CSI Biopharmaceutical Manufacturing: How Manufacturing Failures are Investigated

1. 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 • Belward Small Scale – contains two (2) Manufacturing suites • Microbial – 750 liter production fermenter • Mammalian – two (2)1,600 liter production bioreactors • Large Scale Manufacturing (LSM) – two (2) 20,000 liter production bioreactors Microbial: 87,000 ft 2 Mammalian: 43,000 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. Depth Filter75m2 Disc-StackCentrifuge Biopharmaceutical Manufacturing - Upstream Media Prep START Vial Thaw / Inoculum Expansion 50-Liter Bioreactor Filtration 500-Liter Bioreactor 5,000-Liter Bioreactor 20,000-Liter Bioreactor FINISH Material is Transferred to Purification -“Downstream”

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

8. 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

9. Investigation Process Outline • Define the problem • Assess product impact • Brainstorm potential causes • Investigate potential causes • Identify cause • 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: • What is the problem? • Where is it observed? • When is (was) it occurring? • What is the magnitude of the problem (Trend or Extent)? • What might have been the cause?

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

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

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

14. 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?