Learn how to write SOP for out of specification (OOS) investigations to ensure compliance, accuracy, and quality control in pharmaceutical laboratories.
1. PURPOSE
To describe a standardized approach for identifying, investigating, and addressing Out of Specification (OOS) results in pharmaceutical quality control testing to ensure compliance with regulatory standards and product quality.
2. SCOPE
This SOP is applicable to all Quality Control (QC) laboratory personnel and relevant stakeholders involved in the testing and release of raw materials, in-process materials, finished products, and stability samples.
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3. RESPONSIBILITIES
3.1 Quality Control Executive/ Analyst are responsible for initial investigation of the test parameters and identify, document, and notify OOS results immediately.
3.2 Sr. Executive, QC is responsible to decide for re-sampling or taking final decision after review and to implement preventive measures.
3.3 Quality Control Manager is responsible to review OOS results, approve investigations, and ensure proper documentation.
3.4Production Executive is responsible to provide information or support as required during the investigation.
3.5 Quality Assurance Manager is responsible to verify and review the investigation process and approve final decisions.
4. ACCOUNTABILITY
Head of the Quality Assurance Department
5. ASSOCIATED DOCUMENTS / REFERENCES
5.1 SOP for Corrective and Preventive Actions (CAPA)
5.2 SOP for Sampling of Raw material
5.3 SOP for Sampling of Bulk Semi-finished product
6. PRECAUTIONS
6.1 Wear the proper clothes and safety gear for each examined location.
7. PROCEDURE
7.1 Initial Response to OOS Results
7.1.1 The QC Analyst performing the test must immediately document any OOS result in the raw data sheet or laboratory information system.
7.1.2 Notify the QC Manager and QA department immediately about the OOS result.
7.1.3 Review all analytical data, including calculations, instrument logs, and raw data, to confirm the OOS result.
7.1.4 Ensure proper retention of all solutions, test units, Glassware, sample etc. Until initial investigation
7.1.5 Discuss the test method with the analyst to confirm analyst knowledge of and performance of the correct procedure.
7.1.6 Check and record the present conditions according to the check list (Annex-1)
7.1.7 Check Laboratory error, Laboratory method error to determine his cause of OOS results.
7.1.8 Bring to the attention of Sr. Executive, QC.
7.1.9 Change normal to tighten when 2 out of 5 or less consecutive batch has been rejected.
7.2 Laboratory Phase of an Investigation Reanalysis
7.2.1 Initiate a preliminary investigation within 24 hours of identifying the OOS result.
7.2.2 Cary out the reanalysis when equipment malfunction is suspected or as a part of laboratory investigation.
7.2.3 Reanalyze the same dilution of samples or of same aliquots.
7.2.4 Do not reanalyze the sample which is chemically, physically or microbiologically unstable materials.
7.2.5 Handle all light sensitive samples/ materials in amber glass ware.
7.2.6 Handle all moisture sensitive samples/ materials in humid conditions with minimum exposure. Use dedicator where possible.
7.2.7 Don’t change the previous circumstances during e-analysis.
7.2.8 Record all the activities carried out during re-analysis.
7.2.9 Re-analysis only justified when there is a doubtful of susceptible error during operation of method used or of missing parameter.
7.2.10 Do not re-sample or re-prepare another aliquot for re-analysis.
7.2.11 The first analyst can perform the reanalysis as per the instruction by the QC Executive.
7.2.12 If no assignable laboratory error is identified, escalate the investigation to include:
Check and review raw material vendor lists.
Check and review manufacturing processes and deviations.
Check and review Environmental monitoring data records.
7.2.13 Conduct a Root Cause Analysis (RCA) using tools like fishbone diagrams or the “5 Whys” technique.
7.2.14 Collaborate with production and other departments to address potential non-laboratory causes.
7.3 Retest
7.3.1 Carry out the retest by second analyst.
7.3.2 Check the reference standard, standardized solution (s). Buffer 9s), indicators (s) and all eagles are correct and accordingly standardized and labeled before testing.
7.3.3 Use the same homogenous material that was first taken from the lot for the retesting sample, test it, and obtain the OOS results. It may be an additional weighing from same sample composite that had been prepared by the analyst.
7.3.4 Clean thoroughly and properly. The glassware to be used
7.3.5 Ensure the calibration of respective equipment.
7.3.6 Follow the respective test method carefully step by step.
7.3.7 Mix and grind the samples thoroughly (for solids) for proper homogeneity.
7.3.8 Weigh separately three samples from the same mix or grind and run at a time with the reference standard.
7.3.9 Retain the samples, solution (s)/dilutions(s) until the result (s) are reviewed and approved/ rejected.
7.3.10 Record properly the activities carried out during retesting as well as any abnormalities found.
7.3.11 Consider the analyst if the three concurrent results differ from each other.
7.3.12 Average the results when three retesting results are reproducible.
7.3.13 Do not average the results when obtained different from same mix or grind i.e. not reproducible.
7.3.14 Consider re-sampling if three result s fail to meet specification, before taking final decision but never ignore the previous data of OOS results because resample alone cannot invalidate an initial OOS result.
