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Angie Drakulich was editorial director of BioPharm International.
Representatives from leading CROs weigh in on key challenges tied to the biopharmaceutical R&D, including issues regarding bioequivalence, platform technologies, process analytics, and more.
Representatives from leading contract research organizations (CROs) weigh in on key challenges tied to the biopharmaceutical R&D, including issues regarding bioequivalence, platform technologies, process analytics, and more. Particpating in the BioPharm International roundtable are: Nancy Gillett, PhD, corporate executive vice-president and president of Global Preclinical Services at Charles River Laboratories; Jon S. Kauffman, PhD, director of Biopharmaceutical Services and Analytical Method Development/Validation at Lancaster Laboratories; Alan Breau, PhD, vice-president of Scientific Affairs–Analytical Sciences at MPI Research; Fiona Greer, Global Director of BioPharm Services Development, SGS M-Scan; and Andrew J. Reason, Group Manager, SGS M-Scan Europe.
Andrew J. Reason, SGS M-Scan Europe
BioPharm: Biologics are clearly more complex to develop and characterize than small-molecule drug products. What would you say are the key unique challenges associated with biopharmaceutical development and testing?
Gillett (Charles River): Choice of models is key. Products need to be screened for the intended human activity against targets from one to several models. In addition, they need to be tested for a loss of potency. This testing requires varied technologies for binding and activity assessment–early staging of these tests is important for reducing costs and avoiding unnecessary studies.
Nancy Gillett, Charles River Laboratories
Immune reactions on the part of the model to human protein, cell, or gene-based treatments can be complex and are required not only to detect antibodies to drug, but also to interpret toxicology results. Occasionally, this comparison of kinetic, biomarker, and immune-reaction assessments reveal that a drug's toxicity is due to immune reactions. In such a case, the drug can be freed from an "alert" and continued through development without interruption. Without the bioanalytical assays and careful scientific review of assay results, however, a drug program might be terminated for the wrong reasons.
Kauffman (Lancaster Labs): One unique challenge is the vast array of testing required to fully characterize a biologic. Assays can range from simple pH measurements to peptide mapping to cell-based potency assays. In some instances, orthogonal techniques are also required. Therefore, the contract laboratory needs to have state-of-the-art equipment and staff with specific skill sets and expertise. Further, the laboratory needs to have redundancy of high-end equipment and specialized capabilities to be able to support multiple projects on short timelines.
Jon S. Kauffman, Lancaster Laboratories
Another challenge is that the process, not just product, must be characterized and understood. Potential contaminants are not just synthetic chemicals like those found in small-molecule manufacturing. Testing for more complex organisms, such as adventitious viruses, bacteria, yeast, fungi and mycoplasma, along with a wide array of antibiotics, and other additives, may need to be performed.
Breau (MPI): I see three key challenges: handling, analysis, and disposition. Unlike small molecules, biological drug candidates require ordered secondary and tertiary structures to exert their desired activity, making their storage and handling much more complicated. For example, vigorous mixing of a small-molecule solution usually is not a problem; yet a similar procedure would likely denature a biologic drug, which could compromise its potency.
Alan Breau, MPI Research
Assay development for small molecules usually consists of test article analysis using components and instruments that are generally available, such as extraction cartridges, high-performance liquid chromatography (HPLC) columns, and liquid chromatography/mass spectrometry (LC/MS) systems. Because most biologics are analyzed by immunoassay methods, specific reagents must be developed for a particular biologic. This requires time to produce novel, well-characterized reagents, as well as assay development time, which can lengthen the time needed to complete the full analysis of the studies required to file for product registration. However, in preclinical species, it may be possible to use readily-available antibodies that bind to the constant region (Fc) on a humanized monoclonal antibody (mAb) candidate for immunoassay detection, thus eliminating the need for reagent development.
Ultimately, the sponsor and CRO must work together to define and fulfill the reagent requirements at the onset of a project to mutually understand the sequence of developmental activities required to meet project timeline expectations.
Finally, with rare exceptions, small molecules undergo absorption, metabolism, and excretion after administration, using well-defined enzymatic and physiological pathways. The development and regulatory paradigm to evaluate small molecule disposition has been well studied and characterized. The disposition of biologics, on the other hand, is typically not well characterized during development.
Biologics must be assessed for the potential to develop neutralizing antibodies. There is no appropriate surrogate to assess the clinical development of neutralizing antibodies, which can be critical for endogenous biologic replacement therapy. The development of neutralizing antibodies to an endogenous protein can produce auto-immunity against a key physiological process. The sponsor and CRO therefore must develop a well-designed plan to assess neutralizing antibodies in nonhuman primates and in the clinic, as this is an important component of biologics development, especially when the biologic is meant to serve as a replacement therapy for an endogenous compound.
