Kim Sandell discusses next generation manufacturing processes and the most crucial action points in their development. He highlights the importance of balanced processes, clearly defining one batch processes and tact. The concept of one batch process is a facility capable of handling a whole process flowing through as one batch with no requirement to pool fermentation batches prior to purification. Tact measures the rate at which the facility is capable of putting out batches. In a facility with one batch process this will be the measurement for the whole process, but in a facility with varying capabilities e.g. fermentation and purification, this might vary and cause unnecessary delays in the process. Bottle necks and de-bottlenecking will be discussed and to conclude the presentation, a case study will highlight the benefits of having a well designed approach to the operation of a facility early in the design process. In this case study, an implementation of a new process for Genotropin, the well known human growth hormone, will serve as the example.

Novo Nordisk is committed to conducting business in a financially, environmentally and socially responsible way. As climate change has global implications on all three dimensions, taking steps to reduce the company’s impact is both an act of corporate responsibility and critical risk mitigation. In 2003, Novo Nordisk began shaping its strategic response to climate change and in January 2006, Novo Nordisk joined the WWF Climate Savers Programme. The agreement between WWF and Novo Nordisk commits the company to restructure en-ergy consumption from Novo Nordisk’s production sites so that the company’s total CO2 emissions by 2014 will be 10% less than in 2004. The 10% absolute reduction target is voluntary and bold. In light of the projected significant growth in production capacity, the absolute target represents a relative reduction of approximately 65%. It requires that growth in production is decoupled from growth in energy consumption and calls for both incremental advances and radically innovative solutions. The reduction is achieved through three levers. Optimisation through the Novo Nord-isk LEAN programme, cLEAN®, energy savings in production and conversion to re-newable energy.

Markus Schneider is Head of the Novartis Biotechnology Centre in Huningue (France). His main responsibilities in Huningue cover the commercial supply of the recombinant anti-IgE antibody Xolair® and transforming the facility, initially built as mono-product, into a flexible multi-product operation. Markus Schneider joined Novartis in April 2007. Before that he was employed by Serono, today Merck Serono, in different positions in Engineering, Project Management and Manufacturing since 1996. Markus Schneider studied Biotechnology at the Swiss Federal Institute of Technology in Zurich (ETH) and holds a Doctorate in Chemical Engineering from the Swiss Federal Institute of Technology in Lausanne (EPFL).

"The only constant in life is change.” Change has gained so much momentum in the 21st century, that by the time you read this abstract, changes in world events will have no doubt affected history. Subsequently, the work place is not immune from change. At work, everyone plays the change game. Winners and Losers; Heroes and Villains; Success and Failure are all decided by how people effectively adapt to change. With rapidly occurring changes to process, technology and infrastructure, today’s employee, more than ever, is forced to deal with change. While most companies claim to be experts in change initiatives, why is it then that many of them do not recover their original investment? The answer: dealing with change requires a systematic way of thinking. By studying the success and failure of change initiatives, experts are able to isolate the dimensions of risk that lead to these outcomes. In addition, by understanding the risks associated with successful change execution, one may increase the probability of launching and benefiting from these change initiatives. The three most common change execution risks and mitigation strategies will be discussed in details. Associate Director, PROP Operational Excellence Fadel has an extensive background in the strategy and execution of process improvement initiatives. He began his Lean Six Sigma experience in the semiconductor industry where he pioneered process improvement principles in the high volume, high product mix manufacturing environment. Over the past seven years, Fadel has been working in the biotech industry at Amgen and Genentech. As an innovator, Fadel transformed the biotech culture by ensuring the successful deployment of Lean Six Sigma mindset. Fadel’s background combines skills in leadership, quality, operations, manufacturing and technical management. He is a frequently a keynote speaker at International conferences. Fadel holds a doctorate in mechanical engineering from UC Berkeley and he is an ASQ certified Six Sigma black belt and quality engineer.

