Oot Oos Stability Study

6/22/2017
INVESTIGATE OOT AND OOS

IN STABILITY STUDIES
Kim Huynh-Ba
Executive Director
Pharmalytik LLC
www.pharmalytik.com
BIOGRAPHY
Kim Huynh-Ba has over 25 years of experience in analytical development, project management, strategic drug
development and stability sciences. She currently is the Executive Director of Pharmalytik (www.pharmalytik.com), where
she provides consulting and training services to pharmaceutical companies, including companies operating under FDA’s
Consent Decree on harmonization and optimization of analytical best practices since 2003. In 2011-2012, she took a 2-
year leave to join the U.S. Pharmacopeia (USP) as their Director of Pharmacopeial Education Department, where she
invigorated their education programs worldwide. Her clients range from large pharmaceutical companies to small contract
laboratories in U.S. and also internationally.
Kim is an Adjunct Professor at Temple University-School of Pharmacy, Widener University and Illinois Institute of
Technology (IIT) teaching Pharmaceutical Analysis, cGMPs, ICH guidelines and Quality Audit graduate courses. She is
also a short course instructor on cGMP compliance and quality topics for several global organizations such as American
Chemical Society (ACS), American Association of Pharmaceutical Scientists (AAPS), Pittsburgh Conference, and many
other international training groups.
Kim is a member of the USP Council of Experts (2015-2020), where she chairs the Chemical Medicines IV Expert
Committee. She is also a member of the Impurities of Drug Products Expert Panel and Food Adulteration Expert Panel.
She was the Chair of the USP Good Documentation Practices (GDP) Expert Panel. She is an active member of AAPS and
an Alternate Councilor of ACS-Delaware Section. She serves on steering committees of AAPS Stability, CMC, and
Pharmaceutical Impurities Focus Groups. She is a member of the Executive Committee of Governing Board of Eastern
Analytical Symposium (EAS) and was their 2013 President. She is also a member of PQRI-Stability Shelf Life Committee.
Kim has authored numerous technical publications, and book chapters. She is the editor of 2 well-known Stability books:
the “Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices” (2008)
and “Pharmaceutical Stability Testing to Support Global Markets” (2010). She is also working on a manuscript for the
“Analytical Chemistry: An Introduction to Pharmaceutical GMP Laboratory”, that is expected to be available in 2018.
Kim can be reached at kim.huynhba@pharmalytik.com
www.pharmalytik.com (copyright)
6/22/2017
TOPICS OF DISCUSSION
• Regulatory Expectations on OOS/OOT
• Identification of OOT results
• Identification of OOS results
• Interactive Exercise
WHAT GOES WRONG?

OOS continues to be the leading cause of Audit Observations and
Warning Letters Citations.
Common OOS Observations:

• Ignoring failing results
• Reporting only passing results without just
• averaging failing and passing results
• no effort to determine root cause of OOS result
• no corrective or preventive actions
• no SOP on handling of OOS results
• testing sample into compliance
• no proper documentation
• not expand the OOS to other lots or products
6/22/2017
DEFINITION OF
OUT-OF-SPECIFICATION
(OOS) AND
OUT-OF-TREND (OOT)
OUT OF SPECIFICATION RESULTS

• With a control process:
• the method is validated
• analysts are qualified
• equipment is calibrated and well-maintained
• notebooks have full record of testing
• HOW can you have an OOS?
• Specs are determined based on clinical data
• If there is an OOS, what does it say about safety and efficacy?
• If you don’t know the specification, can you get an OOS?
• But we don’t live in an ideal world….
6/22/2017
HOW TO IDENTIFY OOS RESULTS

• Compare result with specification
• Be sure that specification is to required degree of
accuracy and round the result to this value.
Example: Results is 94.9% PASS

Specifications= 95 – 105% of label
FAIL
Specifications= 95.0 – 105.0% of label
Example: Results is 95%
IDENTIFY OOS RESULTS -

IMPURITIES
Specifications= 95 – 105% of label
Example: Impurities spec NMT 0.10%
Example 1: Result is 0.09%,

PASS
Report as 0.1% or <0.1%
FAIL
Example 2: Result is 0.086%
Report as <0.1%
Example 3: Results are 0.07% and 0.12%

• Option A: 0.07+0.12= 0.19%, result is 0.095, <0.10%
• Option B: <0.10+0.12= 0.12%, result is 0.06, <0.10%
• Option C: <0.1 + 0.1 = 0.1, result is 0.05, <0.1%
6/22/2017
HOW TO IDENTIFY OOT RESULTS

