Presentations and publications in this field often deal with the question how to develop a good formulation of a biological, focusing on the scientific and analytic approach, i.e. what kind of screening matrix, e.g. with regard to the buffer composition could be used; what are the most appropriate analytical tools to assess the attributes critical to quality and which of them are predictive for stability i.e. for the later shelf life of the respective biotherapeutic. Thus the challenging questions: “Formulations for pre-clinical, clinical- and market-supply – how similar should they be?” is hardly presented and if addressed heavily and controversially discussed. The general answer is: The more similar the better, however it is helpful to have strategies and tools in place to assess similarity and to evaluate the need for similarity i.e. how critical similarity is for the intended use. The presentation therefore will focus on some aspects of strategic approaches which allow the assessment and the evaluation of this question. The content covers: In vitro and in vivo analytical tools, an outline of a formulation strategy for preclinical and clinical development. Examples will be given on how a risk assessment can be performed with regard to changes for the use of standard formulation during early development. Assessing the impact of changes in the primary packaging material will also be shortly addressed. In Addition some economical aspects with regard to attrition rates as well as regulatory requirements and guidelines will be highlighted.

Ursula graduated from University of Bonn with a diploma in Chemistry, received a Masters Degree from the University of California and a PhD in Organic Chemistry from University of Bonn in 1986. From 1986 to 1994 she worked with smaller Pharma respectively Biotech companies focusing on pharmaceutically active proteins. This included responsibilities in Research, Technical Development and Quality Control/Assurance of recombinant proteins and related drug products. In 1994 Ursula joined the Pharmaceutical & Analytical R&D department at Hoffmann La Roche , Basel, where she held various positions. In 2001 she took over global coordination of Nonclinical Development departments in Pharma Research, then located in Basel, Nutley and Palo Alto and assumed global leadership of Technical Sciences, the early part of Roche’s TR&D organization in 2007. In this responsibility she has led and build technical capabilities of API and drug product for various therapeutic modalities supporting an extensive portfolio across multiple disease areas.

Barbara Lueckel joined Roche as a Global Drug Delivery Evaluator in February 2007. She is responsible for identifying external drug delivery technology opportunities for both project-specific and strategic evaluations, leading feasibility studies as well as managing Roche’s strategic alliances with drug delivery partners. In that role, she is working with projects teams as well as technology area strategy teams to fulfill their drug delivery related needs. In addition, Barbara is also responsible for the delivery strategy of certain areas such as peptides. Barbara is a member of both the Drug Delivery Partnering Group within Roche Pharma Partnering as well as the Pharmaceutical & Analytical R&D department of Roche Pharma Research. Prior to joining Roche, Barbara held various roles at Novartis from 1997 onwards: starting as laboratory head working on formulation principles for poorly soluble drugs such as cyclosporine, she became a project leader within the Lifecycle Management & Drug Delivery Technologies section of Technical R&D. In that role she was in charge of evaluating reformulation opportunities based on external drug delivery technologies as potential line extension products. In addition, she supervised three PhD projects on various topics such as solubilization and oral modified release approaches. Barbara trained as a pharmacist and holds a PhD from the University of Basel.

Dr. Samarsky earned a Ph.D. in biochemistry and molecular biology from the University of Massachusetts, Amherst, in 1998. From 1998 to 2001 he was the H. Arthur Smith Fellow for Cancer Research at the laboratory of Dr. Michael Green, a Howard Hughes Medical Institute investigator at the University of Massachusetts Medical School. From 2001 to 2003, Dr. Samarsky led business and technology development at Sequitur, till acquisition of this company by Invitrogen. From 2003 to 2005, Dr. Samarsky served as Business Development Manager at Invitrogen, where he focused on promoting RNAi and other genomics technologies. Most recently, Dmitry Samarsky served as Director of Technology Development at Dharmacon/Thermo Fisher, where his team was responsible for promoting Dharmacon's RNAi program worldwide. In addition, he established and led an RNAi applications laboratory. Dr. Samarsky has authored numerous research articles, reviews and book chapters in the field of RNA.

