OUT OF SPECIFICATIONS (OOS)

OUT OF SPECIFICATIONS (OOS)

  • Out of Specification (OOS) means the test result that falls outside the specifications or acceptance criteria which has been specified in the official compendia monographs or the finished product specification in registration dossiers.

OOS IS OBSERVED IN THE ANALYSIS OF:

  • Stability study
  • Finished product
  • In-process
  • Raw materials
  • Packing materials

Identification of OOS/OOT Result •

Out of Specification (OOS) Result –

A test result that does not comply with the pre-determined acceptance criteria.

Test results that fall outside of established acceptance criteria that have been established in official compendia

Out of Trend (OOT) Result –

  • A stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study.
  • The trends of starting materials and in-process samples
  • Yield out-of-trend data.
  • Environmental trend analysis such as for viable and non-viable data (action limit or warning limit trends)

Atypical / Aberrant / Anomalous Result –

  • Results that are still within specification but are unexpected, questionable, irregular, deviant, or abnormal. Examples would be chromatograms that show unexpected peaks, unexpected results for stability test points, etc.

US FDA: GUIDELINE FOR INDUSTRY INVESTIGATING OOS TESTING RESULTS FOR PHARMACEUTICAL PRODUCTION

  • PHASE I: LABORATORY INVESTIGATION should include an initial assessment of the accuracy of the laboratory’s data.
  • PHASE II: FULL-SCALE OOS INVESTIGATION consists of a production process review and/or additional laboratory work

OOS Objective:

To identify the route cause

To conclude with a decision on either batch rejection or release

To take appropriate corrective and preventive action Should Be

  • Through
  • Timely
  • Unbiased
  • Well documented
  • Scientifically sound Investigation

Phase I laboratory investigation

  • The investigation should include an initial assessment of laboratory data
  • The investigation should be done before discarding test preparation
  • A hypothesis test can be conducted using the original test preparations
  • If an obvious error is found laboratory test result should be invalidated and a retest should be done Investigation

Phase II / Full-Scale Investigation

No obvious laboratory error found in the initial laboratory investigation

For a contract laboratory, the laboratory should send the data obtained to manufacturers for full-scale investigation

  • Should be conducted using a predefined procedure (SOP)
  • Production procedure review
  • Sampling procedure review
  • Additional laboratory testing
  • Highest priority Investigation
  • Manufacturing investigation Additional Laboratory Test Investigation

Manufacturing/ Production Process Review

  • Should be conducted by QA
  • Should involve all other relevant department i.e. production, development, engineering, if needed
  • If contract manufacturer then all sites (contract manufacturing site)
  • Timely, thorough, and well-documented Investigation

Phase III investigation

Review the completed manufacturing investigation and combined laboratory investigation into the suspect analytical results, and method validation for possible causes of the results obtained.

To conclude the investigation all of the results must be evaluated.

The investigation report should contain a summary of the investigations performed and a detailed conclusion.

For microbiological investigations, where appropriate, use risk analysis tools to support the decisions taken and conclusions drawn. It may not have been possible to determine the actual root cause therefore a robust most probable root cause may have to be given.

The batch quality must be determined and disposition decisions are taken.

LABORATORY ERROR

Laboratory error is the cause of OOS results which may occur from the instrument, reagent, reference standard, environment condition, test method, analyst, and calculation within the laboratory.

TYPES OF LABORATORY ERRORS 15

PROCEDURE OF OOS

  • REPORTING TO LABORATORY SUPERVISOR
  • RECORDING AND NUMBERING OF OOS
  • INVESTIGATION BY ANALYST
  • LABORATORY TESTING
  • APPROVAL BY LAB. SUPERVISOR
  • TESTING BY ANALYST
  • PROCEDURE OF OOS

INVESTIGATION:

  • A written record of the review should include the following information
  • A clear statement of the reason for the investigation.
  • A summary of the aspects of the manufacturing process that may have caused the problem.
  • The results of a documentation review, with the assignment of actual or probable cause.
  • The results of a review were made to determine if the problem has occurred previously.
  • A description of corrective actions taken. Manufacturing/ Production Process Review Investigation

If an error is found, the investigation is terminated & product rejected

  • However, a failure investigation that extends to other batches or products that may have been associated with the specific failure must be completed
  • If reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel
  • Appropriate CAPA should be taken Manufacturing/ Production Process Review Investigation

Should be conducted by QA

Should involve all another relevant department i.e. production, development, engineering, if needed

If contract manufacturer then all sites (contract manufacturing site)

Timely, thorough, and well-documented Manufacturing/ Production Process Review Investigation

Additional Laboratory Testing Retesting Resampling Investigation

Additional Laboratory Testing :

  • Decisions should be taken based on the objective of the testing & should have sound scientific judgment
  • Should have a predefined retesting plan
  • Should be done by an analyst other than the original analyst
  • 2nd analyst should be qualified at least like the original analyst
  • should be from the same sample portion which has generated OOS results Investigation Retesting

