Sterility can be defined as the freedom from the presence of viable microorganisms. However, the conditions that guarantee absolute sterility are usually too harsh for active ingredients, and the definition of sterility for a medicinal product must be defined in functional terms.

What do you do when you encounter a sterility failure?

It depends on your perspective!

If you are a Lab Technician you get worried and cry…if you are a Lab Manager you get furious and try to find out who messed up…if you are QA you reject the batch…and if you are part of the manufacturing unit you reject the batch.

How can you settle all these concerns methodically?

The problem can be solved by conducting root cause of the failure.

Investigate:

• What went wrong?
• Where did it go wrong?
• What went wrong?
• How did it go wrong?
• How can it go wrong?
• What & who all are involved?

Investigate the Procedure
The investigation shall be done by a team of professional experts based on company specific written procedures and SOP’s.

Conduct based on Risk
Sterility Failure investigation shall be conducted on a System based Approach.

Laboratory System Investigations

Culture Media

• Media Preparation Details (in-house / ready to use / dehydrated media)
• Negative controls results (passes / fails)
• Growth promotion test results (passes / fails)

Sterilizer & Sterilization

• Media sterilization details
• Sterilizer filter Integrity testing records
• Sterilizer Qualification Reports – any cold spots?

Test Procedure

• Test Procedure / SOP
• Sterilizer filter Integrity testing records
• Analytical manipulations done during testing : Reconstitution / Mixing of the Product

Test Equipment

• Open Sterility Equipments -Requires independent Sterilization and assembly
• Closed Sterility Equipments- Ready to use containers

Test Samples

• Sample Transportation and Handling Procedures
• Records of Sanitization / Decontamination of the sample surface

Analyst

• Qualified
• Training Records
• Self Assessment During Stress Conditions

Cleaning & Disinfection

• Records of preparation of the solution
• Filter integrity testing records
• Reports of disinfection agent effectiveness on the recovered organism

Environmental Monitoring

• Trend Analysis: Recent Out of Trend data
• Comparison of the recovered organism with that of data bank
• Identification of the organism to species level
• Any typical or atypical organism observed

Test Environment

• Sterility Performed in a Uni-Directional Air Flow unit in a classified cleanroom
• Investigate reports for : Preventive maintenence , Air velocity, differential pressure, leak rates , sanitization cycles, cleaning records
• Sterility Performed in an Isolator

Manufacturing System Investigations

[table id=1 /]

Concluding Sterility Test Failure Investigations

When concluding sterility test failure investigations, the root cause investigation should lead to the answers to the following:

What went wrong?
Was this the result of something relating to the manufacturing process or to the filling of the final product, or was this a false positive result out of a contaminant transferred during the sterility test operations?

Where did it go wrong?
The specific Manufacturing Process Step / Lab Test Step / Loop Holes in Facility

How did it go wrong?
Facility Failure / Process Failure / Qualification Failure /Operator Failure

What & who all are involved?
Decide it yourself!!

The final sterility test failure investigation report should be comprehensive and must cover important points identified during the root cause investigation. Regulatory authorities always expect a logical, detailed and well-presented investigation report.