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Innovative technologies and services meet needs for existing and emerging biologic-based therapies.
Advances in technology are helping to accelerate biopharmaceutical development; however, many challenges still exist. More sensitive instruments and bioassays, scalable platforms, and single-use systems are providing needed enhancements as demands for new types of biologic therapies progress through development cycles.
Pharmaceutical Technology Europe spoke with representatives of contract laboratories and contract development and manufacturing firms about the current state of technology for biopharmaceutical development, analysis, and manufacturing. The panelists include: John Allinson, head of biomarker strategy, drug development services at LGC; Martha S. Rook, head of novel therapies, process solutions, Merck; Joe Codamo, general manager, Patheon; Brian Hampson, vice-president, Global Manufacturing Sciences and Technology, PCT, a Caladrius Company; Stephen Gacheru, executive director-Biopharmaceutical Product Development, PPD Laboratories; Bruce Stouffer, executive director-Immunochemistry Department, PPD Laboratories; Mark Rogers, VP USA-Life Science, SGS; Don Paul Kovarcik, technical marketing specialist, Ajinomoto Althea; Robert H. DeWit, president of MPI Research; Michael Lehmann, president, global sales and marketing, Patheon; and Peter Soelkner, managing director, Vetter Pharma International.
PTE: What pressing technical challenges have you seen? What actions has your company taken to resolve the challenge?
Gacheru (PPD Laboratories): One challenge is the absence of well-established processes to fully understand critical quality attributes of protein aggregation for biologic products in early development. Lack of this knowledge and additional analytical data can lead to significant delays during the late stage scale-up process.
PPD is able to provide analytical services that look for potential aggregation attributes from extractables/leachables, incoming excipient quality, and post-translational modification (PTM) of proteins. Phase-appropriate validations within the industry are being discussed, but there is still no acceptance of what this means in the drug-development process. We are working to align the analytical development and qualification with the phases of the drug-development process to facilitate quick turnaround times and faster drug-development processes.
Rook (Merck): There is a real need in the field for scalable production platforms with well-understood critical process parameters and their impact on critical quality parameters. Often companies are leery of moving away from their early, often more research-defined processes because they are based on proven technology. However, this can be a problem when it comes to scalability and often process robustness. It’s much more efficient to do two large production runs rather than 10 small productions, but this requires good planning, process development, characterization, and validation, as well as taking the time to generate sufficient data to define operating windows for critical process parameters and developing a robust, scalable process. Merck is helping bridge the risk for our customers by developing more standardized process templates for the most commonly used viral vectors. We believe the product expertise from Merck coupled with the years of experience manufacturing viral vectors at our SAFC Carlsbad facility will allow us to develop templates that can accelerate the transition from a manual, adherent stack-based process to a more automated scalable process.
Codamo (Patheon): The increasing demand for data to be available on key product quality attributes at the very early stages of bioprocess development, especially with advances in high throughput screening [is a challenge]. Patheon now routinely uses the AMBR 15 48 micro-bioreactor system (Sartorius Stedim), together with an automated one-step protein purification system, to assist in the rapid screening of key product quality attributes during clone screening.
Hampson (PCT): With off-the-shelf biopharmaceuticals, one batch is manufactured to treat multiple patients. Therefore, economies of scale drive down the per-dose cost of the final product. With patient-specific cell therapies, a separate batch is manufactured for each patient. Economies of scale are therefore limited, and reducing the cost of these patient-specific cell therapies requires advances in engineering and manufacturing technology such as reducing the number of complex, labour-intensive steps.
Rogers (SGS): As in several areas of testing, many analytical challenges encountered in the biologics field may be considered as self-inflicted--improvements in chromatographic technology can result in the detection of hitherto unknown sample components, leading to a demanding programme of identification.
For biotherapeutics, one of the most challenging technical areas is in the structural definition of process-related and stress-related impurities. While these may be readily detected in the product, the precise identification of these impurities often proves to be extremely difficult.
Not only is the potential number of primary structural modifications very high, but higher order changes also have to be considered. The impurities are often observed at trace levels, and the investigative tools have to be carefully controlled to avoid introduction of additional and unintended structural modifications leading to incorrect identification.
Stouffer (PPD Laboratories): Availability of antibody reagents can be limited at times because of the difficult nature and time required (three to six months) for their production. There also have been limitations to the sensitivity of older immunoassay platforms. These technical hurdles have been met through advances in how quickly specific reagents can be made and evaluated, as well as new platforms that can increase the sensitivity of detecting reagents in those systems. Another challenge in the growing market is the need to deliver results faster to enable competitive development of new treatments for patients.
