Out of Specification Process Flow

Manufacturer Predetermined Specification

Established Limit
OOS

Result Outside

OOT Statistical Process Control

Criteria / Trends

Historical Data Value

Laboratory

Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production Guidance for
Industry.
May 2022 , Pharmaceutical Quality/Manufacturing Standards , Current Good Manufacturing
Practice (CGMP) , Revision 1
Purpose : The purpose of this guidance is to provide the FDA’s current thinking on how to evaluate
out-of-specification (OOS) test results, including the responsibilities of laboratory personnel, the
laboratory phase of the investigation, additional testing that may be necessary, when to expand the
investigation outside the laboratory, and the final evaluation of all test results.

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Scope : The scope of this guidance includes chemistry-based laboratory testing of drugs regulated by
CDER and in-house testing of drug product components that are purchased by a manufacturer and can
be used by contract firms performing production and/or laboratory testing responsibilities.
Definition : The FDA defines OOS as 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. Additionally, OOS applies to all in-process laboratory tests that are outside of
established specifications.
There are several sections of 21 CFR 211: Current Good Manufacturing Practice for Finished
Pharmaceuticals that are applicable to OOS investigations, including §211.84 Testing and approval or
rejection of components, drug product containers, and closures, §211.113 Control of microbiological
contamination, §211.160 General requirements, §211.165 Testing and release for distribution,
and §211.194 Laboratory records.
These sections address requirements for laboratory testing and validation requirements to ensure
components, containers and closures, in-process materials, and finished products conform to
specifications. CGMPs also apply to active pharmaceutical ingredients (APIs).
API cGMPs include raw material testing, in-process monitoring, release and stability testing, process
validation, and investigations of any OOS results. Manufacturers and contract testing laboratories are
required and responsible for meeting these requirements.
What is OOS (Out of Specification)?
During the course of a drug or drug product’s development and as the product is nearing completion,
it needs to be tested to ensure that it performs as expected, within the specified limits as mentioned in
the compendia, drug master file, or drug application.
When it does not and falls outside the specified limits, it is said to be OOS or out of specification.
If this happens often, it is an indication of the manufacturing and analytical procedures not being in
control. It can lead to frequent customer complaints and the rejection of commercial batches. As a
result, the pharmaceutical business will face a heavy inventory loss. It may also compromise the safety
of patients and their handlers. Therefore, any incident of OOS result occurrence must be investigated
and the root cause addressed.
Typically, the specified limits are detailed in documents such as the compendia, drug master file, or
drug application. This happens right at the product design stage after the product has been
conceptualized and the details of the nature of the product, its goals, and the raw materials to be used
are specified. The testing criteria are also laid down at this stage, explaining how the product should
be tested and who will be testing it.

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One of the important aspects of drug and drug product development is providing specifications that
must be conformed to for the product to be considered acceptable for its intended use.
According to the definition by the International Conference on Harmonization (ICH), specifications
refer to “a list of tests, references to analytical procedures, and appropriate acceptance criteria, which
are numerical limits, ranges, or other criteria for the tests described.” This is a critical quality standard
where the manufacturers propose and justify the conditions that form the basis for the approval by
regulatory authorities.
The specifications are detailed during the product design stage, clearly defining the objectives the
product is expected to achieve using specific components, containers, closures, in-process materials,
and finished products.

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 Investigation of out of specification (OOS)
Section & Subsection of Investigation of out of specification (OOS) as per FDA Guideline , May 2022 , Revision 1
Phase I Phase II Phase III
IDENTIFYING AND ASSESSING OOS TEST INVESTIGATING OOS TEST RESULTS -
RESULTS - PHASE I: LABORATORY PHASE II: FULL-SCALE OOS CONCLUDING THE INVESTIGATION
INVESTIGATION INVESTIGATION
Laboratory Investigation is related to the
Process related investigation is to be
Quality Control department along with
carried out by production department
rechecking of documents with same
along with the Resampling and re
analysts and re-testing with different
analysis
analyst with original sample
Identification Phase Investigating Phase Concluding Phase
A. Responsibility of the Analyst A. Review of Production A. Interpretation of Investigation Results As per FDA
B. Responsibilities of the Laboratory
B. Additional Laboratory Testing B. Cautions
Supervisor
1. Averaging results from multiple sample
1. Retesting
preparations from the original sample
2. Averaging results from same final sample
2. Resampling
preparation
3. Borderline results that are within
C. Reporting Testing Results
specification
1. Averaging C. Field Alert Reports
2. Outlier Tests
Section & Subsection of Investigation of out of specification (OOS) as per MHRA
Phase I Phase II Phase III
Laboratory Investigation Manufacturing Investigation Extended Manufacturing Investigation
Phase Ia Phase IIb Process Parameter
Drying Parameter As per MHRA
Primary Extended Input RM Quality Sampling error , Authorized for Resampling ,
Laboratory Laboratory Training of Personnel Re analysis ,
Investigation Investigation Cleaning of Equipment
Environmental monitoring