• Out of Trend or unusual results are generally results that:
• Meet the product specification
• Are outside the control limits of the process, where
control charts are used
or
• Are different to results usually obtained
spec: 95.0 – 110.0
usual results: 98.0 – 101.0
OOT result: 96.4
How to determine ‘TREND”?
ASSESSING OOS RESULTS

• Understand the Drug Product well:
• product history
• Process history
• test history
• reliability of equipment
• precision of the test
6/22/2017
REGULATORY REQUIREMENTS OF
ANALYTICAL DATA
CGMP REGULATIONS
• CFR 211.1 SCOPE (a) The regulations in this part contain

the minimum current GMP practice for preparation of drug
products for administration to humans or animals.
• CFR 211.22 - Quality Unit is responsible:

• Approve or reject all components
• Review production records (no errors occurred or it’ll be
fully investigated.)
• Approve or reject all procedures or specifications
• These procedures shall be in writing and followed.
6/22/2017
CGMP REGULATIONS
• Sec 211.160 General Requirements
• Establishment (and change) of specs, standards,
sampling plans, test procedures is required
• Must be followed and documented at time of
performance
• Deviation must be recorded and justified
• Sec 21 CFR 211.160(b)(4) requires the analyst to ensure
that all instruments used meet established specifications
and were properly calibrated.
• Validation activities
• Stability Studies
• Supplier changes
CGMP REGULATIONS
• Sec 211.165 Testing and Release for Distribution

• Conforms to specifications prior to release
• Free of objectionable microorganisms
• Sampling and testing plans are described in written
procedures
• Must have acceptance criteria
• (e) The accuracy, sensitivity, specificity, and
reproducibility of test methods shall be established and
documented. Such validation and documentation may
be accomplished in accordance with Sec.
211.194(a)(2).
6/22/2017
CGMP REGULATIONS
• Sec 211.165(f) specifies that products that fail to meet

established standards and other relevant quality
control criteria will be rejected.
• Even if a batch is rejected, an investigation is
required to determine if the OOS is associated with
other products or lots.
• A written record of the investigation is required. It
must include the conclusions and any follow-up.
CGMP REGULATIONS
• Sec. 211.180 General Requirements:

• Records shall be maintained for all components,
drug product containers, closures and labeling..
• Such records shall be available for inspection
• Such records can be used for evaluating at least
annually to determine quality standards of drug
products
6/22/2017
CGMP REGULATIONS
• Sec 211.192 Production Record Review

• Record must be reviewed by a Quality Unit.
• Investigate any unexplained discrepancies
• Investigate any failure of the batch or its components,
even if it is not distributed
• Investigation shall extend to other batches of DP or
other associated DP
• Written record with conclusion and follow up
CGMP REGULATIONS
• Sec 211.194 Laboratory Records
• Complete record of data (charts, graphs, spectra,..)
• Description of sample (location, quantity, lot, date received,
etc)
• Method used, modification including reason and data to verify
• Records of reagents and standards
• Record of all calculations performed including units,
conversion factors, and equivalency factors
• Complete records of periodic calibration of instruments
• Complete records maintained of all Stability Testing
6/22/2017
FDA - GUIDE TO INSPECTIONS
• 4.A. GENERAL:
• Most manufacturers use systems that provide for the
investigation of laboratory test failures. These are generally
recorded in some type of log. Ask to see results of
analyses of lots of product that have failed to meet
specifications and review the analysis of lots that have
been retested, rejected, or reworked. Evaluate the decision
to release lots of product when the laboratory results
indicate that the lot failed to meet specifications and
determine who released them.
GUIDE TO INSPECTIONS
5.B. LABORATORY INVESTIGATIONS:
• It is unrealistic to expect that analyst error will always be

determined and documented. The inability to identify an error’s
cause with confidence affects retesting procedures, not the
investigation inquiry required for the initial OOS result.
FAILURE INVESTIGATIONS
• At least annually, QA and QC management should review failure

reports to detect trends or unacceptable rates of failure related to
an assay, process intermediate, or product.
• The reviews should be conducted in keeping with GMP

requirements and must be documented.
6/22/2017
GUIDE TO INSPECTIONS
RETESTING
• Retesting following an OOS result is ruled appropriate only after the

failure investigation is underway and the failure investigation determined
in part whether retesting is appropriate.
INCONCLUSIVE LOT FAILURE
• It is appropriate when analyst error is documented or the review of the

analyst’s work is “inconclusive”, but is not appropriate for known and
undisputed non-process or process related errors.
• In that case, you need to step up surveillance of future lots.
GUIDANCE FOR INDUSTRY

