Transcript CSI Presentation

CSI Biopharmaceutical Manufacturing:
How Manufacturing Failures are
Investigated
Katie Stewart – Technical Training Manager
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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How do we create new
Biopharmaceuticals?
•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
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How do we create new
Biopharmaceuticals?
Gene
Nucleus of cell
where the DNA
exists
Cell
A “gene,” which codes for the drug product
(protein or antibody) is inserted into a cell’s
DNA
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Cell
How do we create new
Biopharmaceuticals?
The cell then secretes the product
outside of itself
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
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Manufacturing Biopharmaceuticals
Production
Product
Cells
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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
Manufacturing
Biopharmaceuticals - Upstream
START
Media
Prep
Vial Thaw /
Inoculum
Expansion
Filtration
50-Liter
Bioreactor
500-Liter
Bioreactor
5,000-Liter Bioreactor
20,000-Liter Bioreactor
FINISH
Material is
Transferred to
Purification “Downstream”
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Filter
Centrifuge
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.
2.
3.
4.
5.
Define the problem
Brainstorm potential causes
Investigate potential causes
Identify cause
Implement corrections
1. Define the Problem
5 Steps to Developing a Problem
• Describe the problem in terms of 5 factors:
1.
2.
3.
4.
What is the problem?
Where is it observed?
When is (was) it occurring?
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
–
–
–
–
–
–
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Man (& Woman),
Machine,
Mother nature,
Methods,
Materials,
Measures
3. Investigate Potential Causes
4. 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
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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
Fishbone Example
Problem:
The presence of bacteria was found in a sterile cell culture solution in a bioreactor
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
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Man
•Procedures weren’t followed
•Operators were not trained
Measures
•Temperature probe broken
•False positive bacteria result
Methods
•Procedures weren’t clear
•Process flaw
•Deviations occurred