Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing

Investigations (MIR): A Overview | Sagar Kishor Savale

Out of specification (OOS) and Out of Trend (OOT) analysis in

Pharmaceutical Manufacturing Investigations (MIR): A Overview

Mr. Sagar Kishor Savale, (M. Pharm (Pharmaceutics)), avengersagar16@gmail.com

Introduction

Out of specification (OOS): The test results that fall outside the acceptance criteria established
in SOP. (Against Specification limit).

Out of Trend (OOT): The test results that may be within specification but show significant
variation from the historical results.

OOS (out of specification) is the comparison of one result versus predetermined specification

criteria while OOT (Out of Trend) is the comparison of many historical data values versus time.

OOS investigations focus on determining the truth about that one value while OOT
investigations focus on understanding non-random changes

Example:

The specification limit for assay is: 95.0-105.0 % w/w of label claim

Case-1: For a particular batch, the result obtained 94.2 % w/w -This result is out of the

specification limit. This is called OOS.

Case-2: The result obtained 95.8 % w/w. Although the results are well within the

specifications, we should compare the result with the previous batches trend. If we found the

average value of the trend as 99.0 % w/w then this batch result (95.8 % w/w) is called out of

trend.

Out-of-Expectation Results (OOE)

An atypical, aberrant or anomalous result within a series of results obtained over a short period

of time is an OOE result. An OOE result is a result that meets specifications, but is outside the

expected variability of the analytical procedure.

SAGAR KISHOR SAVALE 1

 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

Differences between OOS and OOS

OOS OOT
OOS: out of Specification OOT: out of trend
Comparison of results vs. a Predetermined Comparison of many historical data values
specs criteria. vs. time.

History of OOS guideline

Event Year
USFDA audited Barr Laboratory, identified attempt of “Test until pass “
1989/1991/ 1992
and other abnormality, Resulted in 483
FDA prosecuted Barr Laboratory, Court directed to FDA to draft the OOS
Feb 1993
guidelines
FDA generated draft OOS guideline Sept 1998
FDA published final OOS guideline Oct 2006

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 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

OOS Pharmaceutical Investigation

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 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

OOS Investigation

Laboratory Investigation (Phase I)

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….

Laboratory Investigation (Phase I)

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.

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 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

Extended Investigation (Phase II)

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)

Difference between Phase I and Phase II Investigations

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 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

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 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

Tool for OOS Investigation & Related Corrective and Preventive action

1. 6M Method for Cause and Effect Analysis

2. Root Cause Analysis

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 Out of specification (OOS) and Out of Trend (OOT) analysis in Pharmaceutical Manufacturing
Investigations (MIR): A Overview | Sagar Kishor Savale

3. Corrective and Preventive action (CAPA)

 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.

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