INVESTIGATING OOS TEST RESULTS
FOR PHARMACEUTICAL PRODUCTION
Review of FDA Guidance
October 2006
6/22/2017
DRAFT GUIDANCE FOR

INDUSTRY
“For purposes of this document the term OOS results
includes all test results that fall outside the specifications or
acceptance criteria established in drug applications, DMFs,
official compendia or by the manufacturer.”
It also applies to all in-process laboratory tests that are

outside of established specifications.
[FDA guidance For Industry - Draft - Investigating Out-Of-Specification Test Results for Pharmaceutical
Production – Oct 2006]
SCOPE
• This guidance applies to:
• chemistry-based laboratory testing of drugs regulated
by CDER.
• traditional drug testing and release methods.
• active pharmaceutical ingredients, excipients and other
components, in-process materials, and finished drug
products
• In-house testing of purchased drug product
components
• CRO performing production or lab testing.
• Excludes PAT approaches
6/22/2017
PHASE I: LAB INVESTIGATION
PHASE I: LAB INVESTIGATION

• Identifying and Assessing OOS results
• Purpose: determine the cause of OOS
PHASE II: FULL SCALE OOS
INVESTIGATION
• Investigating OOS test results
• When the initial assessment can’t find the cause and
the OOS is confirmed.
ASSESSING OOS TEST RESULTS

• The investigation should be thorough, timely, unbiased,
well-documented, and scientifically sound
• Even if a batch is rejected based on an OOS result, the
investigation is necessary to determine if the result is
associated with other batches of the same drug product or
other products.
• Batch rejection does not negate the need to perform the
investigation.
• The source of the OOS result should be identified either as
• an aberration of the measurement process
• or an aberration of the manufacturing process.
6/22/2017
ASSESSING OOS TEST RESULTS
• Contract Lab
• System suitability Performance
• Responsibility of Analyst
• Responsibility of Supervisor
• Error Assessment
• Is it an obvious error?
• Responsibility of Laboratory Management
LABORATORY ERROR AND CAPA

• Laboratory error should be relatively rare.
• Frequent errors suggest a problem that might be due to
• inadequate training of analysts,
• poorly maintained or improperly calibrated equipment,
• or careless work.
• Whenever laboratory error is identified, the firm should determine the

source of that error and take corrective action to prevent recurrence.
• To ensure full compliance with the CGMP regulations, the manufacturer

also should maintain adequate documentation of the corrective action.
6/22/2017
PHASE 2 OF THE INVESTIGATION

• When
• When the initial assessment does not determine that
laboratory error caused the OOS result and testing results
appear to be accurate
• Objective
• To identify the root cause of the OOS result and take
appropriate corrective and preventative action.
• A full-scale investigation should include
• review of production and sampling procedures
• and will often include additional laboratory testing
• impact of OOS result(s) on already distributed batches.
PHASE 2
• The investigation should be conducted by the QCU

and should involve all other departments
• manufacturing,
• process development
• maintenance
• engineering
6/22/2017
PHASE 2 INVESTIGATION
1. Production process review

2. Additional laboratory work
• Objective: to identify the root cause of OOS result and take

appropriate CAPA.
• Evaluate the impact of OOS result(s) on already distributed

batches.
OOS FOLLOW UP
• OOS results may indicate a flaw in product or process
design. For example,
• a lack of robustness in product formulation,
inadequate raw material characterization or
control,
• substantial variation introduced by one or more
unit operations of the manufacturing process, or
• a combination of these factors can be the cause of
inconsistent product quality.
• In such cases, it is essential that redesign of the
product or process be undertaken to ensure
reproducible product quality
6/22/2017
ADDITIONAL LAB TESTING:

RETESTING
• Must be from the same homogenous material
• Done by 2nd analyst
• Predefine testing plan
• Predefine max # of retests.
• Take method variability into account when making the plan
• Take sample variability into account when making the plan
• No adjust after results obtained.
• Use scientific principles
REPORTING OF RESULTS
• With clear identified lab error, original test result is
invalidated and replaced.
• Result must be considered if there is no lab or
calculation errors
• One sample, one result
• Number of replicates must be specified in test methods
• Confirmed OOS, then batch must be rejected.
• QCU is responsible to interpret investigation result.
6/22/2017
AVERAGING
• If some of the individual results are OOS and some are

