Handling of out of specification results Michael Koupparis University of Athens

Handling of out of specification results 1.0 Purpose: To provide instruction for handling of out of specification results. 2.0 Objective: To provide a documented procedure for handling of out of specification results. 3.0 Scope: This procedure is applicable for handling of out of specification results. 4.0 Responsibility: – Primary: Officer – QC – Secondary: Officer-QA / Officer-QC

5.0 Procedure Initiation of OOS (Phase I): QC chemist shall report to QC In-charge, as and when he notices out of specification. The analyst should retain the entire sample / standard solution. QC In-charge shall initiate Phase I investigation as per the format given in the SOP Initial results have to be reported along with the certificate of analysis and worksheets. Then the investigation is to be done by QC In- charge for the following types of the OOS failure:

5.0 Procedure: Material failure: Review and Comparison of the party certificates of analysis of raw material used. – Material shall not match the specifications. – If OOS is identified, reject the material. Production: Change in reaction time / sequential addition of the components / Functioning of the equipment / review of BMR (Batch Manufacturing Record). – If OOS is identified reject the product of the reprocess –If OOS does not identified, investigate as laboratory error. Laboratory: In laboratory, there are four possibilities for error:

5.0 Procedure: Clerical error: Correction to be made according to clerical error, training shall be given to analyst. And release the material. System failure: Power failure / calibration failure check / any spillage or contamination in standard and sample / unsuitable instrument is used / instrument parameters set incorrectly. Analyst failure: Errors in dilution / Usage of appropriate and valid standard / method followed / sample stored appropriately / status of balance / Homogeneity of the sampling procedure / status of Instruments. Sampling procedure failure: Sample preparation method followed / sample taken is representative / sampling plan followed / sampling equipments status.

5.0 Procedure: If not found from all the above-mentioned failures, product can be considered as the material failure on the basis of trend analysis. The QC In-charge will fill the phase I investigation form with duly signed to QA for further actions. Upon conclusion, and remark initiation of the OOS phase-II is to be done.

5.0 Procedure: Phase II investigation of OOS: Nature of OOS is to be decided as per phase- I conclusion. Reason / Remark is to be noted for the nature of the OOS. Repeat testing can only be performed after an investigation of failure is initiated.

5.0 Procedure: Phase II investigation of OOS: Determine if the cause of the OOS is based on clerical error. – If the review of the OOS result demonstrates the result is attributable to error based on incorrect calculation, transcription error, etc. correct the entry (ies) in accordance with current laboratory notebook entry error corrections procedure and re-review the result. – If the corrected result is within specifications and acceptable based on historical test result trends, record and report the result. –A formal investigation report is not required in this case.

5.0 Procedure: Phase II investigation of OOS: Conduct additional analyst training and/or review the test or process procedure for clarity to minimize future inconsistencies.

5.0 Procedure: If the preliminary investigation of the OOS result demonstrates the result is attributable to a determinate analytical identifiable error(s) (e.g. non-adherence to monograph instructions, instrument response drift, observed technique/instrument abnormalities, etc.): – the OOS result is recorded in the laboratory notebook with suitable explanation as part of the batch or process record, and – repeat testing can be performed. –This initial OOS result, demonstrated to be attributable to determinate error, is not considered in the final release of the material or process

5.0 Procedure: When the investigation demonstrates that the OOS result is attributable to determinate analytical identifiable error: – conduct repeat testing by the original analyst A following any corrective action indicated by the investigation. –Record and report the repeat results. –These repeat results are considered in the final disposition of the material or process.

5.0 Procedure: If the preliminary investigation of the OOS test result demonstrates that it is not attributable to determinate identifiable error, but is attributable to indeterminate error (unknown): –Document the conclusion of the investigation. –Record the results in the laboratory notebook and include as part of the batch or process record. –This initial OOS result is considered in the final disposition of the material or process.

5.0 Procedure: Where repeat testing is warranted after the investigation has disclosed indeterminate error: –repeat the test in duplicate by the original Analyst A and another Analyst B on the original sample unless the preliminary failure investigation demonstrated that the original sample was non-representative.

5.0 Procedure: Note: If the initial aliquot from the original sample is not sufficient for retest, a second aliquot from the original sample is used. In the event that the original sample has been consumed during analysis, a second sample (new sampling) can be used. Re-sampling / Re-processing is to be done in case of the sampling procedure failure / In-process sample failure.

5.0 Procedure: If one or both repeat results of Analyst A are out-of-specification and one or both of repeat results of Analyst B are out-of- specification: – record both repeat results of Analyst A and Analyst B and the original OOS results of Analyst A as part of the batch or process record. –Indicate the material as failing the specification.

5.0 Procedure: If both repeat results from Analyst A and both results from Analyst B are within normal specification range (review historical result trend): – record all repeat results as part of the batch or process record. –Indicate the material as passing the specification.

