Investigation of out of specifications (OOS) results during laboratory testing of samples.

1.0 OBJECTIVE 

To lay down the procedure for Conducting investigation of out of specifications (OOS) results during laboratory testing of samples.

2.0 SCOPE

This SOP is applicable for handling of OOS results in company Name

3.0 BACKGROUND

NIL

4.0 RESPONSIBILITY

4.1 All Analytical Research personnel shall follow the SOP.

4.2 Group leader Analytical research for conducting the investigations and to take corrective actions. 

4.3 Head Analytical research to ensure overall compliance.

5.0 PROCEDURE

5.1 The person conducting the test shall immediately inform the Head Analytical Research or his designee that the test results are out of specification. He / She shall store samples at appropriate storage conditions of the standard preparation test preparations and other preparations. He / She shall address the OOS in “Laboratory investigation of OOS Results” (Refer Annexure-1).

5.2 Filled Laboratory investigation of OOS results (Annexure-1) shall be allotted a OOS investigation report number by Head Analytical Research after logging     into the “Register for OOS Investigation Report” by entering all the details in (Annexure-3).

5.3  Numbering of OOS investigation report:

5.3.1 Each OOS report shall be allotted a sequential number consists of 13 characters.

5.3.2 The first two characters are alphabets “AR” indicating Analytical Research.

5.3.3 The Third character ´-´ denotes dash.

5.3.4 Next Three characters are alphabets “OOS” Indicating out of specifications

5.3.5 The next character is ´-´ dash.

5.3.6 The next three characters are numerical in sequential order starting from 001.

5.3.7 The next character is ´-´ dash.

5.3.8 The next two characters denotes last two digits of current year.

For Example : 

The first OOS investigation report in 2015 shall be numbered as AR-OOS-001-15.

5.4 Head Analytical Research or his designee along with the analyst shall investigate reasons for OOS results by using “Checklist for investigation of laboratory OOS results” as (Annexure -2) 

Note: OOS shall be raised in case of the following condition but not limited to 

1) Any observation value is not within the specified limit.

2) If one of the trail is out of limit with respect to any analysis.

3) In case of average results passes, but individual value is out of limit.

4) In case of bracketing standard failure, for a set of given injected samples,      

OOS shall  be raised for the samples which are observed to be out of limit.

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

5.6 The investigation should be thorough, timely, unbiased, well documented and Scientifically defensible.

5.7 Investigation of OOS test results – Hypothesis Testing :

The first phase of such an investigation should include an initial assessment of accuracy of the laboratory’s data, before test solutions are discarded, whenever    possible. This way, Hypothesis regarding laboratory error or instrument malfunctions may be tested using the same test solutions.

5.8 The assignment of a cause for OOS results will be greatly facilitated if the retained    Sample preparations are examined promptly.

5.9 Examination of the retained solutions should be performed as part of the laboratory investigation. Analyst shall fill the “Protocol for retesting the OOS results”  (Annexure-4), in that description must fully explained, theoretically root cause what samples should be tested, the exact execution of the testing, how the data will be evaluated, and thereby dilution error, instrument malfunction can be identified.

5.9.1 Solutions can be re-injected as part of an investigation where a transient equipment malfunction is suspected. This type of reinjections can provide strong evidence that the problem should be attributed due to the instrument rather than the sample or its preparation.

Re-injections include the following but not limited to:

1. Re-injecting the sample vial.

2. Transferring the final sample solution into a new vial and injecting the same.

3. If dilutions are made in the sample preparation, final dilution can be made from the Stock solution and injecting the solution.

5.9.2 Each step in the investigation should be fully documented.

5.10 During the above investigation, if the cause of OOS results is identified and both the analyst and the Head AR agree on it the test shall be discarded.

5.11 Whenever lab error is identified, identify the source of that error and take corrective action to prevent recurrence.

5.12 The analyst shall record the issue briefly in Record of Analysis. Analyst shall repeat the test in duplicate with same sample for testing  ,Blend content uniformity and UOD, retest the same number of units as normally required by compendia  with proper care to omit the errors identified.

5.13If the test results are within the limits, report the results. Analyst shall document the Results in “Laboratory investigation of OOS Results” Annexure-1.

5.14 Investigating OOS test results-Full scale OOS investigation:

5.14.1 When the initial assessment does not determine the laboratory error caused the OOS results and testing results found to be accurate, a full scale OOS investigation should be conducted.

5.14.2 A full scale investigation should include additional laboratory testing.

5.14.3 If the cause of OOS results is not identified in the initial assessment of laboratory investigation, document the issue in “Laboratory investigation of OOS results” Annexure-1 and inform to AR Head or his designee for further investigation.

5.14.4 Review of Research

5.14.4.1 Head Analytical Research or his designee shall conduct the investigation.

5.14.4.2 The records and documentation of the malfunctioning process should be fully reviewed to determine the possible cause of the OOS results.

