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