OOS Results in FDA
Warning Letters
How to Perform Appropriate Investigation,
and a Touch of CAPA plus Case Studies
Abbass Kamalizad, Ph.D.
President, ACPC Group
kamalizad@acpcgroup.com
Presented to SCPDG, Nov. 8, 2012
Outline
Introduction to OOS
Definition
U.S.A. vs. Barr Labs, Inc.
Regulatory CGMP’s 21CFR 210, 211
FDA Guidance
Warning Letters
Case Studies
Introduction
Barr Decision, Feb. 1993
US FDA Draft Guidance, 10 Sept 1998
USFDA Final Guidance, 12 October 2006 in
the Federal Register
21 CFR 210 & 211, Federal Food, Drug, and
Cosmetic Act (the Act) (section 501(a)(2)(B)
EMA, MHRA, WHO, Health CANADA, TGA,
Definition
A specification (often abbreviated as spec) is
an explicit set of requirements to be satisfied
by a material, product, or service. Should a
material, product or service fail to meet one or
more of the applicable specifications, it may be
referred to as being out of specification; the
abbreviation OOS is generally used.
Where OOS is found
..All test results that fall outside the
specifications or acceptance criteria
established in drug applications, drug master
files (DMFs), official compendia, or by the
manufacturer. The term also applies to all inprocess laboratory tests that are outside of
established specifications.”
Drug Products, Drug substances, Excipients,
Validation, Qualification, Water, Stability
Barr Decision
The US vs. Barr, Inc.
Cannot average OOS results with in-Spec to
get a Passing Result.
Cannot conduct multiple retest with no defined
end point.
Cannot use outlier test to reject results.
Should have a retest policy and procedure.
Over 3400 pages of testimony and 500 exhibits. FDA’s OOS
Investigation Draft Issued in Sept 1998 was based on this
rulings.
Barr Decision
“Testing lies at the heart of a drug
manufacturer’s successful operation.
Through testing companies validate
their processes and ensure the quality
of batches for release.”
Judge Wolin
OOS Issues in Barr Court
Out of specification results
Product “failure”
Informal and formal investigations
Testing and retesting
Sampling and resampling
Averaging
Outliers
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.”
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.”
Guidance for Industry
Investigating Out-of-Specification (OOS)
Test Results for Pharmaceutical Production
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2006
Pharmaceutical CGMPs
Applicability
Chemistry-based lab testing of drugs regulated by CDER.
Tests are performed on API, excipients and other components,
in-process materials, and finished drug products.
Products purchased outside but tested in house.
Contract firms performing testig on such products.
As long as CGMP regulations (21 CFR 210 and 211 and the
FD&C Act Section 501(a)(2)(B) apply.
Guidance for Industry
OOS Investigation
FDA requires that:
Finished Pharmaceuticals (DP)
and
Active Pharmaceutical Ingredients (APIs)
to be manufactured in accordance with current good
manufacturing practice under section 501(a)(2)(B) of
the Act.
Guidance for Industry
OOS Investigation
Current good manufacturing practice for APIs includes the
performance of scientifically sound
Raw material testing,
In-process monitoring,
Release and stability testing,
Process validation,
and adequate investigations of any OOS result
obtained from such testing.
Guidance for Industry
OOS Investigation
The responsibility of a contract testing
laboratory in meeting these requirements is
equivalent to that of a manufacturing firm.
Guidance for Industry
OOS Investigation
FDA regulations require investigation for any OOS.
The source of OOS is either
1. Aberration of measurement process or
2. Aberration of manufacturing process
The purpose of investigation is to find the cause of
OOS.
PHASE I: LABORATORY INVESTIGATION
• The first phase includes
Assessment of the Accuracy of the
laboratory’s Data
The investigation should be thorough, timely,
unbiased, well-documented, and scientifically
sound.
.
PHASE I: LABORATORY INVESTIGATION
Test preparations (including the composite or
the homogenous source of the aliquot tested)
are not to be discarded as they are necessary
for investigation
For contract laboratories, the laboratory should
convey its data, findings, and supporting
documentation to the manufacturing firm’s
Quality Control Unit (QA), who should then
initiate the full-scale OOS investigation.
PHASE I: LABORATORY INVESTIGATION
The Analyst’s Responsibilities
“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 …”
PHASE I: LABORATORY INVESTIGATION
The Analyst’s Responsibilities
Check all steps of preparation
Check all equipment (21CFR 211.160 (b)(4)
System Suitability and bracketing standard
If there is indication of system problem, the data from
the suspect time period should not be used. However,
investigation is needed.
