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Biopharmaceutical Process Development: Good Manufacturing Practices or Breaking Bad?


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These are the slides from a presentation "Biopharmaceutical Process Development: Good Manufacturing Practices or Breaking Bad?" given by Andrew Warr as part of the 2015 Careers After Biological Sciences programme at the University of Leicester UK

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Biopharmaceutical Process Development: Good Manufacturing Practices or Breaking Bad?

  1. 1. Biopharmaceutical Process Development: Good Manufacturing Practices or Breaking Bad? Andrew Warr
  2. 2. Overview 1. Overview of Biopharmaceutical Industry 2. Process Development 1. What is PD? 2. ‘Andrew, what do you actually do?’ 3. Actavis Biologics 1. Who are they? 2. What do they do? 4. Advice. Leicester to Liverpool. Questions.
  3. 3. What is a Biopharmaceutical? ‘A biopharmaceutical, also known as a biologic medical product or more simply as a biologic, is any medicinal product manufactured in or extracted from biological sources.’  Most often used to describe products that are produced by recombinant DNA technology  Monoclonal antibodies (mAbs)  Hormones  First approved commercial product was Humulin® (Genentech/Eli Lilly), 1982 Biosimilars ‘A drug similar to a biologic drug that has already been approved (the “originator”). The active ingredient of a biosimilar is like that contained in the originator biologic.’ Biologics made by different manufacturers differ from the original product and from each other.
  4. 4. Good Manufacturing Practices or Breaking Bad? Activities in the development and manufacture of therapeutic products to help ensure that a manufacturer can consistently control and produce these products to meet the identity, strength, purity and quality appropriate to their intended use.  Qualified and trained personnel  Materials must meet specified quality attributes  Standard Operating Procedures (SOPs) must be established and followed • manufacture, testing, cleaning, validation  Facilities must be suitable for their intended purpose with proper lighting, air handling, plumbing and sanitation  Records to demonstrate GMP compliance must be properly maintained
  5. 5. “One that is not only safe and efficacious, but that patients don’t dread taking to the point that they don’t take their medication.” “A product that meets the patients requirements, in a manner that can be supported by the local healthcare provider, with a supply chain that can reliably support demand, whilst creating a return on investment to the developer of the product.” “From a manufacturer’s perspective, a successful commercial biological product is one with a robust process that can be manufactured time and time again to give a consistent product that meets the regulatory specification.” “ The best commercial products are those that significantly improve patient lives (with minimal adverse events) and have a reliability of supply.” “Firstly there’s a need for the product, secondly the product is efficacious and thirdly it’s cost effective.” What Makes a Successful Biological Product?
  6. 6. Combined Revenue of Top 10 Global Biopharm Companies?
  7. 7. $442 bn Combined Revenue of Top 10 Global Biopharm Companies
  8. 8. Biopharmaceutical Industry
  9. 9. Product Quality Manufacturability What Is Process Development?
  10. 10. What Do Process Development Scientists Do?  Devise new, or refine existing processes to optimise the performance of the manufacturing process  Improve the efficiency and profitability of the manufacturing process by reducing cost of goods, or implementing new technology to improve efficiency  Implement process controls to make sure the products are of a high quality and are manufactured in a reproducible manner  Scale up the production process via plant trials, making changes to process parameters to ensure quality is maintained during large scale production  Technical reports and specifications
  11. 11. Cell Line Development Upstream Process Development Downstream Process Development
  12. 12. Host Line Example Product Examples Chinese Hamster Ovary (CHO) CHOK1 Activase® Murine Sp2/0, NS0 Remicade®, Erbitux®, Synagis® Cell Line Development CHO as the ‘Industry Standard’  8 out of top-ten selling biologics are produced in mammalian cells  7 produced in CHO cells  $57 billion sales (2011) Why?  Well characterised with high titres  Propagate few human viruses  Allow post-translational modifications
  13. 13. Upstream Process Development (1)
  14. 14.  Fed-batch and perfusion processes  Mixing achieved by one or two impellers  Gas mass transfer via gas sparging  2 – 10 L bench top at lab-scale (glass / polycarbonate)  Up to 20000 L production scale (stainless steel) / 2000 L single-use Stirred Tank Bioreactors Feed Alkali pH temp DO Gases: Air, N2, CO2, O2 RPM
  15. 15. Fed-Batch Processes + Relatively simple, flexible, and potentially shorter time to develop + Typically 10 – 14 days + Concentrated feed addition + VCD up to 10 – 20 x106 cells / mL + 2 – 5 g/L product titre + Single harvest --- Waste products build up during culture
  16. 16. Perfusion Processes + Longer run duration than fed-batch + ~1.0 g/L/day + Smaller vessels may be used compared to fed-batch + Fresh medium added and waste medium (waste metabolites) removed continuously at same rate 1. Extended fed-batch: Product retained within bioreactor and purified as single harvest (~20 days, ultra-high VCD, 10x productivity) 2. Perfusion: Continuous product harvest from bioreactor and purified in multiple batches (up to 60 days) Future: continuous upstream and downstream to increase speed and efficiency
  17. 17. Alternating Tangential Flow
  18. 18. Bioreactor Process Optimisation  Shake flasks, mini- or lab-scale bioreactors  Design of experiments (DoE) studies to evaluate interactions between multiple variables  Medium / feed components, culture duration, bioreactor control parameters (pH, DOT, temperature, pCO2)  Maximise growth, productivity, product quality 1. Increase the time integral of viable cell concentration (IVC) 2. Increase the specific production rate (Qp) of the cells
  19. 19. Quality Attributes Contaminants Product Related Substances Impurities Quality Attributes Aspects of drug product that have the potential to impact patient safety and/or efficacy
  20. 20.  Founded in Liverpool as Eden Biodesign in 2000  Originally a CMO before being acquired by Watson Pharmaceuticals in 2010  Grown to approx. 180 employees  Actavis’ Centre of Excellence for the development and manufacture of all biologics  Process development and GMP manufacturing  Single use facility Actavis Biologics
  21. 21. Actavis Biologics
  22. 22. Leicester to Liverpool 1. Experience  Industrial placement year  Summer placement  Volunteer 2. Interview  Prepare  Question  Relax 3. Open mind  CABS  Do you already know what you want to do?  Relocation
  23. 23. Why Do I Like My Job? 1. Relevant and rewarding 2. Perspective 3. Biotechnology is at the forefront of healthcare 4. Travel 5. “I’ve never met a scientist before”