Out of Specification Investigation Phase II & III (MHRA)

Out of Specification Investigation Phase II (Unknown Cause / No Assignable  Cause ) & Phase III

Phase II Investigation  – Unknown Cause / No Assignable  Cause

These are difficult to perform as the result can be 1 to 2 weeks after the analysis was performed and maybe weeks after the batch was manufactured. 

It is important to evaluate the test conditions carefully and determine what the boundary of samples/products/manufacturing area is.  you do not determine the boundary of the suspect results it is difficult to determine if it one or more batches impacted.

The laboratory and manufacturing investigations need to be in depth. The investigations should clearly state the hypothesis and who will be responsible for the identified tasks.

Are the organisms of an expected type, determine likely source – would it be likely to be found where it was?

Review the media – prepared in house or bought in pre-prepared, supplier history, sterilization history

Equipment/utilities used – validation, maintenance, and cleaning status. Evaluate area/environmental trends for test area and support areas.

Cleaning and maintenance of the test environment

Disinfectant used

Use appropriate root cause analysis to help brainstorm all possibilities It is likely that there may be more than one root cause

Review decisions and actions are taken in light of any new information.

Due to the variability of microbiological results don’t limit the investigation to the specific batch it should be broader to review historical results and trends

Unusual events should be included to understand potential impacts. What is the justification to perform a repeat analysis (is sample left); re-test or resample

Any identifications may need to be at DNA/RNA level (bioburden failures)

All potential sources of contamination need to be considered – process flow the issue from sample storage to the test environment.

Use scientific decisions/justifications and risk based analysis.

The investigation may include working closely with the manufacturing team

During the investigation, it is an advantage to go and look at where the contamination occurred.

Ask how relevant plant is cleaned, tested for integrity, checked for wear, checked for material suitability and maintained at the occurrence site may reveal possible causes.

Where possible talk directly to the staff involved as some information may be missed if not looked at from the chemist/ microbiologist point of view.

Look for other documentation such as deviations and engineering notifications around the area of concern (this is applicable to the laboratory as well as manufacturing).

Trending can have species drift which may also be worthy of an action limit style investigation.

Statistical analysis for microbiology can include lots of zero results so recovery rates or similar may have to be used.

If a sample is invalidated the remaining level of assurance needs to be carefully considered, is their sufficient residual information?   Corrective actions may be appropriate for more than one root cause.

Stability – OOS/OOT:

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 OOS should link to the Product Recall procedures.

OOT

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.

Stability:

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 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).

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.

Phase III Investigation

The phase 3 investigation should review the completed manufacturing investigation and combined laboratory investigation into the suspect analytical results, and/or method validation for possible causes into 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 decision taken.

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

The decision to reject cannot be reversed as a result of further testing.

The impact of OOS result on other batches, ongoing stability studies, validated processes and testing procedures should be determined by Quality Control and Quality Assurance and be documented in the conclusion, along with appropriate corrective and preventive actions.

Batch Disposition

Conclusion:

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, and 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.

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

Reference :- MHRA OOS/OOT PPT

Out Of Specification Investigation Phase II (MHRA)

Out Of Specification Investigation Phase II (MHRA)

Conducted when the phase I investigations did not  reveal an assignable laboratory error.  Phase II investigations are driven by written and approved instructions against hypothesis.  Prior to further testing a manufacturing investigation should be started to determine whether there was a possible manufacturing root cause.

If not already notified the contract giver/MAH/QP (in accordance with the responsibilities in the TA) should be notified along with production and QA if a manufacturing site.

It is important when considering performing additional testing that it is performed using a predefined retesting plan to include retests performed by an analyst other than the one who performed the original test.  A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst.

If the investigation determines analyst error all analysis using the same technique performed by the concerned analyst should be reviewed.

Hypothesis/Investigative Testing

Is testing performed to help confirm or discount a possible root cause i.e what might have happened that can be tested:- for example it may include further testing regarding sample filtration, sonication /extraction; and potential equipment failures etc. Multiple hypothesis can be explored.

Re-Test

Performing the test over again using material from the original sample composite, if it has not been compromised and/or is still available. If not, a new sample will be used.

Re-sample

A new sample from the original container where possible, required in the event of insufficient material remaining from original sample composite or proven issue with original sample integrity.

