The document discusses guidelines and regulations related to testing and investigation of out-of-specification (OOS) results in pharmaceutical production, emphasizing the necessity for thorough investigations whenever discrepancies arise. It covers the responsibilities of analysts, quality control units, and manufacturing teams in ensuring compliance with testing specifications, as well as the procedures for retesting and reporting. Furthermore, it highlights the legal implications and the importance of accurate documentation throughout the testing and investigation processes.

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Presentation prepared by Drug Regulations – a not for
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the latest in Pharmaceuticals.
06-11-2015

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 CGMP’s 21 211.192
 U.S.A. vs. Barr Laboratories, Inc.
 Able Laboratories
 Reportable Results
 Specifications
 OOS flowchart
 Specific OOS topics
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 “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.”
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 “ 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.”
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 Civil action by FDA, June 12, 1992.
 Judge Alfred M. Wolin
 Can the FDA expand the CGMP ’ s
interpretation into the statistical areas of
outliers, retesting, resampling, averaging and
sample size and other areas of failure
investigations, …”
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 “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.”
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 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.
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 “ 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
 If we can’t trust our measurements, we don’t
have anything.
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 September 30 , 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.

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 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

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 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

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 Definition of reportable values?
 Use of averaging?
 Number of retests?
 Second analyst?
 Use of outlier testing?
 What specification limits?
 Defining testing into compliance?
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 “… 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?

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 “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.

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 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 …”

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 “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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This determination is
considered
◦One test and
◦One result.

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 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.

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Batch
Sample
Preparation
Figure 1
Reportable
Value, RV
Inj
Torbeck, Pharm Tech, Oct 2002

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Batch
Sample
Inj1
Preparation 3Preparation 2Preparation 1
Inj 2 Inj 3
Figure 2
Inj 7 Inj 8 Inj 9
Reportable
Value, RV
Inj 4 Inj 5 Inj 6
Torbeck, Pharm Tech, Oct 2002

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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
Torbeck, Pharm Tech, Oct 2002

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 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.

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 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.

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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 ?

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 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.

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 For contract laboratories, the laboratory
should convey its data, findings, and
supporting documentation to the
manufacturing firm’s quality control unit who
should then initiate the full scale
investigation.

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 “ 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 …”

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 “ 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.

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 Supervisors assessment should be:
◦ Objective
◦ Timely
◦ No preconceived assumptions
◦ Prompt assessment of data
◦ Laboratory or manufacturing?

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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

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 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

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 Quality Control Unit conducts the
investigation.
 Other departments participate:
1. Manufacturing
2. Process Development
3. Maintenance
4. Engineering

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 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.

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 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.

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 A retest is another test of a portion of the
original sample brought into the lab.
 FDA prefers a second analysts do the retest.
 Don’t “test into compliance.”
 Specify the number of retests.
 Prepare a protocol before retesting.
 If the error is found the retest substitutes.

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 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

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 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.

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 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

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 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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 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.

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 We can average determinations to get the
reportable value.
 We do not average reportable values.
 QA must see all of the reportable values.
 Don’t average OOS with in spec results.

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 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.

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 "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."

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 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.

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 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.

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 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 ….”

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Presentation prepared by Drug Regulations – a not for
profit organization. Visit www.drugregulations.org for
the latest in Pharmaceuticals.
06-11-2015