Greer (SGS): Undoubtedly, the main issues associated with biopharmaceutical products have to do with the fact that these products are 'manufactured' in living systems. In addition to being larger and more complex, biologic products are invariably a mixture of closely related proteins with the potential for a large variety of post-translational modifications which are not predictable from the gene sequence. Thus, key challenges include: how to develop a process that will consistently yield a product of defined quality; how to develop sensitive and robust analytical tests to characterize primary and higher order structure of the molecule, including degradents and impurities; and how to predict or detect highly undesirable immunogenicity. These analytical studies are crucial to better predict how the compound will work and enable support of clinical-trial design.
Fiona Greer, SGS M-Scan
Another challenge tied to biologics analytical testing is the development and validation of robust and reliable potency assays. Among potency assays, cell-based assays are probably the most adequate predictive as they allow the measurement of the drug's efficacy in an in-vitro model. However, due to the intrinsic biological variability of cell and the complexity of cellular signaling pathways, it can be difficult to define the correct read-out for an assay. The choice of the right cellular model, biomarker, or physiological activity are important parameters that require expertise and specific technologies, such as flow-cytometry or multiplexing capabilities.
BioPharm: In your company's experience, how can a CRO best plan to meet regulatory and sponsor expectations for biologics development and testing?
Gillett (Charles River): The important message for all biologics developers is that there isn't one plan that all biological products can follow. Some programs, such as those involving embryonic stem cells, are extensive and require tumorigenicity testing, while other programs can be based on purely in-vitro data. Each program needs to verify that the drug can produce and retain exposure and effects, and that studies gauge the doses where effects turn harmful.
Kauffman (Lancaster Labs): Based on the analytical challenges noted above, a contract testing laboratory must have experience developing and qualifying extremely sensitive assays for a broad set of contaminants in complex bioprocess matrices. Further, because there has been increasing scrutiny of these contaminants from regulators, the laboratory must have a broad familiarity of international regulatory guidelines.
Greer (SGS): To assist clients in meeting analytical challenges, a CRO should be fully aware of the complexity of task. It should be sensitive to expectations of regulatory authorities and have an arsenal of appropriate analytical methods, assays, and clinical-trial techniques that are capable of providing reliable scientific data so that informed decisions can be made regarding product safety and quality.
BioPharm: How have sponsor companies' expectations for biopharmaceutical contract R&D and testing changed over the past few years? What do you think has led to these changes?
Gillett (Charles River): In the past, biologics were developed by mid-sized pharmaceutical firms. Increasingly, we're seeing small virtual firms, or nascent biotech companies, assuming sponsorship and taking compounds from early stages into Phase I and II clinical trials. Additionally, more sponsors are risk-sharing by partnering early in development. In these cases, collaborations can involve multiple consultants, teleconferences, and web meetings. It's especially important to establish communication and primary contacts to ensure a solid and confidential connection. At Charles River, we have increased our support for these companies and find the experience is rewarding on both sides because we learn from each other and bridge gaps that start closer to compound discovery. For example, we often suggest the experiments that sponsors start in university labs, and then transfer the technology to good laboratory practice (GLP) settings when product quality and biomarkers are established.
The models of development need to shift as well to accommodate changes in public policy, regulatory law, international outsourcing of chemical manufacturing—all of which impact costs. Biopharmaceutics are combining genetic, cellular, device, and nanotechnology. These new approaches require access to specialized facilities and expertise. Although traditional models are in place for Big Pharma, they are shifting to more open collaborations as well.
Kauffman (Lancaster Labs): Sponsors are looking for partners to help get their products to the market faster in an environment where regulations are becoming more stringent. At Lancaster Laboratories, many clients are looking to compress timelines and accelerate speed to market. Development of biologics is extremely expensive, so sponsor companies are also looking to consolidate vendors and reduce costs.
Breau (MPI): In the past, most pharmaceutical companies kept preclinical functions, such as assay development, initial GLP studies, and first-in-man human pharmacokinetic analyses in-house, to control these critical components of the development process. Today, many companies have downsized their preclinical departments and rely more on CROs for an ever-increasing array of services.
