Out of specification shravan
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An out of specification (OOS) occurs when analytical results fall outside established specification ranges. There are guidelines from organizations like MHRA, CDER, and PIC/S for handling OOS events. OOS can occur during stability studies, finished products, or raw materials due to laboratory errors, process issues, or sample homogeneity problems. Investigations follow a phased approach starting with the quality control laboratory and then involving manufacturing operations if needed. The fate of an OOS batch may include reprocessing, reworking, or destruction depending on the investigation conclusions.
Out of specification shravan
- 1. 1 Out of Specification By: Shravan Kumar
- 2. 2 Definition If the analytical result(s) of a batch or material is/are falling out side of the established specification ranges, is called / considered as Out of Specification. Or The term OOS test results includes all suspect results that fall outside the predetermined Specification
- 3. 3 Out of Specifications There are lot of guidelines are available for defining to handle the OOS products/materials/batches as: MHRA guideline for OOS CDER guideline for OOS PIC/S guideline for OOS
- 4. 4 Out of Specifications The OOS may be observed during the analysis of: Stability study Finished API Intermediates In-process Raw materials Packing materials
- 5. 5 Out of Specifications OOS found due to the following reasons but not limited to: OOS Laboratory Process related Sample homogeneity
- 6. 6 Out of Specifications Laboratory errors: Laboratory errors Method of Analysis Use of Non Calibrated instruments Error in calculation Analyst error Instrument Failure
- 7. 7 Out of Specifications Process Related: Process Related Operator Error Equipment Failure Deviation form the validated procedure Quality of Raw material / Intermediate used In-Process Control During Manufacturing
- 8. 8 Out of Specifications Homogeneity sample : Sample Homogeneity Sampling error Handlin of samples Pooling of sample
- 9. 9 OOS Investigations As per MHRA (EU GMP) Phase – I Investigation (Primary & extended lab investigation) Phase – II Investigation (Manufacturing investigation) Phase – III Investigation (Extended manufacturing, Re-sampling and re-analysis) Procedures of OOS investigations As per CDER (US FDA) Phase – I Investigation (Primary & extended lab investigation) Phase – II Investigation (Manufacturing investigation and re- sampling and re-analysis)
- 10. 10 OOS Investigations Phase – I Investigation: Laboratory investigation Laboratory investigation is related to the Quality control department along with rechecking of documents with same analyst and re-testing with different analyst with original sample. Phase – I is sub divided in to two sections as: Phase – Ia (Primary Lab investigation), and Phase -Ib (Extended Lab investigation) As per MHRA (EU GMP)
- 11. 11 OOS Investigations Phase – II Investigation: Manufacturing Investigations In manufacturing investigation, production person investigate : Process parameters Drying parameters Input raw materials quality training of persons Cleaning of equipment Environmental information Contamination & etc…. As per MHRA (EU GMP)
- 12. 12 OOS Investigations Phase – III Investigation: Extended Manufacturing Investigations In Phase III investigation, Quality Control / Quality Assurance & Production department investigate the following: Sampling error by person Authorized for re sampling (if required) Re-analysis of re-sampled material with different Analyst If root cause found, define the CAPA or if not Diverted the matter to R&D / ADL or PD Lab Conclusion by all team member (QA, QC, PRD, ADL R&D, PD Lab) Decide the fate of batch by QA Head As per MHRA (EU GMP)
- 13. 13 OOS Investigations Re-testing: The analysis of original sample at the time of phase- I laboratory investigation. Re-sampling: The original batch is sampled by QA second time after QA head authorization for re- analysis. Re-analysis: The analysis of re-sampled material for the verification of results, if manufacturing investigation does not have root cause.
