Oos Guidance

Sept 6, 2007 L.
Torbeck 1
OOS
Guidance
SOCMA
September 6, 2007
Sept 6, 2007 L. Torbeck 2
Overview
CGMPs 21 211.192
U.S.A. vs. Barr Laboratories, Inc.
Able Laboratories
Reportable Results
Specifications
OOS flowchart
Specific OOS topics
Specific Topics
OOS definition
Initial and full investigations
Testing and retesting
Sampling and resampling
Averaging and Outliers

CGMPs 21 CFR 211.192
Any unexplained discrepancy of the failure
of a batch or any of its contents to meet any
of its specifications shall be thoroughly
investigated, whether or not the batch has
already been distributed.
CGMPs 21 CFR 211.192
The investigation shall extend to other
batches of the same drug product and other
drug products that may have been
associated with the specific failure or
discrepancy.
A written record of the investigation shall
be made and shall include the conclusions
and follow-up.
Barr Court Case
Civil action by FDA, June 12, 1992.
Judge Alfred M. Wolin
Can the FDA expand the CGMPs
interpretation into the statistical areas of
outliers, retesting, resampling, averaging
and sample size and other areas of failure
investigations,
Barr Background
The current conflict surrounding these
rules is best characterized as a confrontation
between a humorless warden and his
uncooperative prisoner. These witnesses
revealed an industry mired in uncertainty
and conflict, guided by vague regulations
which produce tugs-of-war of varying
intensity.
Able Laboratories
On May 23, 2005, Able labs issued a Class
II recall of all of its 46 drug products
The company immediately suspended
operations and laid off 200 employees.
The stock price in the last two weeks of
May dropped by more than 90%.
The company went out of business.
OOS Philosophy
Testing lies at the heart of a drug
manufacturers successful operation.
Through testing companies validate their
processes and ensure the quality of batches
for release. Judge Wolin
If we cant trust our measurements, we
dont have anything.
Draft Version
30 September 1998
Guidance for Industry Investigating Out
of Specification (OOS) Test Results for
Pharmaceutical Production
Submitted comments by 30 November 1998
These comments can be inspected by going
to the FDA offices.
Final Guidance
12 October 2006 in the Federal Register
FDA authors include:
Richard Friedman Director of the Division of
Manufacturing & Product Quality
Paul Haynie is responsible for the Guidance
(301) 827-9020
Hayniep@cder.fda.gov
Controversial Topics
Definition of reportable values?
Use of averaging?
Number of retests?
Second analyst?
Use of outlier testing?
What specification limits?
Defining testing into compliance?
OOS Definition
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 Major Issues:
What test results?
What specifications?
Scope
These laboratory tests are performed on active
pharmaceutical ingredients, excipients and other
components, in-process materials and finished
drug products.
Laboratory testing is necessary to confirm that
components, container and closures, in-process
materials and finished products conform to
specifications, including stability specifications.
Scope
This guidance applies to chemistry-based
laboratory testing of drugs regulated by
CDER.
The term also applies to all in-process
laboratory tests .
applies to in-house testing of drug
product components that are purchased
Reportable Values
for Out-of-Specification
Test results
Lynn Torbeck
Pharmaceutical Technology
Vol. 23, No. 2, February 1999
Special Supplement
FDA 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.
FDA Definition
This determination is
considered one test and
one result.
Implied 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 the value used for statistical analysis.
Figure 1
Batch
Sample
Preparation
Figure 1
Reportable
Value, RV
Inj
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
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
Interpretation
The individual determinations do not have
to meet the specification.
Determinations are not reported out of the
lab.
The variability of determinations is like a
system suitability issue.
Set an upper limit on the standard deviation
or %RSD.
Interpretation
All reportable values must be documented
Do not average OOS with in spec to get an
in spec results to release with.
Do not average reportable values for QA to
make a decision. QA must see all R.V.
If after QA makes a decision, and a value is
needed for a COA, then average them.
Specifications
Types of Limits ?
1. Regulatory specifications (External)
2. Accept/reject limits (Includes stability)
3. Action (Cpk=1.33 ?)
4. Alert or Trend (Cpk=1.0 ?)
5. In-process adjustment limits ?

