SOP for Handling Out of Specification (OOS)

OBJECTIVE

To describe the procedure for handling of Out Of Specification (OOS) laboratory test results to ensure that the OOS test results are properly investigated and corrective actions are taken to avoid recurrence.

SCOPE

• This SOP shall be applicable at PharmaInfo Ltd.,
• This SOP is applicable to all the OOS results, which are obtained for Raw Materials, Semi-Finished Products, Finished products, and Stability samples.
• If an out-of-specification result is generated for dissolution/drug release, uniformity of dosage units, weight variation, disintegration, and friability, Preliminary investigation shall be carried out in such cases, and respective Pharmacopoeia guidelines or criteria shall be applied.
• This SOP is not applicable to samples of various stages like scale-up batches, cleaning validation, swab analysis, Pre-shipment samples, miscellaneous items, description and solubility tests, and tests where tentative limits are given.
• This SOP is not applicable for OOS to tests like Bulk density, Sieve analysis, Particle sizing, and other physical parameters.
• This SOP is not applicable for incomplete analysis (due to malfunction of equipment) where results are not derived.

RESPONSIBILITY

• Chemist QC: To inform the OOS test result Superior or Manager QC: To initiate the laboratory investigation on OOS test results and forward the laboratory investigation report to Quality Assurance for final disposition, in case of real OOS test.
• Manager-QC / designee: To review and approve all investigations of OOS results before forwarding to Quality Assurance.
• Manager-QA / designee: To decide on the final disposition of material/products.

DEFINITION

• OOS: An unacceptable result that is the outcome of analysis. The result which does not meet the pre-established specification of the test product shall be termed an OOS (out of Specification) result.
• Evaluation samples: Samples, which are of deviation batch, recovery batch, market complaint, pre-shipment sample, study, and trial purposes.
• Questionable results: A result, which does not confirm but is out of limit at the first analysis is considered as questionable and needs to be investigated.
• Assignable cause: A cause that has been identified as the reason to invalidate a questionable test result. The assignable cause is a conclusion derived from direct or indirect evidence found during the investigation process, from the interpretation of analytical data or a combination of both.
• Investigation: An investigation jointly conducted by an investigator and the analyst. The purpose of the analytical investigation is to verify that a valid result was obtained or discover what occurred to explain an invalid result. It must be thorough enough to discover any analyst or equipment error if one occurs.

PROCEDURE

• This procedure shall cover OOS test results and investigation
• Definition: The term “OOS test results” includes all suspect test results that fall outside the established specifications.
• Causes of OOS test result

An OOS test result can be due to

1. Assignable cause
2. Non-assignable cause

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An assignable cause for OOS test results can be due to,

1. Laboratory error during analysis
2. Error in sampling, handling, or storage of sample
3. Non-process related or Operator error
4. Process related error
5. Laboratory error can occur when an analyst makes a mistake in following the method of analysis, uses a non-calibrated instrument, uses an incorrect or invalid working standard, makes a mistake in calculation, or any other reason associated with lab analysis.
6. All such laboratory errors shall be investigated during a laboratory investigation (primary investigation), which shall be started immediately upon getting an OOS test result.

Laboratory Investigation (Primary Investigation)

• The procedure described shall be followed if a laboratory test result for the finished product sample fails to meet the established specifications. The flow chart for investigating an OOS test result is given at the end of this procedure.
• The analyst shall check the analytical data, for compliance with applicable specifications, before discarding the test preparations.
• On obtaining an OOS test result, the concerned analyst shall immediately report the OOS test result to his next superior through OOS notification (Annexure-1) and OOS test result report (Annexure-2 and shall assign and register the OOS No. in the OOS register by following the below order: 

OOS No. OOS/XXX/YYYY (XXX- Serial No. , YYYY- Current Year)

• The analyst shall retain all the test preparations, glassware used, portions of a test sample, sample blend, etc., till the review and investigations are concluded.
• The analyst and the immediate superior shall carry out a Laboratory investigation as per the checklist (refer to Annexure-3).
• The Laboratory investigation checklist shall cover various possible reasons involving laboratory operations such as: weighing, dilution, sample preparation/work-up, labeling, glass-wares usage, cleaning of testing tools/glass-wares, calculations, transcription of data, and others listed in the checklist.