Additional Laboratory Testing:

  • Should be done to identify instrument malfunction, sample handling error e.g. dilution error
  • Testing to compliance is prohibited
  • The maximum number of retests should be defined in SOP and should not be adjusted depending on the obtained result
  • The firm’s predetermined retesting procedures should contain a point at which the additional testing ends and the batch is evaluated
  • If the results are unsatisfactory at this point, the batch is suspect and must be rejected or held pending further investigation Investigation Retesting
  • Any deviation from SOP should be rare and any deviations from written specifications, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.
  • In such cases, before starting additional retesting, a protocol should be prepared (subject to approval by the QA) that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data. Investigation Retesting
  • In the case of a clearly identified laboratory error, the retest results would substitute for the original test result. All original data should be retained, however, and an explanation recorded This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments.
  • If no laboratory or calculation errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported and considered in batch release decisions. (In other words, all data are reported in, for example, quality control reports, batch records, and Certificates of Analysis) Investigation Retesting

Resampling:

  • Should rarely occur
  • If an insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed upon by QA/Contract Giver/QA equivalent. The process of obtaining the resample should be recorded within the laboratory investigation.
  • Re-sampling should be performed by the same qualified methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method shall be developed, qualified, and documented.
  • It involves collecting a new sample from the batch.
  • Will occur when the original sample was not truly representative of the batch or there was a documented/traceable lab error in its preparation.
  • Evidence indicates that the sample is compromised or invalid.
  • Sound scientific justification must be employed if re-sampling is to occur. Investigation

If the batch is rejected there still needs to be an investigation.

  • To determine:
  • if other batches or products are affected.
  • Identification and implementation of corrective and preventative action.

Conduct Phase III Investigation Investigation

PREPARATION OF TEST REPORT

  • EVALUATION OF SUSPECT RESULTS
  • INVESTIGATION BY TECHNICAL MANAGEMENT TEAM
  • CONCLUSION AND REPORT OF DATA
  • EVALUATION BY QUALITY MANAGER

OOS INVESTIGATIONS

Investigations of “Out of Specification (OOS) / Out of Trend (OOT)/ Atypical results” have to be done in cases of

  • Batch release testing and testing of starting materials.
  • In-Process Control testing: if data is used for batch calculations/decisions and if in a dossier and on Certificates of Analysis.
  • Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going/follow-up stability (no stress tests)
  • Previously released batch used as a reference sample in an OOS investigation showing OOS or suspect results.
  • Batches for clinical trials.
  • All solutions and reagents should be retained until all data has been second person verified as being within the defined acceptance criteria.
  • Pharmacopeia has specific criteria for additional analyses of specific tests (i.e. dissolution level specification for S1, S2 & S3 testing; Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing).
  • If the sample test criteria are usually the first level of testing and a sample has to be tested to the next level this should be investigated as it is not following the normal trend.
  • The OOS process is not applicable for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g. process validation at variable parameters). Investigation

Re-testing: The analysis of the original sample at the time of phase- I laboratory investigation.

Re-sampling: The original batch is sampled by QA a second time after QA head authorization for re-analysis.

Re-analysis: The analysis of re-sampled material for the verification of results, if the manufacturing investigation does not have a root cause.

REGULATORY IMPACT ON OOS

  • Stability study required
  • OOS should be reported to RA
  • OOS batch should not be sold to the Regulatory market
  • OOS batch can not be blend with fresh approved batch
  • OOS batch can not be directly sold to the market

Reporting Test Result Result: Averaging Appropriate Inappropriate Outlier Reporting

Interpretation of investigation results

  • The QA is responsible for interpreting the results of the investigation
  • Initial OOS result does not necessarily mean the subject batch fails and must be rejected.
  • OOS results should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection.
  • Where an investigation has revealed a cause, and the suspect result is invalidated, the result should not be used to evaluate the quality of the batch or lot
  • Where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. Reporting
  • A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch’s rejection.

For inconclusive investigations — in cases where an investigation

(1) does not reveal a cause for the OOS test result

(2) does not confirm the OOS result The OOS result should be given full consideration in the batch or lot disposition decision.

In the first case (OOS confirmed), the investigation changes from an OOS investigation into a batch failure investigation, which must be extended to other batches or products that may have been associated with the specific failure.

Batch Disposition

If no laboratory or calculation errors are identified in Phase I and Phase II there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported (in all QC documents and any Certificates of Analysis) and all data has to be considered in batch release decisions.

If the investigation determines that the initial sampling method was inherently inadequate, a new accurate sampling method must be developed, documented, reviewed, and approved by the Quality Assurance responsible for the release.

Consideration should be given to other lots sampled by the same method.

An initial OOS result does not necessarily mean the subject batch fails and must be rejected. The OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection which should be fully documented.

Disposition of Batch

In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch’s rejection and proper disposition. Other lots should be reviewed to assess impact.

