13^th International Conference on Biopharma and Biotherapeutics October 24-25, 2018 Boston, Massachusetts, USA

Neil Schauer is the Principal Consultant at Schauer Biologics Consulting where he provides strategic planning and tactical support for process development and manufacturing activities at startup and established biologics companies. At Avaxia Biologics, he was Senior VP of Technical Operations; where he was responsible for process development, manufacturing, quality and program management. In previous positions (Inspiration Biopharmaceuticals, Hospira, Millipore, Biogen Idec and Genetics InstituteWyeth), he held positions of increasing responsibility associated with biologics: technology, manufacturing, process development and projectprogramportfolio management.

The development of biosimilars presents a unique risk profile to biopharmaceutical companies when compared to proprietary biologics development. This risk profile will be examined and used to explain why biosimilars must be developed and manufactured differently than originator molecules, in order to insure commercial success. For biosimilars, commercial

endpoint oriented process development should start earlier for biosimilars than for originator products. To buy down risk, at-scale manufacturing may be desirable as early as nonclinical / phase I manufacturing.

Louis Boon received his PhD in Biochemistry at the University of Amsterdam. In 2003 he was one of the founders of Bioceros BV were he currently hold a position of CSO. In addition, he held positions as CSO for 4AZA Bioscience NV and for FF Pharma: he was VP Preclinical for PanGenetics BV and Tanox. He is an author of over 280 papers in international scientific journals in the field of medical biotechnology. Bioceros generates production cell lines and production processes for the industry and uses its proprietary CHOBC® platform and its SPOT™ technology to generate a portfolio of cell lines producing biosimilar monoclonal antibodies. He developed a complete process modulation toolbox to fit biosimilar CQAs. Currently, he is also involved in the development of innovative new molecular antibody entities, which now within the Polpharma Biologics group can be progressed to GMP production and clinical testing.

Innovative cell line generation and early process development are the cornerstones of the success of a biosimilar antibody since the costs of goods (COGs) needs to be very low. To achieve this, a high producing cell line in combination with a modulatory upstream processing (USP) strategy to meet similarity to the originator that do not limit productivity are obligatory. The major strategy generally used in USP to optimize productivity, is an elevation of viable cell density (VCD) in the fermenter. This USP solution however creates difficulties in downstream processing (DSP), since clarification will be difficult and in addition host cell related impurities will be high. Since Bioceros recognizes the biosimilar process as USP and DSP together, we have a different USP strategy for productivity optimization. Ultimately COGs are determined by USP and DSP together. Therefore, we create using our SPOT™ technology to increase Qp values, already during the cell line generation. The high Qp values facilitate high volumetric productivity at low VCD of these cell lines which enables a simple and efficient DSP process. Alongside we observed that irrespective of the VCDs, cell lines with a high productivity had a very high demand for oxygen, agitation, gasflow and nutrients. These high demands result in process issues, like oxidation of the product, shear stress, high sparging rates and high costs. Furthermore, these high demands will limit the ultimate innovations to further increase productivity. To avoid these issues we applied metabolic engineering and developed the SLIM™ technology on our CHOBC® platform. The SLIM™ technology decreases oxygen and feed consumption and also decreases sparging and agitation rates in the bioreactors showing the high efficiency of these process on which the SLIM™ technology was applied. Together, SPOT™ and SLIM™ technology in our CHOBC® platform reduce the cost of goods of biosimilars.

Anupam Chanda has his expertise in creating innovative design in packaging material and device technical book “ Packaging Technology An advance Practical approach “published from germany and amazon is distributing to 77 countries. Book is available in www.amazon for Biologics, biosimilar, anti Cancer and HIV products. He is having two decades ( approx. 25 years) of experience in India and abroad. He is a renowned speaker, widely travel throughout the world. Gain and share his thoughts with scientist from various institution and industry professionals. Author’s.de, www.amazon.com and www.morebooks.de. He is attached with various charitable institutions and research institutes.

Presently packaging plays a significant role for biosimilar product. The process of selecting materials and the type of packaging offers an opportunity for the packaging scientist to look for new biological delivery choices. Most injectable

protein products were supplied in some sort of glass vial, prefilled syringe and cartridge. Those products having high pH content there is a chance of “delamination” from inner surface of glass vial. With protein-based drugs, the biggest issue is the effect of packaging derivatives on the protein’s three-dimensional and surface structure. These are any effects that relate to denaturation or aggregation of the protein due to oxidation or interactions from contaminants or impurities in the preparation. The potential for these effects needs to be carefully considered in choosing the container and the container closure system to avoid putting patients in jeopardy.

