The document is a seminar report discussing Out Of Specification (OOS) results in pharmaceutical quality assurance, including definitions, investigations, and guidelines from regulatory bodies like MHRA and CDER. It highlights the reasons for OOS results, such as laboratory errors and process-related issues, and provides a case study involving Barr Laboratories that emphasizes the importance of proper testing protocols. The report concludes with key lessons on managing OOS results and the necessity of robust investigation plans.

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

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NAAC &
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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

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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

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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

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NAAC &
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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

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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

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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

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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

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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)

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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 11

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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

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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) )

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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).

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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

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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.

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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.

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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

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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.

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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.

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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 21
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