BioPharmINTERNATIONAL

The Science & Business of Biopharmaceuticals

ELECTRONICALLY REPRINTED FROM JUNE 2015

Biopharma Advances Demand Specialized Expertise

Contract service providers share insights on biopharma market developments and the implications of biosimilar drug approvals.

THE EDITORS OF BIOPHARM INTERNATIONAL

The approval of the first biosimilar in the United States, as well as continuing consolida-tion in the biopharma and contract develop-ment and manufacturing markets, are just two indicators of the ongoing evolution of biophar-

maceutical development. Representatives of contract service providers shared observations, trends and pro-jections with BioPharm International.

Roundtable participants are Gary Chambers, busi-ness 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, devel-opment and analytical solutions, Catalent Pharma Solutions; and Mark Rogers, vice-president, SGS Life Science Services, USA.

REGULATORY AND BUSINESS TRENDSBioPharm: What regulatory changes have positively or negatively impacted biopharmaceutical development/manufacturing processes?

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McNally (PPD Consulting): FDA establ ished a new Off ice of Pharmaceutical Quality in 2014, which we anticipate will have major impacts on the biopharmaceuti-cal development and manufactur-ing process. This reorganization was designed to enhance quality drug assessment by realigning sev-eral elements of the preapproval and surveillance inspection pro-cess. 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 biophar-maceutical development and manu-facturing process.

H a r t z e l ( C a t a l e n t P h a r m a Solutions): In today’s market, there are significant manufacturing challenges in traditional glass vial filling applications. These chal-lenges 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 posit ively or negatively impacted biopharmaceutical devel-opment/manufacturing processes?

H a r t z e l ( C a t a l e n t P h a r m a Solutions): Today there is a stronger emphasis in the development life-cycle on the delivery of the mol-ecule 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 devel-opment 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 cli-ent to ensure timely development.

Lorimer (Patheon Biologics): The trend of small biotech partner-ing with large pharma for clinical manufacturing and development has certainly facilitated the full development of more novel mol-ecules. Also, the increasing trend toward outsourcing of GMP biolog-ics manufacturing ensures biopro-cessing 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 TRENDSBioPharm: Can you describe pro-ductivity improvements your com-pany has experienced from new technologies?

Patel (Catalent Pharma Solutions): Catalent Pharma Solutions has sig-nificant ongoing investments in enhancing our large-molecule ana-lytical capabilities and productiv-ity to meet and advance current industry needs. Recent invest-ments include the updated/new technologies, new assay strategies, and updated electronic systems and processes.

Lively (PPD): Evolving character-ization expectations for biologics have driven improvements in ana-lytical equipment, processes, and systems. Ultra performance liquid chromatography (UPLC) systems have improved resolution and sen-sitivity, while reducing run times. In addition, 2D high-performance liquid chromatography (HPLC)/

high-resolution mass spectrom-etry (MS) allows for analysis of samples incompatible with tradi-tional MS. Reporter gene bioassays apply genetically engineered cell lines both to directly model mech-anisms 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 through-put of products in Patheon’s mul-tiproduct biopharmaceutical GMP facilities. Single-use disposable bioreactors and similar single-use bioprocess equipment minimize plant downtime, which is tradi-tionally required for line clearance and product changeover. The com-plexity of product changeovers is reduced by single-use technology, which decreases the need for clean-in-place, steam-in-place, and qual-ity control testing. Typically, line

Approval of the first biosimilar in the United States, as well as consolidation in the biopharma and contract development and manufacturing markets, are just two indicators of the ongoing evolution of biopharmaceutical development.

clearance time is reduced by sev-eral days.

R o g e r s ( S G S L i f e S c i e n c e Services): As an analytical ser-vice provider, SGS is constantly in search of means to improve its laboratory efficiencies, partic-ularly those that enhance turn-around time without adversely effecting quality. With this in mind, substitution of HPLC for UPLC, rapid microbiolog ica l screening methods, and invest-ment in automated approaches to complex analytical problems such as protein sequencing are now being used within the SGS labora-tory network.