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 Initial Laboratory Investigation including assessment of analytical data/Instrumentation/ Interview of analyst / review of

Phase I ---- Identification Phase sampling, calculation and data collection process / Verification of initial preparations i.e. re measurement, re-injection, re-

dilution, re-filtration, investigation using root cause analysis etc.

General Description about the Phase I

 OOS results fall into five categories:
 Laboratory error (analyst or instrumental or procedural or other).
 Out sourced raw material failure.
 Manufacturing error.
 Sampling error.
 Stability Failure.
 The First Phase of OOS Laboratory Investigation Report contains six sections.
 Section I Reporting of OOS test result,
 Section II Assessment of analytical data by Team Leader
 Section III Experimentation,
 Section IV Assignable Cause Identified
 Section V Full Scale OOS Investigation (Cause Not Identified)
 Section VI Evaluation, Conclusion, Corrective And Preventive Action.
 The Preliminary laboratory investigation shall be concluded within very short period from the date of generation of OOS.
 The first phase includes assessment of the accuracy of the Laboratory’s data by Team Leader or designee and Lab QA or QC Supervisors as per below ----
 Interview of the analyst and verification of competency.
 Assessment of data for proper methodology, instrumentation and calculations performed.
 Review of sampling, analytical data and data collection process.
 Re-injections, re-extractions and re-dilutions of the original solutions.

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  Derivation of hypothesis and execution of experimentation to determine root cause.
 Assessment using further investigation tools such as root cause analysis (RCA) using fishbone, 5-WHY analysis, etc. if initial review assessment
could not determine root cause of OOS test results.
 The initial laboratory investigation (Assessment of data, review and verification of solutions) should be completed within 48 hours of reporting the OOS test
results. Experimentation may exceed 48 hours. If for any reason the initial verification is not completed within 48 hours of OOS reporting time, then
justification for the same shouldbe included in the investigation.
 If the verification is not possible to perform on the same day of OOS reporting, the Sample solution / Standard solution should be stored at appropriate storage
condition (e.g. 2-8°C), if the solutions are degradable.
 Any deviation from this shall be justified and documented along with the OOS investigation form.

 The investigation should be thorough, timely, unbiased, well documented and scientifically defensible.

 During the investigation the supervisor or team lead following the assessment as per below
 Discuss the event with the analyst to verify the analyst’s knowledge and understanding of the procedure as specified in specification, evaluate technical
competency, verify instrument operation and test performed.
 Verify relevant training record of analyst for critical technique like particle size determination by laser diffraction, analysis of metered dose inhalers for
priming and actuation consistency, etc.
 Examine solutions, test units description, glassware, instruments used, etc. which might provide more credibility to confirm instrumental or procedural
or analyst or other error. In case of extraneous peaks or assay test showing lower content, examine glassware to identify any contamination or
insufficient extraction as cause of failure.
 Examine working standards, solvents, reagents and solutions used and verify that they met specifications and are valid. Check manufacturing source of
working standard used and compare with source of batch under investigation. Difference in crystallization structure or purity may lead to different
response e.g. IR pattern may differ due to final purification.
 If pretreatment of standard such as drying before use (as per instruction) is suspected to be not done, correlate extent of impact by computing LOD /
water content of standard as per specification and confirm the results.
 Evaluate the performance of the instruments (calibration, maintenance, cleanliness, system suitability) and test method used. Check for any pressure

