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 taken to avoid recurrence.

SCOPE

This SOP shall be applicable at XYZ Ltd.,
This SOP is applicable to all the OOS results, which are obtained for Raw Material, Semi Finished Products, Finished products and Stability samples.
If an out-of-specification results is generated for dissolution / drug release, uniformity of dosage units, weight variation, disintegration and friability, Preliminary investigation shall be carried out in such cases, 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 test 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’s) where results are not derived.

RESPONSIBILITY

Chemist QC: To inform the OOS test result to the 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 for final disposition of material / products.

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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 as OOS (out of Specification) result.
Evaluation samples: Samples, which are of deviation batch, recovery batch, market complaint, pre-shipment sample, study and trial purpose.
Questionable results: A result, which does not confirm but is out of limit at the first analysis 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 occurred.

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

Assignable cause
Non-assignable cause

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

Laboratory error during analysis
Error in sampling, handling or storage of sample
Non-process related or Operator error
Process related error
Laboratory error can occur when an analyst makes a mistake in following the method of analysis, uses a non-calibrated instrument, uses incorrect or invalid working standard, does a mistake in calculation or any such other reason associated with lab analysis.
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 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 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 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 the 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

The two repeat analysis results (by Analyst B & C) are within specifications.
For a quantitative determination the overall RSD for the two repeat analysis 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 analysis (analyst B &C) (refer 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 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 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 OOS test result. For re- sampling approval refer 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 ‘Secondary Investigation’ (Production investigation) by approving the ‘Production Investigation Initiation’ form (Refer 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 detailed production investigation along with respective production department and jointly prepare the ‘Production Investigation report’ (Refer Annexure - 7)
When 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 re – Analysis.

Re-analysis

Re-analysis shall be performed on same sample / sample composite (i.e. 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 :

All the six individual results of Re-analysis are within the specification
For quantitative determination, the overall RSD of all the 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 average value by 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 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,

Process related.
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 the Manufacturing Location Head and Head QA about the rejected batch
OOS Investigation report shall outline the corrective actions necessary to save batch and prevent 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

REFERENCE(s)

NIL

ABBREVIATION(s)

SOP - Standard Operating Procedure
Q.A - Quality Assurance
No. - Number
Q.C - Quality control
OOS - Out of specification
% - Percentage
RSD - Relative standard deviation

ANNEXURE(s)

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