Biopharma Demands Better Analytical Assays

Improved analytic technology is recognized as supporting better biomanufacturing processes, improving product quality and reducing costs. The study shows that the industry is turning its focus on process improvement, and product quality. This is driving the demand for more and better analytical technologies and equipment at every stage in biopharmaceutical R&D and manufacturing. Survey results parallel and confirm a number of trends leading to increasing use of chemical analysis of biopharmaceuticals. These include advancing technologies, and expectations of regulatory agencies who, with more data available, will likely increase their expectations for more extensive and diverse analytical information. In addition, the global growth in biosimilars, whose approvals are largely dependent on analytical data, is facilitating the focus on improved analytics.  New Technologies Becoming AvailableAnalysis of bioprocess intermediates and end-products is becoming an integral part of biomanufacturing, from R&D through product manufacturing. Advancing technologies present opportunities for product improvement, cost-savings, and streamlined manufacturing. But technological improvements also pose a quandary: not only do analytical costs increase, but the possibility of finding problems not identified using prior technology also grows. Difficult decisions need to be made, including what technologies and equipment to use, when to adopt, how much testing should be done, and where should it be done—in-house, or with contract testing laboratories.Advancing technology is making an array of analytical testing more available, yet much of this is new and has yet to be considered by regulatory agencies. And while adopting new analytical technologies may provide some ultimate cost-savings, the acquisition of new expensive equipment and expertise may become a requirement, based on what regulatory agencies expect.  Regulatory uncertainties are bound to arise as agencies come to request more and more analytical data, which can either speed up or delay approvals. Industry Views of Analytical BottlenecksThis year’s survey shows that analytical equipment remains a major concern. In addition to finding that 31% of the industry is demanding improvements in analytical assays, 26.2% cited “Analytical testing and drug product release” as a major factor likely to constrain their organization’s production capacity over the next five years. We found industry concerns regarding production constraints, which were mirrored when we asked about factors creating improvements in production operations. Of the 15 areas we evaluated, the largest portion, 72.6%, cited “overall better control of the process.” We also found that 60.6% cited “better analytical testing and release services” as being responsible for improved performance (Figure 2).The study also compared European vs. U.S.-based manufacturers’ responses. We found Europeans reported greater performance improvements from “Better analytical testing services” (64% of European respondents, vs 57% of U.S.); in addition, we found that 83% of Europeans indicated “Better process control” was “improving” or “significantly improving” biomanufacturing performance, vs 66% of U.S. respondents.The Need for Improved Analytical MethodsImproved assays and analytical methods were cited by a majority of biomanufacturers as creating capacity constraints, and reducing productivity. We measured 26 assays and testing methods, and the top concern this year was for glycosylation assays (Figure 3). This is related to the ability to prove drug comparability between manufacturing batches/lots as well as biosimilarity between different products. For both these areas, nearly half, 44.8%, of industry respondents noted them as needing improved testing methods. This was followed by host cell protein assays (39.4%), biophysical characterizations during process development, and in-process testing methods.  Other key areas of interest for improved single use assays included dissolved oxygen, cell density and cell viability. When we compared responses from biomanufacturers and CMOs, we found that CMOs were more concerned with glycosylation, pre- calibrated disposable sensors, pH disposables, and qPCR. Biomanufacturers’ focus is on biotech drug comparability (in-house manufacturing changes and biosimilars), biophysical characterization during process development and better stability assays.  When comparing U.S. vs. Western Europe, the U.S. indicated that “biotech drug comparability (in-house manufacturing changes and biosimilars)” was their top concern (48% of U.S. vs. 37% of European manufacturers). Glycosylation ranked number one for Western Europe at 51% vs. the U.S. at 42%.The data show that bioprocessing professionals recognize the value and need for improved analytical capabilities; want more analytical probes, sensors and equipment, particularly single-use and for process control; and realize that this is a fast-moving area with advances and practical improvements readily observable in even just a year.Regulatory-Associated Quality InitiativesProcess Analytical Technology (PAT), Quality by Design (QbD) and other process analytical measurement-based quality programs are efforts to better quantify, model, and understand manufacturing processes and their effects on products. The presumption is that quality should be built into a product with a thorough understanding of the product and the processes by which it is developed and manufactured. This up-front planning, information-based approach is replacing the approaches to quality by QC testing or quality after design and manufacture. In many respects these new initiatives involve no specific additional requirements, but these programs puts analysis in a more rigorous framework. While adoption has been relatively slow, the industry can be expected to increase its use of PAT and improved analytics methods, including for existing bioprocesses, as these show improved productivity, increased yields, increased automation, and, particularly, avoidance of potentially costly quality-associated problems. And as bioprocessing becomes increasingly monitored by improved methods and assays, including more single-use sensors/probes, the resulting data will be used to support mathematical modeling and risk analysis, major goals of these quality initiatives. Biosimilars and Analytical EquipmentBiosimilars and the commercial opportunities they are providing are advancing the state-of-the-art and expanding the market for analytical equipment. With biosimilars likely to be marketed for most successful biopharmaceuticals, and with over 150 recombinant proteins currently marketed in the U.S. and Europe [2], the number of biopharmaceutical developers will increase.  