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

1. Biopharmaceutical Process Development:
Good Manufacturing Practices or Breaking Bad?
Andrew Warr

3. 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.

4. 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.

5. 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

6. “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?

8. Combined Revenue of Top 10 Global Biopharm Companies?

9. $442 bn
Combined Revenue of Top 10 Global Biopharm Companies

10. Biopharmaceutical Industry

11. Product Quality Manufacturability
What Is Process Development?

12. 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

13. Cell Line
Development
Upstream
Process
Development
Downstream
Process
Development

14. 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

15. Upstream Process Development (1)

16.  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

17. 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

18. 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

19. Alternating Tangential Flow

20. 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

21. Quality Attributes
Contaminants
Product Related Substances
Impurities
Quality Attributes
Aspects of drug
product that have the
potential to impact
patient safety and/or
efficacy

22.  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

23. Actavis Biologics

24. 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

25. 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”