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 fluctuation, leakage, air bubbles in the mobile phase lines or any other instrument malfunction
 Review the raw data of the analysis and identify anomalous or suspect information like Spectra / chromatograms for retention time, peak area
response, response ratio, system suitability compliance, bracketing standard response, excessive fronting or tailing, splitting of peak, improper
chromatographic pattern, shoulder or co-eluting peak, shape of curve in case of potentiometric analysis, etc. and compare it with the specimen or
spectra / chromatograms of previous analysis.
 The Preliminary laboratory investigation is to determine whether has been a clear obvious error due to external circumstances such as power failure ,

calculating error , Equipment failure , testing error , incorrect instrument parameters , unsuitable instrument used , standard / sample spoiled by spillage

/contamination or those that the analyst has detected prior to generating data such as spilling sample that will neglect the requirement of a phase-II

investigation.

 If no obvious error is identified analyst and supervisor should initiate the further investigation as per below:

 Correct methodology followed

 Test preparations

 Correct sampling procedure followed.

 Proper calibrated instruments/ equipment’s are used.

 Equipment and other log entries are available.

 Appropriate standards are being used.

 Correct glassware used.

 System suitability conditions are followed.

 If assignable cause is identified during investigation done by analyst and supervisor, invalid the initial test data.

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 On completion of analyst and supervisor investigation, re-measurement can start once the hypothesis plan is documented and is only support the investigation

testing.

 If hypothesis is proven, repeat the analysis in triplicate by the same analyst. If same analyst is not available, second analyst with equal qualification can perform

the analysis.

 Record the results. Generate the CAPA and close the investigation

 If no assignable cause or evidence of error is identified during the Phase I , Phase-II investigation is to be started .

 FDA regulations require that an investigation be conducted whenever an OOS test result is obtained (§ 211.192).

 The purpose of the investigation is to determine the cause of the OOS result.

 The source of the OOS result should be identified either as an aberration of the measurement process or an

aberration of the manufacturing process.

 The regulations require that a written record of the investigation be made, including the conclusions and follow-up (§
IDENTIFYING AND ASSESSING OOS
211.192).
TEST RESULTS - PHASE I :
 To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, and scientifically
LABORATORY INVESTIGATION
sound.

 The first phase of such an investigation should include an initial assessment of the accuracy of the laboratory's

data.

 If this initial assessment indicates that no causative errors were made in the analytical method used to arrive at the

data, a full-scale OOS investigation should be conducted.

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  For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the

manufacturing firm’s quality unit (QU). The manufacturing firm’s QU should then initiate the Phase 2 (full-scale) OOS

investigation, whenever no clearly causative laboratory error was identified.

 The first responsibility for achieving accurate laboratory testing results lies with the analyst who is performing the

test.

 The analyst should be aware of potential problems that could occur during the testing process and should watch

for problems that could create inaccurate results.

 In accordance with the CGMP regulations in § 211.160(b)(4), the analyst should ensure that only those instruments

meeting established performance specifications are used and that all instruments are properly calibrated.

 Certain analytical methods have system suitability requirements, and systems not meeting these requirements should

A. Responsibility of the Analyst not be used.

 Analysts should check the data for compliance with test specifications before discarding test preparations or standard

preparations.

 Obvious causes:

These include those clear and obvious errors which are generated due to external circumstances or those that the

analyst has detected prior to generating data such as

 Spilling Sample

 Power Failure

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  Equipment Failure

 Incomplete Transfer of a Sample

 Incorrect Instrument Parameters

 Use of Non-Calibrated Instruments or Apparatus

 Use of Contaminated Apparatus and Glassware’s

 Improper Handling and Storage of Sample etc.

Analyst shall not knowingly continue an analysis they expect to invalidate at a later time for an obvious cause (Analysis

shall not be completed for the purpose of seeing what results can be obtained when obvious errors are known).

These shall be investigated through preliminary laboratory investigation.