Manufacturing processes for therapeutic proteins derived from plasma were developed several decades previously using Cohn-fractionation. The upstream part of plasma fractionation involves multiple precipitation steps — unique to plasma industry—while the unit-operations involved in downstream operations has much in common with the Recombinant industry. Since plasma is pooled from thousands of individuals, by definition, results in varying feed stream. The lot-to-lot variation in feed stream coupled with the scale of operations—often an order of magnitude higher than the Recombinant industry— provides a unique challenge toward implementing PAT & QbD in plasma protein fractionation. In this talk I will discuss strategies, process maps and tools to seamlessly integrate process analytics, operations and regulatory filing.

Many biotech companies use collaborations with external manufacturing partners to source some or all of their products. In determining which manufacturing strategy best suits its needs, a company must decide between in-house manufacture or outsourcing. The presentation will outline the complexity of influencing factors that determine a company's best production strategy. It will focus on the crucial make or buy decision and how to select the right manufacturing partner and collaboration model. Special emphasis is put on best practices how to manage external manufacturing relationships. What structures and processes must a company have in place to effectively manage external manufacturing partners? Dr. Ulrich Rümenapp is Head of Biotech Projects in Contract Manufacturing Biotech at Bayer Schering Pharma AG, providing team leadership, manufacturing process and project management expertise to ensure reliability in supply, quality and economy of costs for products from existing and up-coming external cooperations.

As a modern biotech company imusyn deals with intelligent biomedical diagnostic applications designed for medical fields of transplantation and transfusion. The human immune system owns a huge variety of recognizing agents ensuring the proper treatment of own and foreign cells which enter the body. Accordance in tissue attributes remains to be guaranteed before performing transplantations of stem cells and solid organs and represents a great market for applications based on diagnostic and therapeutic recombinant proteins. Broad-gauge production of a huge variety of different recombinant proteins faces controlling elements of lean management and capacity planning. In this case biological production requires optimization more than enlargement based on a robust biotech platform which resists highs demands of quality and allows simple product expansion. As director of recombinant protein production Dr. Grote-Westrick possesses strong expertises in development and establishment of industrial production platforms and lean adjustments in professional production scenarios. Capacity planning for broad-gauge biological production enabled realization of parallel productions and a basement for a progressive product portfolio, not at least through intensive information transfer at the 7th biological production forum in Munich 2008. By application of aspects concerning lean management and platform strategies well-organized activities within production processes have been adapted to high-class conditions

Bill is one of the godfathers of generics, having worked closely with Senator Henry Waxman to initiate and negotiate the 1984 Drug Price Competition and Patent Restoration Act (Hatch-Waxman). He is now on the front wave of the fight to bring biosimilars into the mainstream and is looking forward to sharing his knowledge of subject with a European audience! Bill Haddad is a generic drug manufacturer, a founder of the generic trade association and its chairman/president for over a decade. Was vice chairman and CEO of solid dosage manufacturing for Schein Pharmaceutical, one of the largest generic companies. He initiated and negotiated the Drug Price Competition and Patent Restoration Act (Hatch-Waxman); helped to organize the team leading to the reducing of AIDS prices in Africa from $12-15,000 a year to less than a dollar a day. He began his studies/hearings/writings on the multinational pharmaceutical companies as an assistant to the late Senator Estes Kefavuer. Was one of the founders, Associate Director and Inspector General of the Peace Corps and the poverty program (OEO). He worked as an assistant to Robert Kennedy and during the presidential campaign as a liaison between Robert and Jack Kennedy. He was Mario Cuomo's campaign manager in his first successful effort to win the governorship in New York. He is currently attempting to create a generic biotech industry where the issues are not scientific, but political.

The total value of the animal health industry is 17.7 billion dollars per year (2006), rising at a CAGR of about 5% per annum. Historically, the industry has been split between Biological products, feed ingredients and Pharmaceuticals. In recent years, the use of feed ingredients has been discouraged, which has resulted in a larger share of the market being focused on animal health Biological and Biopharmaceutical products. Conventional vaccine manufacture originally relied on whole animal systems, egg culture, primary cell culture, and basic fermentation systems. Increasingly, these technologies are being overtaken by bioreactor technology and the use of established cell lines, animal origin free primary ingredients, and define culture media, driven not only by cost but also by legislation against extraneous agents such as transmissible spongiform encephalopathies (TSEs). Purification methods and adjuvant technologies have also moved quickly forward due to the need to balance product effectiveness with target animal and user safety. Animal health vaccines have embraced many new technologies and there are well over 100 products on the market in various geographical regions that use GMOs, vector based systems, DNA and recombinant proteins, whether bacterial, viral, protozoal, or eukaryotic-derived.