Most probable cause

Scientifically justified determination that the result appears to be laboratory error.

Phase II Investigation  – Unknown Cause / No Assignable  Cause

Hypothesis Testing (Applicable to Phase Ia and Phase II):

Should be started as part of Phase Ia and continue into Phase II if no assignable cause found.

Description of the testing should be written, and then approved by QA/Contract Giver/QA equivalent prior to initiating investigational testing.  The requirements of investigational testing listed below:

The description must fully document

•The hypothesis to the test the root cause being investigated.

•What samples will be tested. 

•The exact execution of the testing.

•How the data will be evaluated

This Hypothesis testing may continue from the re-measurement of the original preparations.

Investigational testing may not be used to replace an original suspect analytical results.  It may only be used to confirm or discount a probable cause.

If no assignable cause that could explain the results can be identified during the manufacturing investigation or the assay failure investigation retesting may be considered.  Part of the investigation may involve retesting a portion of the original sample.

Retesting:

•Performed on the original sample not a different sample.

•Can be a 2nd aliquot from the same sample that was the source of the original failure.

•If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent.  The process of obtaining the resample should be recorded within the laboratory investigation.

•The decision to retest should be based on sound scientific judgement.  The  test plan must be approved before re testing occurs. The minimum number of retests should be documented within the procedure and be based upon scientifically sound principles.  Any statistical review  with regards to %RSD and repeatability should relate to the values obtained during method validation (accuracy, precision, and intermediate precision).  The number of retests should be statistically valid; papers have suggested 5, 7, or 9.

•The retests should be performed by a different analyst where possible.  The second analyst should be at least as experienced and qualified in the method as the original analyst.

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.

•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.

•Consideration of the 95% Confidence Limits (CL 95% ) of the mean would show the variability when averaging is used.

Averaging continued: Consideration of using 95% Confidence Limits (CL 95% ) of the mean would show the variability when averaging is used.

The confidence interval is calculated from the formula:

CL= sample mean ± t 95% sample standard deviation/ √ n

–Where t is a value obtained from tables

–Where n is the sample size

–Table:

n t 95%
2 12.71
3 4.30
4 3.18
5 2.78
6 2.57
7 2.45
10 2.26
20 2.09
120 1.98
1.96

Re-sampling:

Should rarely occur, If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed 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 the 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.

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 error in the testing procedure, rather than inherent variability in the sample being tested. Statistical analysis for Outlier test results can be as 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

Reference :- MHRA OOS & OOT Investigation PPT.

Out Of Spesification Phase Ia & Ib ( MHRA)

How to Investigate Out Of Specification(OOS) Test Results….??? ( USFDA Phase -II)

How to Investigate Out Of Specification(OOS) Test Results….??? ( USFDA Phase -II)

Out Of Specification( OOS ) :-  The all test results which goes outside the specification or acceptance criteria established in Drug Dossiers, Drug Master files, Its official Pharmacopeias, Or the manufacturer comes Under Out of Specification( OOS ).

We have seen in last post about Phase -I Investigation of Out of Specification (OOS) Test Results. Now we will see Phase -II of Investigation of Out of Specification (OOS) Test Results.

 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 results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be conducted. This investigation may consist of a production process review and/or additional laboratory work. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective and preventative action.7 A full-scale investigation should include a review of production and sampling procedures, and will often include additional laboratory testing. Such investigations should be given the highest priority. Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batches.

 

  1. Review of Production

The investigation should be conducted by the QCU and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering. 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. Other potential problems should be identified and investigated

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.

 

  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. However, a failure investigation that extends to other batches or products that may have been associated with the specific failure must be completed (§ 211.192). If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel.

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.

  1. Additional Laboratory

 

Testing A full-scale OOS investigation may include additional laboratory testing. A number of practices are used during the laboratory phase of an investigation. These include (1) retesting a portion of the original sample and (2) resampling.

  1. Retesting

Part of the investigation may involve retesting of a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid, it may be an additional weighing from the same sample composite prepared for the original test.

Situations where retesting is indicated include investigating testing instrument malfunctions or to identify a possible sample handling problem, for example, a suspected dilution error. Decisions to retest should be based on the objectives of the testing and sound scientific judgment. It is often important for the predefined retesting plan to include retests performed by an analyst other than the one who performed the original test. A second analyst performing a retest should be at least as experienced and qualified in the method as the original analyst.

