This document discusses guidelines for handling Out of Specification (OOS) test results in the pharmaceutical industry. It provides an overview of the history of OOS guidelines, including FDA audits in the 1980s-90s that identified issues like "testing until pass", which led the FDA to publish formal OOS guidelines in 2006. The document outlines the OOS investigation process, which should first thoroughly check for laboratory errors and assign a cause, then may proceed to extended investigations including retesting or plant investigations if no error is found. Tools like 5M analysis and the five whys technique can be used to identify and analyze the root cause.

1. Dr Ravi Kinhikar
Handling OOS
(Out of Specification)

2. What is Out of Specification (OOS)
The result obtained out of defined test limit is called
out of specification.
USFDA guideline “Investigating Out of Specification
(OOS) Test Results for Pharmaceutical Industry”
Published by CDER in Oct 2006.
Quality unit should have well define SOP for OOS
The scope of SOP should be well define
Dr Ravi Kinhikar - General Manager -QC

3. History Of OOS guideline
Event Year
USFDA audited Barr Laboratory, identified attempt
of “Test until pass “ and other abnormality,
Resulted in 483
1989/1991/
1992
FDA prosecuted Barr Laboratory, Court directed to
FDA to draft the OOS guidelines
Feb 1993
FDA generated draft OOS guideline Sept 1998
FDA published final OOS guideline Oct 2006
Dr Ravi Kinhikar - General Manager -QC

4. OOS Investigation
Laboratory Investigation
.
Must be
• Thorough
• Timely
• Unbiased
• Well documented
• Scientifically sound
Dr Ravi Kinhikar - General Manager -QC

5. OOS Investigation –(Phase I)
.
Laboratory Investigation
Check list to identify obvious Laboratory error
1. Analyst qualification and training on intended work
2. Correctness Test specification and Method
3. Instrument calibration or performance
4. Preparation test solutions and dilutions
5. Validity of Reagents and standards
6. Performance of system suitability
7. Correctness of calculation and etc….
Dr Ravi Kinhikar - General
Manager -QC

6. OOS Investigation –(Phase I)
.
Laboratory Investigation
If Analyst Error identified, it should be
• logical and appropriate
• not on hypothetical basis
Identify appropriate assignable cause for Laboratory error
Correct the error, and repeat the analysis to invalidate the
OOS.
Suggest the Corrective and Preventive actions e.g. training
to the Analyst, Requalification of Analyst etc. whatever the
scientifically appropriate.
Dr Ravi Kinhikar - General Manager -QC

7. OOS Investigation –(Phase II)
.
Extended Investigation
If No assignable cause found in phase I investigation,
Phase II investigation should be initiated
• Retesting of Material with other analyst (n≥ 3)
• Resampling and testing
• Investigation at Plant
• Further Extend investigation (upon rejection)
Dr Ravi Kinhikar - General Manager -QC

8. Tool for OOS Investigation &
Related Corrective and
Preventive action
Dr Ravi Kinhikar

9. Identify the Suspect
5M –Tool to Identify the Route cause
Man
Machine
Material
Method
Movement
Dr Ravi Kinhikar - General Manager -QC

10. Scan the Suspect
Target the suspect
Use 5 why technique to reach at root cause
Ask Why, Why, Why, Why and Why five times and try to
reach at more probable reason
To check the reason scientifically sound - Process each
reason with six sigma technique -DMAIC
Dr Ravi Kinhikar - General Manager -QC

11. Process the Root cause
Six sigma technique (DMAIC)
Define
Measure
Analyze
Improve
Control
Dr Ravi Kinhikar - General Manager -QC

12. Corrective And Preventive Action
Draw appropriate root cause.
Root cause should be logical and scientific.
Collect the historical evidence if any with same process or any
other process in the plant.
Identify the need for extend the investigation to past or future
batches…
Provide corrective action with evidence
Suggest preventive action
( corrective action should be reviewed against similar process in
the plant for no impact)
Conclude the activity in timely manner.
Dr Ravi Kinhikar - General Manager -QC

13. Admire your Questions…
Thanks!!!
Dr Ravi Kinhikar - General Manager -QC