The duration of drug development cycles are continuously challenged by an increasingly competitive industrial environment. Due to modern high-throughput technologies the number of new chemical entities intended for preclinical and clinical development has increased tremendously over the last few years. In addition, the properties of the NCEs emerging from the research pipelines are more and more challenging. Scientists are frequently faced with drug candidates showing poor solubility and poor permeability. In very short time these difficult drug candidates have to be formulated for preclinical programs as well as human clinical studies. Therefore, smart development strategies are needed in order to shorten the overall development timelines and to address the compound related issues adequately and in a timely manner. The presentation will give an insight in the implementation of the frontloading strategy within Solvay Pharmaceuticals. It will show how the right formulation approach is selected earlier in order to give enough time for proper scale up and a process development according to QbD principles.

Mario Maio is Formulation & Process Development Director at Merck-Serono, since 2007. At present, he is responsible for NCE drug product development, from early clinical investigation until transfer to commercial manufacturing. As well, he is responsible to implement and scale-up new drug delivery technologies that can be beneficial for products’ performance and patients’ convenience improvement. During his professional career, he has developed several oral and injectable formulations for Investigational Medicinal Products that are currently in Phase I-III clinical development. Moreover, he contributed to start-up a new R&D center in Rome, with laboratories and GMP pilot plants for the production of IMPs. Previously, he worked at Serono (2003-2007) as Formulation Development Manager with responsibility for development and clinical production of NCEs, at Patheon (2002-2003) as European Technology Capacity Planning Manager, coordinating the introduction of new products and new technologies in the EU sites’ network, and at Istituto Ricerca Cesare Serono (2000-2002) where he was Laboratory Head of Drug Delivery Systems Scale-Up, working on process optimisation for injectable microparticles and solid lipid nanospheres of NCEs and NBEs. From 1997 until 2000 he was Formulation Team Leader at Eurand International, where he got extensive experience in sustained and modified release oral formulations, taste-masking and microencapsulation. Initially, he worked at Roche (1991-1997), as Formulation Researcher and Production Supervisor. During this period he contributed to several NCE formulations development and life-cycle management of marketed drugs, gaining expertise in high-shear granulation, fluid-bed granulation, spray-chilled pelletisation, tabletting, film-coating and solid-state characterization technologies. He studied at University of Turin, where he received a degree in Pharmacy and a degree in Pharmaceutical Chemistry and Technology.

The ever growing portfolio of low soluble compounds emerging form the biotech industry and drug discovery groups in big pharma requires additional pre-clinical resources in order to assess, evaluate and implement technical and business solutions based on an in-depth scientific understanding of the subject matter. Two of the key challenges to be addressed are firstly developability and secondly manufacturability despite a positive biological endpoint read-out. Technical concepts will be presented tackling the solubility challenge and analysed against the criteria of ensuring a sustainable operation in order to justify either a capital investment into new equipment to manufacture a substantial percentage of the portfolio or to employ existing improved technologies to process niche opportunities driven by SME’s. In the end, a business model and several ideas are posed to facilitate decision making.

At MerckSerono, Drug substance production and Fill/Finish operations are not necessarily performed on the same manufacturing site. One of the main stability issues for the liquid DS is related to the temperature and mechanical stresses encountered during shipment. In order to minimize the impact of these stresses on the product, the composition of liquid bulk DS has to be carefully optimized. In this presentation, we will show how a simple experimental setup could be used to evaluate the impact of shipment and Freeze/Thaw related stresses on a model protein and to rapidly screen for excipients, which will prevent product degradation. We will show how different techniques, including Differential Scanning Calorimetry, can be used to assess protein integrity and the potential for degradation.

Clive Washington gained a PhD in Physical Chemistry from Sheffield University in 1981, and performed postdoctoral work in chemistry before being appointed as Lecturer in Pharmaceutics at Nottingham University. Subsequently he was promoted to Senior Lecturer before accepting a chair of Materials Chemistry at Salford University. In 2001 he left academia to join AstraZeneca as Principal Scientist in Product Development. His research interests include drug delivery, disperse and colloidal systems preparation and characterisation, surface-active and liquid crystal materials and the use of computational tools in pharmaceutical development.