Klaus Graumann, Ph.D. (25.04.1967, Austrian) Ph.D. in Biotechnology from the University of Life Sciences and Renewable Resources (BOKU) in Vienna, Austria (Prof. Alois Jungbauer). Since 2001, at Sandoz (former Biochemie) in Kundl (Austria), in several positions within biopharmaceutical development. Since 04/2009, Global Head Technical Development (a.i.), Novartis Biopharmaceutical Operations.

Chromatography is the most important unit operation for capturing of protein biopharmaceuticals from clarified feedstocks; irrespective the proteins are produced by E.coli, yeast or mammalian expression systems. Predominantly ion-exchange chromatography is used for this purpose, although for antibody purification affinity chromatography with staphylococcal protein A is standard. With increasing titer the capacity of chromatography may reach a physical limit. Alternative strategies such as precipitation and bulk crystallisation for recovery of protein biopharmaceuticals will be discussed.

Dr. Arunakumari is Senior Director of Process Development at Medarex, the worldwide developer of human antibody therapeutics. In her role, she oversees the development, scale up and transfer of cell culture and purification processes. Her extensive 16 years of experience in management roles at Enzon, Bristol Myers-Squibb, and Medarex, have been instrumental in integrating upstream and downstream processes. She significantly improved over all facility output, batch processing time and cost of goods by developing simple non-protein A purification processes in fewer processing steps and column cycles. Her technique not only optimized conditions to remove all process related contaminants on ion exchange resin comparable to that of affinity chromatography, but also modified the process schemes with two chromatography steps that require less validation costs with the implementation of disposables. These ‘ion exchange-processes’ were scaled to handle 5000 liters of cell culture harvest. Arunakumari’s critical contribution to Medarex platform technology produced 14 different humab processes to transfer to Medarex manufacturing facility and CMOs.

This presentation will review an industrial case study addressing the challenges and trade-offs of a high yielding process on the purification operation of a marketed product. The purification process was developed to recover twice the amount of product for which an existing plant was originally designed for, while maintaining high yield and product quality, and being transferable to multiple manufacturing sites.

The complexity of the manufacture of biologicals sets high standards for quality oversight and regulatory control processes. The various steps in the upstream, downstream and fill & finish process often take often place at different locations around the globe and should be managed from one focal point. As the product matures in routine production, process changes are often inevitable to increase efficiency and to prevent huge product losses. An effective change control process with involvement of the various disciplines within the company should ensure smooth implementation of changes with timely regulatory approval in order to prevent stock-out situations in specific regions. This presentation discusses some real-life examples of reasons for process changes, organisation of change controls systems, business impact assessments and at last implementation of changes for biologicals

An important part of process transfer from development to manufacturing is to supply a process model. This model is used to predict and compare process performance across scales under various operating conditions. Additionally, the model can be used to predict performance outside the range evaluated during development, which can streamline the development process. In this work, we present several specific examples of how process modelling can be used to facilitate the transfer of a large scale process. Additionally, process models were used as a tool to troubleshoot unexpected challenges faced at large scale, as well as to formulate solutions to address the challenges.

Crucell and The Aeras Global TB Foundation are collaborating in the development of a recombinant adenovirus (rAd) based Tuberculosis vaccine for which Phase II studies are currently ongoing. The manufacturing process supporting these Phase II studies was developed using the PER.C6® cell substrate. At the productivity of this production process, scale-up to 10,000-liter bioreactor will be required to provide a minimum of 100-200,000,000 doses to assure an immediate global impact on disease burden immediately after licensure. Given the uncertainties attendant to the CAPEX commitment required to develop a facility for a 10,000-liter bioreactor process and the unprecedented need to develop a viral vaccine manufacturing process at 10,000L scale under BSL 2 conditions, our approach is to focus on intensification of the rAd35 manufacturing process. Accordingly, we have set as an objective, a 10-20 fold intensification of the Upstream Manufacturing Process to be realized through increases in volumetric productivity. This presentation will review our approach to upscale an intensified rAd35 process, focusing on both decreases of process times and increase in productivities.