Cause of Delamination:

• Formulations with a high pH include phosphate and citrate buffers increase the risk of glass delamination.

• High alkali content in glass could accelerate erosion.

• High temperature during the vial-forming process increases the risk of glass delamination.

• Terminal sterilization (irradiated at 20-40 kGy for 150 min) also is a risk factor for specific products (veterinary parenteral

administration), could cause delamination.

• High product-storage temperatures and long exposure times can increase the rate and severity of glass delamination.

• How to prevent Delamination

• Treating the surface of the glass vials with materials, such as ammonium sulfate or siliconization can reduce the rate of

glass erosion.

• Consider alternative sterilization methods only in rare cases.

• The correct specification for the glass to ensure its suitability for the pH of the product.

• Use COC/COP vial

Present market demand is syringe barrel and/or plunger coated with silicone. Non-uniform silicone coatings can affect protein stability. The proteins can absorb into the walls of the container. While silicone can reduce absorbtion, excess silicone can form suspended oil-like droplets. Proteins can form around those droplets and change their natural state. New lubricant coatings, such as inert fluoropolymers, are being introduced to replace silicone. As a very inert material, fluoropolymer provides smoothness for the syringe plunger without the irregularities or the issues that have come with silicone. Other new coating

materials are being introduced with new types of packaging related to self-injectors, especially injector pens, patches and transdermal and wearable devices for self-infusion. Extractable and leachable are most important for inhalers and catheters.

Sung Nyeo Shim has approximately 18 years of experience in the field of QA, QC, Compliance Of Biologics; QMS; Gmp Training & Biologics Analytical Test Methods Tech Transfer; Filing Support with Regulatory Affairs. She is enthusiastic, energetic, organized, the multifunctional individual with integrity, highly self-motivated. She has delivered milestones in a timely manner. She has QC lab qualification, analytical method development, qualification and validation per International Council for Harmonization (ICH) guidelines. She has also Monitored biologics manufacturing, data integrity/analysis/troubleshooting.

Biosimilar products (follow-on versions of pioneering biopharmaceutical products which are already licensed) are complex structurally and functionally. Regulatory authorities require biosimilars to have appropriate and comparable safety, quality and efficacy with a corresponding reference biologic product. In order to investigate the critical quality attributes of a biosimilar and a reference product for interchangeability and comparability, various analytical approaches are employed, such as LC/MS, Peptide mapping, Thermal analysis, SDS-PAGE, Isoelectric focusing and Capillary isoelectric focusing, Particulate matter analysis, In-vivo and In-vitro bioassay, etc. An analytical similarity of a biosimilar to a reference biological product is assessed with the state-of-the-art of analytical strategies. One of the key analytical techniques is Mass Spectrometry (MS) for assessment of similarity, detection and identification of primary sequence differences and evaluation of batch variability. Analytical differences observed need to be characterized and understood for a cross-confirmation of the data using orthogonal methods to prove the differences are not clinically relevant. Post-translational modifications, three-dimensional structures and protein aggregation have been identified as three important characteristics in developing strategies for the biosimilar. For quality control of the biosimilar production process and product, in-process samples, drug substance and drug product are evaluated in terms of protein content, purity, potency, identity and impurity. All analytical data includes the stability study data impact on clinical trials, the product expiration date and the product approval.

Anita Burrell is Vice President, Global Market Access at Health Strategies Group where she is responsible for leading and growing the global market access practice including syndicated and custom market research services. Prior to joining Health Strategies Group, she spent over 18 years with legacy Sanofi companies (23 years in the pharmaceutical industry) where she led worldwide strategy for launch pricing and reimbursement including evidence generation strategies. She was also the product champion for Aubagio (oral MS therapy) and coordinated commercial effectiveness for diabetes franchise. Her work is regularly published and presented at conferences. She is frequently invited to speak on real-world evidence, managed entry agreements, value proposition development and value frameworks.

