampling. This not only decreases risk but enables heightened operational efficiency.

 How would simplifying downstream purification steps offer a better solution than ramping up the complexity of the process?

 Downstream processing is already complex, and its optimization is more difficult than that of upstream processing. Downstream production involves several steps, including multiple chromatography steps. Each step demands a different set of specialized resins, buffers, fluid transfer systems, and other technologies and materials. On top of that, ensuring quality and finding efficiencies require complicated analysis and optimization activities.

Because of all these steps, downstream processing can account for well over half the cost of drug production. Plus, the need for a variety of materials increases the amount of storage space needed and the probability of supply chain issues. Simplifying downstream processing would reduce the cost and time burdens in all these areas. Ultimately, this would also reduce the cost per gram of drug products, making them more accessible to patients.