Emiliano Toso has been with RBM Merk Serono since 1999, for the last five years as Head of the Molecular Biology Laboratory in the GMP Biological Quality Control department. He has a PhD on Human Biology: molecular and cellular basis from Turin University. Since 2000 he has set up and validated (GLP/GMP) PCR and qPCR detection of viruses and retroviruses in cell banks and bulk harvests, as well as genotypic characterization of human, CHO and bacterial cell lines, microbial identification of environmental monitoring and in process control samples with genotypic methods, mycoplasma detection by PCR and qPCR, residual DNA determination by qPCR on in process control and on drug substances, and DNA profiling for identifying human cell lines. In 2008 he won the MerckSerono Best Pharma Award. He has been invited to speak at several international conferences organized by PDA, IBC, Informa and CHI in Europe, USA and Asia

This presentation will discuss global expectations when making changes and/or transferring products to new sites. Gain greater understanding of the following: • Regulatory expectations for major process changes and multiple manufacturing sites, examples where QbD can help • Timing and bridging stock planning • Where CMC and Clinical Development overlap, is harmonization the keystone to comparability? Shelley Suggett is Product Manager with Global Supply Chain in Genentech Inc.’s Product Operations Organization (PROP), providing team leadership and Commercial Product Planning expertise to deliver product strategies which enable PROP to safely, reliably, and cost effectively deliver quality products to all our patients. She leads a cross-functional team comprised of senior individuals with specialties within the manufacturing, quality, and regulatory organizations. Currently, Ms Suggett is the Avastin PROP Product Manager and Team Lead , and is the designated launch team lead for Trastuzumab-DM1. In her role, Ms. Suggett is a member of several Core and Franchise teams for the products, providing CMC input for global development programs. Prior to her role as a product manager, Ms Suggett was a member of Genentech Regulatory Affairs and was responsible for worldwide CMC regulatory strategy for numerous marketed and development biotechnological products. Prior to Regulatory Affairs, she was a member of the Genentech’s Research Immunology Group, focusing on antibody discovery, development and characterization, including affinity maturation and humanization; this group’s effort led to many of the marketed and development molecules in Genentech’s pipeline today. At the UCSF affiliate J. David Gladstone Institutes, she focused on vaccine development, and neurobiological and HIV research for the Department of Immunology. Ms. Suggett is published in various scientific journals and holds patents for her work in antibody development. She received a Bachelor's of Science Degree in Biochemistry from California Polytechnic State University, San Luis Obispo.

Cation exchange (CEX) capture followed by anion exchange polishing step yielded effective and economic two-step non-affinity purification scheme for certain HuMabs. In these processes, primary recovery (PR) with concentration and diafiltration TFF was essential prior to loading on CEX. Here, we describe an alternative and scalable contaminant precipitation procedure to successfully replace PR TFF. The significant reduction of host cell protein (HCP) by precipitation method (~ 3 log reduction) enabled easier integration into two-step ion exchange purification scheme for many HuMabs. Product quality after a single chromatography step yielded less than 10 ng/mg CHO HCP and provided the best economics to use disposable membrane polishing chromatography which is mainly placed in this case for viral removal strategy. Data from several HuMabs case studies will be presented.

Understanding and control of the manufacturing process are coinciding key criteria of process development and the FDA's PAT and QbD initiative. These mutual interests are impaired by the complexity of bioprocesses and the challenge of in-, on- and/or at-line measurement of physiologically relevant variables. An opportunity to overcome this problem is the application of a chemometric approach to integrate and correlate physical and chemical variables with a broad spectrum of off-line data sets. The implementation of novel on-line sensor systems like multi-wavelength on-line fluorescence spectroscopy or proton transfer reaction mass spectrometry and the expansion of off-line analysis to high-through-out off-line techniques (omics-technologies) strongly support this concept. Altogether, the application of PAT and chemometrics opens new dimensions in process understanding, enables identification and monitoring and/or prediction of critical process parameters (CPP) that have significant influence on critical quality attributes (CQA) and is therefore the base to implement the QbD concepts.

