Jun 15, 2015
By BioPharm International Editors
BioPharm International eBooks
Volume 28, Issue 13
The approval of the first biosimilar in the United States, as well as continuing consolidation in the biopharma and contract development and manufacturing markets, are just two indicators of the ongoing evolution of biopharmaceutical development. Representatives of contract service providers shared observations, trends and projections with BioPharm International.
Roundtable participants are Gary Chambers, business manager biopharma labs, Europe, SGS; Bill Hartzel, director of strategic execution, Catalent Pharma Solutions; Chris R. Lively, PhD, director of biopharmaceutical services, PPD; Scott Lorimer, VP Global Operations, Patheon Biologics; Eugene McNally, PhD, executive director, PPD Consulting; Rekha Patel, global director, large molecules, development and analytical solutions, Catalent Pharma Solutions; and Mark Rogers, vice-president, SGS Life Science Services, USA.
Regulatory and business trends
BioPharm: What regulatory changes have positively or negatively impacted biopharmaceutical development/manufacturing processes?
McNally (PPD Consulting): FDA established a new Office of Pharmaceutical Quality in 2014, which we anticipate will have major impacts on the biopharmaceutical development and manufacturing process. This reorganization was designed to enhance quality drug assessment by realigning several elements of the preapproval and surveillance inspection process. Integrating risk-based review, GMP inspection, implementation of quality by design, and the new FDA process validation guidance within one office is expected to significantly change the biopharmaceutical development and manufacturing process.
Hartzel (Catalent Pharma Solutions): In today’s market, there are significant manufacturing challenges in traditional glass vial filling applications. These challenges manifest in quality issues with the final container closure and may be related to microbial contamination, glass particulates, and foreign materials that lead to necessary market action causing supply issues.
Lorimer (Patheon Biologics): The greatest regulatory change in recent times is the acceptance and approval of biosimilars.
BioPharm: What business trends have positively or negatively impacted biopharmaceutical development/manufacturing processes?
Hartzel (Catalent Pharma Solutions): Today there is a stronger emphasis in the development lifecycle on the delivery of the molecule to the patient and not just the molecule itself. Delivery/device experts are being added to teams at Phase II to improve the delivery beyond the traditional vial.
Lively (PPD): Growing interest in biopharmaceutical drug development necessitates partnering between clients and contractors to increase industry capacity, breadth of capabilities, expertise, and the experience required to bring these drugs to market. The client will receive the most benefit by selecting a high-quality contract research organization (CRO) lab that is able to meet its needs and work collaboratively with the client to ensure timely development.
Lorimer (Patheon Biologics): The trend of small biotech partnering with large pharma for clinical manufacturing and development has certainly facilitated the full development of more novel molecules. Also, the increasing trend toward outsourcing of GMP biologics manufacturing ensures bioprocessing and testing is performed by expert manufacturers with proven track records in quality and biomanufacturing. This helps to reduce the risk to clinical programs and product safety.
Technical/scientific trends
BioPharm: Can you describe productivity improvements your company has experienced from new technologies?
Patel (Catalent Pharma Solutions): Catalent Pharma Solutions has significant ongoing investments in enhancing our large-molecule analytical capabilities and productivity to meet and advance current industry needs. Recent investments include the updated/new technologies, new assay strategies, and updated electronic systems and processes.
Lively (PPD): Evolving characterization expectations for biologics have driven improvements in analytical equipment, processes, and systems. Ultra performance liquid chromatography (UPLC) systems have improved resolution and sensitivity, while reducing run times. In addition, 2D high-performance liquid chromatography (HPLC)/high-resolution mass spectrometry (MS) allows for analysis of samples incompatible with traditional MS. Reporter gene bioassays apply genetically engineered cell lines both to directly model mechanisms of action and to amplify assays for improved performance with shorter incubations and increased signal/noise relative to standard bioassays.
Lorimer (Patheon Biologics): The main productivity improvement has been increasing the throughput of products in Patheon’s multiproduct biopharmaceutical GMP facilities. Single-use disposable bioreactors and similar single-use bioprocess equipment minimize plant downtime, which is traditionally required for line clearance and product changeover. The complexity of product changeovers is reduced by single-use technology, which decreases the need for clean-in-place, steam-in-place, and quality control testing. Typically, line clearance time is reduced by several days.
