CSI Biopharmaceutical Manufacturing: How Manufacturing Failures are Investigated Human Genome Sciences Inc. Katie Stewart – Technical Training Supervisor Gordon Dunsmore – Manufacturing Excellence Supervisor

2 Human Genome Sciences – Your Local Biopharmaceutical Company Founded in 1992 Located in Rockville, Maryland and Düsseldorf, Germany Over 1000 employees Publicly traded on NASDAQ Pipeline of products in early to mid stage clinical development Over 550 patents to date. State of the art manufacturing facilities designed for flexibility, multiple products and high quality

3 Manufacturing Buildings HGS has two (2) Manufacturing Buildings 1.Belward Small Scale – contains two (2) Manufacturing suites Microbial – 750 liter production fermenter Mammalian – two (2)1,600 liter production bioreactors 2.Large Scale Manufacturing (LSM) – two (2) 20,000 liter production bioreactors Mammalian: 43,000 ft 2 Microbial: 87,000 ft 2

4 Biopharmaceuticals What are Biopharmaceuticals? – Protein or nucleic acid based pharmaceutical therapeutics – Produced by means other than: 1) Direct extraction from a biological source 2) Or chemical synthesis Biopharmaceutical examples – Recombinant protein – Insulin from e.coli – Monoclonal Antibody – to work with immune system – Antisense DNA – blocks protein production

5 Example of an Antibody produced by HGS  BENLYSTA is a Fully Human Monoclonal Antibody that recognizes and inhibits the biological activity of B-Lymphocyte Stimulator (BLyS)  BLyS is a naturally occurring protein that is needed for B cells, the body’s first line of defense against infection, to survive  However, studies have shown that high levels of BLyS are associated with autoimmune diseases such as lupus and rheumatoid arthritis

6 Biopharmaceutical Manufacturing - Upstream Disc-Stack Centrifuge Depth Filter 75m 2 Vial Thaw / Inoculum Expansion 500-Liter Bioreactor 50-Liter Bioreactor Filtration Media Prep 5,000-Liter Bioreactor 20,000-Liter Bioreactor Material is Transferred to Purification - “Downstream” START FINISH

7 Bulk Filtration (BDS) Intermediate Storage UF/DF Step Intermediate Storage Intermediate Storage Viral Filtration Capture Column Intermediate Column Polishing Column CryoPreservation System Biopharmaceutical Manufacturing - Downstream Buffer Prep

Deviations – Why Investigate? Deviation – Any variance from approved, written procedures or any anomalous circumstance that may have the potential to affect the identity, strength, quality or purity of a product material Thorough deviation investigations are mandatory in the eyes of regulatory agencies (eg, FDA) Consequences of incomplete investigations: – No FDA approval Loss of hundreds (+) jobs Unmet patient needs Impact to shareholders ($$$$$$) – Endangering of patients Impure or potentially dangerous product Incomplete deviation investigations is a top FDA finding during most biopharmaceutical audits

Investigation Process Outline 1.Define the problem 2.Assess product impact 3.Brainstorm potential causes 4.Investigate potential causes 5.Identify cause 6.Implement corrective actions and preventative actions (CAPA)

10 Identifying and Documenting the Problem 5 Steps to Developing a Problem Describe the problem in terms of 5 factors: 1.What is the problem? 2.Where is it observed? 3.When is (was) it occurring? 4.What is the magnitude of the problem (Trend or Extent)? 5.What might have been the cause?

11 Root Cause Analysis Different Approaches Fishbone - Investigation Tool List potential causes under the following 6 categories – Man (& Woman), – Machine, – Mother nature, – Methods, – Materials, – Measures

12 Fishbone Example Mother Nature Cleanliness of room Power outage Machine Equipment not sterile Poor equipment condition Broken controller Materials Solution sterility Cell culture sterility Filter integrity Bioreactor Bag & line integrity Measures Temperature probe broken False positive bacteria result Man Procedures weren’t followed Operators were not trained Methods Procedures weren’t clear Process flaw Deviations occurred Problem: The presence of bacteria was found in a sterile cell culture solution in a bioreactor

13 Investigate in Detail From the Fishbone list gather all of the facts to determine whether each item is or is not the root cause Photo(s) Material affected Technician Interviews Equipment Condition and Maintenance Training Records Recent Changes Documentation and Procedures

Implementing CAPAs CAPA = Corrective Action/Preventative Action – Corrective Action: Corrects the root cause – Preventative Action: Ensure the deviation does not reoccur – Example: A procedure was incorrectly written and caused the test to fail Corrective Action - Revise the procedure Preventative Action - Review all documents in the area to ensure they are accurate and complete

15 Questions?