Process economic issues associated with manufacturing antibodies have attracted increasing concerns due to the requirement on the timely and cost effectively development of drug candidates. Process economic models can be used to evaluate the efficiency and cost effectiveness of alternative manufacturing strategies, especially in searching for alternative downstream processing approaches to cope with the increasing titers in mammalian cell cultures. The application of Cost of Goods analysis in biopharmaceutical industry will help to achieve more effective decision-making in the design and operation of antibody manufacturing process, including process development, process scale-up and technology transfer to GMP manufacturing.

Successfully purifying monoclonal antibodies (mAbs) at process scale from any expression system need not be overly difficult; the purification process should deliver pure mAbs, in good yield, irrespective of the level of mAb expression impurities. Bio-Rad introduces a simple yet effective purification process, based on a high specificity capture media, followed by two polishing steps that use simple pH adjustment, without the need for buffer exchanges. This method effectively removes host cell proteins (HCPs), ribosomal DNA, and mAb aggregates. Lastly, it uses media designed for commercial-scale production, so users can easily scale up a given process from laboratory to pilot and production scales without difficulty.

Depth filters have established themselves over the recent years as first choice separation tool in cell culture processing and related bioprocessing applications. Second generation filters are often installed downstream of a first centrigution step and use typically integrated prefiltration to maximise dirt hold capacities and provide filtrate qualities required for the next processing steps. In full scale production, cleaning requirements, handling aspects and hold-up volumes impact on the overall process economy. The workshop will introduce a novel design of fully disposable capsule filters and present on scale-up performance and case study material.

Upstream equipment manufacturers initially focused on the bioreactor bag and aeration, sensor manufacturers continued selling existing products, and system integrators applied their stainless steel reactor control principles to single-use bioreactors. As a result, the supply chain for single-use systems has fragmented into bioreactor/bag suppliers, providers of control systems, and sensor companies, with few completely integrated solutions. Finesse’s family of “Tru”-products for measurement and control of single-use bioreactors that offers a fully integrated, flexible solution designed to optimize bio-process performance will be introduced. The evolution of the optimal single-use system, from custom to configure-to-order, will also be discussed.

Andreas Schneider is Director global Sales of innovatis AG, headquartered in Bielefeld - Germany. After graduating in Business Administration (BA) 1990 he worked in leading positions in IT business e.g. data management, data integration and information management for various branches of industries. In 2003 Andreas Schneider joined innovatis where he held various positions including Head of Sales DACH, Head of Business Development Europa and Director Operations US. Since 2007 he is responsible for global sales at Innovatis AG, one of the leading companies in automated cell analysis in pharmaceutical market. Mr. Schneider has a broad range of global experience in PAT, Process Automation and Data Integration projects especially in biopharmaceutical industry. Within the ISPE organization he is active member of the PAT Community of Practice (CoP) and takes the co-chair of the global PAT Data Management Team.

Manufacturers are applying an increasing number of qualification criteria to their production culture media and process supplements. They now specify SFM and strongly recommend animal component-free materials. Recombinant and plant-derived proteins and hydrolysates are currently acceptable, whereas the demand for completely chemically defined formulations is growing. Defined media reduce material lot-to-lot and common cause variability, and facilitate process verification and understanding. Optimization of nutrients, cofactors, and ion-concentration/ratios is now simply a starting point in the development of high-efficiency platform production media and supplements. This presentation provides contemporary data on SFM and culture feed materials designed to support such increased demands.

Gerd Walter, Born 17.09.1966 Frankfurt Germany Study from 1988 - 1993 Dipl. Ing. Chemische Technologie (FH) Darmstadt From 1994 - 1997 working as Pharmareferent for Schwarz Pharma GmbH From 1997 - 1999 working as Application Specialist Area NRW (Germany) at Millipore GmbH From 1999 - 2001 working as System Specialist Area Europe at Millipore GmbH From 2001 - 2003 working as Technology Manager EU Chromatography Hardware at Millipore GmbH From 2004 - 2007 working as Technology Manager EU TFF & Chromatography Hardware at Millipore GmbH From 2008 till now working as Technology Manager EU Downstream Process at Millipore GmbH

A critical success factor for achieving the goals of QbD is to provide on-demand access to all the process data for end users in process development and manufacturing in a collaborative investigational analytics, trending and reporting environment. Requirements include a single user-centric interface for direct access to all the data in context from disparate sources including paper record, and automatic accounting of batch genealogy to enable upstream/downstream correlations. This presentation will illustrate how these requirements can be satisfied with technologies readily available today.