Eddie French is currently Director of the UK Pharmaceutical Sciences Vaccines Delivery Group within Pfizer Global R&D. He has been at Pfizer for over 15 years working in the area of drug delivery, formulation and analytical science. His main interest is in the field of biotechnology looking at the pre-formulation, formulation and characterisation of biopharmaceuticals, notably proteins and nucleotides. He also has a wide experience of drug product development for Pfizer’s inhaled drug portfolio. This included involvement in the inhaled insulin (Exubera™) project. Eddie has a BSc in Biochemistry and gained a PhD in the area of transdermal drug delivery from the School of Pharmacy at the University of Bath. After his PhD he remained at Bath and was appointed as a lecturer in Pharmaceutics, a position he held for 3 years. Following this, he transitioned to industry first working for the drug delivery company RP Scherer in Swindon after which he joined Pfizer Global R and D at Sandwich. Eddie is the current Chairman of the Academy of Pharmaceutical Scientists of Great Britian (APSGB) and also a visiting senior lecturer at Kings College London.

Intravenous delivery of poorly soluble drugs is an ongoing challenge. Formulation design should involve a thorough investigation of physicochemical drug properties for establishing the "formulation space". However, while solubility testing is believed to be simple methodical pitfalls endanger correct interpretation of results. Now new techniques enable the measurement of even complex solubility behavior of drugs. The formulation space frames which solubillization techniques are in-scope for delivering the desired dose and allows to rationalize feasibility testing towards the different formulation approaches. Marketed drugs show which technologies and dosing regimens are acceptable for certain indications.

Lyophilisation is an important technology for stabilising sensitive vaccine. Those molecules only stable for days at liquid state, will end-up with shelf life of years after freeze-drying. The talk will describe the rational approach to develop freeze-drying cycle. The analytical tools available for cycle development will be reviewed The scale-up of the process from early stage to manufacturing facilities will be explained. Optimisation of cycle time and homogeneity study inside the freeze-dryer will be analysed. Finally the talk will focus on how to achieve molecules stability through process and formulation optimisation

Wim Jiskoot graduated as a pharmacist at Utrecht University (1987). In 1991 he obtained his PhD degree at Utrecht University on a thesis entitled: 'Pharmaceutical Aspects of Monoclonal Antibodies'. As a postdoctoral fellow at the University of Utah (1991-1993) he studied protein-ligand interactions using biophysical techniques. After his return to The Netherlands (1994), he became head of the Department of Bacterial Vaccine Development at the Laboratory for Product and Process Development, National Institute of Public Health and the Environment (RIVM), Bilthoven, where he was in charge of the development of production processes for bacterial vaccines. In 1998 he became a staff member at the Department of Pharmaceutics, Utrecht University, where he worked in the field of formulation, delivery and physicochemical characterization of therapeutic proteins and vaccines. In March 2006 he became full professor at the Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University. His main research areas are vaccine delivery and unwanted immunogenicity of therapeutic proteins in relation with protein structure and formulation, on which he published about 135 papers and book chapters. Picture: Astrid Koppers © 2008 Leiden University

Dr. Mak Jawadekar is currently a Director at Pfizer Inc. within Portfolio Management & Analytics Group, a part of Worldwide Bio Pharmaceutical Businesses in Groton-New London. In the recent past, he was responsible for Drug Delivery Technology Assessment function involving external ‘Drug Delivery’ technologies. He has extensive experience in creating and cultivating external partnerships and alliances for drug delivery technologies for Pfizer Global R & D. He began his professional career at Pfizer Central Research in early 1982, after having completed his Ph.D. in Pharmaceutics at the University of Minnesota.

There are several case studies in the public domain that address QbD as applied to solid dosage forms. Currently there are no examples for injectable products. Therefore case studies to provide some examples of how a P2 section might look for a parenteral product were developed using an enhanced QbD approach to development as envisaged in ICH Q8. The quality target product profile considering route of administration, dosage form and stability is the starting point of the development of Symplain citrate i.v. solution. The development of formulation, packaging and manufacturing process of Symplain i.v. were established on prior knowledge, by applying risk management tools and by using DoE. As symplain is heat sensitive a compromise had to be identified between sterilization time and sterilization temperature on the one hand and the level of decomposition products being acceptable on the other hand. Formal experimental design was applied to identify the design space of the sterilization process and the acceptable sterilization time and temperature from a quality point of view. A control strategy and post marketing management plan have been suggested.