Chambers (SGS): From a CRO point of view, the main produc-tivity improvements in analytics have been from higher through-put 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 cli-ents in terms, who win on faster to market times and faster go/no decisions.

BioPharm: What additional tech-nology improvements are needed to improve the efficiency of bio-processing?

Lorimer (Patheon Biologics): Process analytical technology (PAT) for continuous monitoring of bioprocesses is helping reduce the variability on biopharmaceutical manufacturing.

Also, biopharmaceutical devel-opment and process validation have been accelerated by the use of mini-bioreactor systems, which enable a large amount of process development data to be gener-ated within a very short timeline. These multi-bioreactor systems can reduce process develop -ment timelines by months when applied to early-stage or late-stage bioprocesses.

Rogers (SGS Life Science Services): The development of many tech-nologies follows a common path from academia to commercial application and nowhere is this more evident than in the field of bioprocessing. In almost all exam-ples, the key to this progression lies in the ability to simplify opera-tional aspects of the technology and improve throughput. This has, in the past, been clearly demon-strated 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 biophar-maceutical 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 medi-cines. 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 man-ufacturing costs versus economies of scale.

Lively (PPD): Application of ana-lytical techniques to better char-acterize innovator and biosimilar or follow-on products by physico-chemical and functional methods are required and will continue to be driven by the complexity of biologics development. For exam-ple, changes in formulations may cause different leachable profiles requiring increasing emphasis on extractables/leachables techniques (i.e., high-resolution MS) to sup-port characterization of formu-lation 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 over-come, and the technologies for development and manufactur-ing 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 chal-lenge above all others in today’s biopharmaceutical industry is very difficult. The complexity of biotherapeutics often results in considerable technical difficul-ties as, for example, in the area of impurities; recognition of host- cell proteins (HCPs) and identi-fication 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 qual-ity control release environment is also not without problems.

BioPharm: What are the pros-pects for continuous manufac-turing to be firmly established in bioprocessing? What are the road-blocks to implementation?

Lorimer (Patheon Biologics): Continuous product ion f rom mammalian cell cultures has been operated in perfusion bioreactors for many years. The main road-block 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 ame-nable to continuous processing.

THE RISE OF BIOSIMILARSBioPharm: What impact w i l l biosimilar drugs have on bio-pharma businesses, bioprocessing approaches, and the contract ser-vices market?

Rogers (SGS Life Science Services): The European biopharma land-scape has already experienced impact of the biosimilar drug mar-ket 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 pro-viding a potential new line of busi-ness for established pharmaceutical companies. Contract service pro-viders such as SGS, who already have considerable experience with biosimilars, are able to offer exper-tise to businesses new to this mar-ket and will no doubt benefit from such expansion in the US.

Lively (PPD): Increased invest-ment in biosimilars is driving interest in improving and stream-lining the development processes, as well as the sensitivity and scope of characterization assays used to compare biosimilars and innova-tor drugs. The expanding capac-ity needs result in partnerships between clients and their contrac-tors with the systems, experience, and expertise to achieve the qual-ity and speed required, while meet-ing all regulatory expectations for product approval.

Chambers (SGS): With nearly 20 years exper ience perform-ing biosimilar analysis, the big-gest 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

CMOs Add Capabilities

Consolidation in the contract development and manufacturing market has resulted in new capabilities and facility expansions.

In May 2015, CMC Biologics announced that it is expanding its Copenhagen, Denmark facility to increase its manufacturing capacity through the installation of six 2000-L bioreactors. The bioreactors can be run singly or in groups, simultaneously or sequentially, and are part of the company’s signature Bioreactor 6Pack single-use program. The Copenhagen installation will begin initial GMP production in November 2015 and will feature three bioreactors to start. Three bioreactors will be added at a later date to complete the configuration. Meanwhile, the Bioreactor 6Pack at CMC’s Seattle facility will complete its first GMP run in mid-2015 and will be ready for commercial launch by the end of the year. Through its recent expansions, CMC plans to expand its global capacity by more than 30,000 liters in the United States and Europe.