The CGMP regulations require the establishment of specifications, standards, sampling plans, test procedures, and other laboratory control mechanisms (§ 211.160).

FDA inspections have revealed that some firms use a strategy of repeated testing until a passing result is obtained, then disregarding the OOS results without scientific justification. This practice of “testing into compliance” is unscientific and objectionable under CGMPs. The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP). The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound principles. The number of retests should not be adjusted depending on the results obtained. 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 (§ 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. In such cases, before starting additional retesting, a protocol should be prepared (subject to approval by the QCU) that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data.

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. (See section III of this guidance for more details on a laboratory investigation.)

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.

 

  1. Resampling

 

While retesting refers to analysis of the original, homogenous sample material, 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, should that be necessary

The original sample from a batch should be sufficiently large to accommodate additional testing in the event an OOS result is obtained.

When all data have been evaluated, an investigation might conclude that the original sample was prepared improperly and was therefore not representative of the batch quality (§ 211.160(b)(3)). Improper sample preparation might be indicated, for example, by widely varied results obtained from several aliquots of an original composite (after determining there was no error in the performance of the analysis). Resampling should be performed by the same qualified, validated methods that were used for the initial sample.

 

  1. Reporting Testing Results

 

Practices used in reporting and interpretation of test results include (1) averaging and (2) outlier tests.

  1. Averaging

There are both appropriate and inappropriate uses of averaging test data during original testing and during an OOS investigation:

  1. Appropriate uses

Averaging data can be a valid approach, but its use depends upon the sample and its purpose. For example, in an optical rotation test, several discrete measurements are averaged to determine the optical rotation for a sample, and this average is reported as the test result. If the sample can be assumed to be homogeneous, (i.e., an individual sample preparation designed to be homogenous), using averages can provide a more accurate result. In the case of microbiological assays, the U.S. Pharmacopeia (USP) prefers the use of averages because of the innate variability of the biological test system.

In some cases, a series of complete tests (full run-throughs of the test procedure), such as assays, are part of the test method. It may be appropriate to specify in the test method that the average of these multiple assays is considered one test and represents one reportable result. In this case, limits on acceptable variability among the individual assay results should be based on the known variability of the method and should also be specified in the test methodology. A set of assay results not meeting these limits should not be used.

These appropriate uses of averaging test data should be used during an OOS investigation only if they were used during the original testing that produced the OOS result

 

  1. Inappropriate uses

 

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 can also conceal variations in different portions of a batch, or within a sample. For example, the use of averages is inappropriate when performing powder blend/mixture uniformity or dosage form content uniformity determinations. In these cases, testing is intended to measure variability within the product, and individual results provide the information for such an evaluation.

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 the QCU, which is responsible for approving or rejecting, e.g., drug products, in-process materials (§ 211.22)

For example, in an assay of a finished drug with a specification of 90 to 110 percent, an initial OOS result of 89 percent followed by additional retest results of 90 percent and 91 percent would produce an average of 90 percent. While this average would meet specifications,11 the additional test results also tend to confirm the original OOS result. However, in another situation with the same specifications, an initial OOS result of 80 percent followed by additional test results of 85 percent and 105 percent would also produce an average of 90 percent, but present a much different picture. These results do not confirm the original OOS result but show high variability and may not be reliable. In both examples, the individual results, not the average, should be used to evaluate the quality of the product.

 

  1. Outlier Tests

 

The CGMP regulations require that statistically valid quality control criteria include appropriate acceptance and/or rejection levels (§ 211.165(d)). On rare occasions, a value may be obtained that is markedly different from the others in a series obtained using a validated method. Such a value may qualify as a statistical outlier. 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 error in the testing procedure, rather than inherent variability in the sample being tested.

Outlier testing is a statistical procedure for identifying from an array those data that are extreme. The possible use of outlier tests should be determined in advance. This 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. The SOPs should specify the minimum number of results required to obtain a statistically significant assessment from the specified outlier test.