5.14.4.3 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 malfunctioning process that may have caused the problem.

3. The results of the 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.

5.14.4.4 If this part of the OOS investigation confirms the OOS results and is successful in identifying its root cause, the OOS investigation may be terminated.

5.14.4.5If the reason is not identified in the research investigation, the same shall be forwarded to QA.

5.14.5 Additional Laboratory Testing:

5.14.5.Head AR   or his designee shall instruct the second Analyst to perform the test in quadruplicate (four preparations with single injection) from same “Sample for testing “( In case of Dissolution, Blend content uniformity and UOD, retest the same number of units as normally required by compendia) by following same STP / SOP / GTP.

5.14.5.3 The second Analyst should be at least as experienced and qualified in the method as the final analyst.

5.14.5.4 If the test results of second analyst are out of specifications and comparable with the first analyst, it shall be concluded that the material / product is not meeting the specifications and report the initial results of first analyst.

5.14.5.5 If the results of second analyst are within the limits, Head AR or his designee shall review the results and ask the first analyst to repeat the test in quadruplicate(four preparations with single injection) from same “Sample for testing “( in case of Dissolution, Blend content uniformity and UOD, retest the same number of units as normally required by compendia)  with proper care.

5.14.5.6 If the retest results of first analyst are matching with the results of second analyst  and within the limits, report the results of first analyst and second analyst. In case of dissolution and content uniformity, report the latest results of first analyst.

Note: Training shall be given to the first analyst for the failure or initial analysis.

5.14.5.7 If the retest results of the first analyst are again out of specified limits. Head AR or his designee shall review and investigate the reason for failure and attach the report. He shall instruct  third analyst to test the same “Sample for testing” test in quadruplicate (four preparations with single injection).

5.14.5.8 If third analyst results are within limit, report the average results of third analyst and second analyst. In case of Dissolution, Blend content uniformity and UOD, report the latest results i.e third analyst results. If third analyst results are out of specification it shall be concluded that the product/material not meeting the specification  and report the initial results of first analyst.

Note: 1. In case of third analyst results pass, reason for failure by first analyst shall be identified and training shall be given.

2.  In case of third analyst results are not within limit, training shall be given to second analyst for the passed results.

5.14.6 During the investigation, if it is concluded that the OOS results are due to sampling error or initial sample quantity is not sufficient to carry out the additional testing, then only resembling shall be performed on the same  “Sample for testing”.

5.14.8 Concluding the Investigation:

5.14.8.1 Head AR is responsible for interpreting the results of the investigation.

5.14.8.2 An 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.

5.14.8.3 OOS results identified and invalidated:

The comprehensive investigation has revealed a cause and the suspect result is invalidated, the result should not be used to evaluate the quality of the batch.

5.14.8.4 OOS results identified and not invalidated: 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. A confirmed OOS results indicate that the batch does not meet the established  standards or specifications and the batch should be rejected .In this case the investigation changes from an OOS investigation into a batch failure investigation, which must be extended to other batches or products that  might have been associated with the specific failure.

5.14.8.5 Inconclusive Investigations:

In cases where Investigations does not reveal a cause for the OOS test result and does not confirm the OOS result,  the OOS result should be retained in the record and scientific judgement should be used to determine whether the OOS data point should be included in the averaging. In this case QA might still ultimately decide to approve the batch by concluding that the initial OOS result did not reflect the true quality of the batch after a thorough investigation.

5.14.9 Document   the issue in “Laboratory investigation of OOS results” (Annexure-1) and forward the report to QA for review and disposal along with related analytical records.

5.14.10 Head-QA or his designee shall review the OOS report for completeness. If found complete, Head QA shall dispose the OOS by signing of the disposition column.

5.14.11 Investigation must be completed within 20 working days, from the day of occurrence of OOS results.

5.14.12 Incase of rejection of of material Head QA or his designee shall inform the supplier of the failure and request for appropriate investigation and corrective preventive action.

5.14.13 In case of rejection of batch or drug product , Head QA or his designee shall notify Head Analytical Research to conduct an investigation of failure.

5.14.14 In case of failure of stability sample, Head-QA or his designee shall notify Head of Analytical Research to conduct an investigation into the failure.

5.14.15 File the original copy of OOS investigation report in the “File for OOS investigation report” kept in QA office and OOS reference no. shall be mentioned in the respective documents.

5.14.16 Trending of OOS shall be done once in 6 months by QA personnel

6.0 VERSION HISTORY

7.0 ANNEXURES 

Annexure-1:   Laboratory Investigation of OOS results 

Annexure-2:   Flow chart for investigation and reporting of OOS results Sample 

Annexure-3:   Register for OOS Investigation report 

Annexure-4:   Protocol for retesting the OOS result