Biosimilars were touted as a payer’s tool to gain savings in specialty markets, but a recent survey by Avalere of the top 25 payers in the U.S. (about 189 million covered lives) using publicly available coverage policies found that biosimilars are commonly subject to step through policies, including those that require the patient to “fail” first on a branded product and only then will the payer cover a biosimilar of that same branded product (i.e., the biosimilar’s reference product). Policies like this may be why although the Congressional Budget Office (CBO) originally estimated a 10-year decrease in federal spending of $5.9 billion attributable to “follow-on biologics”/biosimilars in 2009, it is estimated the actual savings have only been 8 percent of that amount (approximately $241 million). Some of the biggest challenges to biosimilar uptake are patent and intellectual property (IP) issues since we have 12 approved agents but only three which have been launched commercially. While the USA is currently the largest single market in the world overall by dollar value, the healthcare system comprises of thousands of payers and a lot of the incentives on how their choices are made are less than transparent. Contracting incentives from originator companies may play a part in the lackluster performance of those biosimilars which are available on the market but the bigger issue for a multisource market is that the promise of increased access for patients is not currently being realized. This presentation will review the barriers and possible future opportunities for biosimilar uptake in the USA.

Karlheinz Landauer holds a PhD in Applied Microbiology, focus on animal cell culture technologies, with 20 years of work experience. He has specialized in cell line engineering, upstream process development, scale-up and tech transfer strategies, GMP operations and was a program manager of an NBE (New biological entity). He had several positions in the above-mentioned fields with increasing responsibilities. His career started at igeneon GmbH in Vienna, later he moved to Celltrion R&D Center when in 2011 he eventually was Head Manufacturing and COO at Celonic AG in Basel. In 2016, he has founded QBDC, with its core focus on consultancy for biotech companies in CMC matters, process development, tech transfer & scale-up, facility layout & design, project management and QM & QA. At QBDC, he is driving the company towards high-quality standards and problem-solving communication strategies. For QBDC’s customers, he is an easily accessible, goal-oriented technical solution provider.

With the big success of biologicals and the experience in generics, the biosimilar development was born. In Europe, the first biosimilars were already approved in the 2006 and since then many more followed. Regulators, especially in Europe,developed new guidelines promising fast access and fewer investment costs for biosimilar development programs. With the approval of Celltrion’s Remsima the first monoclonal antibody reached the market and today many companies around the world are increasing the efforts to develop and market their own biosimilars. Often the companies and here especially small molecule pharma companies, do not intend to market their products worldwide but are addressing their own regional markets where they are already well established. Entering the biosimilar development and finally, markets is a risky venture. There are many candidate originators which could be copied and thus need to be analyzed form business opportunity perspective but also from a manufacturing/technology perspective. As already mentioned, the companies often quite well understand their markets, thus business analysis is performed in detail and thoroughly. However, the manufacturability of biosimilars, like the type of originator cell line, mode of fermentation, the stability of formulation, etc. are not analyzed and understood in detail and not appropriately taken into account. After the decision for a specific biosimilar, newcomers underestimate the needs for thorough originator characterization and process development needs and the effort for process characterizations prior entering phase I clinical trial. Not only one company failed based on amino acid aberrations of their product, could not copy post-translational modification or even fail in needed formulation stability and finally, but the program was also stopped. Most often companies, who are intending to enter the biosimilar world, do not have R&D nor production capacities, thus they need to start with contract development and manufacturing organization for their development programs and at the same time invest resources in the planning and construction of production facilities. Another trend is to in-license already established and approved products and starts with fill/finish works in-house and working itself backward till finally own R&D and APIproduction capabilities are established, based on the revenues from the in-licensed products. We are presenting an overall investment analysis tool for biosimilars, a quick method to see how much resources need to be invested when and effects on the program if not done in a timely manner. After the main road was defined as a second tool, to select the best candidate molecule will be shown in detail based on 30 analyzed molecules and finally, our standard CDMO selection guide will be briefly discussed. Having done these first three steps, biosimilar development is still not an automatic success, but it will help to overcome many obstacles by being aware that biosimilar development programs are time-consuming, resource intensive and for sure no generics.