For biological assays having a high variability, an outlier test may be an appropriate statistical analysis to identify those results that are statistically extreme observations. The USP describes outlier tests in the general chapter on Design and Analysis of Biological Assays <111>.  In these cases, the outlier observation is omitted from calculations. The USP also states that “arbitrary rejection or retention of an apparently aberrant response can be a serious source of bias… the rejection of observations solely on the basis of their relative magnitudes is a procedure to be used sparingly” (USP <111>).

For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of a composite of a dosage form drug to determine strength), an outlier test is only a statistical analysis of the data obtained from testing and retesting. It will not identify the cause of an extreme observation and, therefore, should not be used to invalidate the suspect result. Occasionally, an outlier test may be of some value in estimating the probability that the OOS result is discordant from a data set, and this information can be used in an auxiliary fashion, along with all other data from the investigation, to evaluate the significance of the result.

Outlier tests have no applicability in cases where the variability in the product is what is being assessed, such as for content uniformity, dissolution, or release rate determinations. In these applications, a value perceived to be an outlier may in fact be an accurate result of a nonuniform product.

When using these practices during the additional testing performed in an OOS investigation, the laboratory will obtain multiple results. It is again critical for the laboratory to provide all test results for evaluation and consideration by the QCU in its final disposition decision. In addition, when investigation by a contract laboratory does not determine an assignable cause, all test results should be reported to the customer on the certificate of analysis

 

  1. CONCLUDING THE INVESTIGATION

To conclude 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 a corrective action can be taken.

 

  1. Interpretation of Investigation Results

The QCU is responsible for interpreting the results of the investigation. 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 (§ 211.165).

In those instances 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. Invalidation of a discrete test result may be done only upon the observation and documentation of a test event that can reasonably be determined to have caused the OOS result.

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, in accordance with § 211.165(f), and proper disposition. 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 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 (§ 211.192). In the second case (inconclusive), the QCU might still ultimately decide to release the batch. For example, a firm might consider release of the product under the following scenario:

A product has an acceptable composite assay range of 90.0 to 110.0 percent. The initial (OOS) assay result is 89.5 percent. Subsequent sample preparations from the original sample yield the following retest results: 99.0, 98.9, 99.0, 99.1, 98.8, 99.1, and 99.0 percent. A comprehensive laboratory investigation (Phase 1) fails to reveal any laboratory error. Review of events during production of the batch reveals no aberrations or indication of unusual process variation. Review of the manufacturing process and product history demonstrates that the process is robust. The seven passing retest results are all well within the known limits of variability of the method used. Batch results from in-process monitoring, content uniformity, dissolution, and other tests are consistent with the passing retest results. After a thorough investigation, a firm’s QCU might conclude that the initial OOS result did not reflect the true quality of the batch.

It is noteworthy in this scenario that the original, thorough laboratory investigation failed to find any assignable cause. However, if subsequent investigation nonetheless concludes that the source of the OOS result was a cause unrelated to the manufacturing process, in response to this atypical failure to detect the laboratory deviation, it is essential that the investigation include appropriate follow-up and scrutiny to prevent recurrence of the laboratory error(s) that could have led to the OOS result.

As the above example illustrates, 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, the QCU should always err on the side of caution.

  1. Cautions

In cases where a series of assay results (to produce a single reportable result) 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. For this reason, a firm should err on the side of caution and treat the reportable average of these values as an OOS result, even if that average is within specification. This approach is consistent with the principle outlined in the USP General Notices that an official article shall comply with the compendial standard any time a compendial test is applied.15 Thus, every individual application of the official test should be expected to produce a result that meets specifications.

An assay result that is low, but within specifications, should also raise a concern. One cause of the result could be that the batch was not formulated properly. 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)). This would also be a situation where the analytical result meets specifications, but caution should be used in the release or reject decision.

As with all analytical testing conducted to evaluate the quality of a drug, all records pertaining to the OOS test result should be retained. Records must be kept of complete data derived from all tests performed to ensure compliance with established specifications and standards (§ 211.194).

  1. Field Alert Reports

For those products that are the subject of approved full and abbreviated new drug applications, regulations require submitting within 3 working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)). OOS test results on these products are considered to be one kind of “information concerning any failure” described in this regulation. Unless the OOS result on the distributed batch is found to be invalid within 3 days, an initial FAR should be submitted. A follow-up FAR should be submitted when the OOS investigation is completed.