5/12/2014 9:33 PM Preventing OOS Deficiencies 1

Preventing OOS Deficiencies

Lynn Torbeck
5/12/2014 9:33 PM Preventing OOS Deficiencies 2
List of Topics
Briefly review:
Barr Case
FDA OOS Guidance
Able Laboratories Story
PDA Scientific Advisory Board Committees
Troublesome fundamentals
Unresolved issues
Preventing OOS deficiencies
Final recommendations

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Barr Case
Audited in 1989, 1991 and 1992.
Refused to accept a consent decree.
FDA was forced to go to court.
Civil action taken June 1992.
Decision in favor of the FDA on
February 4, 1993.
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Barr and Statistical Issues
Initial investigations
Full investigations
Testing
Retesting
Averaging
Outliers techniques
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Test
Out of Spec?
Report out
results
No
Yes
Known Physical
Reason?
USP allows
resamples?
No
Yes
2 nd Stage
(i.e. Content
Uniformity)
Passes?
Yes
Begin Lab Initial
Investigation
No
No
Resample as
needed
Invalidate data,
Document,
Start Over
Document
Original sample
representative?
No
Yes
Lab or
Analyst
error?
Yes
Retest Passes?
Yes
No
Other
reason?
Yes
Finish
Investigation
Yes
Document
and report
Full
Investigation
No
USP <111> Outlier ID
Historical Data
Review is
inconclusive
Retest
justified?
No
Retest n times
Document
justification
All pass?
No
Finish
investigation
Yes
Yes
OOS Logic
by Lynn Torbeck
No
March 1999
Copyri ght 1999 by
L. Torbeck
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Barr: Lessons Learned
FDA takes OOS issues very seriously.
OOS SOPs, laboratory logs and
documented investigations will be part
of any Quality System review.
Companies are still getting Form 483
observations for not having an
adequate SOP or for not following the
SOP.

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Barr: OOS Prevention
Analysts, supervisors and managers
should read and discuss the Barr case
and understand the OOS issues in
context.
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FDA Guidance
Investigating Out of Specification
(OOS) Test Results for Pharmaceutical
Production.
Issued as a draft in September 1998.
Still in draft as of today.
FDA has sent it to the attorneys.
Final version could be out this year.
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Draft: OOS Prevention
All laboratory personnel, analysts,
supervisors and managers should read,
study and discuss in-depth, sentence by
sentence if necessary, the draft OOS
guidance.
Then do it again when the final
guidance is released.
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Able Labs Cranbury, NJ
Massive number of OOS errors
Recall of all 46 products
3,184 lots recalled
Five ANDAs withdrawn
Hundreds of staff laid off
Sold to Sun Pharm in December 2005
www.ablelabs.com
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Able Labs: Lessons Learned
It is still possible to have wide spread
misunderstanding of the Barr case, the
OOS guidance and OOS SOPs.
Apparently the analysts felt they could
not give an incorrect result.
Management needs to instill and
cultivate a GMP Culture in the
analytical laboratory.
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Able Labs: OOS Prevention
Review the Able Labs web site.
Discuss the Able Labs story with
laboratory analysts, supervisors and
managers.
Discuss what a GMP Culture means in
the analytical laboratory and how to
develop and reward it.
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PDA OOS Committees
Chemical OOS:
Lynn Torbeck, Chair
Eight members
Draft technical report reviewed by the FDA
Planning a PDA/FDA conference
Microbial Data Deviations:
Jeanne Moldenhauer, Chair
Draft in revision

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Troublesome Fundamentals:
Outliers
Reportable Values
Averaging
Testing into compliance
Full consideration
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Outliers - Defined
Extreme values vs outliers:


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Outliers Judge Wolin
"The USP expressly allows firms to
apply this test (outlier) to biological and
antibiotic assays, ..., but is silent on its
use with chemical tests.
"In the Court's view the silence of the
USP with respect to chemical testing
and outliers is prohibitory."
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Outliers - Investigation
"In chemical procedures, where method
accuracy variation is small, an outlier test
may be appropriate as part of an OOS
investigation, provided the sample and test
procedure assumes homogeneity ... as in the
composite strength assays. Our current
thinking is that outlier tests are never
appropriate where the purpose of the sample
is to measure uniformity" Paul Vogel,
September 10, 1993.
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Outliers - Tests
Dixon's criteria, the test in USP<111>, is
general in nature and not specific to
biological issues. It can be used anywhere
the statistical assumptions can be met.
In general, statisticians agree with the
philosophy that outlier tests should be used
infrequently and with great caution.
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Outliers - Recommendations
Don't use any outlier rejection test for
rejection of chemical test results. But it can
be used as supporting information in an OOS
investigation to consider retesting.
Keep all data, especially suspect data, for
future review. Unusual data when seen in
context and with other historical data often is
not unusual at all, but in fact forms a known
and well-behaved statistical distribution.
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Reportable Values
Reportable Values for Out of
Specification Test Results
Lynn Torbeck
Pharmaceutical Technology
Vol. 23, No. 2, February 1999
Special Supplement