Jürgen Borlak was a Cancer Research Campaign-founded postdoctoral research scientist and in 1990 joined the Marion Merrel Dow Research Institute in Strasbourg, France, as Principal Investigator. In 1998, he was appointed Director of the Center of Drug Research and Molecular Pharmacology at the Fraunhofer Institute of Toxicology and Experimental Medicine; the centre focuses largely on the molecular effects of drugs and xenobiotics, using a wide range of methods and technologies in cell biology, genomics and molecular biology. In 2000, Jürgen Borlak was habilitated in pharmacology and toxicology and received the venia legendi at the Medical School of Hannover. In 2002 he was appointed as Full Professor to the chair of Pharmaco- and Toxicogenomics at the Medical School of Hannover. He was also appointed as Professor of Molecular Anatomy at the Medical Faculty of the University Leipzig in 2003. Jürgen Borlak is author of 183 original publications and 25 book chapters. He is reviewer and member of the editorial board for various scientific journals. Amongst others he is member of the Council on Basic Cardiovascular Sciences and an appointed expert of the World Health Organisation.

Dr. Berthold Bödeker is heading pilot plants and cell culture at the CMC unit of Global Drug Discovery-Biological Development of Bayer Schering Pharma AG in Wuppertal, Germany, which is responsible for the technical development and clinical material production of microbial and mammalian proteins. Before that he held several positions in research, development and production of proteins from mammalian cell culture within the Bayer AG group. Among others he was responsible for the technical development and manufacturing of recombinant factor VIII, Kogenate®, the first world-wide licensed recombinant protein from continuous perfusion culture. In addition he is also responsible for contract development and production of Biologics for external clients as well as acts as manager for outsourced development projects.

Andy trained as a pharmacist, and has eight years experience in the pharmaceutical and biotech industries, having previously worked for Zeneca, Pfizer and RegenTec before joining Critical Pharmaceuticals as Head of Formulation Development. His research has focused on the delivery of macromolecules particularly sustained release, transmucosal delivery and regenerative medicine. He has published widely and has filed a number of patents in the field. He is a member of the Royal Pharmaceutical Society of Great Britain, the Academy of Pharmaceuticals Scientists, and serves on the Scientific Advisory Board of the Controlled Release Society.

A combination of nanotechnology and NanoCrystal formulation (in-licensed from Elan) has been used to manufacture a long-acting formulation for intramuscular (IM) or subcutaneous (SC) injection of an antiretroviral named TMC278 (rilpivirine). TMC278, a next generation NNRTI, has potent activity against HIV-1 infection at daily oral doses of 25 mg. This oral dose was selected on the basis of a 96 week Phase IIb study and is currently being investigated in Phase III trials (ECHO, THRIVE) in treatment-naïve patients. The long-acting formulation of TMC278 was tested in a double blind, randomized, placebo-controlled, Phase I study in healthy volunteers using IM (gluteal, deltoid) or SC (abdomen) single injections of 200, 400 or 600 mg doses. Tolerability and PK of TMC278 were assessed first daily, then weekly for at least 12 weeks after dosing and until the plasma concentration fell below a predefined threshold of 10 ng/mL. This formulation was found to be safe and well tolerated and plasma levels were sustained for weeks achieving levels comparable to trough levels observed with a 25 mg oral dose of TMC278. Low frequency parenteral dosing may improve adherence to drug regimens during maintenance therapy in HIV-1 infected patients or during prophylactic use of antiretrovirals in uninfected people at risk of HIV-1 infection.

Vaccines have a long standing history of efficacy and safety. After water sanitization vaccines, are probably the most successful method to prevent deadly or highly devastating infectious disease. Broadly speaking, a vaccine could be regarded as a controlled way to expose the human immune system to a small sample of a disease-causing microorganism and prepare it to fight it off. Unfortunately, several hurdles reduce vaccine efficacy on some populations or toward some disease. To overcome these limitations more potent vaccines are necessary. Novel molecules like Adjuvants, capable of eliciting vaccine efficacy, can be added to a vaccine formulation to more finely modulate and teach the immune system how to recognize the pathogen and to prepare it for an efficient response. With new Adjuvants also comes the challenge of formulation characterization and stability. I’ll describe some of the more recent Adjuvant approaches that Novartis Vaccines & Diagnostic is pursuing to improve vaccine formulation and efficacy.