 Assignable Cause: An assignable cause is an identifiable, specific cause of variation in an analysis or measurement. A

cause of variation that is not random and does not occur by chance is “Assignable”. Some of the common Laboratory

error during analysis are as follows, but not limited to:

 Error in the method of analysis

 Error in specification

 Error in calculation

 Wrong transcription of data

 Use of invalid incorrect working standard

 Lack of training or knowledge

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  Use of expired or old chemicals, reagents or solvents

 Software error

 Error in sampling procedure

 Inadequate transfer of analyst / solution / wrong weighing

 Dilution Stability

 Non -Assignable Cause: In such cases, additional data must be generated to assess whether the initial atypical result

is a statistical outlier. Non Assignable Causes for OOS results may include, but not limited to:

 Non-process related or operator error

 Process related or manufacturing errors

 Deviation from the validated process

 Quality of intermediate, raw materials used

 In-Process control during manufacturing

 When unexpected results are obtained and no obvious explanation exists, test preparations should be retained, if

stable, and the analyst should inform the supervisor. An assessment of the accuracy of the results should be started

immediately.

 If errors are obvious, such as the spilling of a sample solution or the incomplete transfer of a sample composite, the

analyst should immediately document what happened. Analysts should not knowingly continue an analysis they

expect to invalidate at a later time for an assignable cause (i.e., analyses should not be completed for the sole purpose

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 of seeing what results can be obtained when obvious errors are known).

 Once an OOS result has been identified, the supervisor's assessment should be objective and timely.

 There should be no preconceived assumptions as to the cause of the OOS result.

 Data should be assessed promptly to ascertain if the results might be attributed to laboratory error, or whether the

results could indicate problems in the manufacturing process.

 An immediate assessment could include re-examination of the actual solutions, test units, and glassware used in the

original measurements and preparations, which might provide more credibility for laboratory error hypotheses.

As per FDA the following steps should be taken as part of the supervisor's assessment:

1. Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct
B. Responsibilities of the Laboratory
procedure.
Supervisor
2. Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or

suspect information.

3. Verify that the calculations used to convert raw data values into a final test result are scientifically sound,

appropriate, and correct; also determine if unauthorized or unvalidated changes have been made to automated

calculation methods.

4. Confirm the performance of the instruments.

5. Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they

met quality control specifications.

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 6. Evaluate the performance of the test method to ensure that it is performing according to the standard expected

based on method validation data and historical data.

7. Fully document and preserve records of this laboratory assessment.

 The assignment of a cause for OOS results will be greatly facilitated if the retained sample preparations are examined

promptly. Hypotheses regarding what might have happened (e.g., dilution error, instrument malfunction) should be

tested. Examination of the retained solutions should be performed as part of the laboratory investigation.

 Examination of the retained solutions should be performed as part of the laboratory investigation.

 It is important that each step in the investigation be fully documented. Laboratory management should ascertain not

only the reliability of the individual value obtained, but also the significance these OOS results represent to the

laboratory quality assurance program. Laboratory management should be especially alert to developing trends. As

part of an effective quality system, a firm’s upper management should appropriately monitor these trends and ensure

that any problematic areas are addressed.

 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.

 In summary, when clear evidence of laboratory error exists, laboratory testing results should be invalidated. When

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 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.

As during initial investigation of OOS , cause could not be determined or Team Leader of Quality Control Unit not identified the assignable cause in the
Laboratory Investigation Report and the Head Unit Quality Control should immediately notify Unit QA to initiate a formal production review for in-house
material / product, or a review of trend and historical data for out sourced material.
Unit QA should conduct review and document the findings in the summary of Section of Laboratory Investigation Report.
The Further Investigation shall be started i.e. “Full Scale OOS Investigation”.
The second phase of investigation includes
Review of Production
Additional laboratory testing by second analyst, followed by further additional laboratorytesting by third or initial analyst.
OR
Additional laboratory testing as per pre-defined approved protocol.
Review of manufacturing and quality trends.
Batch disposition decision.

INVESTIGATING OOS TEST RESULTS - PHASE II: FULL-SCALE OOS INVESTIGATION

When the initial assessment does not determine that laboratory error caused the OOS result and testing

Phase II ------ Investigating Phase results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be
conducted.
The objective of such an investigation should be to identify the root cause of the OOS result and take
appropriate corrective action and preventive action.

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 A full-scale investigation should include a review of production and sampling procedures and will often
include additional laboratory testing.
Phase II investigations should be given the highest priority.