- 14. 14 OOS Investigations Phase – I Investigation: Laboratory investigation Laboratory investigation is related to the Quality control department along with rechecking of documents with same analyst and re-testing with different analyst with original sample. Phase – II Investigation: Manufacturing investigation Process related investigation is to be carried out by Production department along with re-sampling and re- analysis. As per CDER (US FDA)
- 15. 15 OOS Investigations Phase – I Investigation: Laboratory investigation Analyst observed the OOS result Re-calculate the results (if required) If analytical results remain same Report the OOS result to QC In-charge Log the OOS Start the Primary Laboratory investigation Review the documents along with solutions as (Potency / STP & Specs / buffer solutions / calibration of instruments / standard solutions / Column efficiency / weights / storage condition of sample and many more)
- 16. 16 OOS Investigations Phase – I Investigation: Laboratory investigation If there is no abnormality observed during the primary lab investigation then Report same results and considered as valid OOS and report Quality Head review the primary lab investigation and evaluate for re-testing (if QA Head permits) Repeat the analysis as thrice with original sample with different analyst Report the average result of repeat analysis Report the average result
- 17. 17 OOS Investigations Phase – I Investigation: Laboratory investigation If the result complies Report as complies and invalidate the OOS Release the batch If any of result if not complies (among three) Report as OOS and continue the OOS Report to QA head QA head will recommend for the Phase – II investigation (manufacturing investigation)
- 18. 18 OOS Investigations Phase – II Investigation: Manufacturing investigation Production persons shall investigate the following: Input quantity of raw material Input RM quality Process parameters details Critical process parameter details (time / temp) In-process results Out put of the material Re-conciliation of raw materials Utility pressures Calibration / Preventive maintenance of equipment Attached ancillaries status
- 19. 19 OOS Investigations Phase – II Investigation: Manufacturing investigation Production persons shall investigate the following: Cleaning of equipments Training of personnel Brain storming with operators Contamination verifications Environmental review If there is no assignable cause observed during manufacturing investigations, same is to be reported to Quality Assurance Head.
- 20. 20 OOS Investigations Phase – II Investigation: Manufacturing investigation QA, QC and production department will evaluate the investigations and after that: Sampling procedure review, if suspected QA head may recommend for re-sampling QC analyst shall analyze the sample as per STP Report the result (Pass / Failed) If Pass Define the CAPA Release the Batch If failed Reject the batch Divert the matter to R&D / ADL / PD Lab
- 21. 21 OOS Investigations Phase – II Investigation: Manufacturing investigation R&D / ADL / PD Lab shall: Take the user trial with the material Investigate the failure based on experiments / experiences Various types of experiments To find out the root cause To identify, is this material can b e reprocessed / reworked Make a summary report Defined the corrective actions
- 22. 22 OOS Investigations Phase – II Investigation: Manufacturing investigation QA/QC/Production department shall: QA head shall define the fate of batch for reprocess / rework / destruction Accept the corrective and preventive actions Training to all concerned for root cause / corrective action / preventive action Monitor the activity for corrective actions Evaluate the results of corrective actions Implement the preventive actions Verify the implementation of preventive actions After satisfactory implementation close the OOS & CAPA
- 23. 23 OOS Investigations All these activity for investigation / corrective actions / preventive actions should be recorded and reviewed and archived.
- 24. 24 OOS Investigations If OOS batch is to be reprocessed / re-work: Follow the written approved BMR for re-process / Rework Sample as per SOP for sampling of material Analyze the material according to the specification and STP Evaluate the quality of the batch Keep this batch for stability (Accelerated / Long term) Evaluate the stability results of the batch Communicate the OOS to the customers (as mentioned in to the Quality agreement)
- 25. 25 OOS Investigations Impact of OOS on REGULATORY: Stability study required OOS should be reported to RA OOS batch should not be sold to Regulatory market OOS batch can not be blend with fresh approved batch OOS batch can not be directly sell to the market
- 26. 26 Abbreviations CDER : Center for drug evaluation and research OOS : Out of specification RA : Regulatory affairs STP : Standard testing procedure EU-GMP : European good manufacturing practices PIC/s : Pharmaceutical inspection co-operation scheme
- 27. 27 Thank You