The appetite for outsourcing product development and manufacture by pharmaceutical companies is significant and growing rapidly. Outsourcing is one way that large pharma companies seek to improve the attractiveness of their businesses. However, outsourcing should be considered only when there has been a strategic review of core/ non-core activities within the company. The value proposition for internal development compared with outsourcing will be explored in the presentation. The decision to outsource development is likely to have significant consequences for a pharma company in terms of its skill base and size as well as the ease of accessing advanced technologies. The change in the marketplace will depend on whether pharma companies concentrate on standard formulations or high technology activities. In any case contract suppliers will grow in size and number and will need to adapt by acquiring different capabilities. Selection of contractors is becoming more thorough and critical.

René Holm received his pharmaceutical training at the Royal Danish School of Pharmacy, now the Pharmaceutical faculty at University of Copenhagen, Denmark, in 1998. He received his PhD in biopharmaceutics from the same institution in 2002, based upon a thesis focusing on lipid based formulations impact on the intestinal lymphatic transport of low aqueous soluble drugs. Dr. Holm joined pharmaceutical development at H. Lundbeck in 2001, as a pharmaceutical scientist, was appoint pharmaceutical specialist in 2005. In 2006 he moved to head of section of biopharmaceutics, with main responsibility and focus on incorporation of the physical chemical and pharmaceutical disciplines in drug discovery and the non-clinical development. In 2007 he was appointed head of preformulation, a department responsible for the physical chemical characterisations and input, both in liquid and solid state to the entire organisation, from drug discovery, over development and trouble shooting in production with e.g. polymorphism. Dr. Holm is (co-) author of 20 original articles in peer-reviewed journals in the field of biopharmaceutics and preformulation and is named as (co-) inventor of 6 patents within the same fields.

Short, single stranded LNA oligonucleotides delivered systemically as naked molecules are able to potently and safely inhibit therapeutically attractive miRNAs in a range of tissues in experimental animals. The presentation will provide an update on the unique features of LNA oligonucleotides in miRNA therapeutics with particular emphasis on SPC3649, an LNA-antimiR targeting miRNA-122 that is being developed as a novel treatment for HCV

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 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 are relatively inexpensive and readily available. Stabilitech is a private company based in London, UK in the Imperial College Incubator. During the workshop, Stabilitech’s technology will be described, illustrating its ease of integration into cGMP manufacturing processes, with case studies presenting data on both vaccines and biopharmaceuticals.

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 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 are relatively inexpensive and readily available. Stabilitech is a private company based in London, UK in the Imperial College Incubator. During the workshop, Stabilitech’s technology will be described, illustrating its ease of integration into cGMP manufacturing processes, with case studies presenting data on both vaccines and biopharmaceuticals.

Dr. Varma has completed his B.S. in pharmacy from Andhra University, India and MS and Ph.D. in Pharmaceutics from University of Mississippi (Ole Miss), USA. He is a Member of Rho Chi, Sigma Xi and Dean’s honor roll at Ole Miss. Worked for over 14 years in USA at various innovator companies (Syntex Research, BMS, Roche) in various technical and administrative roles. Played a key role in introducing multiple NDA products to the global market including US, Europe and Japan. Well versed in the overall drug development from discovery support thru commercialization. Currently heading Aizant® which provides specialized solutions in the areas of preformulation, formulation development, clinical supplies, clinical studies and commercial manufacturing of finished dosage forms. Core strengths include technical, identifying opportunities, building quality teams etc. Experience ranges from pre-formulation through commercial manufacturing including clinical development of various dosage forms for global filing. Multiple publications and poster presentations in peer reviewed journals. Research interests are in the areas of characterization of excipients and developing poorly soluble drugs having low permeability. Global Technical Champion and Board Member for Process Analytical Technologies (PAT) and Consortium for Advanced Development and Manufacturing Practices (CAMP) in USA. Invited speaker at various scientific meetings and by the Food & Drug Administration (FDA) to train their chemists and investigators in drug development and manufacturing. Governing Board member of a reputed pharmacy college in Andhra Pradesh, India.