Evaluation of new immune-analytical technologies such as MSD (Meso Scale Discovery), Gyros (Gyros Protein Technologies), and others using electro-chemiluminescent or fluorescent detection have improved capability for lower-level (nanogram or picogram) detection of biologics. Advances over the past several years in the area of liquid chromatography-mass spectrometry (LC-MS), usually employed for small-molecule bioanalysis, now have shown great additions to the tool kits of analytical scientists in the biologics arena. Continued efforts in automation in these areas has helped tremendously to speed the overall process, delivering data faster to the clinicians.
PTE: What advances do you see in science or technology in the next five years?
Codamo (Patheon): Advances include improved membrane-based depth filtration and chromatography technologies that will facilitate faster process development, faster processing in manufacturing, and reduce raw material costs, especially for early-stage clinical manufacturing.
Allinson (LGC): There will be increasing development of different technologies to meet the market’s rapidly evolving needs. Currently, there is increased interest in platforms designed around microfluidics or miniaturized technology, which can help reduce the cost of assays and sample volume requirements. Furthermore, we are also seeing potential in new multiplexing platforms, allowing us to perform multiple assays simultaneously on the same sample. These are being developed in areas such as immunogenicity and biomarkers, lending themselves to the technologies that may be required in biological drug development.
Hampson (PCT): In order for the cell therapy industry as a whole to become commercially viable, we must take steps towards developing the ‘factory of the future,’ aiming to achieve the following attributes:
Rook (Merck): There are real opportunities to improve production yield as well as viral vector purity through the combination of cell line and media development, bioreactor-based expansion, and downstream processing improvements. This is an area where we need to take the next big step forward to enable cell and gene therapy. The combination of vector optimization, process innovation, and single-use process platforms will be key to enabling the commercialization of gene and gene-modified cell therapy products.
Gacheru (PPD Laboratories): Personalized medicine and cellular therapy will demand new analytical tools in the quality control and process development of these products. Gene therapy products and new tools for antibody conjugates will require a new paradigm in quality control testing laboratories. Next generation sequencing adaptation to cell characterization and cell banking processes will introduce new ways of clonal selection and provide an early read on the product target profile at the cellular level.
Stouffer (PPD Laboratories): Continued advances in immune-analytical platforms, LC-MS, and automation should continue to drive success in this sector. Advances in data handling also will speed up the process.
PTE: Are you seeing shifts in demand for particular types of services? What is the most requested type of service?
Hampson (PCT): Cell-therapy developers desire guidance regarding how to optimize their manufacturing process at every stage of development. As a result, PCT created the Strategic Manufacturing Assessment (SMA); an objective, systematic appraisal of the manufacturing process, with immediately actionable recommendations to drive product development and commercialization timelines. The SMA incorporates elements of development by design (quality, cost of goods, scalability, and sustainability), opportunities for incorporation of advanced technology, and strategic considerations for commercially viable manufacturing.
Allinson (LGC): Demands have stayed relatively unchanged, and I have not witnessed any real major shift particularly from a drug-development perspective. People still want a mixture of pharmacokinetics, anti-drug antibody, and biomarker work, and there is much ongoing discussion and development within the latter two areas (regulatory and scientific). There is an increasing demand for a varied mix of analytical platforms in bioanalytical laboratories to meet all of these requirements. Clearly there are also factors from a manufacturing perspective, such as pharmaceutical analysis and stability testing, for biologicals and non-biologicals that are also important.
Rook (Merck): We’ve seen a real shift from adenovirus to Adeno-associated Virus (AAV) and lentiviral vectors in the past few years as the field has adopted them, particularly with the success of CAR T therapies in the clinic. We’re also beginning to get more requests for the use of automated bioreactor platforms. We’re also finding that the customers value our full services portfolio from cell banking, process development, and GMP bulk production but also importantly our testing services with Bioreliance. There is real value in the manufacturing and testing being integrated within one company both for the standard safety release tests but also the assistance we can offer in developing custom assays that can be used either in process or eventually validated for GMP release all within one organization.
Codamo (Patheon): Patheon’s clients routinely want more product quality data to be available at much earlier stages of bioprocess development, especially during clone evaluation, to mitigate risk at later stages.
Rogers (SGS): In the past decade, there has been a clear shift in experimental design toward the application of orthogonal methods even in comparability studies where the same molecular feature may be defined by multiple techniques. In such programmes of analysis, demands from larger companies are often for exact replication of their own in-house methods while small and mid-size companies tend to accept platform methodologies developed by the service provider, albeit with modifications to suit the specific molecule under investigation.
Despite trends in processing to try to simplify the structural complexities of modern biotherapeutics, many of the analytical techniques applied in this field remain relatively involved. Thus, customers’ demands are not only for the most up-to-date equipment but also, and perhaps even more importantly, for the highest level of expertise both in experimental planning as well as data interpretation.