The investigation should be conducted by the QU and should involve all other departments that could be
implicated, including manufacturing, process development, maintenance, and engineering. (i.e. Should be
conducted by cross functional team.)
In cases where manufacturing occurs off-site (i.e., performed by a contract manufacturer or at multiple
manufacturing sites , P2P , LL ), all sites potentially involved should be included in the investigation.
The records and documentation of the manufacturing process should be fully reviewed to determine the
possible cause of the OOS result(s).
A full-scale OOS investigation should consist of a timely, thorough, and well-documented review. A written
record of the review should include the following information.
A. Review of Production 1. A clear statement of the reason for the investigation.
2. A summary of the aspects of the manufacturing process that may have caused the problem.
3. The results of a documentation review, with the assignment of actual or probable cause.
4. The results of a review made to determine if the problem has occurred previously.
5. A description of corrective actions taken.
If this part of the OOS investigation confirms the OOS result and is successful in identifying its root cause,
the OOS investigation may be terminated and the product rejected.
The failure investigation that extends to other batches or products that may have been associated with the
specific failure must be completed (§ 211.192).
OOS results may indicate a flaw / error / defect / mistake /fault in product or process design.

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 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
A full-scale OOS investigation may include additional laboratory testing beyond the testing performed in
B. Additional Laboratory Testing
Phase I. These include (1) retesting a portion of the original sample and (2) Resampling.
Re-testing:
 Sample should be taken from same homogenous lot which resulted in OOS.
 Determine instrument/sample handling error.
 Retesting should be based on scientific rationale.
1. Retesting
 Number if retestings, should be mentioned in SOP.
 If additional testing required, to be done on protocol basis.
 If clear lab error, retest data substituted with original results.
 If no lab error both initial and retest results shall be documented for batch disposition decission.
Re-sampling:
 Analysing specimen sample collected by same method or additional sample collected from Retesting
should be done by another analyst.
2. Resampling
 Such sampling & testing can conclude that original sample was not properly prepared & hence not
represent quality of the batch.
 It determines that original sampling method was inadequate, new accurate method should be developed.

C. Reporting Testing Results

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 Averaging:
 Appropriate Use: Use of replicates to arrive at single result & number of replicates used should be
specified. Acceptance limit for variability among replicates should be defined.
 Averaging should be used only if it is used during original analysis.
1. Averaging  Inappropriate use: Averaging has potential of hiding variability in test results. All individual test should be
reported as individual result. Use of averaging is inappropriate during powder blend/mixture uniformity
or dosage form content uniformity as test is intended to measure variability within the product
 If additional testing is done during OOS investigation, averaging should not be done with original result.
Relying on average is misleading when some results are OOS and other are within specifications.
Outlier tests:
 There should be a statistically valid QC criteria with appropriate acceptance or rejection level.
 In some cases , a value may be obtained which is different from others in a seies due to deviation of test
method or variability in sample.
2. Outlier Tests  There should be no assumption related to error in test method.
 Outlier testing identifies extreme from a data, this testing should be done in advance as per a defined SOP.
 Minimum number of results required to obtain statiscally significant assessment for outlier test should be
defined in the SOP.
 QC or contract testing lab shall provide all the individual test results to QA for batch disposition

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Phase III CONCLUDING THE INVESTIGATION

The QU is responsible for interpreting the results of OOS investigations.

Initial OOS results do not mean the batch fails and must be rejected.
OOS results should be investigated, and the findings of the investigation, including retest results, interpreted to evaluate the batch and reach a
decision regarding release or rejection.
Where an investigation has revealed a root cause, and the suspect result is invalidated, the result should not be used to evaluate the quality of the
batch or lot.
When the investigation indicates an OOS result is caused by a factor affecting the batch quality, the result should be used in evaluating the quality of
the batch or lot.
In cases where a series of results from multiple sample preparations from the original sample are required by the test procedure and some of the
individual results are OOS, some are within specification, and all are within the known variability of the method, the passing results are no more likely
to represent the true value for the sample than the OOS results.
The manufacturer should err on the side of caution and treat the average of these values as an OOS result, even if that average is within specification.
If you are averaging results from the same final sample preparation, there may be cases where the test method specifies appropriate acceptance
criteria for variability and a predefined number of replicates from the final diluted sample solution to arrive at a result. In these cases, and given the
acceptance criteria for variability are met, the result of any individual replicate in and of itself should not cause the reportable result to be OOS.
Borderline results that are within specification, such as an assay result that is low but within specifications, should raise a concern.
A. Interpretation of Investigation Results
The interpretation of the findings of the full scale investigation along with retest will be done by quality control and quality assurance functions to
ensure that, under no circumstance the laboratory invalidates the OOS result based on passing retest results alone. If any of the individual retest
results are not complying with the specification the OOS will be considered as valid and a manufacturing investigation will be initiated. Based on the
findings in the investigations QA will perform the final assessment and recommend for material disposition.

