Handling OOS and OOT Results:

FDA’s Current Expectations

Prepared by
Precision Consultants, Inc.

Carmen Medina, M.P.H., Former FDA Investigator

2000 by
b Precision
P i i Consultants,
C lt t Inc.
I All rights
i ht reserved.
d Reproduction
R d ti in i partt or in
i whole
h l without
ith t written
itt permission
i i is i strictly
t i tl prohibited.
hibit d
Precision Consultants, Inc. is a registered name.
 Optimize current OOS and OOT Investigation

Procedures

– Judge Wolin’s Ruling (aka Barr Decision)

– Current OOS Investigation Requirements
– Out-of-Trend Issues
– Annual Product Review: QC Profiles

OOS—Out-of-Specification
OOT—Out-of-Trend

2
 Judge
g Wolin’s Rulingg

Some of the items in the Barr decision and areas

relevant are:
Retesting
The decision to retest “must be based on
the objectives of the testing and sound
scientific judgment.
judgment Rational retesting
should be done by a second analyst.”
-Judge
Judge Alfred Wolin
 Judge
g Wolin’s Rulingg

Retesting There should be a retest procedure

defining the number of tests. Must not try
t retest
to t t a product
d t into
i t compliance
li
(averaging, etc.)
If there are grounds for invalidating an
original result and replacing it with the
retest value, the original
g data must be kept
p
along with an explanation of what and
why.

4
 Judge
g Wolin’s Rulingg

Averaging May be a valid strategy, depending

Results upon the sample and how the
technique is used.

Averaging
A i - in
i certain
t i situations-
it ti
can provide a truer picture of reality,
but when used inappropriately
inappropriately, can
hide important variations.

5
 Judge
g Wolin’s Rulingg

Resampling
Should rarely occur! Will occur when
the original sample was not truly
representative of the batch or there was a
documented/traceable lab error in its
preparation. Sound scientific
justification must be employed if re-
sampling is to occur.

6
 Failure Investigations

DOCUMENTATION OF OOS

• Phase
ase I:: Who,
W o, How
ow (Lab)
( ab)

• Phase II: Who, How (QA/QC Mgr/Supervisor)

7
 Fail re Investigations
Failure In estigations
PHASE II - FORMAL INVESTIGATION

• Ruled out laboratoryy error

• QA/QC ppersonnel with lab staff

• Standardized form (UIR, DR, etc.)

8
 Fail re Investigations
Failure In estigations

LABORATORY ERROR OR ANALYST ERROR

(LABORATORY -- INFORMAL INVESTIGATION)

• Incorrect standard

• Calculation error

• Instrument malfunction

9
 Fail re Investigations
Failure In estigations

NON-PROCESS ERROR (INFORMAL INVESTIGATION)

• Human or mechanical malfunctions (e.g.,

(e g an
uncalibrated meter; incorrect amount of raw
material;; wrongg ingredient)
g )

10
 Fail re Investigations
Failure In estigations
PHASE 1-LABORATORY INVESTIGATION OR
INFORMAL INVESTIGATION

• This information would get generated by the OOS

observer, onto a standardized form.

• The results would determine if a formal

investigation is required.
required

11
 Fail re Investigations
Failure In estigations
An OOS may be invalidated via explanation an/or retesting.

Always
y begin
g byy eliminatingg the followingg possible
p errors:

• Operator

• Laboratory/Analyst

• Process

• Method

• Non process
Non-process

12
 Fail re Investigations
Failure In estigations

If an OOS cannot be demonstrably identified:

• Review batch records or device history file to
identify any trends related to OOS results.

• Revisit the process validation to identify

sources of variability related to OOS results

• Define Failure

13
 Fail re Investigations
Failure In estigations

• Review of full set of test data for the batch to identify

relationship between parameters that may suggest a
cause of error. Start with high and low OOS results.

• Revisit
i i pilot
il batch
b h data.
d Design
i off experiment
i

14
 Fail re Investigations
Failure In estigations

THE SOP:

• O
Out-of-Specification
t f S ifi ti SOP should h ld contain
t i
directions on handling and properly disposing
of an OOS laboratory or QC test results.
results

15
 Fail re Investigations
Failure In estigations

• What is the difference between an out-of-specification

result (OOS) and a “failure”?

• When does an OOS not require an investigation?

16
 Investigation of Out-of-Specification
Laboratory Test Results – General

• cGMP training on the handling of OOS and atypical

results must be part of an analyst training program prior
t commencing
to i workk

• Test results that are invalidated byy an investigation

g are
not used to determine the final result for the test, but
these results must be retained in the test documentation

17
 What Do Yo
You In
Investigate?
estigate?

• OOS test results for any material or process

controlled under specifications

• OOS laboratory test results obtained during the

t t for
test f disposition
di iti off in-process,
i fi l andd
final
stability testing of raw materials, in-process
materials,, finished components
p and finished kits

• OOS laboratoryy test results obtained duringg

validation studies
18
 T pes of Errors
Types

• Clerical Error:
– An error that can be attributed to an incorrect
calculation or transcription error

• Determinate
i Error:
– A known or identifiable error

• Indeterminate Error:
– An error that cannot be identified

19
 T pes of Errors
Types

• Laboratory Error:
– An error that occurs in the process of testing, which
can be ascribed to an analyst error
error, an equipment
error or an unplanned test interruption

