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.