within specification, and all are within the documented
variation of the method, the passing results should not be
given more credence than the failing results.
• To use averaged results for assay reporting, ALL test
results should conform to specifications.
• A high result may lead to concerns about overdosing a
patient, while a low result may indicate formulation
problems with the potential for a subpotent lot.
• Averaging results acceptable for:
• Appropriate for Microbiological assays
OUTLIER TEST
• Statistical procedure for identifying from an array

those data that are extremes
• An outlier may result from
• Deviation from prescribed test method
• Variability in the sample
• The possible use of outlier test should be determined
in advance ( SOP, protocol, etc…)
6/22/2017
OUTLIER TESTS
• Possible use of the outlier test should be determined in advance
• Should be written in an SOP for data interpretation
• Should include the specific test to be used
• Should specify the minimum number of results required to obtain a
statistically significant assessment from the test
CHEMICAL TESTING
• Inherently reliable
• Precision is usually considerably better than for microbiological and
biochemical testing
• Outlier testing is NOT allowed by the FDA guidance, for chemical testing
(usually have less replicates)
OUTLIER TESTING
• The use of outlier tests should be written into SOPs for data
interpretation and be well documented. The SOPs should include
the specific outlier test to be applied with relevant parameters
specified in advance.
• An outlier test will not identify the cause of an extreme observation
and, therefore, should not be used to invalidate data.
• Actually, modern outlier tests are based on the assumption that the
population of the samples is contaminated with a value from a
second population.
• Outlier tests have no applicability in cases where the variability
in the product is what is being assessed.
6/22/2017
STRUCTURE OF AN OOS
INVESTIGATION
Follow the process:
• Identifying and assessing OOS test results
• Phase I: Laboratory Investigation
• Phase II: Full Scale OOS Investigation
• Conclusion and Documentation
• CAPA
ROOT CAUSE ANALYSIS
Materials Methods
Normality etc. calculated correctly
Changes to method
Dish Washing detergent
Solvents
Column Any chemist observations Validation report
Reagents
Any changes to anything relevant to testing
Vials Any assumed steps?
Calculations checked
Caps of vials Changes to gases (GC)
Standards-RT-RF Training of chemist
Glassware Pipettes/manual or automated
Environment
Instrument type
Temp
Humidity of lab Detector Balance
control of Chemist experience
lab
pH meter
Injector Chemist training
Burette size-able to measure differences? Glassware washing-personnel changes

Sonicator
Temperature control of column

Vortexer
Equipment People
K.HuynhBa & S. Thomas, OOS, Stability Testing to Support Global Markets, Springer, 2010.
6/22/2017
FLOW OF OOS INVESTIGATION

OOS Result OOS investigation
Production error
Correct if possible
Lab error Suspect Result Reject batch
Y
Assignable cause? Sampling error
Invalidate results
Perform new test N
Resample
Full Scale Revise SOP
investigation
Report new results
Inconclusive
All result in spec Result OOS
Retest
QA Disposition Reject batch
CONTENTS OF A LIR
• Clear sample description
• Who, What, When
• Equipment checklist
• System checklist
• Procedure checklist
• Standards/samples expiry checklist
• Is it a Lab error? (Yes/No)
• Classification of lab error if any
• Investigation
• Conclusions (OOS or lab error)
6/22/2017
STABILITY ISSUES
 Stability Problems
• Alternative storage condition

• Change package – more protective
• Shorter Expiration Date
• Reformulate product
FULL SCALE OOS INVESTIGATION

• QA responsibility
• Documented in the batch record
• Involves all aspects of manufacture, quality control and
sampling
• Understand the reason for investigation
• Describes corrective actions and endpoint
• Extend to associate batches or products
• Notify appropriate staff - manufacturing and/or packaging
investigation, QA, lab management, etc.
6/22/2017
END OF INVESTIGATION
• Need to determine when to end the investigation and accept the results
• Compilation of the investigation
• Corrective Actions
• Impact on other lots
• Impact on method/validation/if stability sample
• If no lab error or statistical error is identified then the original OOS cannot be
invalidated and all results must be reported and taken into consideration for
batch disposition
• Batch disposition must be based upon scientific justification and overall data
STABILITY OUT OF TREND

• Types of OOT Data
• Analytical Alert
• Process Capability Alert
• Compliance Alert
6/22/2017
WHAT IS OUT-OF-TREND (OOT)?