5.0 Procedure: If one or both results from Analyst B are out-of-specification and both results of Analyst A are within normal specification: –record both repeat results of Analyst A and B and the original OOS results of Analyst A as part of the batch or process record. – And based on the trend analysis material to be rejected or re-sampling to be performed and re-test by analyst B.

5.0 Procedure: If re-test results of Analyst B are out-of- specification: –record re-test results of Analyst B and the original OOS results of Analyst A as part of the batch or process record. –Indicate the material as failing the specification.

5.0 Procedure: If re-test results from Analyst B are within normal specification range (review historical result trend): –record re-test results as part of the batch or process record. –Indicate the material as passing the specification.

5.0 Procedure: When an OOS result has been demonstrated through laboratory investigation to be valid and reflects the true quality of the material: –an investigation is initiated to determine the cause of the material failure. –The Product Failure Investigation, if required based on the outcome of the OOS investigation, must be completed.

5.0 Procedure: Phase II concludes with the result of material / product-released / not released. Attach the available certificate of Analysis and worksheets of all the tests conducted. Mention preventive / Further action. Final closure by QC In-charge and approval by the QA In-charge.

Intimation of the OOS (1) Intimate to materials departments and corporate QA of the OOS in case of rejection. QA Chemist to fill the final rejection note. This note should include the following things: OOS No. / Item code / Used for / Item name / Date of receipt / Control no. / Supplier’s consignment no./ Supplier’s name / Referred specification no. / Reason for rejection.

Intimation of the OOS (2) Party Certificate Of Analysis, XXXXXXXXX Pharmaceuticals Ltd Certificate Of Analysis and samples if available should be attached with the rejection note. Forward this to the material department for further action. If the frequency of the out of specification exceeds more than three times, then the vendor shall be black listed in case of raw / packing material and if in-process then the process shall be considered for change.

6.0 Reference Documents Phase I Investigation Form Decision Tree of Phase II Phase II OOS Form Final rejection note OOS logbook.

6. LOG BOOK FOR OUT OF SPECIFICATION RESULTS Serial no: …………………. OOS no: ………………. Date: …………………… Department: …………… OOS details: ……………. Investigation details: ……. Signature of QA: ………… Remarks: …………………

7.0 Abbreviations: QA = Quality Assurance department SOP = Standard Operating Procedure QC = Quality Control OOS = Out of specification

8.0 Copies to Distribution Sites : QA - Quality Assurance department QC - Quality Control

OUT OF SPECIFICATION INVESTIGATION FORM Format No.: SOP/QA/XXXX/F/1 ParameterLimit (Spec. No)ActualResult Pass / Fail Attachement:First CoA withWork sheet

Phase-I Analyst failure (Yes / No) Is there any Error in calculation? Is there any Error in dilution? Are appropriate and valid standards and reagents used? Are methods followed?

Phase-I Analyst failure (Yes / No) Are the test parameters followed? Is sample stored appropriately? Is the balance used with appropriate accuracy and calibrated? Is the sample Homogenous? Is the calibrated instruments/Glassware used? Is the analyst trained and evaluated?

Phase-I System failure (Yes / No) To check for Power failure Are the system/Instruments are calibrated? (Calibrate again) Is the calibration standard Used appropriate? Is there any spillage/contamination in Standard/sample? Is suitable instrument used? Is the instrument parameters set correctly? Are the Appropriate Equipment Accessories used?

Phase-I Sampling Procedure failure (Yes / No) Is Sample preparation done properly? Is sample taken representative? Is sampling plan followed? Are sampling equipments ok? Were environmental conditioned OK during Sampling? Is Appropriate Sample container / Sample bag Used?

Phase-I Other Checks for In-process Sampling (Yes / No) Check if there is change in reaction time. Is the Sequential addition of components followed? Is functioning of equipment proper? Is BMR/BPR (Batch Manufacturing Record / Batch Process Record) reviewed and found OK? Review & comparison of Party COA of Raw Materials.

Phase-I Conclusion System Failure / Analyst Failure / Sampling Failure / In-process Failure / Material Failure. (According to the above conclusion initiate the OOS Phase II as per flow chart)

Phase-I Remark: QC In charge (Name/ Signature/ Date) __________________________________ Authorized By: QA In Charge (Name/Sign/Date) _______________________________

FINAL REJECTION NOTE Format No.: SOP/QA/xxxx/F4 Material/Product: Date of Initiation Process/Stage: Date of Sampling Lot/Batch No.: OOS Number Lot/Batch size: Manufacturer’s Name: To: Purchase Department / Plant Manager DATE: xxxxxxxxxxxxxx From: QA Site

Please note that the following item is finally rejected: Details: Item Code: Used For: Item Name: Date of Receipt/Manufacturing Control No./Batch No.: Quantity Received: Quantity Rejected: Supplier’s Consignment No.: Supplier’s Name: Ref. Specification:

REASON FOR REJECTION: Further Action Plan: QA In charge Enclosure: Party COA, COA and Samples Cc To: Corporate QA, Supplier through Purchase Department