“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
PHASE I: LABORATORY INVESTIGATION
The Analyst’s Responsibilities
For obvious errors, analyst should document
everything.
Analyst should not continue analysis until a
decision is made
Analyst should inform the supervisor
immediately
PHASE I: LABORATORY INVESTIGATION
The Supervisor’s Responsibilities
Supervisors assessment should be:
–
–
–
–
–
Objective
Timely
No preconceived assumptions
Prompt assessment of data
Laboratory or manufacturing?
PHASE I: LABORATORY INVESTIGATION
The Supervisor’s Responsibilities
1.
2.
3.
4.
5.
6.
7.
8.
Discuss the method with analysts
Examine raw data
Verify calculations
Confirm performance of instruments.
Confirm reference standards, reagents
Evaluate performance of method
Document (most important)
Must prove your hypothesis
INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS INVESTIGATION
In summary, when clear evidence of laboratory
error exists, laboratory testing results should
be invalidated.
When evidence of laboratory error remains
unclear, a full-scale OOS investigation should
be conducted by the manufacturing firm to
determine what caused the unexpected results.
INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS INVESTIGATION
This investigation may consist of a
Production Process Review and/or
Additional Laboratory Work
The objective of such an investigation should be to
identify the root cause of the OOS result and take
appropriate corrective and preventative action.
INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS INVESTIGATION
Quality Control Unit (QA) conducts the
investigation.
Other pertinent departments participate:
1.
2.
3.
4.
5.
Manufacturing
Process Development
Maintenance
Engineering
QC, Metrology, etc.
INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS INVESTIGATION
The key to unlock the OOS problem:
Complete review of all manufacturing and
process development documents with a written
record of the review.
INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS 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.
INVESTIGATING OOS TEST RESULTS —
PHASE II: FULL-SCALE OOS INVESTIGATION
Additional Testing
full-scale OOS investigation may include
additional laboratory testing. A number of
practices are used during the laboratory phase of
an investigation. These include
(1) Retesting (a portion of the original sample)
(2) Resampling.
Additional Testing
Retesting is performed for:
Finding problems with testing instrument
(malfunctions)
to identify a possible sample handling problem
(e.g. a dilution error)
A critical task, because it could determine the
root cause of the OOS.
Retesing
FDA wants a second qualified analysts do the
retest.
Don’t “test into compliance.”
Specify the number of retests (must be in SOP).
Prepare a protocol before retesting.
If the error is clearly identified, the retest
substitutes the OOS results.
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.
“In some situations, however, it may be
appropriate to collect a new sample from the
batch. Control mechanisms for examination of
additional specimens should be in accordance
with predetermined procedures and sampling
strategies see § 211.165(c).
Resampling
Resampling should be a rare event.
Investigation might conclude sampling error
(widely varied results).
For inherently inadequate sampling method, a
new accurate sampling method must be created
with all the controls. See §§ 211.160 and 211.165(c).
Reporting Test Resuts
Averaging
appropriate
inappropriate
Outlier Test
"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."
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 Alert
“For product that are subject of approved full
or 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 ….”
June 3, 2011
Dr. Reddy's Laboratories Limited
3. Your firm's out-of-specification (OOS)
investigations did not include analysis of all available
data.
For example, the inspection revealed that your firm
rejected three consecutive lots of (b)(4) (an
intermediate used in the manufacture of an API for
the product "(b)(4)") on February 26, 2010, for
appearance problems. The deviation investigation
into the cause of the failure did not include an
analysis of all available data including batches
manufactured prior to the failures.
June 3, 2011
Dr. Reddy's Laboratories Limited
The inspection also found many deficiencies regarding handling
OOS investigations. These include the timeliness of closing
investigations, notification of the quality unit (including four to
eight-month delays for reporting failing stability batches), and
failure to follow written procedures. Although some of your
proposed corrections to these individual items appear to be
adequate, we remain concerned that a thorough evaluation of
your investigation approach has not been conducted. Please
include in your response a corrective and preventive action plan
regarding handling investigations.
Oct. 31, 2008
Deltex Pharmaceuticals Inc.
Also, your SOP QC-01 0-1 "Procedure for out of spec
Inspection" is inadequate in that it lacks a defined protocol for the
number of retests allowed, and has no requirement for expansion
of an OOS investigation to manufacturing processes and
procedures or any provision for expansion on an investigation to
other lots potentially impacted.
