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Resolving operational bottlenecks makes mAb manufacturing more efficient.
Traditional biologics, which are predominantly monoclonal antibodies (mAbs), are continuing to see strong market demand, and the pipeline for mAb development is also robust. While the biopharmaceutical industry has had time to work out much of the kinks in mAb manufacturing, there remain some areas in the process that persistently pose a challenge.
Fundamentally, know-how surrounding the production and purification of mAbs throughout manufacturing process flows has been well established in the industry, but bottlenecks still exist in bioprocess optimization, capacity constraints, cost of goods, footprint, dealing with batch failures, and lack of modular systems with plug-and-play interfaces, says Ganesh Kumar, Integrated Solutions manager, Sartorius.
In upstream processing, such restrictions are mostly related to the long-time/high number of intermediate steps required during seeding as well as the productivity, stability, titers, media consumption, impurities and cell densities in the production bioreactor. In downstream processing, the bottlenecks are centered around dealing with intermediate to high cell densities at the harvest in an efficient (high yield) and closed manner; productivity, yield, impurities removal and cost of goods at the chromatography steps; time, footprint and waste management at buffer prep/hold areas; achieving desegregation of manufacturing suites through process closure, Kumar outlines.
“Although many advancements have been made in mAbs manufacturing, they are still difficult to manufacture at scale due to their poor expression, solubility, aggregation, and poor pharmacokinetic profiles. Thus, it is critical to address these challenges to make the mAb manufacturing process efficient, less problematic, and cost-effective,” adds Gaurav Kaushik, Market Entry Strategy manager CCT, Sartorius.
Upstream. One of the challenges in making mAb manufacturing efficient is optimizing recombinant cell lines in the production bioreactor, Kaushik says. He explains that the selection of a robust cell line influences the success and efficiency of the manufacturing process. “This step requires careful consideration in developing different recombinant cell line clones (mainly Chinese hamster ovary [CHO] cell lines) by transfecting them with engineered mammalian expression vectors and then screening them to identify the most robust, productive clone. This is the most time-consuming step in mAb manufacturing,” Kaushik states.
Kaushik also points out another major bottleneck in mAb manufacturing: optimization of culture media conditions, which can influence cell growth and antibody titer and quality. “Process developers screen different media formulations, growth factors, nutrients—including glucose and amino acids concentrations—and optimize critical process parameters (CPPs) and critical quality attributes (CQAs) for mAb production. The crucial part to addressing this challenge is to develop a two-media strategy, where one medium is initially required to support cell expansion and growth and then switched to another medium to support protein (antibody) production. This is the most complex and cost-intensive part in mAb manufacturing,” he explains.
Over the past two decades, mAb productivity has increased by an order of magnitude. Productivity increase has been achieved both in cell amplification and product expression, as well as in the part of the process responsible for the product purification, points out Jean-Pascal Bilgischer, head of Bio Center of Expertise at UCB Switzerland, a biopharmaceutical company focusing on neurology and immunology. “While we still expect some improvements in the coming decade, as the industry seeks to achieve double digits productivities (grams of drug substance per liter of bioreactor), recent plants such as UCB’s have been modified to handle these high intensity processes,” Bilgischer says.
Bilgischer emphasizes that the efficiency of a plant now resides in its capacity to achieve a high level of availability, with fast rotation between batches and fast changeovers between products. Timing is an important aspect of biological manufacturing, specifically the ability to control the timing of operations; once started the processing of a batch cannot be paused, Bilgischer says. “For UCB, an adequate planning of activities is of utmost importance. This is achieved through a dynamic scheduling of operations that is capable to handle any time lost by rescheduling all downstream operations within a production, but also for the batches to follow,” he states.
Jeetendra Vaghjiani, executive director, Clinical Development and Strategic Marketing, Lonza adds that bottlenecks can occur when balancing commitment of capacity for the next phase of development versus waiting for clinical readout. “If the decision is taken prior to the readout, and there is a negative readout, then capacity may be secured that is no longer needed; there may be fees or penalties associated with that. If capacity is secured too late, there may be a delay in the overall timelines as the available capacity may be later than desired,” Vaghjiani says.
Downstream. While biopharma manufacturers have largely overcome blockages in upstream processing through significant investments in technologies and processes that improve yields, improvements in downstream processing have not kept a similar pace, says Ger Brophy, executive vice-president, Biopharma Production, Avantor. Bottlenecks still occur in downstream processing, which takes place over a period of a few weeks and involves many unit operations. Downstream processing moves from cell harvesting, to centrifugation and polishing, to multiple chromatography and filtration steps, before reaching final fill and finish. Over a dozen buffers and cleaning solutions are used as part of the process, Brophy explains.
“Finding ways to remove those bottlenecks and improve yields continues to be a key focus area for biopharma manufacturers, and different strategies can be applied to the process. For instance, manufacturers can improve productivity of the capture step through the selection of high-performance protein A resins, explore ways to make chromatographic buffers more effective by using new kinds of additives, and utilize prepackaged single-use buffer materials to streamline buffer exchange steps or work with buffer concentrates in conjunction with inline dilution,” Brophy states.
Downstream processing is commonly the stage where bottlenecks generally occur in traditional mAb manufacturing, says Seokjin Chang, director of Market Intelligence at Samsung Biologics. “This is because adding a downstream process line requires a relatively large capital expenditure (CapEx) investment. However, because contract development and manufacturing organizations (CDMOs) are increasingly making these large-scale CapEx investments themselves, biopharma and biotech companies are able to outsource these capital-intensive processes and avoid this entire bottleneck scenario altogether,” Chang states.