In addition, there is increased emphasis on in-licensing from biotechnology companies. Rather than rely on in-house discovery, large pharmaceutical companies have increased the proportion of sponsors in early development that are small biotech or virtual start-up companies. The biotech companies rely on quality CROs to provide input into their study designs and development plans. This shift has led CROs to provide more service offerings, including an expansion of program-management services.
Greer (SGS): Our experience at SGS Life Science Services is that sponsors are not just looking for tests to be performed and data returned. They are actively searching for companies with appropriate experience who can guide and advise them during the analytical program. This consultancy might take the form of recommending and providing certain analytical packages or groups of tests for particular types of products.
Although sponsors are now used to the 'one-stop-shop' concept, their expectations have grown. Sponsors want to establish that the CRO has in-depth expertise and crucial techniques. New emphasis from regulatory agencies to obtain data using orthogonal techniques and to mitigate potential biases from particular methods are also changing the way sponsor companies use CROs.
Process analytical technologies
BioPharm: Along these lines, have you witnessed more interest in process analytical technologies (PAT) from sponsor companies? Has your company applied PAT to date or does it plan to?
Kauffman (Lancaster Labs): Lancaster Laboratories has witnessed interest from sponsors and contract manufacturing organizations (CMOs) in using PAT for biopharmaceutical production. Quality-by-design (QbD) processes are used in bioreactors, for example. Although rapid sterility and mycoplasma testing approaches are coming to fruition, the technology is not here at this time to measure other important parameters such as post-translational modifications or adventitious viral agents in real time.
Breau (MPI): Not yet. The presumed future increase in the need for PAT services will be driven as FDA's QbD initiative evolves. We have not seen a dramatic increase in the request to characterize raw materials or other process components.
BioPharm: What is your take on platform technologies to develop and test biopharmaceutical products? Can you offer a CRO's perspective on the pros and cons of such an approach?
Gillett (Charles River): In many ways, platform technologies are both beneficial and essential in the CRO setting to enhance productivity. Processes ranging from immunoassay development to telemetered data collection are constantly improved to increase efficiency. These efficiencies evolve into beta testing and standard operating procedures (SOPs). For example, Charles River recently pushed its reporting timelines to a new standard through platform technologies.
Sponsors could save cost and gain efficiency if one set of 'platform; toxicology data could support multiple products (e.g., a number of agents based on similar chemistry). But implementing this concept is more difficult than it sounds because small chemistry changes can make profound changes in drug distribution and drug effects. Consequently, regulators have been cautious about accepting platform data and generally require individual toxicology programs for each drug substance. We may see a shift in regulatory approach as FDA's modernization program gains momentum and as more data accrues on novel agents, such as gene therapy vectors, or on classes such as biosimilar monoclonals.
Kauffman (Lancaster Labs): There are definitely benefits in the platform technology approach. If a process is well understood and can be applied to produce an array of biopharmaceutical products, then it may, for example, be possible for the sponsor to reduce the amount of viral clearance testing performed on all products manufactured using the same processing platform. Transfer and validation of methods also can be expedited and streamlined. However, one size does not fit all, and it is not always easy to predict when a platform technology will apply. A small change in a process or product may go undetected in a platform method, and this could end up taking more time on the back end to redevelop and validate methods.
Breau (MPI): Novel platform technologies are developed because, presumably, they confer some advantage in certain applications over the alternative competing platforms. MPI conducts a return-on-investment (ROI) analysis to assess whether we should invest in the platform. We are careful in assuring that a thorough assessment is completed before an investment is made.
Sponsors must be aware that moving forward with a cutting-edge platform that could fail or be removed from the marketplace may cause significant rework and delays in development plans. The sustainability of a new platform must be taken into account, as well as the novel advantages that it may confer.
Reason (SGS): Platform analytical technologies, at certain levels are appropriate and can be applied to a wide range of products. However, the more advanced methodologies have to be tailored to suit specific circumstances, particularly with wide variations in formulations, and so forth.
For example, platform technologies can be applied to all IgG1 mAb products, which are similar structurally, but the methods used to purify these products prior to analysis will vary depending on the product formulation. Other glycoprotein products, such as Erythropoietin and FSH, require more in-depth analysis particularly of their glycosylation. This analysis may require further development of methods to be able to characterize the glycans at each of the glycosylation sites within these products.
Bioequivalence and biocomparability testing
BioPharm: Have you seen a rise in projects for bioequivalence or biosimilar comparability testing? If so, what unique challenges does that process present?
Gillett (Charles River): Changes in biologics manufacturing or the development of biosimilars can trigger a regulatory focus on bioequivalence. We support comparability assessment of many types starting in early in discovery, which can include comparison of drug biochemistry, binding and potency curves, and toxicology assessments. These are all used along with clinical data to support a sponsor's claim to comparability and to support international approvals. We expect a rise in these projects as the biosimilars market expands.