Oct. 31, 2008
Deltex Pharmaceuticals Inc.
We acknowledge your correspondence of September 2, 2008, in
response to the FDA-483 in which you outline corrective action
on the calibrations of the spectrometer and balance. The response
is incomplete because it does not include the promised revised
SOP addressing the deficiencies in your written procedures for
handling OOS test results. Additionally, the response fails to
provide any documentation of the corrective actions related to the
balance and spectrometer.
May 5, 2011
Alpha Laboratories, Inc
1. Your firm has not thoroughly investigated the failure of a batch or any of
its components to meet its specifications whether or not the batch has
already been distributed [21 C.F.R. § 211.192].
For example, (b)(4) samples and (b)(4) and (b)(4) failed to meet the assay
specifications. However, no investigation was conducted. The inspection
also found that your analyst did not record these out-of specification results
in the OOS logbook as required by your SOP.
Please include in your response the specific corrective actions taken to
improve your program for handling OOS results, including ensuring that
both analysts and management are properly trained on how to document
and conduct investigations.
May 5, 2011
Alpha Laboratories, Inc
The inspection also documented that your Quality Control Unit reviews
and approves Certificate of Analysis containing OOS results, but without
conducting any investigation.
Your response states that a plan to investigate all OOS results, obtained as
of November 1, 2010, has been implemented. However, there is no
commitment to conduct a retrospective review of all lots tested and found
OOS. Please provide a list of all OOS results obtained during the last 3
years. Include the name of the raw material or finished product, the lot
number, date tested, and customer. Please indicate if all your customers
were notified of these failures and date of notification.
.
May 5, 2011
Alpha Laboratories, Inc
2. Your quality control laboratory has not followed written procedures for
testing and laboratory controls designed to assure that the drug products
you tested have the identity, strength, quality, and purity they purport or are
represented to possess [21 C.F.R. § 211.160(a)(b)(3)(4)].
For example,
a. The inspection revealed that your procedure for Out-Of-specification
results (SOP-GEN-0008 Rev 4) is not followed.
The OOS procedure requires that as part of Phase (b)(4) a re-test be
performed if no assignable cause has been found. The inspection found that
no re-test was performed for OOS samples #542, #545, #546, #521. Your
firm failed to document the reason(s) for not conducting a Phase (b)(4)
investigation for an OOS results and for not documenting that your clients
were notified as in your procedure.
Jue 20, 2012
Ercros S.A.
4. Inadequate or lack of any investigation of critical deviations or a
failure of a batch to meet its specifications or quality standards.
For example, the IR spectra of (b)(4) API lots (b)(4), and (b)(4) did
not match the IR spectrum of the standard. The quality unit released
these lots. The quality unit failed to document and investigate the
presence of bands in the IR spectra that did not match the spectrum
of the standard.
In your response, you indicate that the quality unit did not
investigate because it believed the additional peaks in the IR spectra
were due to ambient (b)(4). Your response failed to explain why
ambient (b)(4) bands appear to only affect the spectra for the abovementioned lots but not the reference standard spectrum. Your
response also did not address under what conditions analysts could
potentially perform background corrections to remove the (b)(4)
bands.
Jue 20, 2012
Ercros S.A.
In your response your firm promised to revise the
procedures for each of these issues. Your response
lacks specific corrective and preventive actions to
ensure that future out of specification results (OOS)
and deviations are thoroughly investigated and
documented. In your response, please describe how
this concern will be addressed for all laboratory and
quality oversight procedures.
Feb. 22, 2012
APP Pharmaceuticals, LLC
c. Your firm failed to identify an assignable cause for a failing
assay result for Heparin Lock Flush (OOS# (b)(4)) and failed
to extend your investigation into other batches of Heparin
Lock Flush.
In your response, you state investigation (b)(4) was completed
to identify the root cause of the out of specification (OOS)
results. We cannot evaluate your response since investigation
(b)(4) was not included in your response. We are also
concerned about a potentially related trend of OOS assay
results for other batches of heparin active pharmaceutical
ingredient (API) and Lock Flush.
Feb. 22, 2012
APP Pharmaceuticals, LLC
Please provide the following information or data: 1) A copy of
investigation (b)(4) including root cause analysis and
corrective actions implemented for this batch; 2) Whether
other associated lots may be affected by this issue; 3) Whether
you have implemented, for commercial production and release,
the new filter and tubing that was being used when you
produced the failing exhibit batch; and 4) A three-year history
of heparin API and Heparin Lock Flush batches that have had
OOS results, the testing results obtained, the root cause, and
the investigation conclusion.