Adventitious agent testing is another systemic bottleneck that is typically encountered during mAb manufacturing, including aseptic filling, says Lindsay Fraser, head of Technical Services at Symbiosis, a UK-based contract manufacturing organization. For instance, for products to enter Symbiosis’ facility, the products must be minimally tested and shown to be free from microbial contamination. Current compendial tests for sterility and mycoplasma, however, are largely still growth-based and can therefore take several weeks to return results, Fraser explains.
“To a certain extent, this testing can be scheduled to coincide with other activities; however, product batches are still often waiting for adventitious test results before they can proceed to the next step in manufacturing,” Fraser says.
Aseptic mAb manufacturing consists of multiple operations, ranging typically from thawing and pooling drug substances, to compounding, microbial pre-filtration/sterile filtration, filling into clean, sterile, and depyrogenated containers (e.g., vials, syringes), possibly lyophilization (freeze-drying), and then closure and capping, says Susanne Jörg, chief customer delivery officer, ten23 health, a Switzerland-based CDMO for development and manufacturing of sterile products.
Jörg emphasizes that product stability and quality must be ensured throughout the entire drug product manufacturing setup, as biologics can easily deteriorate due to inadequate processing during, for example, freeze-thaw or filling. “By implication, due to the rising number of launched antibody products during the past decades, a vast knowledge on manufacturing processes for biologics has been gained, including understanding typical challenges and how to address these,” she states.
Nowadays, however, platform-based aseptic drug product manufacturing processes for mAbs are established by many biopharmaceutical and biotech companies, Jörg adds. “These platform processes allow fast timelines in early clinical development stages and facilitate moving molecules quickly into Tox [toxicity], Phase I, and PoC [proof of concept] studies, with a lean usage of development resources based on prior knowledge,” Jörg says. Nevertheless, mAbs are still far away from being a commodity, and holistic expertise is required to de-risk accelerated development timelines.
Time to market is a crucial factor in any drug development project. If a product is delayed in early development, this can lead to a number of non-systemic project timeline impacts, notes Fraser. Though not seen as a bottleneck point from the manufacturing side, delays in early development can be unanticipated from a developer perspective. “We have found that the time required for formulation and manufacturing process development is often underappreciated,” Fraser says. “For example, a lyophilization process may take several months to develop, and will be impacted if formulation components are changed at a later date. Developers must consider the manufacturing process holistically to avoid delay,” Fraser states.
Moreover, high levels of stabilizing additives, such as dimethyl sulfoxide or alcohols, may make sense for bulk manufacturing, but these additives can cause significant issue in aseptic filling when interacting with plastic components and filters, Fraser adds.
Fortunately, many of the bottlenecks for traditional mAb manufacturing have been resolved, notes Sigma Mostafa, senior vice-president, site head, RTP, N.C., KBI Biopharma. For instance, stable mAb structure, high productivity, stable cell lines, minimization on non-human glycosylation, elimination of mAb reduction in harvest, and removal of hitchhiker host cell proteins have all been achieved. “The current bottlenecks are mostly operational challenges rather than fundamental technology limitations—although we occasionally still see mAb sequences that are hard to express and secrete,” says Mostafa.
Selexis, a sister company to KBI Biopharma, has developed engineered host cell lines with chaperones and has demonstrated significant productivity improvement for hard-to-express proteins, Mostafa adds. In terms of operational challenges, intensified cell culture processes can have up to 10X the cell density of standard processes and usually requires customization of media/feed and a robust harvest solution. “As cell culture titers continue to increase across the industry, the ability of the downstream process to handle the quantity of product continues to pose challenges. Resins with higher binding capacities, adoption of continuous capture and volume control strategies (i.e., SPTFF [single-pass tangential flow filtration]) have helped curtail some of these challenges, but, as titers continue to increase, new solutions may need to be employed,” Mostafa states.
Chang, meanwhile, comments that, since the COVID-19 pandemic, the challenges associated with sourcing raw materials have led to bottlenecks with greater impact than those related to downstream processes. Lockdowns at the beginning of the pandemic prevented manufacturing personnel from going to work, which resulted in supply chain disruptions. “As the pandemic continued, so did the tension on US–China trade relations, putting pressure on each country to reorganize and reprioritize supply chains. Disruptions to the supply chain were further exacerbated during that period because raw materials were dedicated to the production of COVID-19 treatments with vaccines as a priority over production of other products,” Chang explains. Raw material and other shortages across the biopharmaceutical supply chain have yet to be completely resolved, he adds.
Overall, mAbs will likely remain the most stable and effective biotherapeutic treatments available for the foreseeable future, evident in the fact that the global mAbs market is anticipated to grow from $168.70 billion in 2021 to $188.18 billion in 2022 and later increasing to $292.22 in 2026 (1), Chang states.
1. The Business Research Company, Monoclonal Antibodies (MAbS) Global Market Report 2022, marketresearch.com, March 2022.
Feliza Mirasol is the science editor for Pharmaceutical Technology and Pharmaceutical Technology Europe.
Vol. 46, No. 5
When referring to this article, please cite it as F. Mirasol, “Speeding Up Development for Traditional Biologics,” Pharmaceutical Technology 46 (5) 16–19 (2022).