Possibly the most requested type of service in [the analytical] field involves some type of hyphenated mass spectrometry. This is almost certainly due to the versatility of such techniques, which can be applied as R&D and quality control (QC) tools and have the ability to qualitatively and quantitatively analyze different molecular entities. This latter attribute is particularly useful with biotherapeutics, which often contain two or more different molecular types. There is a continuous demand to improve certain aspects of these mass spectrometric techniques such as higher resolution and greater mass accuracy, and this has been somewhat driven by virtue of the structural complexity of biologics.
Gacheru (PPD Laboratories): With new US Food and Drug Administration (FDA) guidance of human factor study, functional assays for device combo-based product--including syringe and multiple-use pen device--are expected to be a new demand from our customers.
With biosimilars entering the global market, there will be increased demand for CRO analytical services for both early- and late-stage development activities.
Oligonucleotide products are growing fast and new analytical tools to support the development and commercialization of these products are driving new service requests in this sector.
Stouffer (PPD Laboratories): Continued growth in biopharmaceuticals, such as monoclonal antibodies, antibody-drug conjugates, peptides, oligonucleotides and vaccines, as well as traditional pharmaceuticals is expected. An increase in analysis of biomarkers to support the development of these therapeutics also is expected. Demand for immunogenicity testing (anti-drug antibody monitoring) for biologics also is continuing to grow.
PTE: What impact has consolidation in the contract services market had on your organization? What has consolidation meant for your customers?
Kovarcik (Ajinomoto Althea): Consolidation reduces competition and client choice in the marketplace. It’s often in response to slowing organic growth. Acquisition of specialized firms expands a contract manufacturing organization’s (CMO’s) service portfolio, allowing a company more opportunities to interact with customers, capture more value, and position themselves as a strategic partner or one-stop-shop. These acquisitions, however, are not without risk. Will the integration of the two businesses be efficient and will the new larger organization operate smoothly? Biologics manufacturing is challenging, and there is risk that a large organization becomes a jack-of-all-trades, but a master of none. Often times, the larger an organization grows, the less flexible and nimble it becomes, and if not managed properly, it can lead to frustrated clients.
DeWit (MPI Research): Consolidation often results in opportunities because with each contract research organization (CRO) consolidation, there are fewer options for pharmaceutical, biotechnology, and medical device companies. For that reason, the mergers and acquisitions ultimately reduce the number of competitors in the market, opening new doors for the remaining providers. Pharmaceutical, biotechnology, and medical device companies generally have preferred CROs that they work with for various functions. If a preferred CRO is acquired by an organization that the company is unfamiliar with or has predisposed opinions of, they may select another CRO to conduct their development work. It’s also common for companies to work with similarly sized CROs; therefore, a company that historically worked with a smaller CRO might seek an alternative provider if their preferred option is acquired by a larger organization.
Soelkner (Vetter): Consolidation has several implications for the healthcare industry. For example, it may limit supplier options for individual services desired by bio/pharmaceutical companies. At the same time these sponsors tend to simplify and reduce their network of development and production partners to achieve wherever possible a ‘one-stop-shop approach’. Also, sponsors are looking to achieve attractive cost models for their bundled contracts from their partner of choice. For Vetter, where it is not uncommon to have an entire pipeline of different products as part of an outsourcing relationship, consolidation means we must continue to be strategic, not simply tactical in our daily work.
Lehmann (Patheon): The global pharmaceutical industry is a large and growing market, where clients are increasingly faced with pricing challenges and competition. These pressures, coupled with the growing demand for quality medicines, lead clients to partner with service providers that bring expertise and scientific knowledge, rather than capacity alone. This will continue to drive consolidation as pharmaceutical companies turn to development and manufacturing providers to simplify the supply chain, decrease costs, and bring new drugs to market faster. In terms of impact on Patheon, the consolidation has driven the development of a broader service offering.
Allinson (LGC): For our organization, the impact has not been felt from the consolidation in the contract services market, but potentially in the consolidation of outsourcing toward the contract services market. Typically, the market wants to reduce the number of companies that they outsource to but in some cases they may lack the in-depth understanding of the science required for what they want to achieve to be able to choose the right services. For example, the small-molecule arena is relatively straightforward in terms of equipment platforms, the science and technology, and the regulatory framework, all factors that have been established over a long period of time. In the biological arena; however, we are still seeing rapid developments taking place particularly in immunogenicity; their needs in terms of contract services are therefore significantly different. Biomarker services are similarly affected.
Pharmaceutical Technology Europe
Vol. 28, Supplement, Issue 2
When referring to this article, please cite it as The Editors of Pharmaceutical Technology Europe, "Contract Service Providers Tackle Biopharma Challenges," APIs, Excipients, and Manufacturing supplement to Pharmaceutical Technology Europe 40, 2016.