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The final disposition of the material will be followed as per the procedure. OOS test results will be included in the Annual product Review. The out of
specification should be completed within 30 working days from the date of OOS result. if this cannot be completed within the time period, take
approval from QA for investigation time extension with justification. All out of specification will be trended every year, verify the repeated failures and
implementation of Corrective and Preventive action and its effectiveness
Manufacturing
Reject the batch for OOS of in-house product if manufacturing discrepancy/deviation impact
Discrepancy deviation
Conclusion based upon the test results and reject out sourced material if no adequate history or trend available.
observed
the Manufacturing
No Manufacturing QA to decide on batch release decision, considering all results, review of trend, stability,
Data
discrepancy / process validation etc. for in-house product and for outsourced material if adequate history
deviation and trend is available. Retain all the results.
QA to decide on batch release decision,
Further additional considering all results, review of trend,
All Result
Additional Laboratory testing by third or stability, process validation etc. for in-house
within the
testing by second initial analyst on at product and for outsourced material if
specification
analyst on at least two least four fresh adequate history and trend is available. Retain
All results within
fresh sample sample preparations all the results.
specification
preparations from from the original Reject the batch for OOS.
original sample in sample in presence of For In house items , QA has to further
presence of Team Team Leader / QC Any one is out investigate and evaluate the root cause of the
Leader and Lab QA. Supervisors and Lab of specification rejection and /or recommend reprocessing.
QA. reworking or batch destruction. For
outsourced items , report initial value and

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 follow up with manufacturer. Study impact on
already distributed batches.
Reject the batch for OOS. For In house items , QA has to further investigate and evaluate the
any one is out of root cause of the rejection and /or recommend reprocessing. reworking or batch destruction.
specification For outsourced items , report initial value and follow up with manufacturer. Study impact on
already distributed batches.
Field Alert Reports
OOS test results for products that are the subject of an approved new drug application or abbreviated new drug application are considered to be one
kind of "information concerning any failure” described in §314.81 Other post marketing reports. Regulations require submission within three
working days of a field alert report (FAR) with information concerning any failure of a distributed batch to meet any of the specifications established
in an application. Unless the OOS result on the distributed batch is found to be invalid within three days, an initial FAR should be submitted. A follow-
up FAR should be submitted when the OOS investigation is completed.
OOS may be observed due to the following errors but is not restricted to these factors.
1. Error related to the analytical laboratory
2. Analytical instruments or equipment used for analysis are not in a valid calibration state.
3. Analytical test procedure not followed properly
4. Analyst Error
5. Error while doing calculations
6. Error due to the instrument failure
7. The test sample is not uniform or homogenous
8. Sampling error i.e. sample is not uniform or proper ., Incorrect handling of the sample

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9. Pooling of samples is not appropriate
10. Error at the time of sample handling
11. Manufacturing process-related error
12. Quality of used excipients, raw materials or intermediates
13. Operator error
14. The validated procedure was not followed correctly or Deviation from the standard procedure
15. At the time of manufacturing in-process checks or control is not done properly
16. Error due to equipment failure
17. Use of wrong reagents
18. Equipment not calibrated
19. Sample not incubated for the correct time and temperature
20. Possible contamination of sample
21. Incorrect reading of the result
22. Not reporting to the correct units of measurement

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 Regulatory Guideline for Out of Specification

1. WHO Technical Report Series, No. 1010, 2018 , Annex 10 , Stability testing of active pharmaceutical ingredients and finished

pharmaceutical products

2.2.11 Ongoing stability studies

Out-of-specification (OOS) results or significant atypical trends should be investigated. Any confirmed

should be reported immediately to the relevant finished product manufacturer. The possible impact on

2. Guidelines batches on the market should be considered in consultation with the relevant finished product

2.1 Active pharmaceutical ingredient manufacturers and the competent authorities.

A summary of all the data generated, including any interim conclusions on the programme, should be

written and maintained and should be available on site. This summary should be subjected to periodic

review.

