• The success rate for biologics in the pipeline
• Process efficiency or titer commercial processes
• Physical capacity if used for multiple products
• Overall regulatory approval time lines for bulk process changes

• Targeting limited development resources and increasing their impact by utilising modelling tools
• Unifying process data with mechanistic and phenomenological models
• What this means for understanding production processes and productivity improvements
• Examples of process mapping exercises that have improved productivity

• Mapping the entire cycle time from raw material to finished product
• What are Lean Operations concepts?
• Monitoring lot progress through the entire plant using tracking tools
• Opportunities in the planning function to reduce inventory levels
• How to reduce changeover time in filling lines

• The key components of a robust collaborative solution
• Knowledge management strategies to ensure all intellectual capital is captured
• Creating a value chain with partners, all concentrating on core competencies
• How to align your collaborative tools with business objectives
• Measuring success: proof points

• Process development strategies   
• Impact on products
• Transfer to manufacturing operations
• Building capacity for large volumes

• Planning for optimal utilisation of capacity with respect to workload and existing constrains
• Utilising enterprise systems to support planning and scheduling
• Prioritisation of sample testing based on business drivers
• Tracking laboratory performance

• The biopharmaceutical market and the expected demand for manufacturing capacity
• Options to meet demand
• Process improvement technology
• Expansion of manufacturing capacity
• The need for flexibility and operational excellence

• Investment strategy
• Capacity utilisation
• Productivity increase
• Inventory management

• Impact on development cycle
• Product valuation
• Technology transfer
• Personalised medicines

• Trends in manufacturing for existing product classes
• Yield improvements
• Transgenics
• Challenges for purification
• New locations
• New product classes – biogenerics, gene therapy and novel vaccines, tissue engineering and cell therapy
• New formulations and delivery systems

• Coping with a diverse range of products
• Strategies for fermentation process development
• The value of a co-ordinated multidisciplinary approach

• Size of the global biopharmaceutical industry (including forecasts)
• Demand vs capacity: contract vs in-house
• Outsourcing trends
• Plans for multi-use facilities and transgenic technologies

With the complexity of serum-free medium formulations and time constraints required in process development, most cell culture systems used in the biopharmaceutical industry are unable to be fully optimized.

We have developed a comprehensive approach to cell culture medium optimization based on three different, but complimentary approaches.

These approaches are statistical, analytical and molecular.

Our statistical approaches utilize Design of Experiment (DOE) statistical methods. Our analytical approach is to examine the concentration of critical components in medium after cells have been cultured (spent medium analysis). Also, we use the analytical approach for better characterization of critical raw materials.

Molecular approaches may allow for a more targeted choice of the components to be tested. We have used these approaches to optimize multiple serum-free, animal component-free formulations for various cell types. In this presentation we will review our approaches in accelerating the medium development process.

• Two ways of increasing the throughput rate in development:
  - increase the number of parallel experiments
  - decrease the duration of the experiments
• Using a combination of PAT and PIMS tools to follow both ways in parallel
• Increasing the number of experiments per unit time by "telescoping" experiments by automation (PIMS)
• Avoiding waiting periods for results of lab based off-line analytics (PAT)
• Reducing the duration of the development

• Monoclonal antibody supply challenges
• Microbial expression technology to produce humanised Fab fragments
• Ways to effectively recover these fragments
• Scale-up for GMP manufacture

• Optimisation of expression technology
• Cell line selection / screening
• Optimisation of the fermentation process
• Impact of upstream process on recovery steps

• Focus of traditional methods of media development
• Impact on yields of the use of rich basal media and rich feed supplements in fed batch systems
• How to simplify basal media and feed supplements to improve the efficiency of fed batch systems resulting in improved product yield
• Problems and solutions in optimising fed batch culture systems

• Versatile expression system for either intracellular or periplasmic localisation of product
• Multiple construct screening to obtain stable high production clones
• Use of the periplasmic space to protect sensitive products from proteolysis
• Rapid product capture from the periplasmic space using homogenisation in combination with expanded bed chromatography

• The ability of transgenics to produce proteins and antibodies that are difficult to express in bioreactors
• Parameters to be discussed for each system:
  - economics    
  - safety
  - regulation    
  - intellectual property
  - ethical and public acceptance  
  - costs
  - downstream processability  
  - capital

• Has the industry met the challenges regarding the contamination of other crops?
• Where do good agricultural practices (GAP) end and good manufacturing practices (GMP) begin?
• Where worries over glycosylation differences were overrated?
• Downstream innovations expected from manufacturing-scale PMB operations

• Innovation and risk tolerance in the downstream arena
• Current trends and techniques: generic platforms vs DOE screening, conti vs batch, disposables vs multi-use, beads vs membranes, crystallisation vs separation, virus removal vs inactivation etc
• Novel virus filters and specialised modes of operating next-generation ultra-filtration membranes
• Improved process economy with whole process design and integrated unit operations
• Risk management and comparability aspects in DSP

• Design considerations for flexible, disposable container systems
• Container film is the critical component that dictates container performance
• Five key performance requirements –
  - container geometry
  - operating environment
  - permeability
  - material compatibility
  - transportation
• Assessment of commercially available flexible, disposable systems

• State-of-the-art facility design optimised for disposable technologies
• Kleenpak disposable Aseptic Connector and Biosafe sterile fluid transfer technology – impact on layout
• Modular building approach for reliability, highest quality and safe secured fast implementation
• Impact of disposables within a modular multi-product plant
• Facility cleandown and turnaround time, labour, throughput, COG analysis

