Out of Specification
By: Shravan Kumar
1
Definition
If the analytical result(s) of a batch or material is/are
falling out side of the established specification
ranges, is called / considered as Out of Specification.
Or
The term OOS test results includes all suspect results
that fall outside the predetermined Specification
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Out of Specifications
There are lot of guidelines are available for defining
to handle the OOS products/materials/batches as:



MHRA guideline for OOS
CDER guideline for OOS
PIC/S guideline for OOS
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Out of Specifications
The OOS may be observed during the analysis of:






Stability study
Finished API
Intermediates
In-process
Raw materials
Packing materials
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Out of Specifications
OOS found due to the following reasons but not
limited to:
OOS
Laboratory
Process
related
Sample
homogeneity
5
Out of Specifications
Laboratory errors:
Laboratory errors
Method of
Analysis
Use of Non
Calibrated
instruments
Error in
calculation
Analyst
error
Instrument
Failure
6
Out of Specifications
Process Related:
Process Related
Operator Error
Equipment
Failure
Deviation form
the validated
procedure
Quality of Raw
material /
Intermediate
used
In-Process
Control During
Manufacturing
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Out of Specifications
Homogeneity sample :
Sample
Homogeneity
Sampling error
Handlin of
samples
Pooling of
sample
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OOS Investigations
Procedures of OOS investigations
As per MHRA (EU GMP)
As per CDER (US FDA)
Phase – I Investigation
Phase – I Investigation
(Primary & extended lab investigation)
(Primary & extended lab investigation)
Phase – II Investigation
(Manufacturing investigation)
(Manufacturing
Phase – III Investigation
(Extended
manufacturing,
Phase – II Investigation
investigation
and
re-
sampling and re-analysis)
Re-sampling
and re-analysis)
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OOS Investigations
As per MHRA (EU GMP)
Phase – I Investigation: Laboratory investigation
Laboratory investigation is related to the Quality control
department along with rechecking of documents with same
analyst and re-testing with different analyst with original sample.
Phase – I is sub divided in to two sections as:
Phase – Ia (Primary Lab investigation), and
Phase -Ib (Extended Lab investigation)
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OOS Investigations
As per MHRA (EU GMP)
Phase – II Investigation: Manufacturing Investigations
In manufacturing investigation, production person investigate :

Process parameters

Drying parameters

Input raw materials quality

training of persons

Cleaning of equipment

Environmental information

Contamination & etc….
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OOS Investigations
As per MHRA (EU GMP)
Phase – III Investigation: Extended Manufacturing Investigations
In Phase III investigation, Quality Control / Quality Assurance & Production
department investigate the following:

Sampling error by person

Authorized for re sampling (if required)

Re-analysis of re-sampled material with different Analyst

If root cause found, define the CAPA or if not

Diverted the matter to R&D / ADL or PD Lab

Conclusion by all team member (QA, QC, PRD, ADL R&D, PD Lab)

Decide the fate of batch by QA Head
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OOS Investigations
Re-testing:
The analysis of original sample at the time of phase- I laboratory investigation.
Re-sampling:
The original batch is sampled by QA second time after QA head authorization for reanalysis.
Re-analysis:
The analysis of re-sampled material for the verification of results, if
manufacturing investigation does not have root cause.
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OOS Investigations
As per CDER (US FDA)
Phase – I Investigation: Laboratory investigation
Laboratory investigation is related to the Quality control
department along with rechecking of documents with
same
analyst and re-testing with different analyst with original
sample.
Phase – II Investigation: Manufacturing investigation
Process related investigation is to be carried out by
Production department along with re-sampling and reanalysis.
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OOS Investigations
Phase – I Investigation: Laboratory investigation

Analyst observed the OOS result

Re-calculate the results (if required)

If analytical results remain same

Report the OOS result to QC In-charge

Log the OOS

Start the Primary Laboratory investigation

Review the documents along with solutions as (Potency / STP
& Specs / buffer solutions / calibration of instruments /
standard solutions / Column efficiency / weights / storage
condition of sample and many more)
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OOS Investigations
Phase – I Investigation: Laboratory investigation

If there is no abnormality observed during the primary
lab investigation then

Report same results and considered as valid OOS and report

Quality Head review the primary lab investigation and
evaluate for re-testing (if QA Head permits)

Repeat the analysis as thrice with original sample with
different analyst

Report the average result of repeat analysis

Report the average result
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OOS Investigations
Phase – I Investigation: Laboratory investigation

If the result complies

Report as complies and invalidate the OOS

Release the batch

If any of result if not complies (among three)

Report as OOS and continue the OOS

Report to QA head
QA head will recommend for the Phase – II investigation (manufacturing
investigation)
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OOS Investigations
Phase – II Investigation: Manufacturing investigation
Production persons shall investigate the following:

Input quantity of raw material

Input RM quality

Process parameters details

Critical process parameter details (time / temp)

In-process results

Out put of the material

Re-conciliation of raw materials

Utility pressures

Calibration / Preventive maintenance of equipment

Attached ancillaries status
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OOS Investigations
Phase – II Investigation: Manufacturing investigation
Production persons shall investigate the following:

Cleaning of equipments

Training of personnel

Brain storming with operators

Contamination verifications

Environmental review
If there is no assignable cause observed during manufacturing
investigations, same is to be reported to Quality Assurance Head.
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OOS Investigations
Phase – II Investigation: Manufacturing investigation
QA, QC and production department will evaluate the investigations and after that:

Sampling procedure review, if suspected

QA head may recommend for re-sampling

QC analyst shall analyze the sample as per STP

Report the result (Pass / Failed)

If Pass


Define the CAPA

Release the Batch
If failed

Reject the batch

Divert the matter to R&D / ADL / PD Lab
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OOS Investigations
Phase – II Investigation: Manufacturing investigation
R&D / ADL / PD Lab shall:

Take the user trial with the material

Investigate the failure based on experiments / experiences

Various types of experiments

To find out the root cause

To identify, is this material can b e reprocessed / reworked

Make a summary report

Defined the corrective actions
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OOS Investigations
Phase – II Investigation: Manufacturing investigation
QA/QC/Production department shall:

QA head shall define the fate of batch for reprocess / rework /
destruction

Accept the corrective and preventive actions

Training to all concerned for root cause / corrective action / preventive
action

Monitor the activity for corrective actions

Evaluate the results of corrective actions

Implement the preventive actions

Verify the implementation of preventive actions

After satisfactory implementation close the OOS & CAPA
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OOS Investigations
All these activity for investigation / corrective actions / preventive
actions should be recorded and reviewed and archived.
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OOS Investigations
If OOS batch is to be reprocessed / re-work:

Follow the written approved BMR for re-process / Rework

Sample as per SOP for sampling of material

Analyze the material according to the specification and STP

Evaluate the quality of the batch

Keep this batch for stability (Accelerated / Long term)

Evaluate the stability results of the batch

Communicate the OOS to the customers (as mentioned in to the
Quality agreement)
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OOS Investigations
Impact of OOS on REGULATORY:

Stability study required

OOS should be reported to RA

OOS batch should not be sold to Regulatory market

OOS batch can not be blend with fresh approved batch

OOS batch can not be directly sell to the market
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Abbreviations

CDER
:
Center for drug evaluation and research

OOS
:
Out of specification

RA
:
Regulatory affairs

STP
:
Standard testing procedure

EU-GMP
:
European good manufacturing practices

PIC/s
:
Pharmaceutical
inspection
co-operation
scheme
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Thank You
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