• Non-Process Related Error:

– An error that occurs during the product
manufacturing
f t i process, which hi h can be
b ascribed
ib d to
t an
operator error, an equipment malfunction or an
unplanned interruption of the manufacturing
process
20
 Wh an OOS T
When Testt R
Result
lt iis Obt
Obtained
i d

• The analyst immediately notifies the area

supervisor / designee of the occurrence of an
OOS result

• Initiate an investigation into the OOS result

according to written procedure described to
determine whether the result can be attributed
to error or whether the result represents the
actual condition of the material or process
being evaluated
21
 Wh an OOS T
When Testt R
Result
lt iis Obt
Obtained
i d

• Any exceptions to the timely initiation and

completion of all investigations must be notified to
and authorized by laboratory management

• All sample preparation materials,

materials such as vials or
solutions, media, working standards, glassware,
pipettes, etc. used in the original analysis must be
retained until the test results are verified and
approved. The stability of solutions must be
considered when utilized for investigation purposes
22
 OOS In
Investigation
estigation Will Include
Incl de

• A review of product history and any stability

trends

• An evaluation of the feasibility of re-analyzing

th stock
the t k or working
ki sample l andd standard
t d d
preparations

• The consideration / use of a second analyst in

conjunction
j with the first analyst
y duringg retestingg

23
 OOS In
Investigation
estigation Will Include
Incl de

• The consideration of using check or reference

samples
p

• Documentation and retention of all results

obtained during the investigation

• A documented final decision based on all of the

valid results obtained during the investigation

24
 What May Be Included in the OOS
I
Investigation
ti ti

• Confirm the correct test method was used for

testing

• Confirm the analyst is qualified to perform the test

method

• Confirm calculations (if applicable) are correct

• Confirm,, if applicable,
pp , all negative
g controls for
media, diluents, and test equipment were negative
25
 What May
y Be Included in the OOS
Investigation

• Confirm environmental samples taken during

testing were satisfactory

• Determine if the sample was taken properly by a

qualified individual

• Confirm instruments used and other laboratory

systems
y ((where applicable)
pp ) were in calibration
and functioning properly
26
 What May
y Be Included in the OOS
Investigation

• Determine if other samples tested in the same

time frame using the same lots of solutions and
standards and testing equipment were
satisfactory

• Review historical data to determine if similar

problems have been previously reported

27
 Repeat Testing

• Repeat testing can be performed only after an

investigation
g of failure is initiated. Repeat
p
testing may be done by either the original
analyst or a second analyst

28
 Investigation of OOS Microbiology
T tR
Test Results
lt

• The
h ffollowing
ll i describes
d ib suggestedd procedures
d to be
b
followed for resolution of out-of-specification microbiology
test results. The same ppractices mayy be utilized,, but is not
mandatory to investigate out-of-trend microbiology test
results

• The following items are suggested, but not limited to and

should be considered and documented as ppart of the
investigation in the most common microbiological testing.
For the tests where a retest procedure is specified in the
method or its associated documentation
documentation, the method
supersedes any OOS result investigation procedure
29
 Investigation
g of OOS Microbiology
gy Test
Results

1.1 Confirm the correct microbiological test method

was used for testing
12
1.2 Confirm the analyst is qualified to perform the test
method
1.3 Confirm calculations ((if applicable)
pp ) are correct
1.4 Confirm all negative controls for media, diluents,
and test equipment were negative
1
1.5 C fi growthh promotion
Confirm i testing
i for
f all ll media
di
were satisfactory
1.6 Confirm environmental samples taken during
testing were satisfactory
30
 Investigation
g of OOS Microbiology
gy Test
Results

1.7 Determine if the sample was taken aseptically by a

qualified individual
1 8 Confirm incubators,
1.8 incubators hoods and isolation chambers and
other laboratory systems (where applicable) were in
calibration and functioning properly
1.9 Determine if other samples tested in the same time frame
using the same lots of media, diluents and testing
equipment were satisfactory
1.10 Review historical data to determine if similar
microbiological problems have been previously reported

31
 Investigation
g of OOS Microbiology
gy Test
Results

• Repeat testing can be performed only after an

investigation of failure is initiated. Repeat
testing may be done by either the original
analyst or a second analyst

• Reporting of mean values of the

microbiological
i bi l i l datad t is
i appropriate
i t when
h
defined by a validated test method

32
 Reporting / Documentation of OOS or
Atypical Results

• All
ll results
l must be
b retained
i d in
i laboratory
l b records.
d Iff data
d isi
rejected, a complete description of the reason for rejection
must be included in the analyst’s
y records with the signatures
g
of both analyst and supervisor

• All results from the original and repeat testing must be

reported except for results that are determined to be invalid

• The results of the failure investigation must be recorded in

the laboratory records, and the OOS or atypical results
report. Implications for previous or subsequent batches
must be assessed by QA, if applicable 33
 OOS Report Incl
Includes
des

• A clear chronology of the investigation

• A summary of the testing that was performed

• An
A analysis
l i off all
ll data
d derived
d i d from
f the
h testing
i

• A
An analysis
l i off any supporting
ti data
d t from
f other
th
tests performed

34
 OOS Report Incl
Includes
des

• The justification for invalidating any data

• The final results and the conformity of the test

and/or the batch

• Any corrective actions required by the outcome

of the investigation

35