Nitin Naik leads the global life sciences practice at Frost and Sullivan and is responsible for aligning cross-functional initiatives to achieve focused business results. He plays a pivotal role in helping life science companies realize their audacious goal of unhinging the most transformative pivots in the precision medicine landscape. He has more than 20years of healthcare industry expertise, including 15 plus years of consulting expertise focusing on the pharmaceutical and biotechnology sector. He works closely with Frost and Sullivan’s leadership and sales teams to expand research services and brand and demand solution footprint. Prior to his current role, he worked with GE Healthcare (national distributor), Frost and Sullivan Asia and A*STAR Singapore in various roles from strategy, marketing to inlicensing, portfolio management, and market planning. His experience and expertise have made him a go-to expert for commentary about emerging industry trends. He studied Biomedical Engineering (Gold Medalist) at Bombay University. He has an MBA (International Business) from S.P. Jain Institute of Management and Research (SPJIMR), India and pursued Advanced Management Program (Corporate Strategy and Finance) from Stanford-NUS.

The global life sciences industry is witnessing a surge in Chief Executive Officer (CEO) confidence from US tax reforms, turbulent equity markets, and the strengthening global economy. The growth of the life sciences industry is boosted by healthcare digitization and democratization creating an explosion in patient data, the emergence of value based reimbursement models, and healthcare consumerism shifting the risk from payers to providers. The convergence of biopharmaceuticals, drug delivery devices, and companion diagnostics enabled by digital connectivity is driving regulatory and commercial changes in many exciting ways for the industry. In this session hear about Frost and Sullivan’s perspective of how business models are changing to maximize growth in life science companies as they embrace the new trends and technology. Key takeaways include top 3 growth opportunities in the biopharmaceutical industry, perspectives from game changing companies on collaborativeprojects, impact on disruptive technology platforms and best practices for implementing new business models. 

Gregory Gierer has over 15 years of experience with health care policy and analysis. Prior to joining America's Health Insurance Plans (AHIP), he served as a senior director for policy at the pharmaceutical research and manufacturers of america (PhRMA) where he worked on developing and managing public policy issues related to comprehensive health care reform, health-system and delivery reforms and public programs such as Medicaid and the Children’s Health Insurance Program (CHIP). He previously served as a senior policy consultant at the Blue Cross and Blue Shield Association (BCBSA) and a Policy Analyst at America’s Health Insurance Plans (AHIP). He also worked on the legislative staff for U.S. Senator Christopher J. Dodd (D-CT) from 1997-1999 and 2001-2002. He received his Bachelor of Arts (B.A.) from Providence College (1995) and a master’s in public policy (M.P.P.) from Georgetown University (2001). AHIP is the national trade association representing the health insurance industry. AHIP’s members provide health and supplemental benefits to more than 200 million Americans through employer-sponsored coverage, the individual insurance market and public programs such as Medicare and Medicaid. AHIP advocates for public policies that expand access to affordable health care coverage for all Americans through a competitive marketplace that fosters choice, quality and innovation.Senior Vice

President for Policy at America’s Health Insurance Plans (AHIP) where he leads policy development work on legislative and regulatory policy issues—with a primary focus on health reform.

Prescription drug spending increases fueled by high launch prices for new therapies and price increases for existing brand name drugs are contributing to unsustainable health care costs growth across the US. In addition to straining the health care system overall, high drug prices also place financial burdens on patients who rely on prescription medicines. Recent advances in medicine which have resulted in new treatment options for patients with serious and chronic conditions have been mostly concentrated in the area of biologics and specialty drugs. While many of these treatments have led to improved health outcomes and quality of life for patients with debilitating conditions, they also lack meaningful competition and as a result are a key driver of increased medical and prescription drug costs. Spending on biologics and other specialty drugs reached $105.5 billion in 2016 and biologics are the fastest growing component of prescription drug spending increasing between 11.3% and 17.7% last year alone. Some treatments for biologics and specialty drugs have annual costs that exceed $250,000. Despite the passage of the biologics price competition and innovation act of 2010 which established a dedicated pathway for FDA approval of biosimilar drugs overall availability and utilization of biosimilar drugs have largely fallen short of market expectations. The FDA has approved 12 biosimilar products but only 4 are currently available to patients including approved biosimilar alternatives to neupogen and remicade. A number of barriers legal, regulatory and others have prevented and limited the availability and widespread adoption of biosimilars in the marketplace. Legal strategies such as aggressive patent litigation by brand name biologic manufacturers have prevented or delayed FDA approved biosimilars from coming to market and being made available to patients. Moreover, legislative and regulatory barriers have also contributed to a biosimilars marketplace that

has failed to meet expectations in terms of product availability, uptake and cost savings. 