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FDA R.V. Definition
It should be noted that a test might
consist of replicates to arrive at a result.
For instance, an HPLC assay result may
be determined by averaging the peak
responses from a number of
consecutive, replicate injections from
the same preparation. The assay result
would be calculated using the peak
response average.
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FDA R.V. Definition
This determination
is considered one
test and one result.
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Implications of FDA Definition
A reportable value is the end result of
the complete measurement method as
documented.
It is the value compared to the
specifications.
It is the value used for official reports.
It is usually the value used for statistical
analysis.
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Figure 1
Batch
Sample
Preparation
Figure 1
Reportable
Value, RV
Inj
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Figure 2
Batch
Sample
Inj1
Preparation 3 Preparation 2 Preparation 1
Inj 2 Inj 3
Figure 2
Inj 7 Inj 8 Inj 9
Reportable
Value, RV
Inj 4 Inj 5 Inj 6
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Figure 3
Batch
Sample Resample
Reinjection
Reportable
Value, RV
Inj1
Preparation 1C
Preparation 1B
Preparation 1A
Inj 2 Inj 3 Inj 4 Inj 5 Inj 6
Repreparation
2C
Repreparation
2B
Inj 7 Inj8 Inj 9
Retest
Remeasure Remeasure
RV RV
Figure 3
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Interpretation
The individual determinations do not have to
meet the specification.
Individual determinations are not reported
out of the lab.
However the variability of the determinations
is a system suitability issue.
Set a limit on the standard deviation or
%RSD.
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R.V.: OOS Prevention
Record in writing the operational
definition of the Reportable Value for
each test method in the method
documentation, any protocols and any
reports.
Add Only this reportable value can be
compared to the specification criteria.
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Averaging
Specifically, the arithmetic mean; the sum of
all of the numbers divided by the count of the
numbers.
More generally, it is a value that represents
the central point of a data set. (In this sense,
it can include the arithmetic average, the
median, the mode, the geometric mean or
the harmonic mean.)
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Averaging
"... as a general rule, firms should avoid this
practice, because averages hide the
variability among individual test results.
"[Averaging] is particularly troubling if
testing generates both out-of-specification
and passing individual results which when
averaged are within specification.
"Here, relying on the average figure without
examining and explaining the individual
out-of-specification results is highly
misleading and unacceptable."
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Averaging
"Averaging the results of tests intended to
measure the uniformity of the test article is
not current good manufacturing practice ...
because it may hide the variability of the
sample the test procedure is intended to
detect. For this reason, all individual test
results must be reported and evaluated on an
independent basis" Paul Vogel, September
10, 1993.
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Averaging: OOS Prevention
Do not average out of specification
reportable values within specification
reportable values to get an in
specification result.
Do not average reportable values for
QA to make a decision. QA must see all
individual reportable values, OOS and
retests.
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Testing Into Compliance
Torbeck, L., Preventing the Practice of
Testing into Compliance, Pharmaceutical
Technology, Oct 2002.
Testing into compliance is the practice of
ignoring valid information that should be used
to make decisions.
Such a practice is at best not scientific and at
worst is fraudulent, illegal, and immoral.
Such practices if found must be stopped.
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Testing Into Compliance
Averaging OOS results with in specification
results to get an in specification result.
Physically averaging powers, granulations and
liquids to get in specifications results.
If not part of the validated process.
Discarding data or not recording data until is
known to be in specification.
Missing samples and rejected cans.
Overwriting HPLC chromatograms.
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Not Testing Into Compliance
Large initial sample sizes are acceptable
if all data generated is reported.
Large number of retests are acceptable
if all data generated is reported.
Failing system suitability is not an OOS.
Out of limits for an in-process
adjustment is not an OOS.
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Compliance: OOS Prevention
Train all laboratory personnel, analysts,
supervisors and managers to be able to
identify specific situations of testing into
compliance.
Train to be able to defend situations
that are not testing into compliance
during an audit.
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Full Consideration
For inconclusive investigations . The
OOS result should be retained in the
record and given full consideration in
the batch or lot disposition decision.
This statement has caused some
discussion as it is considered to be
vague and undefined. It can, I think, be
defined in a simple way.
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Full Consideration
First, all QA decisions are made with the
Reportable Values, both OOS and
retests.
Second, QA looks at the magnitude of
the retest values compared to the
specifications.
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Full Consideration
If the retest values are close to the
target, the lot can be released.
If the retest values are close to the limit
that the OOS exceeded, technically the
lot can be released, but QA should
consider further investigation to
determine why the retests are not at
target.
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Consideration: OOS Prevention
QA should detail and document the
logic and rational for decisions based on
retesting results after a OOS result is
found.
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Unresolved Issues
Specification Limits for OOS?
What size the retest sample?
Second analyst?
Statistical treatment of data?