2.1.13 Ongoing stability studies

2.2 Finished pharmaceutical product OOS results or significant atypical trends should be investigated. Any confirmed significant change or OOS

result should be reported immediately to the relevant competent authorities. The possible impact on

batches on the market should be considered in consultation with the relevant competent authorities.

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 A summary of all the data generated, including any interim conclusions on the programme, should be

written and maintained. This summary should be subjected to periodic review.

2. GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS ICH - Q7

6.6 Laboratory Control Records

6.61 Complete records should also be Out-of-specification (OOS) investigations.

maintained for:

6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch record review
6.7 Batch Production Record Review
before the batch is released.

8.36 Out-of-specification (OOS) investigations are not normally needed for in-process tests that are
8.3 In-process Sampling and Controls
performed for the purpose of monitoring and/or adjusting the process.

8.41 Out-Of-Specification batches should not be blended with other batches for the purpose of meeting

8.4 Blending Batches of Intermediates specifications. Each batch incorporated into the blend should have been manufactured using an established

or APIs process and should have been individually tested and found to meet appropriate specifications prior to

blending.

11.15 Any out-of-specification result obtained should be investigated and documented according to a
11. LABORATORY CONTROLS
procedure. This procedure should require analysis of the data, assessment of whether a significant

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 problem exists, allocation of the tasks for corrective actions, and conclusions. Any Resampling and/or

retesting after OOS results should be performed according to a documented procedure.

3. WHO Technical Report Series, No. 957, 2010 , Annex 1 , WHO good practices for pharmaceutical quality control laboratories

out-of-specification (OOS) result

Glossary All test results that fall outside the specifications or acceptance criteria established in product dossiers,

drug master files, pharmacopoeias or by the manufacturer (5).

2. Quality management system

2.2 The quality manual should contain as (a) a quality policy statement, including at least the following:

a minimum: (n) a policy for handling of OOS results;

2.3 The laboratory should establish,

implement and maintain authorized

written SOPs including, but not limited (n) atypical and OOS results;

to, administrative and technical

operations, such as:

18.2 When a doubtful result (suspected OOS result) has been identified, a review of the different
18. Evaluation of test results
procedures applied during the testing process is to be undertaken by the supervisor with the analyst or

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 technician before retesting is permitted. The following steps should be followed:

(a) confirm with the analyst or technician that the appropriate procedure(s) was (were) applied and

followed correctly;

(b) examine the raw data to identify possible discrepancies;

(c) check all calculations;

(d) check that the equipment used was qualified and calibrated, and that system suitability tests were

performed and were acceptable;

(e) ensure that the appropriate reagents, solvents and reference substances were used;

(f) confirm that the correct glassware was used; and

(g) ensure that original sample preparations are not discarded until the investigation is complete.

18.3 The identification of an error which caused an aberrant result will invalidate the result and a retest of

the sample will be necessary.

Doubtful results can be rejected only if they are clearly due to an identified error. Sometimes the outcome

of the investigation is inconclusive — no obvious cause can be identified — in which case a confirmatory

determination is to be performed by another analyst who should be at least as experienced and competent

in the analytical procedure as the original analyst. A similar value would indicate an OOS result. However,

further confirmation using another validated method, if available, may be advised.

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 18.4 An SOP should be in place for the conduct of an investigation of an OOS test result. The SOP should

give clear guidance on the number of retests allowed (based on sound statistical principles). All

investigations and their conclusions should be recorded. In the event of an error, any corrective action

taken and any preventive measure introduced should be recorded and implemented.