Repeat Analysis

• If Laboratory investigation reveals that the OOS test result is due to laboratory error then a repeat analysis shall be performed. The procedure followed and the scientific rationale for concluding the laboratory error shall be properly documented.
• QC Head, in writing, shall give instructions for Repeat Analysis to a second Analyst (Analyst-B). Analyst-B shall perform the repeat analysis in a single.
• The repeat analysis shall be performed from the same sample portion, which was used for the original analysis.
• If this sample portion is not available or is spoiled, then another portion of the same larger sample pool/sample composite (previously collected for analysis) shall be used.
• If the batch meets the specifications during repeat analysis (performed after finding a laboratory error) then the passing result shall be verified by a third analyst (Analyst-C)
• In case the repeat analysis by Analyst-B gives an OOS test result, then the batch shall be rejected. A secondary investigation shall be performed by the QA Head to find out the reason for batch failure.
• The batch shall be approved if

1. The two repeat analysis results (by Analyst B & C) are within specifications.
2. For a quantitative determination, the overall RSD for the two repeat analyses shall not be more than the following values:

Assay: NMT 2%

Related Substances/impurities: NMT 10%

Residual Solvents: NMT 15% 

• The results shall be reported as an average of two repeat analyses (analyst B &C) (refer to Annexure-4).
• The laboratory investigation report shall be prepared jointly by the analyst and Head QC.
• The laboratory investigation report shall be handed over to the QA Head. In case of an identified laboratory error, the other samples/batches, which were analyzed along with the initial OOS test sample, shall also be reviewed and the impact evaluated, along with the implementation of the necessary corrective action plan.
• Re-sampling (for repeat analysis) shall be performed, only if an investigation of the OOS test result indicates a sampling error, as the reason for the OOS test result. For re-sampling approval refer to Annexure – 5).

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Secondary Investigation

• When a laboratory error is not identified, an investigation shall be extended to the process area/manufacturing area for identifying any operator error / equipment-related error / process-related error.
• QA shall initiate a ‘Secondary Investigation’ (Production investigation) by approving the ‘Production Investigation Initiation’ form (Refer to Annexure - 6). QA shall assign the production investigation number (PIN)
• Assigning a Production investigation number.

                          PIN / AAA / BBB (AAA-Serial No ; BBBB-YEAR)

• QA shall conduct a detailed production investigation along with the respective production department and jointly prepare the ‘Production Investigation report’ (Refer to Annexure - 7)
• When a complete investigation does not reveal any conclusive reason i.e. there is a non-assignable cause for the original OOS test result, QA shall recommend for reanalysis.

Re-analysis

• Re-analysis shall be performed on the same sample/sample composite (i.e. the same portion of the sample used for original analysis / the same sample composite previously collected for analysis) 
• Re-analysis shall be done, in triplicate, by a different Analyst (Analyst-B), other than the original Analyst (Analyst-A).
• In case one or more of the triplicate results of Analyst B is out-of-specification, then the analysis shall be discontinued and the batch shall be rejected.
• If all three results of the triplicate analysis performed by Analyst B, are within the specification, then the analysis shall be repeated, in triplicate, by a third Analyst (say C) for verification.
• The batch shall be approved if :

1. All the six individual results of Re-analysis are within the specification
2. For quantitative determination, the overall RSD of all six values shall not be more than the following values : Assay: NMT 2%, Related Substances/impurities: NMT 10%. Residual solvents: NMT 15%
3. The difference between the average values of the two analysts shall not be more than the following values : Assay: NMT 2%, Related Substances/impurities: NMT 10%, Residual solvents: NMT 15%

• The average of average values reported by individual analysts shall be reported on a certificate of analysis. 
• The original OOS test result shall not be averaged along with repeat analysis results.
• The investigation shall be completed within 30 days of the initial OOS occurrence.
• In case of rejection of a batch, a thorough investigation shall be performed by the Production Head and Quality Assurance Head to determine whether this OOS test result is due to,

1. Process related. 
2. Non-process related error /operator error 

• The secondary investigation report shall be signed by the Production Head and QA Head.
• The QA Head shall communicate with the Manufacturing Location Head and Head of QA about the rejected batch
• OOS Investigation report shall outline the corrective actions necessary to save the batch and prevent a similar recurrence.
• The investigation shall be extended to other batches of the product, possibly affected due to process-related / non-process-related error
• The investigation shall also be extended to other batches and other products, possibly affected due to operator error or malfunctioning of equipment or poor quality utilities, etc.
• QA shall assess the overall investigation and recommend the corrective action to be taken based on the investigation reports. (Refer to Annexure-8)
• QA shall send a copy of the ‘Investigation Assessment Form’ to QC for release of the result.
• QA shall retain the original OOS reports

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REFERENCE

NIL

ABBREVIATION

SOP - Standard Operating Procedure

Q.A - Quality Assurance

No. - Number

Q.C - Quality control

OOS - Out of specification

% - Percentage

RSD - Relative standard deviation

ANNEXURE

Annexure - 1: OOS Notification

Annexure - 2: OOS Test Result Report

Annexure - 3: OOS Laboratory Investigation Checklist

Annexure - 4: Reanalysis / Retest Analysis Report of OOS Results

Annexure - 5: Resample Approval 

Annexure - 6: Production Investigation Initiation

Annexure - 7: Production Investigation Report

Annexure - 8: OOS Investigation Assessment Form

Annexure - 9: OOS Issuance No Record

REVISION HISTORY

Nil

Figure: 1 - OUT OF SPECIFICATION (OOS) PROCESS FLOW

Figure: 2 - Out of specification Flow Diagram - Investigation of OOS Test Result

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