• Benefits of improving product capture steps
• Benefits of improving process yield and reduction of facility residence times, utilisation of factorial experimental design and scaled down process models
• Rationalisation of product supply strategies and tactics
• Disaster recovery scenarios and realities

• Identification of the best affinity ligand
• Development of a qualified binding assay
• cGMP production concept for the affinity matrix up to industrial scale

• Impact of different adsorber matrices on the mass transfer effects and binding kinetics
• Advantages, limitations and future perspectives of membrane adsorber technology
• Critical parameters and features of materials, functions and device and system design for membrane chromatography
• Theoretical and practical scale up considerations
• Evaluation of in-situ sterilisation methods on the performance of membrane chromatography

• Comparison of the different regulatory policies
• Potential impact of these policies on the production and cost of biopharmaceutical clinical trial materials and market supplies
• Capital resources needed to fully implement and comply with the new requirements
• Impact on the financing and timing of new product development
• Strategic options for contract manufacturers and impact of the regulations on global capacity 
• Timelines for compliance with these new guidelines

• How does GMP relate to investigational medicinal products?
• Manufacturing and analytical requirements
• Batch release
• Dealing with products manufactured outside the EU

• FDA update: new GMP guidance and initiatives
• Validation essentials, establishing protocols, cleaning and processes
• Computerised system validation requirements in manufacturing
• Enhancing manufacturing techniques with PATs and real time monitoring
• Implementation of effective investigation with a CAPA programme

• Harmonised, risk-based, science-based quality systems for the 21st century
• What is risk management and what is the FDAÂ’s definition?
• Developing quality by design initiatives and implementing manufacturing science principles
• Regulation assessment versus inspection issues
• Technology integration: enhancing QA and compliance in biopharmaceutical manufacturing

• Generating qualification data for equipment components
• Documentation for automated systems
• Outsourcing process validation to equipment suppliers
• Scale up implications for filtration and separation systems

• The science of well-characterised biologics
• Recent FDA restructuring and EU institutionsÂ’ initiatives
• Industry and international trends
• Public policy trends

• What will be necessary to show essential similarity?
• Is the possibility of using the well-established route procedure a practical one?
• If so, how will you show that the product is similar to one with well-established use?
• What features of the specific biological product will determine what might be the most appropriate route?
• How will things change under the new European legislation?

• The revision of Directive 2001/83 and the recent adoption of the update of the Annex I of that Directive
• The legal basis for the review of marketing authorisation applications
• Is the approval of biosimilar products by the EU institutions inevitable?
• Barriers to biogenerics

• Challenges presented for safety assessment programs for biologics as compared to small molecules
• Unique biologic product development issues
• Key aspects of a product comparability programme to prove therapeutic equivalence
• Scientific issues that bear on safety considerations for follow-on (generic) biologics

• Operations excellence practices from outside the industry
• Adoption of operations excellence in life science
• Current use of best-practice within the industry
• Specific tools the industry can use to drive operational improvement and success

Operations excellence begins with assuring the quality of the material and product produced by suppliers and partners.  In an industry like biotechnology, where having partnerships is a main operational strategy, good management of these suppliers and partners is critical to operational success.

• Choosing and implementing an outsourcing strategy
• Supplier selection and auditing
• Supplier management, including planning and control and quality management

Many of the reasons that biopharmaceutical companies struggle with deviations in production can be traced to the upstream development processes.  Many industries have found the key to operations excellence begins in the development phase by assuring that products are robust before being transitioned to volume production.  Proven techniques exist to make the process of product development support the needs of the manufacturing plant.

• Design for manufacturing
• Design for Six Sigma
• Design for lab testing, repeatability, process "error proofing"

Day-to-day operations excellence practices have historically been designed for the manufacting area,  Concepts that have been in place for years in other industrise can be applied directly to the production floor in biopharmaceuticals.  The impact of these philosophies and tools has been shown to result in dramatic improvements not only in production efficiencies, but also in product quality.

• Design of plants and manufacting strategy options
• Clinical vs. marketed in same plant
• Scheduling and management of resources
• Production quality, maintenance and facilities management

Biopharmaceutical laboratories are comlex environments, with a large mix of products enetering the laboratory on a daily basis.  Many of the tools used to run a large production operation can assist with the lab operation and optimise the impact of this operation on the overall supply chain

• Sample management and labour planning
• Integration of labs into the supply chain
• Use of automation and LIMS
• Mixed mode labs (clinical development, methods development, validation, etc.)
• Labour definitions (job descriptions)

Although traditional operations excellence principles see quality assurance as a non value-added activity, the regulated nature of the indstury requires a certain level of oversight to assure product quality.  The steps in the overall supply chain.  The typical tools of operations excellence can be applied to minimise the impact of quality assurance on the product supply

• Integration of needed functions to drive on-time product release
• Accountability and measurement
• CAPA and reducing deviation events

Full workshop leader details can be found on the Workshop leader page

Tefen is a publicly traded, international operations consulting firm with offices in North America, Europe and Israel. The firm has over 20 years of experience improving the overall operational effectiveness of Fortune 500 clients. Tefen designs and implements solutions enhancing a company’s productivity, efficiency and service level. Tefen has successfully worked with over 30 of the top 50 global Life Sciences businesses, including 8 of the top 10 biopharma companies. Tefen is the facilitator of the BioPharma Operations Excellence Consortium (www.tefen.com/consortium) and is leading the BioBenchmark – the first ever industry-wide operations benchmarking study (www.tefen.com/biobenchmark).