In this slide contains Investigation, reason, case study of OOS. Presented by: K Venkatsai Preasad. (Department of pharmaceutical analysis and quality assurance). RIPER, anantapur.

1. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 1
A Seminar as a part of curricular requirement
for I year M. Pharm I semester
Presented by
K.VENKATASAIPRASAD. (20L81S0402).
M.PHARM
Department of Pharmaceutical Quality Assurance.
Under the guidance/Mentorship of
Dr. P. Ramalingam., Ph.D.
Director- R&D Division,
Professor of pharmaceutical analysis
and medicinal chemistry
CASE STUDY
ON
OUT OF SPECIFICATION(OOS)

2. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 2
S.NO CONTENT
1
Introduction
2
Reason for OOS
3
OOS investigation
4
Case study 1
5
Outcomes
6
References
Content Table

3. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 3
OOS(OUT OF SPECIFICATION):
The term OOS results includes all test results that fall outside the
specification or acceptance criteria established in drug applications,
drug master files, official compendia, or by the manufacturer.
TWO MAOR ISSUES:
• What test results?
• What specifications?
Introduction

4. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 4
• There are lot of guidelines are available for defining and handle the
OOS products/materials/batches as:
 MHRA guideline for OOS
 CDER guideline for OOS
 PIC/S guideline for OOS

5. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 5
• The OOS may be observed during the analysis of:
 Stability study
 Finished API
 Intermediates
 In-process
 Raw materials
 Packing materials

6. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 6
• OOS found due to the following reasons but not limited to:
Reasons
OOS
Laboratory
errors
Process
Related
Sample
homogeneity

7. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 7
Laboratory errors:
•Laboratory errors
Method of
analysis
Use of non
calibrated
instruments
Error in
calculation
Analyst
error
Instrument
failure

8. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 8
Process related:
•Process related
Operator
error
Equipment
failure
Deviation
from the
validated
procedure
Quality of
raw material
or
intermediate
used
In-process
control
during
manufacturi
ng

9. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 9
Sample homogeneity:
•Sample homogeneity
Sampling error
Handling of
sample
Pooling of
sample

10. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 10
OOS investigations
As per MHRA(EU GMP) As per CDER(US FDA)
Phase - I Investigation
(Primary &extended lab
investigation)
Phase - II investigation
(Manufacturing investigation)
Phase - III Investigation
(Extended manufacturing, Re-
sampling and re-analysis)
Phase - I Investigation
(Primary & extended lab
investigation)
Phase - II investigation
(Manufacturing investigation and
re-sampling and re-analysis)

11. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 11

12. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 12
Case study 1

13. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 13
The law:
Under the Federal FDC Act
drug is adulterated
if the methods/facilities/controls used for, its manufacture,
processing, packing or holding
do not conform/not operated in accordance with cGMP to
assure that the drug meets the requirements to safety, identity,
strength, quality and purity characteristics.
(21 U.S.C. § 351(a)(2)(B) )

14. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 14
• FDA Inspection:
 FDA investigators conducted a general inspection of Barr's
Northvale facility during August and September 1989 as well
as separate general inspections of Barr's Northvale and
Pomona facilities from May to September 1991.
 After each inspection, the investigators issued Forms 483
(Inspectional Observations).

15. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 15
 The 1989 Form 483, which contained five general
observations, cited Barr for
 Invalidated manufacturing processes
 Invalidated cleaning processes
 The lack of failure investigations
 Incomplete annual reviews
 Failure to explain retesting

16. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 16
• The Offense:
 Barr Laboratories was accused of having breached GMP
guidelines by routinely re-testing, re-sampling and re-
processing, had effectively persuaded all pharmaceutical
industry laboratories to standardize their protocols for dealing
with out-of-specification results (OSRs).
 The court did not accept the FDA submission that an OSR
necessarily meant a batch failure.

17. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 17
• Key Points: Essence of Barr Labs Decision
 Release of batch:
• Testing must show satisfactory conformance to
specifications, including Strength of each active ingredient.
• Context and history of product and batches inform the final
conclusion.

18. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 18
• Lesson -Have a plan for OOS:
 Don’t test into compliance
 Have a policy and follow it…
 Avoid repeat testing

19. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 19
Outcomes
 OOS investigations can be time consuming, but are necessary.
 Robust OOS investigation SOP is critical.
 Need for employee training and understanding.
 Investigation plans must be pre-defined.
 Multiple departments may be involved.
 Scientific rationale needs to be used at each step.
 QA needs all data in order to make the right decision.
 Implement CAPAs.
 Testing into compliance is not good.

20. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 20
References
 USA vs. Barr Laboratories, Inc. Civil Action No. 92-1744, US
District Court for the district of New Jersey, February 4, 1993.
 FDA, CDER, “Guidance for Industry, Investigating Out of
Specification (OOS) Test Results for Pharmaceutical Production,”
September 1998.
 Torbeck, L., “Reportable Values for Out-of-Specification Test
Results,” Pharmaceutical Technology, February 1999.

21. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 21
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