Technologies, such as high-throughput screening and single-use systems, are facilitating the development and manufacture of large-molecule drugs. Representatives of contract service organizations that develop biologic-based drugs discussed technology trends with the editors of Pharmaceutical Technology.
PharmTech: What scientific or technical advances have positively or negatively impacted drug-development processes in this market segment?
Sandles (Fujifilm Diosynth Biotechnologies): The introduction of high-throughput screening technologies across R&D means that it is much easier to demonstrate rapid and scalable process development. For instance, our recently purchased ambr250 (TAP Biosystems) aids in rapid selection of upstream fermentation conditions. This initial screening timeframe reduction takes process development further off the critical path to in human trials and consequently means the drug development process is reduced with an increased data set to justify forward-working decisions and satisfy regulation.
Pearson (Dr. Reddy’s CPS): Alternative technologies to extend the half-life of biologic drugs are being developed. This has positively impacted the drug-development process by giving more choice. However, the new technologies have yet to be approved by the FDA for use in commercial drugs. A sponsor would have to license a new technology. PEGs are already approved and easy to use. A lot of the emerging technologies would require specialist expertise and be more complex to set up.
Ruff (Catalent Pharma Solutions): The wider use of antibody drug conjugates (ADCs) and the introduction of improved, potentially safer ADCs in particular, will undoubtedly have a positive impact on this market. There are currently only two with FDA approval: Brentuximab vedotin for the treatment of Hodgkin’s and anaplastic large cell lymphoma, and trastuzumab emtansine … for the treatment of HER2+ breast cancer. The current ADC pipeline is large, with more than 100 ADCs currently in clinical trials; this effort underscores the industry’s belief that ADCs will help create safer, effective biotherapeutics.
Single-use technologies, PEGs, and ADCs
PharmTech: What emerging technologies or practices do drug sponsors expect your organization to provide?
Sandles (Fujifilm Diosynth Biotechnologies): For mammalian cell culture there is an increasing demand for single-use technologies and is expected as the norm in this sector. The environmental and financial outcomes are favorable over stainless steel at smaller scales of production; however, at larger scale stainless steel is still a very prominent option. Using single-use means up to 90% less water is needed for cleaning purposes per batch, meaning a reduced contamination risk and cost is incurred against stainless steel.
Pearson (Dr. Reddy’s CPS): Drug sponsors have come to expect CMOs to offer the GMP manufacture of larger volumes of product at competitive prices. CPS has invested in a facility for the manufacture of mPEG alcohols in Mexico and a site at Mirfield, UK that can provide large-scale, multi-metric tonne GMP manufacture of activated mPEGs for biologic drugs. Increasingly, drugs being PEGylated are higher dose, which in turn requires larger-scale production of PEGs for half-life extension.
Strong (Kalon Biotherapeutics): Industry expectations of CMOs for technologies include disposable technologies and single-use systems. A broad, in-house analytical capability is also an expectation. In all cases, however, the bioprocessing technology needs to be scalable to commercial scale.
Ruff (Catalent Pharma Solutions): We have seen increasing demand for biologics and biosimilars development, where we have proven cell line technology and have recently launched new manufacturing facilities in Madison, Wisconsin. ADCs are also attracting much interest. Catalent is developing the oral delivery of vaccines to treat the flu, pneumonia and HPV through our Zydis Bio technology platform. Further innovations for oral macromolecule delivery include our OptiGel Bio technology that may overcome the traditional hurdles by enhancing permeability combined with targeted delivery.
Large and small challenges ahead
PharmTech: What pressing technical challenges have you seen in this market segment? What actions has your company taken to resolve the challenge?
Sandles (Fujifilm Diosynth Biotechnologies): We are finding that customers are expecting material that represents scalability to be produced at much faster rates. Fujifilm has the technology to meet these demands with both microbial and mammalian cell culture expression systems. We have added extra HTS [high throughput screening] capability for upstream and downstream process development to further reduce time to clinic for our customers.
Pearson (Dr. Reddy’s CPS): One challenge is the perception that PEGs can be expensive, potentially immunogenic and may accumulate in the body. Producing PEGs in larger volumes brings costs down and there has been no evidence of adverse events in patients. Other technologies used for increasing half-life have not yet been FDA-approved. Therefore, PEGs remain the preferred half-life extension technology.
Strong (Kalon Biotherapeutics): The most pressing technical challenges are mostly on a case-by-case basis, and more often than not, related to the specific biological product in question. Having technologies that allow for solutions that will scale with the process to commercial scale, as part of the CMO toolbox, remains an important capability. Analytical resources and reliable analytical methods are key to any challenge and its solution.
Ruff (Catalent Pharma Solutions): Technical challenges include ‘big picture’ ones, such as finding more efficient ways to purify protein and better ways to grow cells to obtain higher titers, cleaner starting material, etc., but also smaller, less exciting ones, such as standardization of single-use connectors and films that will also fundamentally effect the industry.
Specialized manufacturing advances expected
PharmTech: What advances do you see in science or technology in this market segment in the next five years?
Sandles (Fujifilm Diosynth Biotechnologies): We expect to see more and wider deployment of single-use technology as the benefits become widely recognized.
Pearson (Dr. Reddy’s CPS): There will be an increase in technologies able to prolong the half-life of biologic molecules. Companies who are looking for an appropriate half-life extension technology will screen several technologies to determine which is best. PEGs is likely to remain a significant technology but probably not the only one in regular use. There will be increasing development and use of mono-disperse PEGs and use of PEGs in new areas such as nanoparticles and niche formulations.
Strong (Kalon Biotherapeutics): Bioprocessing is becoming less of a unit operation and more continuous. Technologies that provide for continuous processing upstream and downstream are at the forefront for the next five years. Being able to process highly concentrated proteins without having to go through a lot of buffer exchange unit operations will impact time on plant, buffer-prep, and QC resources and ultimately affect [cost of goods sold] COGS.
Ruff (Catalent Pharma Solutions): Look for breakthroughs in efficiency in manufacturing and for new technologies, such as ADCs with advanced linker technologies, to drive safer, better treatments. Many of these products will be more complex than current biologics, leading to more extensive characterization and testing. We also expect to see more countries looking within their own borders for biologics manufacturing as they want to control manufacturing of these products due to concerns about supply chain of these products.