CSI Biopharmaceutical Manufacturing:

How Manufacturing Failures are Investigated

Human Genome Sciences Inc.

Katie Stewart – Technical Training SupervisorGordon Dunsmore – Manufacturing Excellence Supervisor

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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

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Manufacturing BuildingsHGS 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 2Microbial: 87,000 ft 2

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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

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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

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Biopharmaceutical Manufacturing - Upstream

Disc-StackCentrifuge

Depth Filter75m2

Vial Thaw / Inoculum Expansion

500-Liter Bioreactor

50-Liter BioreactorFiltration

Media Prep

5,000-Liter Bioreactor

20,000-Liter Bioreactor

Material is Transferred to

Purification -“Downstream”

START

FINISH

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BulkFiltration

(BDS)

IntermediateStorage

UF/DF Step

IntermediateStorage

IntermediateStorage

ViralFiltration

Capture Column Intermediate Column

Polishing ColumnCryoPreservation

System

Biopharmaceutical Manufacturing - Downstream

Buffer Prep

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 problem2. Assess product impact3. Brainstorm potential causes4. Investigate potential causes5. Identify cause6. Implement corrective actions and

preventative actions (CAPA)

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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?

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Root Cause AnalysisDifferent Approaches

• Fishbone - Investigation Tool• List potential causes under

the following 6 categories– Man (& Woman), – Machine, – Mother nature, – Methods, – Materials, – Measures

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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

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Investigate in DetailFrom 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

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Questions?