Date post: | 12-Apr-2017 |
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Health & Medicine |
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Out of Specification
By: Shravan Kumar
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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
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Out of Specifications
Laboratory errors:Laboratory errors
Method of Analysis
Use of Non Calibrated
instrumentsError in
calculationAnalyst
errorInstrument Failure
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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
As per MHRA (EU GMP)
Phase – I Investigation (Primary & extended lab investigation)
Phase – II Investigation(Manufacturing investigation)
Phase – III Investigation(Extended manufacturing, Re-sampling and
re-analysis)
Procedures of OOS investigations
As per CDER (US FDA)
Phase – I Investigation(Primary & extended lab investigation)
Phase – II Investigation(Manufacturing investigation and re-
sampling and re-analysis)
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OOS Investigations
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)
As per MHRA (EU GMP)
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OOS Investigations
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….
As per MHRA (EU GMP)
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OOS Investigations
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
As per MHRA (EU GMP)
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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
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 re- analysis.
As per CDER (US FDA)
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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