Kauffman (Lancaster Labs): Lancaster Laboratories has seen a rise in requests for bioequivalence or biosimilar studies from sponsors in Asia and the US. A key objective is to identify a few crucial tests that can be applied early in product development and performed to demonstrate comparability with the innovator product. At later stages of clinical development, full characterization is performed in accordance with GMPs.
Breau (MPI): Biosimilars are becoming attractive because, with many key biological drugs set to come off patent protection within the next three years, they provide an entry to a lucrative market with minimal risk. Similarly, biosimilars are attractive to consumers and insurance providers because of the potential cost reduction without sacrificing efficacy. However, biologics are, by their nature, more complex than small molecules as noted above, and current technology does not permit complete analysis of biologics to prove identity of the biosimilar, as is the case for small molecules.
Thus, the development of biosimilars may require the successful execution of bioequivalence studies that assess pharmacokinetics parameters, as well as clinical endpoints, and not just plasma pharmacokinetics parameters.
In addition, bioequivalence studies for biologics are executed as parallel studies, rather than crossover studies, due to their long pharmacokinetics half-lives and washout periods. This requires that the clinical studies be sufficiently powered to ensure that bioequivalence is achieved; inter–individual variation is more crucial than in a classic crossover design.
The development of biosimilars is further complicated by the selection of the bioanalytical method used to assess bioequivalence. Antibodies are the major reagents used to develop immunoassays to quantitate biologics. Because the biosimilar is not identical to the innovator's product, it is possible to develop antibodies selective for the biosimilar that bind differently to the originator compound. Although this would appear to be the ideal choice with respect to selectivity, the introduction of additional variables to the development process can lead to failure by not demonstrating bioequivalence, due to change in the bioanalytical method.
Greer (SGS): Biosimilar comparability testing is a major growth area being driven by legal and regulatory requirements. A main challenge is to assess the various international regulatory guidelines that have been established to ascertain what type of testing program would be appropriate for a particular molecule. Although guidances exist—including the recently released ones by FDA—it is clear that authorities examine every submission on a case-by-case basis. In practice, it is important to work in-step with the authorities, providing projected proposals and preliminary data at a much earlier point in the timeline than usual.
At the analytical level, there are a plethora of challenges related to the choice of originator product to be used in the comparison studies, together with the fact that the clinical studies cannot be run in the usual way. Additionally, focus should be directed to choosing the right and sensitive patient population. Similar clinical efficacy should be demonstrated in adequately powered, randomized, parallel group comparative clinical trial(s), preferably double-blind in the most sensitive patient population. Thus preclinical data are key in setting up the best study design and meeting the regulatory requirements with the right justifications.
BioPharm: From a CRO perspective, where do you see biopharmaceutical R&D outsourcing in say 5-10 years from now? What key changes may have occurred by then?
Gillett (Charles River): The driving forces in drug development are pushing all sponsors of all sizes to diversify their portfolios beyond the boundaries of their traditional product lines, to share risks, and to collaborate. In this era of increased collaboration, sponsors and CROs can be a powerful team because they share the common goal of developing successful new therapies, are non-competitive in their financial interests, and have complementary skill sets. CROs' experience can support sponsors who may be reaching outside their comfort zones towards novel technologies and regulatory practices.
Kauffman (Lancaster Labs): We predict a consistent increase in outsourcing. As sponsor companies transfer more of their expertise to contract laboratories, more testing will be outsourced. As pipelines grow, sponsors will look to outsourcing partners to help meet their objectives without having to build the capacity to support all of the work in-house. Key changes will most likely include improved analytical technology and bioinformatics.
Breau (MPI): The number of biologics being developed as a percentage of all pharmaceutical activity is growing. Many recent mergers and acquisitions were executed to increase the biological footprint of the acquiring company. As novel technologies to produce biologically derived products lose patent protection, the growth in this area should accelerate.
Reason (SGS): Market estimates indicate that biologics are taking an increasing share within R&D spending, thus offering huge opportunities. We expect to see R&D outsourcing follow the trend of the number of biopharmaceutical products in development with perhaps an increase in the outsourcing percentage. We also expect there to be an increased requirement among sponsor companies for CROs to provide a one-stop-shop. Finally, there is likely to be an increase in the number of high-level agreements between CROs and biopharmaceutical companies to provide an integrated approach for developing biopharma products.