• An out of trend (OOT) stability result is a result or sequence
of results that are within specification limits but are
unexpected, given the typical analytical and sampling
variation and a measured characteristic’s normal change
over time1
• Definition: A stability out of trend is when a data point or
multiple data points do not fit the typical stability pattern.
Ref.: “Identification of Out-of-Trend Stability Results, Part II PhRMA CMC

Statistics, Stability Expert Teams,” Pharmaceutical Technology, October 2005
ANALYTICAL ALERTS
Some common approaches for Analytical Alerts

• Result is outside +/- 5% of initial result
• Result is outside +/- 3% of previous result
• Result is outside +/- 5% of the mean of all previous results
• Absolute % change from label claim
Analytical Alerts
1. Observed value (for Stable Properties)
2. Change from previous (for Properties with Change over
Time)
6/22/2017
PROCESS CONTROL ALERT

• Several data points are required before this type of trend can be
detected.
• Statistically more complex.
• Can often be found at time of Annual Product Review when stability data
is looked at for multiple batches.
• Good method is slope control chart
• Calculate slope using all data up to time point of interest.
• Calculate interval for slope at each time point.
• Slope for each lot should fall within these limits, if not, the slope is
different then historically found.
COMPLIANCE ALERT
• Similarly to process control alert, can often be detected at time of
annual product review
• Calculate shelf life following procedure found in first section.
• If slopes are different, find shelf life for each batch.
• Check that all shelf life estimates are greater than or equal to
current shelf life.
6/22/2017
SUMMARY
• All test results are subject to some element of doubt
• Use Controls and Validated test methods
• Use replicates where inherent variation exists
• Perform trend analyses and report deviations
• NEVER continue a suspect test
• SOP conforms with current expectations, clear and complete
• At some point, testing ends and a product disposition decision
must be made
• Periodically verify method performance
• Manage investigation as part of lifecycle management or the
product
THANK YOU!
Without data, it would just be another
person’s opinion.
W. Deming
Kim Huynh-Ba
Kim.huynhba@pharmalytik.com

Oot Oos Stability Study

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6/22/2017

INVESTIGATE OOT AND OOS

WHAT GOES WRONG?

Common OOS Observations:

OUT OF SPECIFICATION RESULTS

HOW TO IDENTIFY OOS RESULTS

Example: Results is 94.9% PASS

Example: Results is 95%

IDENTIFY OOS RESULTS -

Example 1: Result is 0.09%,

Example 3: Results are 0.07% and 0.12%

HOW TO IDENTIFY OOT RESULTS

How to determine ‘TREND”?

ASSESSING OOS RESULTS

• CFR 211.1 SCOPE (a) The regulations in this part contain

• CFR 211.22 - Quality Unit is responsible:

• Sec 211.165 Testing and Release for Distribution

• Sec 211.165(f) specifies that products that fail to meet

• Sec. 211.180 General Requirements:

• Sec 211.192 Production Record Review

FDA - GUIDE TO INSPECTIONS

• It is unrealistic to expect that analyst error will always be

• At least annually, QA and QC management should review failure

• The reviews should be conducted in keeping with GMP

• Retesting following an OOS result is ruled appropriate only after the

INCONCLUSIVE LOT FAILURE

• It is appropriate when analyst error is documented or the review of the

• In that case, you need to step up surveillance of future lots.

GUIDANCE FOR INDUSTRY

DRAFT GUIDANCE FOR

It also applies to all in-process laboratory tests that are

PHASE I: LAB INVESTIGATION

PHASE I: LAB INVESTIGATION

ASSESSING OOS TEST RESULTS

ASSESSING OOS TEST RESULTS

LABORATORY ERROR AND CAPA

• Frequent errors suggest a problem that might be due to

• inadequate training of analysts,

• poorly maintained or improperly calibrated equipment,

• Whenever laboratory error is identified, the firm should determine the

• To ensure full compliance with the CGMP regulations, the manufacturer

PHASE 2 OF THE INVESTIGATION

• The investigation should be conducted by the QCU

1. Production process review

• Objective: to identify the root cause of OOS result and take

• Evaluate the impact of OOS result(s) on already distributed

ADDITIONAL LAB TESTING:

• If some of the individual results are OOS and some are

• Statistical procedure for identifying from an array

ROOT CAUSE ANALYSIS

Burette size-able to measure differences? Glassware washing-personnel changes

Temperature control of column

FLOW OF OOS INVESTIGATION

QA Disposition Reject batch

• Alternative storage condition

FULL SCALE OOS INVESTIGATION

STABILITY OUT OF TREND

WHAT IS OUT-OF-TREND (OOT)?

Ref.: “Identification of Out-of-Trend Stability Results, Part II PhRMA CMC

Some common approaches for Analytical Alerts

PROCESS CONTROL ALERT

• Statistically more complex.

• Good method is slope control chart

• Calculate slope using all data up to time point of interest.