Rogers (SGS Life Science Services): As an analytical service provider, SGS is constantly in search of means to improve its laboratory efficiencies, particularly those that enhance turnaround time without adversely effecting quality. With this in mind, substitution of HPLC for UPLC, rapid microbiological screening methods, and investment in automated approaches to complex analytical problems such as protein sequencing are now being used within the SGS laboratory network.
Chambers (SGS): From a CRO point of view, the main productivity improvements in analytics have been from higher throughput systems and data analysis. The move to these faster systems with semiautomated data processing has allowed us to improve turnaround times, which are passed on to clients in terms, who win on faster to market times and faster go/no decisions.
BioPharm: What additional technology improvements are needed to improve the efficiency of bioprocessing?
Lorimer (Patheon Biologics): Process analytical technology (PAT) for continuous monitoring of bioprocesses is helping reduce the variability on biopharmaceutical manufacturing.
Also, biopharmaceutical development and process validation have been accelerated by the use of mini-bioreactor systems, which enable a large amount of process development data to be generated within a very short timeline. These multi-bioreactor systems can reduce process development timelines by months when applied to early-stage or late-stage bioprocesses.
Rogers (SGS Life Science Services): The development of many technologies follows a common path from academia to commercial application and nowhere is this more evident than in the field of bioprocessing. In almost all examples, the key to this progression lies in the ability to simplify operational aspects of the technology and improve throughput. This has, in the past, been clearly demonstrated in, for example, the field of mass spectrometry and is currently evolving with techniques involved in biophysical characterization.
BioPharm: What is the greatest technical challenge facing biopharmaceutical companies today?
Hartzel (Catalent Pharma Solutions): Cost to manufacture will continue to be a major challenge for the industry, especially with the rise of biosimilars and market pressures to drive down the cost of medicines. However, the products that are coming to market are more targeted, which leads to smaller batch sizes. This is counter to the manufacturing adage of being able to leverage economies of scale to drive out costs, hence the need to focus on alternatives technologies and innovation to reduce the manufacturing costs versus economies of scale.
Lively (PPD): Application of analytical techniques to better characterize innovator and biosimilar or follow-on products by physicochemical and functional methods are required and will continue to be driven by the complexity of biologics development. For example, changes in formulations may cause different leachable profiles requiring increasing emphasis on extractables/leachables techniques (i.e., high-resolution MS) to support characterization of formulation effects, identification of degradation and impurities, and determination of their potential impact through application of potency bioassays.
Lorimer (Patheon Biologics): Most of the technical challenges for manufacturing have been overcome, and the technologies for development and manufacturing have been widely adopted. Perhaps the greatest challenge is in clinical development of novel and originator molecules, where in-vitro model systems are still not a great predictor of clinical performance.
Rogers (SGS Life Science Services): To highlight one technical challenge above all others in today’s biopharmaceutical industry is very difficult. The complexity of biotherapeutics often results in considerable technical difficulties as, for example, in the area of impurities; recognition of host- cell proteins (HCPs) and identification of structural variants at trace levels are certainly high on the list of technical concerns. The necessary inclusion of relatively elaborate analytical techniques such as sedimentation velocity analytical ultracentrifugation (SV-AUC) within a traditional quality control release environment is also not without problems.
BioPharm: What are the prospects for continuous manufacturing to be firmly established in bioprocessing? What are the roadblocks to implementation?
Lorimer (Patheon Biologics): Continuous production from mammalian cell cultures has been operated in perfusion bioreactors for many years. The main roadblock for continuous processing is downstream processing of proteins, which currently demands discrete and distinct unit operations for removal of impurities, removal of contaminants, concentration of the products and formulation; each in separate, controlled steps and which are not currently amenable to continuous processing.
The rise of biosimilars
BioPharm: What impact will biosimilar drugs have on biopharma businesses, bioprocessing approaches, and the contract services market?
Rogers (SGS Life Science Services): The European biopharma landscape has already experienced impact of the biosimilar drug market leading to rapid expansion of traditional small molecule, generic manufactures into the bio arena. Recent FDA approval of the Sandoz biosimilar, Zarixo, may be the seed for similar changes in the US providing a potential new line of business for established pharmaceutical companies. Contract service providers such as SGS, who already have considerable experience with biosimilars, are able to offer expertise to businesses new to this market and will no doubt benefit from such expansion in the US.