4. European Medicines Agency , November 2000 , note for guidance on good manufacturing practice for active Pharmaceutical

ingredients

5. USFDA 2022 -Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production Guidance for Industry-May 2022

Revision 1

Investigating Out-of-Specification (OOS) Regulatory Guidance for Laboratory Phase 1 and Phase 2 Investigations

Test Results for Pharmaceutical Laboratory testing, which is required by the CGMP regulations (§§ 211.160 and 211.165), is necessary to

Production confirm that components, containers and closures, in-process materials, and finished products conform to

Guidance for Industry. specifications, including stability specifications.

May 2022 General CGMP regulations covering laboratory operations can be found in part 211, subparts I (Laboratory
Pharmaceutical Quality/Manufacturing Controls) and J (Records and Reports). These regulations provide for the establishment of scientifically

Standards Current Good Manufacturing sound and appropriate specifications, standards, and test procedures that are designed to ensure that

Practice (CGMP) components, containers and closures, in-process materials, and finished drug products conform to the

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Revision 1 established standards.

Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet

established standards, specifications, or other relevant quality control criteria must be rejected.

Specifications must be scientifically sound and appropriate (§ 211.160(b)), test procedures must be

validated as to their accuracy, sensitivity, specificity, and reproducibility (§ 211.165(e)), and the suitability

of the test procedures under actual conditions of use must be documented (§ 211.194(a)(2)). For products

that are the subjects of new drug applications (NDAs), abbreviated new drug applications (ANDAs), or

investigational new drug applications (INDs), specifications are contained in the application or DMF.

Specifications for nonapplication products may be found in official compendia or established by the

manufacturer.

FDA regulations require that an investigation be conducted whenever an OOS test result is obtained (§

211.192).

The regulations require that a written record of the investigation be made, including the conclusions and

follow-up (§ 211.192).

In accordance with the CGMP regulations in § 211.160(b)(4), the analyst should ensure that only those

instruments meeting established performance specifications are used and that all instruments are properly

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 calibrated.

§ 211.192 requires a thorough investigation of any discrepancy, including documentation of conclusions

and follow-up.

failure investigation that extends to other batches or products that may have been associated with the

specific failure must be completed (§ 211.192).

The CGMP regulations require the establishment of specifications, standards, sampling plans, test

procedures, and other laboratory control mechanisms (§ 211.160).

If the results are unsatisfactory at this point, the batch is suspect and must be rejected or held pending

further investigation (§ 211.165(f)).

Any deviation from this SOP should be rare and done in accordance with § 211.160(a), which states that

any deviations from written specifications, sampling plans, test procedures, or other laboratory control

mechanisms shall be recorded and justified.

all original data must be retained (§ 211.180) and an explanation should be recorded.

Control mechanisms for examination of additional specimens should be in accordance with predetermined

procedures and sampling strategies (§ 211.165(c)).

the batch is suspect and must be rejected or held pending further investigation (§ 211.165(f)).

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 Any deviation from this SOP should be rare and done in accordance with § 211.160(a), which states that

any deviations from written specifications, sampling plans, test procedures, or other laboratory control

mechanisms shall be recorded and justified.

all original data must be retained (§ 211.180) and an explanation should be recorded

Batches must be formulated with the intent to provide not less than 100 percent of the labeled or

established amount of active ingredient (§ 211.101(a)).

Records must be kept of complete data derived from all tests performed to ensure compliance with

established specifications and standards (§ 211.194).

6. MHRA first published guidance to industry on how to handle Out Of Specification (OOS) investigations in August 2013.

7. ECA Guidelines for the Evaluation and Investigation of Microbiological Deviations - Chapter 1 - Deviation Handling of Microbiological

Environmental Monitoring Excursions in Non Sterile Pharmaceutical Manufacturing - Chapter 2 - Lab Investigations – Endotoxin Out of

Specification (OOS)/ Out of Trend (OOT)/ Atypical Results Investigations - Chapter 3 - Guidance for Sterility Test Failures.

8. ECA Standard Operating Procedure (SOP): Laboratory Data Management - Out of Specification (OOS) Results.

9. MHRA Guideline on Out of Specification. 2018

The MHRA first published guidance to industry on how to handle Out Of Specification (OOS) investigations in August 2013. It is reviewed and

improved for ease of use and published on October 2018.

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