7.4 Re-sampling
7.4.1 Decide for re-sampling, only when no error was detected in analytical method, analyst, machine/equipment, calculation and documentation in initial review or resample the batch if the analysis indicates that the first sample was not characteristic of the batch
7.4.2 Collect sample properly from different containers following sampling SOP.
7.4.3 Composite/combined the collected sample.
7.4.4 Carry out the test very carefully with fresh sample by third analyst.
7.4.5 Record properly all the activities carried out during re-sampling and further testing.
7.4.6 Do not average the test result for following tests (individual result should be reported):
Assay parameters
Content Uniformity parameters
Dissolution parameters
7.5 Review the Documents
7.5.1 Investigate the OOS by forming a team
7.5.2 Include team members from production, Quality control, Compliance, and engineering (if required).
7.5.3 Conduct a review of OOS
7.5.4 Note the findings of review appropriately in test result record sheet.
7.5.5 Review of all calculations.
7.5.6 Review of all test procedures/methods.
7.5.7 Review of the equipment and its history (e.g. calibration and maintenance records. Previous analysis)
7.5.8 Review of related past incident reports.
7.5.9 Review of sample, standard and reagents for correct labeling.
7.5.10 Review the record and documentation of the manufacturing process to determine the possible cause of the OOS.
7.6 Review the Process
7.6.1 Check the manufacturing process sequences that may have caused the problem and summarize the findings.
7.6.2 Fill up the check list for OOS result by them member following Annex-2.
7.6.3 Interpretation of investigation Results
7.6.4 Investigate the OOS results, and the findings of the investigation, including test results, should be interpreted ot evaluated the batch and reach a decision regarding release of rejection.
7.6.5 Reject the batch when investigation indicates an OOS results is caused by a factor affecting the batch quality, the conformed OOS result indicates that the batch does not meet established standard or specifications. 7.6.6 Dispose the batch properly.
7.6.7 Give the full consideration in the batch or lot disposition decision for inconclusive investigations-in cases where an investigation.
7.6.8 Record the complete data derived from all tests performed to ensure compliance with established specifications and standards.
7.7 Corrective and Preventive Actions (CAPA)
7.7.1 Identify corrective actions to address the root cause (e.g., re-training, method validation, equipment maintenance).
7.7.2 Implement preventive measures to avoid recurrence (e.g., updating SOPs, improving processes).
7.7.3 Document and track CAPA implementation and effectiveness.
7.8 QA will review the investigation report and approve the final disposition of the product (e.g., release, reprocess, or rejection).
7.9 Communicate the decision to relevant departments and regulatory authorities, if applicable.
8. DEFINITIONS AND ABBREVIATIONS
8.1 Out of Specification (OOS) Results: OOS results are test outcomes that fall outside the predefined acceptance criteria set forth in the specifications, regulatory requirements, or pharmacopeial standards. These results indicate potential non-conformance and require thorough investigation to determine the root cause.
8.2 Laboratory Investigation: A systematic process initiated to identify the root cause of OOS results. It involves reviewing laboratory operations, testing procedures, equipment, reagents, and personnel activities to assess whether the error occurred within the laboratory.
8.3 Laboratory Method Error: A deviation or mistake in the testing process caused by incorrect analytical procedures, improper calibration, unsuitable reagents, or human error in the application of laboratory methods.
8.4 Resample: The collection of a new sample from the original batch or lot under investigation to confirm or refute the OOS result. Resampling is only permissible under justified conditions and requires prior approval following the investigation.
8.5 Review: A detailed examination of all relevant documentation, including analytical data, calculations, equipment logs, and testing records, to verify compliance with the procedure and identify potential errors.
8.6 Reanalysis: The re-evaluation of the original sample using the same analytical procedure and equipment to confirm the accuracy of the initial result. Reanalysis is typically performed to rule out errors in the first test.
8.7 Retest: The process of repeating the analytical test using a new portion of the same sample. Retesting aim to determine whether the initial OOS result was an anomaly or if it accurately reflects the sample’s quality.
8.8 CAPA: Corrective and Preventive Actions
8.9 OOS: Out of Specification
8.10 RCA: Root Cause Analysis
8.11 SOP: Standard Operating Procedure
8.12 QC: Quality Control
9. ANNEXES
9.1 Annex-1: Notification Form of Out of specification Result
9.2 Annex-2: Investigation Check list for Out of Specification
10. Revision History
| Version | Date | Description of Change | Reviewed By | Approved By |
| 1.0 |
Abdus Sobhan Salim is professional experienced pharmacist in pharmaceuticals, author and founder of pharmabossbd.com, the Bangladeshi pharmaceutical blogger since 2019.