Lively (PPD): Increased investment in biosimilars is driving interest in improving and streamlining the development processes, as well as the sensitivity and scope of characterization assays used to compare biosimilars and innovator drugs. The expanding capacity needs result in partnerships between clients and their contractors with the systems, experience, and expertise to achieve the quality and speed required, while meeting all regulatory expectations for product approval.
Chambers (SGS): With nearly 20 years experience performing biosimilar analysis, the biggest impact had been the massive increase in the characterization needed for biosimilars compared to innovators (although higher standards are now needed for new innovators too). This has resulted in challenges in data handling, interpretation and data presentation. Biosimilars have also caused the re-emergence of orthogonal techniques like size exclusion chromatography-multi-angle laser light scattering (SEC-MALL) and SV-AUC for aggregation and circular dichroism (CD) and fourier transform infrared spectroscopy (FTIR) for higher-order structure as critical analyses to understand and compare and detect subtle higher-order structural differences between innovator and biosimilar samples.
Hartzel (Catalent Pharma Solutions): The rise of biosimilar drugs will dawn the next generation of biologic manufacturing and force the industry to look at new ways of manufacturing to drive down costs. Therefore, the industry will seek new manufacturing partners with strong technical expertise to drive out costs through innovation and operational excellence.
Lorimer (Patheon Biologics): Generally, biosimilar drugs will encourage competitiveness within the biopharma sector. Biomanufacturers expect increased pressure on cost of goods and pricing. Biopharmaceutical contract service providers with a flexible, multi-product operation and proven track record in the industry are well placed to ensure careful control of manufacturing costs and product quality. Processing approaches won’t change in terms of technology, but there will be a greater emphasis on operational excellence to reduce costly inefficiencies and improve yields from bioprocesses. As more biosimilars come to the forefront and as the industry trend for outsourcing continues, increasing operational flexibility, while maintaining the highest quality standards, will be the keys to success.
Business challenges
BioPharm: What is the greatest business challenge facing biopharmaceutical companies today?
Lively (PPD): As with all pharmaceutical drug development, the greatest challenge is getting new life-changing and potentially lifesaving drug candidates to market. Biopharmaceuticals face more challenges than traditional small-molecule drug products because the science of characterization of such biologic drugs is rapidly evolving, along with the regulatory landscape. Those companies that are best able to successfully characterize and differentiate innovator and biosimilar products for safety and efficacy will have the greatest opportunity to benefit.
The knowledge gap
BioPharm: In what areas do you see knowledge or expertise gaps in current biopharmaceutical companies? Why do these gaps exist?
Lorimer (Patheon Biologics): There is a gap in translating good science to industrial applications of technologies that provide for reliable, efficient, cost effective manufacturing at commercial scale. Maintaining a focus during early development on eventual commercial manufacturing requirements, while balancing limited development resources requires a broad base of coordinated, organizational skillsets and a disciplined approach.
Hartzel (Catalent Pharma Solutions): Device/delivery expertise is an area that has a potential gap. For biologics, the historic default container closure has been a traditional glass vial. As the healthcare industry seeks ways to improve patient care and reduce costs, the delivery to the patient needs to adopt new technologies and this is why we have seen a rise of prefilled syringes and autoinjectors. These technologies will continue to evolve and so will the demand for device/delivery experts.
Lively (PPD): One of the challenges we see is the various levels of knowledge and expertise that exist between biopharmaceutical R&D and the testing and regulatory industries. That differential is impacting those industries’ ability to fully consider and effectively implement expectations and guidance for physicochemical and functional characterization expectations of biologic drugs.
Lorimer (Patheon Biologics): The commercial biopharmaceutical industry demands global sourcing of materials, services, supply, and ultimately distribution to each patient. This requires a robust integrated supply chain to deliver high value products to patients, on-time and at the right quality. Doing this reliably and efficiently with long production lead times and uncertain market sales forecasts is an industry wide challenge.
Speed-to-market remains a key challenge to the development of biopharmaceuticals. Speedy first-time-in-man clinical trials can be a major hurdle for small biotech companies and large pharma alike.
Rogers (SGS Life Science Services): I believe there continues to be a significant problem in the level of fundamental scientific expertise within many biopharmaceutical businesses. In part, this may be attributed to the ‘kit’ and ‘black box’ approach of many modern day technologies. Due to the complexity of many biopharmaceuticals, their development and success as therapeutics requires a comprehensive range of scientific disciplines and expertise, which can be difficult to fully realize internally, particularly for small and mid-size companies.