Phase I Investigations
An investigation is required for an OOS.
The purpose is to find the cause of the OOS.
Is it measurement or manufacturing?
Batch rejection does not negate the need to
perform the investigation.
The first phase should include an
assessment of the accuracy of results.
Phase I Investigations
For contract laboratories, the laboratory
should convey its data, findings, and
supporting documentation to the
manufacturing firms quality control unit
who should then initiate the full scale
investigation.?
Responsibility of the Analysts
The first responsibility for achieving
accurate laboratory results lies with the
analysts who is performing the test.
The analysts should be aware of potential
problems that could occur
Responsibility of the Analysts
Analysts should check the data for
compliance with test specifications before
discarding test preparations or standard
preparations.
An assessment of the accuracy of the results
should be started immediately.
Responsibility of the Supervisor
Supervisors assessment should be:
Objective
Timely
No preconceived assumptions
Prompt assessment of data
Laboratory or manufacturing?
Supervisors Steps
1. Discuss the method with analysts
2. Examine raw data
3. Verify calculations
4. Confirm performance of instruments.
5. Confirm reference standards, reagents
6. Evaluate performance of method
7. Document, document, document
Phase II Investigations
Unconfirmed OOS requires a full scale
OOS investigation with predefined
procedure.
Find the root cause and do CAPA
Review production and sampling
procedures
Investigations given the highest priority
Review of Production
Quality Control Unit conducts the
investigation.
Other departments participate:
1. Manufacturing
2. Process Development
3. Maintenance
4. Engineering
Review of Production
In cases where manufacturing occurs off-
site (i.e., performed by a contract
manufacturer or at multiple manufacturing
sites), all sites potentially involved should
be included in the investigation.
Review all documents and records of the
manufacturing process.
Full Scale Investigation
A written record of the review includes:
1. A clear statement of the reason
2. Summary of manufacturing process aspects
that could cause the problem
3. Results of documentation review with
probable cause.
4. Results of previous reviews
5. Description of corrective actions to be taken.

Retesting
A retest is another test of a portion of the
original sample brought into the lab.
FDA prefers a second analysts do the retest.
Dont test into compliance.
Specify the number of retests.
Prepare a protocol before retesting.
If the error is found the retest substitutes.
How Big the Retest Sample?
This is still and unresolved issue and the
statisticians are still publishing journal
articles and discussing it.
Bar case n=7 not fully supported by
statistics
Could be too much or not enough
Currently n= 3 to n=9
Testing Into Compliance
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 must be found and stopped.
See Torbeck, Pharm Tech, Oct 2002
Testing Into Compliance
Averaging OOS with in specification results
to get an in specification result.
Physically averaging powers, granulations
and liquids to get in specifications results.
Not recording data until is known to be in
specification.
Missing samples
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
Resampling
Resampling involves analyzing a specimen
from any additional units collected as part
of the original sampling procedure or from a
new sample collected from the batch.
Original should be large enough for retests
Original sample must representative
Resampling should be a rare event.
Averaging
We can average determinations to get the
reportable value.
We do not average reportable values.
QA must see all of the reportable values.
Dont average OOS with in spec results.

Outliers
"In a sample of n observations it is possible for a
limited number to be so far separated in value
from the remainder that they give rise to the
question whether they are not from a different
population, or that the sampling technique is at
fault. Such values are called outliers. Tests are
available to ascertain whether they can be
accepted as homogeneous with the rest of the
sample." Marriott, 1990.
Outliers
"The USP expressly allows firms to apply
this test 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."
Outlier Tests
Use of outlier tests is determined in advance
Specify the test and the sample size.
Can reject biological data but not chemical.
The outlier can be omitted.
Outlier tests to be used sparingly.
No application variability or homogeneity is
being assessed.
Concluding the Investigation
If a cause is found, invalidate the initial
result and use the retest value(s) in its place.
If the OOS is confirmed the batch is
rejected.
If the OOS is inconclusive and the retests
are within specification, then QA may be
able to justify releasing the batch.
Field Alerts
For those product that are the subject of
approved full and abbreviated new drug
applications, regulation require submitting
within 3 working days a field alert report of
information concerning any failure of a
distributed batch to meet any of the
specifications .
Conclusion

Oos Guidance

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