Sept. 1, 2011
Deibel Laboratories of Illinois, Inc.
4. Your firm has not thoroughly investigated the
failure of a batch or any of its components to meet
its specifications, whether or not the batch has
already been distributed [21 C.F.R. § 211.192].
For example:
a. Your firm failed to conduct an investigation
when you were made aware on March 15, 2011,
that a lot of Butterfield Phosphate Buffer (Lot
(b)(4) was Out-of-Specification (OOS) for pH.
Sept. 1, 2011
Deibel Laboratories of Illinois, Inc.
Your firm continued to use this buffer until March 30,
2011, to test approximately (b)(4) drug products.
Your response is not adequate because you did not
provide copies of the investigation or the pH test
results.
Your response also minimizes and attempts to justify
the failure to initiate an investigation by indicating
that the buffer's pH was within 5% of the target value.
In accordance with 21 C.F.R. § 211.192, any
deviations from the specification are considered to be
discrepancies and must be investigated.
Sept. 1, 2011
Deibel Laboratories of Illinois, Inc.
b. Your firm has failed to conduct an investigation for numerous OOS
results (e.g., for colony forming units, conductivity, assay, etc.). Many of
these OOS results were not reported to your client.
In your response, your firm indicates that you will revise your procedure
for nonconformances to state that investigations for raw materials, water,
swabs, and stability samples will only be initiated upon client request. As
discussed above, when your laboratory obtains out-of-specification results,
it is imperative that you promptly initiate an investigation to determine
whether your laboratory's practices led to the failure (analysts error,
equipment failure, etc.) or the results are valid. Your firm is responsible for
fully meeting CGMP for operations that you conduct. Accordingly, your
firm is responsible for investigating all non-conformances associated with
your laboratory and testing.
Please see FDA's Guidance for Industry entitled, "Investigating Out-ofSpecification (OOS) Test Results for Pharmaceutical Production" (October
2006).
Summary of FDA Warning Letter
2011-2012
Failure to investigate and document out-ofspecification results obtained for … .
Your firm has not thoroughly investigated the
failure of a batch or any of its components to meet
its specifications whether or not the batch has
already been distributed, and you failed to extend
the investigation to other batches of the same drug
product that may have been associated with the
specific failure or discrepancy.
Summary of FDA Warning Letter
2011-2012
Your QCU approved and released a batch of …
despite an initial OOS bulk assay result. These results
were later confirmed through repeat testing, but
further testing of additional samples produced passing
results. Your QCU released the batch even though the
investigation did not identify a discernable cause.
Your QCU did not require a second, independent
person to review the raw data, calculations and
records before releasing these lots for distribution.
Summary of FDA Warning Letter
2011-2012
Your QCU failed to detect multiple discrepancies in
sample weights and dilution factors between the
analyst's notebook and the Calculation Sheet. As a
result, incorrect data was recorded for multiple
products and finished products not meeting
specifications were released. Specifically, a lot of …
was released and distributed even though it did not
meet the established specification of … % label
claim. The correct calculation would have reported a
… % label claim.
Summary of FDA Warning Letter
2011-2012
The inspection also found that your analyst did
not record these out-of specification results in the
OOS logbook as required by your SOP.
Your investigation failed to follow your
procedures when your firm … initiated Phase 2
sample testing prior to completing Phase 1 of the
investigation, and … only analyzed two samples
as opposed to the required three samples
Summary of FDA Warning Letter
2011-2012
Your firm's out-of-specification (OOS) investigations
did not include analysis of all available data.
Inadequate or lack of an investigation of critical
deviations or a failure of a batch to meet its
specifications or quality standards.
Your firm has failed to conduct an investigation for
numerous OOS results (e.g., for colony forming units,
conductivity, assay, etc.). Many of these OOS results
were not reported to your client.
Case Study I
Mislabelling
In the morning of March 9, we received a call from our client
regarding a mislabeled antibiotic shipment of their reference
standard to their PR plant. Based on this call
An immediate investigation was initiated
Determined where else, if any, the reference was shipped
Recalled all the vials for inspection and investigation
Develop a CAPA plan
Case Study I
Mislabelling
We opened all vials and compared the content with
the retained ref. std. in our site. We found 7 vials
contained the same mateial but different label.
