The document provides an in-depth overview of 'Out of Specifications' (OOS) results in regulatory practices, explaining the definition, causes, and investigation procedures as per MHRA and CDER guidelines. It details the phases of investigations, including laboratory and manufacturing inquiries, as well as protocols for re-sampling and re-analysis. Furthermore, it outlines the regulatory implications of OOS results, such as reporting requirements and restrictions on product handling and sales.

1. GOOD REGULATORY PRACTICES
(MRA 101T)
UNIT – V
OUT OF SPECIFICATIONS (OOS)
MOHAMED FAZIL M
P1821003
M.PHARM – 1st SEM
REGULATORY AFFAIRS
MOB: 8870884215

2. OUT OF SPECIFICATIONS (OOS)
Out of Specification (OOS) means the result that falls
outside the specifications or acceptance criteria which has been
specified in the official compendia monographs or the finished
product specifications in the registration dossiers.
The analytical result(s) of a batch or material is/are
falling out side of the established specification ranges,
considered as Out of Specification.
The term OOS test results includes all suspect results
that fall outside the predetermined Specification.

3. There are lot of guidelines are available for
defining to handle the products/materials/batches
as:
•
• MHRA guideline for OOS
• CDER guideline for OOS
• PIC/S guideline for OOS

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

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

6. LABORATORY ERRORS
Method of analysis
Use of Non calibrated
instruments
Error in calculation
Analyst error
Instrument failure

7. PROCESS RELATED
Operator Error
Equipment Failure
Deviation form the Validated procedure
Quality of Raw material / Intermediate
used
In-Process Control During
Manufacturing

8. SAMPLE HOMOGENEITY
Sampling error
Handling of samples
Pooling of sample

9. PROCEDURES OF 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)

10. As per CDER (US FDA)
Phase-I
Investigation (Primary & extended lab
investigation)
Phase- II
Investigation (Manufacturing
investigation and resampling and re-
analysis)

11. As per MHRA (EU GMP)
Phase - I Investigation: Laboratory investigation
Laboratory investigation is related to
the Quality control department along with rechecking of
document with the 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)
Phase -Ib (Extended Lab investigation)

12. 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..



13. Phase – III Investigtion Extended
Manufacturing Investigations
In Phase III investigation, Quality Control /
Quakity 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

14. 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.

15. 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 &
reanalysis.

16. 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
solutions / Column efficiency /
weights / storage condition of sample
and many more)

17. If there is no abnormality observed during the primary lab investigation then
Report same results and considered as valid O0S 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

18. 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)

19. Phase II Investigation: Manufacturing investigation
• 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
Production persons shall investigate the following:

20. 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.

21. Phase-II Investigation: Manufacturing
investigation
QA, QC and production department
will evaluate nvestigations 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)

22. • Define the CAPA
• Release the Batch If failed
If Pass
• Reject the batch
• Divert the matter to R&D/ADL / PD Lab
If failed

23. 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 be reprocessed / reworked
Make a summary report
Defined the corrective actions

24. 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 of corrective action

25. Evaluate the results of corrective actions
Implement the preventive actions
Verify the implementation of preventive actions
After satisfactory implementation close the OOS & CAPA
All these activity for investigation / corrective actions preventive
actions should be recorded and reviewed and archived

26. 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

27. •
• 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)
IMPACT OF ON REGULATORY
 Stability study required
 OOS should be reported to RA
 OOS batch should not be sold regulatory
market
 OOS batch can not be blend with fresh
approved batch
 OOS batch can not be directly sell to the
market
•