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Specification Limits for OOS?
Regulatory Limits
Release: accept/reject
Action limits, Cpk=1.33
Alert, Cpk=1.0
Warning limits
Trend
Validation limits
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Specification Limits
Cpk=1.0
Cpk=1.33
Accept/Reject
Regulatory
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Specification: OOS Prevention
Define in writing the levels of
specification criteria.
Justify in writing which specifications
are considered applicable to OOS and
why or why not.
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What Size the Retest Sample?
a matter of scientific judgment,
retesting cannot continue ad infinitum.
Such a conclusion cannot be based on on 3
of 4 or 5 of 6 passing results, but possibly 7
of 8.
will vary on a case by case basis
an inflexible retesting rule is
inappropriate.
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What Size the Retest Sample?
The number of retests should be specified
in advance
The number of tests should not be adjusted
on-the-fly, as results are being generated.
a firms predetermined testing procedure
should contain a point at which testing ends
and the product is evaluated.
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What Size the Retest Sample?
This is an unresolved issue and the
statisticians are still publishing journal
articles and discussing it.
Barr case n=7.
Could be too much or not enough.
Currently n= 3 to n=9.
PDA OOS committee will recommend.
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Retest References
Hofer, J., Considerations when
determining routine sample size for a
retest procedure, Pharmaceutical
Technology, Nov. 2003.
Anderson, S., An alternative to the ESD
approach, Pharmaceutical Technology,
May 2004.
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Retest: OOS Prevention
Define in writing the sample size for
retests or define the procedure to be
used to determine the sample size.
Provide scientific justification.
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Second Analyst
Guidance suggests a second analyst.
Issues:
Added complication and variation
May not have a second analyst
May not find the root cause
Second analyst may not be as proficient
Recommend that the manager decide
and justify decision in writing.
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Statistical Treatment of Data
Statistical treatments of data should
not be used to invalidate a discrete
chemical test result.
a statistical analysis may be
valuable as one assessment of the
probability of the OOS result
Another way to say outlier rejection.
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Preventing OOS Deficiencies:
Setting specification criteria
Statistical Thinking
Sources of variation
Common cause vs. special cause
Variation reduction
Training
Education
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Setting Specification Criteria:
Two sides to the OOS issue.
Incorrect limits are the major source of
OOS.
Many specifications were set early in
the development process and may not
be appropriate for the current process.
Many specification were set using
wishful thinking or incorrect approach.
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Setting Specification Criteria:
Use historical data
Use distribution analysis
Normal, log-normal, exponential
Dont use X bar 3S
Use Statistical Tolerance Intervals
X bar K S for the alert limits
where K is based on confidence and
percent of future values
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Setting Specification Criteria
For action limits, permit the average to
vary and widen the Tolerance Limits
For accept/reject limits, add a further
allowance for stability.
Consider the clinical results as part of
the justification for limits.
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Statistical Thinking
1. All work occurs in a system of
interconnected processes.
2. All processes have variability.
3. Process understanding and variability
reduction is the key to success.

Variation is the enemy.
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Sources of Variation:
Common cause variation:
People
Materials
Methods
Measurement
Machines
Environment
Special cause variation:
One single factor changed
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Common vs. Special Causes
A plot of the data
with natural limits
illustrates common
cause variation.
A value that is larger
than would be
expected by chance
alone is assumed to
be due to a special
cause. Use CAPA to
find it.
0 50 100
96
97
98
99
100
101
102
103
104
105
106
Observation Number
I
n
d
i
v
i
d
u
a
l

V
a
l
u
e
I Chart for Yield%
1
Mean=100
UCL=103
LCL=97
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Variability Reduction:
Display boards
Operational definitions
Work to target, Target ( Low, High )
Flexible consistency
Hold constant
Mistake proofing
High tech equipment

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Training
Training is for a specific task or SOP.
The goal is consistency.
Freelancing causes problems.
Little background is provided.
An in-depth understanding is not
needed to be in compliance if the SOP
is followed.
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Education
Someone needs to:
Learn and understand the basic philosophy
and principles.
Know the background as it relates to the
topic.
Understand the material well enough to be
able to make difficult decisions with
confidence and be able to defend them.
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Need for Understanding
Why was Able Labs out of compliance?
Defend Reportable Values.
Defend specifications applicable to OOS
Defend not testing into compliance.
Defend retest sample size.
Why variability reduction is needed.
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Final Recommendations
Read and understand the Barr Case.
Read and study in-depth the OOS
Guidance. Once is not enough.
Audit the company SOP against the
Guidance line by line.
Have an active program to reduce OOS
results.
Keep management informed.
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Thank You
That ends my presentation.
We are now ready for questions and
answers.
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References
1. USA vs. Barr Laboratories, Inc. Civil Action No. 92-1744, US District
Court for the district of New Jersey, February 4, 1993.
2. FDA, CDER, Guidance for Industry, Investigating Out of
Specification (OOS) Test Results for Pharmaceutical Production,
September 1998.
3. WWW.AbleLabs.com
4. Torbeck, L., Reportable Values for Out-of-Specification Test
Results, Pharmaceutical Technology, February 1999.
5. Torbeck, L., Preventing the Practice of Testing into compliance,
Pharmaceutical Technology, October 2002.
6. Hahn, G and Meeker, W., Statistical Intervals, John Wiley & Sons,
1991.
7. Torbeck, L., Statistical Thinking, Pharmaceutical Technology, July
2001.