For inconclusive investigations — in cases where an investigation:-

(1) does not reveal a cause for the OOS test result and

(2) does not confirm the OOS result

The OOS result should be given full consideration (most probable cause determined) in the batch or lot disposition decision by the certifying QP and the potential for a batch-specific variation also needs considering.

Any decision to release a batch, in spite of an initial OOS result that has not been invalidated, should come only after a full investigation has shown that the OOS result does not reflect the quality of the batch. In making such a decision, Quality Assurance/QP should always err on the side of caution.

Concluding The Investigation

The results should be evaluated, the batch quality should be determined, and a release decision should be made by the QCU. • The SOPs should be followed in arriving at this point.

Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that corrective action can be taken. Reporting

Averaging

The validity of averaging depends upon the sample and its purpose. Using averages can provide more accurate results.

For example, in the case of microbiological assays, the use of averages because of the innate variability of the microbiological test system. The kinetic scan of individual wells, or endotoxin data from a number of consecutive measurements, or with HPLC consecutive replicate injections from the same preparation (the determination is considered one test and one result), however, unexpected variation in replicate determinations should trigger investigation and documentation requirements.

Averaging cannot be used in cases when testing is intended to measure variability within the product, such as powder blend/mixture uniformity or dosage form content uniformity.

Reliance on averaging has the disadvantage of hiding variability among individual test results. For this reason, all individual test results should normally be reported as separate values. Where averaging of separate tests is appropriately specified by the test method, a single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is reported with the individual unit dose test results.

Averaging

In the context of additional testing performed during an OOS investigation, averaging the result (s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results. Relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by Quality Assurance (Contract Giver/QP).

All test results should conform to specifications (Note: a batch must be formulated with the intent to provide not less than 100 percent of the labelled or established amount of the active ingredient.

Averaging must be specified by the test method.

Outlier Test

An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is an error in the testing procedure, rather than inherent variability in the sample being tested.

Statistical analysis for Outlier test results can be part of the investigation and analysis. However, for validated chemical tests with relatively small variance and that the sample was considered homogeneous it cannot be used to justify the rejection of data.

While OOS guidance is not directly intended for bioassay analysis, it can be used as a starting point for the investigation. Compendia such as the BP, PhEur and USP, provide guidance on outliers for these types of analysis. Reporting

OUT OF TRENDS (OOT)

WHAT IS OUT OF TREND (OOT) ?

A result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study.

More complicated than a comparison to specification limits.

CRITERIA TO CONSIDER A RESULT AS OOT

For ASSAY: 5% Change in the initial value of assay.

For IMPURITIES: Between 0.1 to 0.2 % increase or decrease as per initial reports.

OOT CAN BE DUE TO:-

  • ASSIGNABLE CAUSE: Laboratory errors
  • NON- ASSIGNABLE CAUSE: Non-laboratory errors.

METHOD FOR IDENTIFYING OOT

  • For the purpose of this study, data from ongoing stability studies of a final drug product with a shelf life of 36 months is used.
  • The ongoing studies were conducted on 10 batches of Product X. (solid dosage form)
  • The ongoing studies were conducted for 36 months in stability chambers at a constant temperature of 25 °C ± 2 °C and relative humidity of 60% ± 5% in accordance with the ICH guideline Q1A.
  • The analyst should carry out an essay at a time point of 0,3,6,9,12,18,24 and 36 months for all batches.

TYPES OF OOT DETERMINATION:

  • Regression-control-chart-method. The regression-control-chart method is used to compare the results within the batch and detect present OOT results. For the purpose of this method, the tenth batch is examined.
  • By-time-point method. The by-time-point method is used to determine whether a result is within expectations on the basis of experiences from other batches measured at the same stability time point.

Stability OOS/OOT situations should be escalated as soon as the suspect result is found. Follow the investigation as above for Phase I and Phase II. For OOS Situations Regulatory agencies will require notification within a short time point of discovery due to recall potential.

  • If abnormal results are found at any stability interval which predicts that the test results may be OOS before the next testing interval, schedule additional testing before the next scheduled testing interval. This will help better determine appropriate actions to be taken.
  • The stability of OOS should link to the Product Recall procedures.

To facilitate the prompt identification of potential issues, and to ensure data quality, it is advantageous to use objective (often statistical) methods that detect potential out-of-trend (OOT) stability data quickly.

OOT alerts can be classified into three categories to help identify the appropriate depth for an investigation. OOT stability alerts can be referred to as:

  • Analytical
  • Process control, and
  • Compliance alerts,

As the alert level increases from analytical to process control to compliance alert, the depth of investigation should increase.

A compliance alert defines a case in which an OOT result suggests the potential or likelihood for OOS results to occur before the expiration date within the same stability study (or for other studies) on the same product.

  • The stability of OOS should link to the Product Recall procedures.
  • Historical data are needed to identify OOT alerts.
  • An analytical alert is observed when a single result is aberrant but within specification limits (i.e., outside normal analytical or sampling variation and normal change over time).

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