The number of development projects is ever increasing. High throughput process development (HTPD) tools and workflows need to be established to minimize the efforts spent per molecule while success is still not established but also to generate knowledge about a wide design space during development of the successful ones. Flexibility is the key term describing operations in pilot facilities and GMP facilities for clinical material. Even large scale manufacturing sees more and more different products entering the production floor, often with uncertain or varying predictions for scale. Tools are needed to support flexibility and enable the best possible utilization of invested capital. This presentation will provide examples from development and different parts of the process chain to illustrate how the challenge could be met. Dr. Günter Jagschies is in his 25th year with GE Healthcare Life Sciences (former Amersham) and has held senior management positions in sales, marketing, and R&D within the bioprocess division of the company. His current role is Senior Director Strategic Customer Relations (R&D) working globally with industrial collaborations and as business advisor for the Life Sciences R&D and Business team. He is co-author of “Process Chromatography”, a recent handbook for the biopharmaceutical industry and numerous papers on the development and manufacturing of biotherapeutics. He is based in Uppsala, Sweden

A. Habel studied biology at the University of Tuebingen (Germany) before moving to Paris, where he specialised in molecular virology at the Institute Pasteur (Paris, France). His Ph.D. thesis dealt with several vaccine candidates against Lentiviruses (HIV, SIV & FIV) After his Ph.D. thesis André stayed at the Pasteur Institute as a staff scientist before joining InterCell Ag in Vienna, Austria, in 2001: first as a staff scientist, and later as Department Head. As InterCell acquired the world wide license for a viral vaccine and a state-of-the-art manufacturing plant in Scotland, he moved to Edinburgh in 2004, to ensure the tech transfer and up scaling of the vaccine to be moved into the final Phase 3. This vaccine has been licensed by the FDA and EMEA in early 2009. After the successful launch of this Phase 3, he joined Crucell-Berna Biotech (Bern, Switzerland) in early 2007 as the Director of viral vaccine manufacturing, where he was responsible for the MR (measles & rubella vaccine) and the YF (yellow fever vaccine) manufacturing. In March 2008 Dr. André Habel joined Stabilitech Ltd. in London (UK) as Business Development Executive. Dr. Habel has published numerous articles in peer reviewed scientific journals and holds several patents in the vaccine field. Stabilitech has developed a novel proprietary technology which stabilizes vaccines, biopharmaceuticals and other biological products. Currently, to ensure potency, vaccines and biopharmaceuticals require storage and transport under strictly controlled temperatures in a cold chain. Stabilitech’s technology will enable the long term stable storage of vaccines and other biological products over a wide range of temperatures. The technology has been successfully applied to live viral vaccines, inactivated viruses and sub-unit vaccines as well as to antibodies, peptides, enzymes, growth factors and other proteins. Stabilitech’s approach involves the addition of carefully selected excipients at optimized concentrations and ratios, followed by freeze drying. The excipients have all been previously used in clinical settings, and all are relatively inexpensive and readily available. Stabilitech is a private company based in London, in the Imperial College Incubator.

Stabilitech has developed a novel proprietary technology which stabilizes vaccines, biopharmaceuticals and other biological products. Currently, to ensure potency, vaccines and biopharmaceuticals require storage and transport under strictly controlled temperatures in a cold chain. Stabilitech’s technology will enable the long term stable storage of vaccines and other biological products over a wide range of temperatures. The technology has been successfully applied to live viral vaccines, inactivated viruses and sub-unit vaccines as well as to antibodies, peptides, enzymes, growth factors and other proteins. Stabilitech’s approach involves the addition of carefully selected excipients at optimized concentrations and ratios, followed by freeze drying. The excipients have all been previously used in clinical settings, and all are relatively inexpensive and readily available. Stabilitech is a private company based in London, in the Imperial College Incubator.