Out of
Specification
Vineet Joshi
1
Definiti
on
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
Process Sample
Laboratory
homogeneity
related
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Out of
Specifications
Laboratory errors:
Laboratory errors
Method of Use of Non
Error in Analyst Instrument
Analysis Calibrated
instruments calculation error Failure
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Out of
Specifications
Process Related:
Process Related
Quality of Raw
Equipment Deviation form In-Process
Operator Error material /
the validated Control During
Failure Intermediate
procedure used
Manufacturing
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Out of
Specifications
Homogeneity sample :
Sample
Homogeneity
Handlin of Pooling of
Sampling error
samples 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 Phase – II Investigation
(Manufacturing investigation)
(Manufacturing investigation and
Phase – III Investigation re- sampling and re-analysis)
(Extended manufacturing, 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 re-
analysis.
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 control
department along withQuality
rechecking of documents with same
analyst and re-testing with different analyst original
with sample.
Phase – II Investigation: Manufacturing investigation
Process related investigation is to be out by
carried
Production department along with re-sampling and re-
analysis.
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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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Abbreviati
ons
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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