We reviewed dispatch of more than 15 lots sent to 5
different labs throughout the world and found no
problem.
The likelihood of mislabeling was possible shortage
of the label so the chemist continued using labels
available to him and not realizing the proper lable had
been depleted.
Case Study I
Mislabelling
We found we did not have proper control on
the number of labels needed and printed.
We changed SOP to reflect that based on the
number of vials to be dispatched (requested by
the and client approved by QA), exact number
plus 2 is printed in one “lot” (no mixing of
labels on the same sheet).
Created log book and trained all the personnel
Case Study II
ABC (Coated) Caplet
Out of Specification (OOS) results were
obtained for a number of ABC samples. The
samples were tested for Calcium by ICP per an
approved and validated test procedure
Case Study II
ABC (Coated) Caplet
Investigation of the record of analysis showed that:
Correct reagent and solvents were used for the sample and standard
preparation.
ICP instrument was set up correctly
The instrument passed calibration and system suitability requirements
before sample analysis.
Sample and standard solution were executed correctly.
Standard checks throughout the run were consistent and passed the
requirements.
Review of the sample preparation and interview with the chemists showed
that during the initial charring of the samples on the hot plate, the samples
may not have been charred completely.
Case Study II
ABC (Coated) Caplet
Lot #
30058275
30058051
30058252
30058253
30058254
30058263
30058264
First Test mg/Caplet
Reanalysis,
mg/Caplet
124
120
122
129
112
120
100
118
100
97
103
100
120
115
117
99
95
88
120
121
121
123
125
124
137
132
135
134
134
134
124
132
128
139
132
136
119
115
114
142
135
139
Case Study III
Nanopure® Water
During the course of routine analysis of water from
our NanoPure® systems, two units, one located in the
QC Labs, ID # 0075-00 and the second unit located in
the R & D Department, ID # 0792-00, generated out
of specifications results for a period from Sept 2, until
Oct. 13. Water samples were taken once every week
and tested for conductivity, total organic carbon
(TOC) and microbial plate. During the stated period,
specifically, the results of TOC for the water samples
were out of specification.
Case Study III
Nanopure® Water
Report of Analysis of the QC Labs
Date
Sampled
Date Tested
Plate Count,
Heterotrophic, Water
09/02/03
10/17/03
1 CFU/mL
0.43 ppm
0.70 µmho/cm
09/08/03
10/22/03
1 CFU/mL
0.11 ppm
0.80 µmho/cm
09/15/03
10/24/03
1 CFU/mL
0.14 ppm
0.70 µmho/cm
09/22/03
10/22/03
1 CFU/mL
0.29 ppm
0.80 µmho/cm
09/29/03
10/22/03
<1 CFU/mL
0.16 ppm
1.16 µmho/cm
10/06/03
10/22/03
<1 CFU/mL
0.06 ppm
0.78 µmho/cm
10/13/03
10/23/03
1 CFU/mL
0.18 ppm
1.50 µmho/cm
Organic Carbon, Total
Conductivity
Similar Results were obtained for the R&D Labs
Case Study III
Nanopure® Water
HPLC analysis of Feed Water, and water
samples from QC and R& D Labs using an
aminoacid derivitizing agent and an internal
standard revealed indication of contamination
consistant with TOC analysis.
Chromatographic Data From Analysis of Water
DI Water
Ammonia
AABA
NanoPure Room 115
(ID # 0075-00)
NanoPure Room 225
(ID # 0972-00)
tR min.
Area
tR min.
Area
tR min.
Area
30.1
34.7
265572
1339912
30.2
34.8
1463368
1192145
30.3
34.8
1862470
1479593
Case Study III
Nanopure® Water
Chromatogram of NanoPure® Water (Fed from DI Water)
Case Study III
Nanopure® Water
The samples were not run in a timely manner and this was
mainly due to capacity and resource in the sense that samples
from clients were run first and therefore, our water samples
were all tested late.
The function of the NanoPure® systems was questionable,
possibly due to the “bad” filter and/or beds in the systems
Case Study III
Nanopure® Water
CAPA
We changed all the filters and beds of the two
NanoPure® systems and revalidated the two systems
based on a newly revised and approved protocol.
Changed SOP to reflect weekly water samples
would be tested within 24 hours of sampling for
TOC to avoid possible OOS due to late testing.
Assigned appropriate responsibilities and controls
and performed training.
Thank You