Jose Carlos Ferreyra Lopez, MBA, is currently President of the Pharmaceutical Institute in Mexico (Institute of Research and Pharmaceutical Innovation), a thinktank and research center for access barriers specialized in the Mexican market. Worked for Eli Lilly as a Demand Realization Project Manager (2000 to 2005) and has been a consultant for more than 200 pharmaceutical companies established in Mexico. He has been either chairman or keynote speaker in several international congresses in Mexico, Bucharest, USA and Italy. Speaks 3 languages and his background includes being the congressman for the Nuevo Leon administration in 2007.

In this presentation, I will explain the composition of one of the biggest and complex public health systems in the world. Over 150 public buyers in Mexico provide health services to over 125 million beneficiaries. Mexico public health system is managed by 33 independent (yet organized) health ministers, managing over 9,500 medical units and hospitals. The total pharma market value is worth over 4,500 MUSD per year and 1,750 million units. Also, will explain the access roadmap to get to the 150 government public buyers, including timings and procedures.

Joel I Osorio is an innovative businessman with a distinct entrepreneurial mindset concentrated adding value on areas of Biotechnology (mRNA), reprogramming & regenerative medicine for translational use in humans and a variety of clinical applications aimed for both the private and the public health sectors. He is the founder, president and CEO of RegenerAge Clinic and RegenerAge Beauty initiatives for transnational implementations. Vice President and International Clinical Developer for Bioquark, Inc. Executive Vice President: Chairman of the WAMS Americas Division, member of the WAMS Executive Council (WAMS Executive Board), a member of the WAMS Education & Training Board (ETB), a member of the WAMS Editorial Board, an Honorary Member of the Academy Faculty FWAMS, an Honorary Fellow of the Academy & is also a Senior Partner at WAMS, The World Academy of Medical Sciences.

Bioquantine a mRNA extract from Xenopus laevis frog oocytes (purified from intra- and extra-oocyte liquid phases of electroporated oocytes), showed potential as a treatment for a wide range of conditions in animal models, including Spinal Cord Injury (SCI) and Traumatic Brain Injuries (TBI) among others. The current study observed beneficial changes with Bioquantine administration in a patient with a severe SCI. Pluripotent stem cells have therapeutic and regenerative potential in clinical situations CNS disorders. One method of reprogramming somatic cells into pluripotent stem cells is to expose

them to extracts prepared from Xenopus laevis oocytes. Due to ethical reasons and legal restrictions we selected a no option patient, deciding to include in our protocol the RestoreSensor SureScan to complete it. Based on the electrical stimulation for rehabilitation and regeneration after spinal cord injury published by Hamid and MacEwan, we designed an improved delivery method for the in-situ application of MSCs and Bioquantine in combination with the RestoreSensor SureScan. To the present day the patient who suffered a complete section of spinal cord at T12-L1 shows an improvement in sensitivity, strength in striated muscle and smooth muscle connection, 14 months after the first Bioquantine and MSCs treatment and 9 months after the placement of RestoreSensor at the level of the lesion, showing an evident improvement on his therapy of physical rehabilitation (legs movement) on crawling forward and backwards and standing on his feet for the first time and showing a progressively important functionality on both limbs.

Sabiruddin Mirza is currently a Senior Research Fellow at the School of Engineering and Applied Sciences at Harvard University, Cambridge, MA, USA and an Adjunct professor at the University of Helsinki, Helsinki, Finland. After several years in the full-time industry, he escaped to academia and earned his PhD degree inpharmaceutical technology from the University of Helsinki in 2007. His dissertation research has been awarded the 2008 American Association of Pharmaceutical Scientist’s Outstanding Graduate Research Award in Pharmaceutical Technologies. His current research is focused on the engineering of advanced Nanosystems for drug delivery applications. In addition, his areas of expertise include pharmaceutical crystallization, cocrystallization and Nano crystallization, droplet based microfluidics and solid-state characterization, preformulation and formulation. Overall, his research has attracted around $550 000 in sustained funding from the Academy of Finland, private foundations and industries. He is the author/coauthor of over 50 peer-reviewed articles and conference proceedings. 

One of the therapies which hold enormous potential for treating many terminal diseases includes protein-based therapies. Yet due to scarcity in development of universal technological approaches that develops protein formulations with targeted attributes blocks the clinical translation of these advanced therapies. The current study emphasized development of protein formulation with using droplet-based microfluidic technology which characterizes size, internal morphology, protein release profile and encapsulation efficiency.