Out of specification PPT as per practicle approach and reference review with guidelines

1. 1
Out of Specification
By: Shravan Kumar

2. 2
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

3. 3
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

4. 4
Out of Specifications
The OOS may be observed during the analysis of:
 Stability study
 Finished API
 Intermediates
 In-process
 Raw materials
 Packing materials

5. 5
Out of Specifications
OOS found due to the following reasons but not
limited to:
OOS
Laboratory
Process
related
Sample
homogeneity

6. 6
Out of Specifications
Laboratory errors:
Laboratory errors
Method of
Analysis
Use of Non
Calibrated
instruments
Error in
calculation
Analyst
error
Instrument
Failure

7. 7
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

8. 8
Out of Specifications
Homogeneity sample :
Sample
Homogeneity
Sampling error
Handlin of
samples
Pooling of
sample

9. 9
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)

10. 10
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)

11. 11
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)

12. 12
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)

13. 13
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.

14. 14
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)

15. 15
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)

16. 16
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

17. 17
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)

18. 18
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

19. 19
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.

20. 20
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

21. 21
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

22. 22
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

23. 23
OOS Investigations
All these activity for investigation / corrective actions / preventive
actions should be recorded and reviewed and archived.

24. 24
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)

25. 25
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

26. 26
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

27. 27
Thank You