CSI Biopharmaceutical Manufacturing: How Manufacturing Failures are Investigated
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Transcript of CSI Biopharmaceutical Manufacturing: How Manufacturing Failures are Investigated
CSI Biopharmaceutical Manufacturing:
How Manufacturing Failures are Investigated
Katie Stewart – Technical Training Manager
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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– Antisense DNA – blocks protein production– Monoclonal Antibody – to work with immune system
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Example of an Antibody Pharmaceutical
BENLYSTA is a Monoclonal Antibody
Treatment for Lupus (autoimmune disease)
Controls immune system
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•Various types of cells can be used to produce biopharmaceuticals
• Mammalian/Animal – typically used for antibody production
• Yeast • Saccharomyces cerevisiae (primarily
used by HGS)• Pichia pastoris
• Plant• Bacteria• Insect
How do we create new Biopharmaceuticals?
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How do we create new Biopharmaceuticals?
A “gene,” which codes for the drug product (protein or antibody) is inserted into a
cell’s DNA
Gene
Cell
Nucleus of cell where the DNA
exists
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The drug product (protein or antibody) is made by the cell using the inserted DNA and the cells machinery (inside the cell) through several steps
The cell then secretes the productoutside of itself
Cell
How do we create new Biopharmaceuticals?
Manufacturing Biopharmaceuticals
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Upstream Production
Cells are grown to large quantities to produce a lot of
product
Downstream (Purification)Product is collected, purified (cleaned) and concentrated
(large to small volume) through multiple
Cells
Product
Production
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Manufacturing Biopharmaceuticals - Upstream
CentrifugeFilter
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
What is a Bioreactor?
•An apparatus for growing organisms (yeast, bacteria, or animal cells) – Controls environment
around cells - temperature, pH, and oxygen levels
– Create homogeneous environment (same throughout) environment by constantly stirring the contents.
Deviation Investigating in Manufacturing
Deviations• Deviation – Any variance that may have the potential to affect the
identity, strength, quality or purity of a product– FDA Regulation - thorough deviation investigations must be conducted
Why investigate? • 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
Investigation Process Outline
1. Define the problem2. Brainstorm potential causes3. Investigate potential causes4. Identify cause5. Implement corrections
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1. Define 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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2. Brainstorm Potential Causes• Fishbone - Investigation Tool• List potential causes under
the following 6 categories– Man (& Woman), – Machine, – Mother nature, – Methods, – Materials, – Measures
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3. Investigate Potential Causes4. Determine Root Cause
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• Operator Interviews• Equipment Condition and Maintenance• Training Records• Recent Changes• Documentation and Procedures
5. Implementing Corrections• Corrective and Preventative Actions– 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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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