Also in May 2015, SAFC announced an expansion to its St. Louis, MO facility to support the commercial-scale production of antibody-drug conjugates. The facility, which is expected to be online and operational in the third quarter of 2015, was designed to meet SafeBridge category 4 compound handling requirements for highly active or cytotoxic compounds. The expansion of an existing Carlsbad, CA location will enable SAFC to offer fill/finish capabilities of viral products to its clients in the gene therapy, viral vaccine, and immunotherapy sectors.

Rentschler announced in March 2015 that a 2000-L bioreactor that the company commissioned and built in six months is up and running. The bioreactor will be integrated into existing manufacturing suites containing two 1000-L single-use bioreactors, according to a company statement. The company’s twin bioreactor system—designed for running two main bioreactors in parallel with one shared downstream processing unit—will be functional by 2017. The twin system is estimated to double the company’s production capacities for cell culture-derived proteins.

In December 2014, FUJIFILM Diosynth Biotechnologies U.S.A. (FDBU) acquired Kalon Biotherapeutics, adding viral and cell-culture vaccine expertise and capabilities. In other activity, FDBU started construction of a three-story, 62,000-ft2 facility in Research Triangle Park, NC, in January 2015 to house the company’s process and analytical research and development, process sciences, and stability groups. The expected completion date is Q4 2015.

In September 2014, PCI, a provider of packaging services, acquired Biotec Services International, a provider of clinical-trial services and temperature-controlled pharmaceutical services headquartered in Bridgend, Wales, UK. The addition expanded PCI’s presence in the European Union and added packaging, storage and distribution capacity, and consultative services for clinical-trial supplies. In January 2015, Biotec announced the validation of its clinical supply facility expansion, which added almost 50% to the company’s clinical trial materials handling capacity.

Posted with permission from the June 2015 issue of BioPharm International ® www.biopharminternational.com. Copyright 2015, Advanstar Communications, Inc. All rights reserved.For more information on the use of this content, contact Wright’s Media at 877-652-5295.

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in challenges in data handling, interpretation and data presenta-tion. 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 cir-cular 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 bio-logic 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): Genera l ly, b ios imi la r d r ugs will encourage competitiveness within the biopharma sector. Biomanufacturers expect increased pressure on cost of goods and pricing. Biopharmaceutical con-tract service providers with a flex-ible, multi-product operation and proven track record in the indus-try are well placed to ensure care-ful 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 inef-ficiencies 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 CHALLENGESBioPharm: What is the greatest business challenge facing biophar-maceutical companies today?

Lively (PPD): As with all phar-maceutical drug development, the greatest challenge is getting new life-changing and potentially life-saving drug candidates to mar-ket. 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 char-acterize and differentiate innovator and biosimilar products for safety and efficacy will have the greatest opportunity to benefit.

THE KNOWLEDGE GAPBioPharm: In what areas do you see knowledge or expertise gaps in current biopharmaceutical compa-nies? Why do these gaps exist?

Lorimer (Patheon Biologics): There is a gap in translating good sci-ence to industrial applications of technologies that provide for reli-able, efficient, cost effective man-ufacturing at commercial scale. Maintaining a focus during early development on eventual commer-cial manufacturing requirements, while balancing limited develop-ment resources requires a broad base of coordinated, organiza-tional 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 con-tainer closure has been a tradi-tional 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 pre-

filled syringes and autoinjectors. These technologies will continue to evolve and so will the demand for device/delivery experts.

Lively (PPD): One of the chal-lenges we see is the various levels of knowledge and expertise that exist between biopharmaceutical R&D and the testing and regula-tory industries. That differential is impacting those industries’ ability to fully consider and effectively implement expectations and guid-ance for physicochemical and functional characterization expec-tations of biologic drugs.

Lorimer (Patheon Biologics): The commercial biopharmaceutical industry demands global sourc-ing of materials, services, supply, and ultimately distribution to each patient. This requires a robust inte-grated 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 uncer-tain 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 biopharma-ceuticals, 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. BP