Biosimilar development and approvals require good analytical data to prove similarities between the reference and biosimilar products. So we can expect an increase in the market for analytical equipment and services. New companies will be acquiring the latest technology and equipment, forcing all facilities to reexamine their current analytical methods to keep up with new industry entrants and regulatory agency expectations. Product quality-associated initiatives by FDA, including PAT and QbD, and other regulatory agencies are also increasing demand for biopharmaceutical analytical technologies.Many functional-, safety-, and efficacy-related characteristics of an active agent, beyond its primary structure (e.g., sequence), depend on its manufacturing process. These include three-dimensional structure(s), presentation of epitopes (immunogenicity), attachment of variable polysaccharide side chains (glycosylation); among others. Analytical testing is used to define these variables and identify variations. Biopharmaceutical active agents’ structure and activities are largely controlled and defined by their methods of manufacture. This classic “process = product” paradigm was originally used by established product companies as a defense against implementation of biosimilar approval mechanisms. Because manufacturing processes are complex, biopharmaceuticals are considered very difficult to exactly replicate. Biosimilars, in this model, are considered very challenging.  However, the availability of advanced analytical methods and equipment has enabled the approval of biosimilars, increasingly enabling the proving of sufficient inherent structural-based (bio)similarities between products such that regulators and the marketplace have confidence that biosimilars can be manufactured, approved based on comparison testing, and used with safety and efficacy. Comparative analytical data can be used to show biosimilars are sufficiently similar to already-approved products such that approvals can be largely based on this, combined with clinical confirmation of sufficiently similar safety and efficacy. The primary goal for biosimilar manufacturers is for their product to emulate and be as identical as possible to its reference/comparator product, based primarily on comparative analytical testing. Developers of biosimilars with strong analytical capabilities will get their products to market more rapidly and less expensively than companies that rely more heavily on clinical comparative testing. Product Failures Pushing the State-of-the-ArtIn our study, we found that improved analytical assays and methods were demanded for agent discovery, screening, characterization and optimization. Improved assays can help spot undesirable agents, and avoid wasting R&D money and time. Spotting problems with active agents, such as undesirable folding, glycosylation, oxidation, etc., through improved analysis during R&D and at each step in bioprocessing enables more rapid identification and resolution of structural, composition and other variations that can lead to problems in purity, potency, safety and efficacy.  An example of a product failure related to analytical testing and biosimilarity/comparability issues is the experience of Genzyme in seeking FDA approval for manufacture of recombinant glucosidase alpha (now Lumizyme) at a new facility using a 2,000 L bioreactor(s) while the original product (Myozyme) was approved and long-marketed as manufactured in 160 L bioreactors. Despite Genzyme (now merged into Sanofi) filing a for supplemental approval with analytical data that it believed showed comparability between the enzymes manufactured at different facilities and scales, FDA perceived significant differences and required the scaled-up product to be approved through a full BLA application, with the scaled-up product simply considered to be a different product. This caused considerable delays and problems for the company.Analytical Methods are AdvancingMethods and equipment for chemical and physical analysis of biopharmaceuticals continue to advance. New technologies are being developed, existing technologies are being improved, and new applications are being found. For example, Raman, mid-infrared, and mass spectrometers are being directly interfaced with process streams, and various analytical probes, such as for pH, dissolved O2 and CO2 levels, are coming out in single-use/disposable versions. These advances are providing increased options for improved process control, enabling steady-state control of bioprocesses, including better real-time monitoring and control of glycosylation and other structure-related parameters.With advancing technology, regulatory agencies demand more clearly defined methods for characterizing active agents and products to ensure safety and efficacy. Structural aspects and charge heterogeneity are among the most crucial attributes to monitor throughout the product development process. The sheer numbers of samples that need to be processed as a result of increased testing requirements in a short period of time is forcing industry to invest and innovate in its analytical support infrastructure, including seeking higher sample throughput and automation.Advances in methods and equipment provide opportunities for cost-saving, driving industry adoption of more and new analytical methods. For example, with equipment capabilities rapidly increasing and prices going down with advancing technology and larger markets, analytical testing that formerly was sent out to contract testing labs can now be cost-effectively done in-house and many more analyses can be performed. But increased adoption of analytical technology also poses many potential problems. Besides the cost of equipment and dedicated staff, new and improved technology may spot problems with bioprocessing and products that were not known before. Also, the proliferation of advanced methods and equipment makes it increasingly difficult to figure out which ones need to be used, which ones are expected by regulatory agencies, and which are most cost-effective and relevant to improved bioprocessing monitoring, control and product testing. With biosimilars entering the market, new assays being developed, a growing approvals pipeline, and increased regulatory scrutiny, industry awareness and adoption of new analytical technologies will surely accelerate.  Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a Rockville, Maryland-based biotechnology and life sciences marketing research and publishing firm established in 1989. He can be reached at [email protected].

References
1.    Langer, E., 8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production:  BioPlan Associates, April 2011, 490 pages, www.bioplanassociates.com
2.    Rader, R.A., BIOPHARMA: Biopharmaceutical Products in the U.S. and European Markets, online database, www.bioplanassociates.com/biopharma