Handling an OOS in a QC Lab
- 1. Handling an OOS in a QC Lab Sasha Nezlin 04 Sept 2012
- 2. Omrix at a glance Handling an OOS in a QC Lab 2 04 Sept 2012
- 3. Barr Laboratories vs. FDA Barr were audited by FDA in 1989, 1991 and 1992 Refused to accept a consent decree FDA was forced to go to court United States of America, Plaintiff V. Barr Laboratories Inc., Defendants, Civil Suite 92-1744, August 17 till October 12, 1992 Judge Wolin decided on February 4, 1993 in favor of the FDA Handling an OOS in a QC Lab 3 04 Sept 2012
- 4. Judge Wolin’s decision Handling an OOS in a QC Lab 4 04 Sept 2012
- 5. 13 years later … Handling an OOS in a QC Lab 5
- 6. and another 5 years … Handling an OOS in a QC Lab 6 04 Sept 2012
- 7. DEFINITION OF RESULTS Batch failure, used by FDA, OOS Results - Test results laying disliked by Judge outside of the specifications Wolin (Barr case) Out of limits (OOL - alert / alarm) Additional unexpected peaks in Questionable chromatogram results (e.g. close to spec / limit) Out of trend Unexpected Results results that are aberrant, abnormal, anomalous, atypical, irregular or deviant Handling an OOS in a QC Lab 7 04 Sept 2012
- 8. FDA DEFINITION OF REPORTABLE VALUE REPORTABLE VALUE: “This determination is considered one test and one result.” A reportable value is the end result of the complete measurement method as documented. A reportable value is the value compared to the specifications. A reportable value is the value used for reporting. A reportable value is the value used for statistical analysis. Record in writing the operational definition of the reportable value for each test method in the method documentation, any protocols and any reports. Add “Only this reportable value can be compared to the specification criteria.” Handling an OOS in a QC Lab 8 04 Sept 2012
- 9. Investigations of OOS results should be performed for: - Batch release testing and testing of starting materials. - In-Process Control testing: if data is used for batch calculations / decisions and if it is in a dossier and on Certificates of Analysis. NOTE: OOS procedure is NOT applicable for in-process testing used for process adjustment (eg - pH, viscosity, etc.), and for validation studies (process - variable parameters, analytics - robustness). - Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, ongoing / follow up stability (NOT applicable for stress / forced degradation tests). - If the previous released GMP batch used as reference sample in an OOS investigation produced OOS or questionable results the investigation should be extended to include it. - Batches for clinical trials – under cGMP, same rules for investigation apply as for commercial batches. Handling an OOS in a QC Lab 9 04 Sept 2012
- 10. Flow of investigation In search of a root cause of OOS result FDA officials say, “If you didn’t document it, it didn’t happen. In God we trust, for everyone else we require documentation.” Handling an OOS in a QC Lab 10 04 Sept 2012
- 11. OOS Logic Test by Lynn Torbeck Document No Report out Out of Spec? results Resample as needed Yes Invalidate data, Yes Known Physical March 1999 Document, Reason? Start Over No No Yes 2 nd Stage Yes Original sample USP allows Yes (i.e. Content Passes? representative? resamples? Uniformity) No No Begin Lab Initial Investigation USP <111> Outlier ID Historical Data Lab or Yes Yes Finish Analyst Retest Passes? Investigation error? No Copyright 1999 by Yes No L. Torbeck Document Other No and report reason? Document Finish Review is Full justification investigation inconclusive Investigation Yes Yes Retest No All pass? Retest n times justified? No Handling an OOS in a QC Lab 11 04 Sept 2012
- 12. Handling an OOS in a QC Lab 04 Sept 2012 Sasha Nezlin 12
- 13. When to open a deviation If the investigation shows no assignable cause for the laboratory based failure - i.e. OOS is confirmed - then full scale manufacturing investigation should be conducted this is a regulatory requirement! When to initiate a manufacturing investigation: – after initial (phase 1) investigation reveals no laboratory errors has occurred? – or after full laboratory investigation (phase 2) was completed without evidence of lab error? Handling an OOS in a QC Lab 13 04 Sept 2012
- 14. RETEST SAMPLE SIZE Handling an OOS in a QC Lab 14 04 Sept 2012
- 15. RETEST SAMPLE SIZE (cont.) Original test Investigation / Retesting One analyst Two analysts, of at least the same level of experience ? One analyst, of higher level of experience ? Same analyst? Same analyst after training? 1 replicate Two tests in duplicates ? 2 replicates Two tests in triplicates ? Three tests in duplicates? 3 replicates Two tests in 4 replicates? Handling an OOS in a QC Lab 15 04 Sept 2012
- 16. RETEST SAMPLE SIZE (cont.) Original 2nd Analyst Analyst Prep Prep Prep Prep #1 #2 #1 #2 Inj 1 Inj 2 Inj 1 Inj 2 Inj 1 Inj 2 Inj 1 Inj 2 Original Instrument Second Instrument Handling an OOS in a QC Lab 16 04 Sept 2012
- 17. RETEST SAMPLE SIZE (cont.) This is an unresolved issue and the statisticians are still at it. Barr case: Judge Wolin indicated 7 retests were enough to discard an invalid result. Could be too much or not enough. Currently n= 3 to n=9. PDA OOS committee promised to recommend... Industry has been doing 2 x 2 x 2 (which is 4 sample preparations with 8 measurements), but your strategy should reflect your assay and its criticality and use. Handling an OOS in a QC Lab 17 04 Sept 2012
- 18. Tracking and Trending Investigations All laboratory corrective/preventive actions, investigations and deviations must be tracked and trended: To track method / instrumentation problems To specifically evaluate analyst performance, and to identify training needs To track product / process problems To trend significant shifts in laboratory data To identify systematic issues and ensure appropriate actions taken Handling an OOS in a QC Lab 18 04 Sept 2012
- 19. Expectations of the regulator / auditor OOS results will be generated by the lab Comprehensive, honest approach to investigation of OOS results is demonstrated Evaluation of OOS results is performed using scientifically valid principles 3G Lab demonstrably learns from the experience Permanent solution to the problem / root cause Prevention, not just correction 3G™ Good science, Good judgment, Good documentation Handling an OOS in a QC Lab 19 04 Sept 2012
- 20. References and useful links 1. FDA: Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, Guidance for Industry, October 2006 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070287.pdf) 2. MHRA “Out Of Specification Investigations” (http://www.mhra.gov.uk/home/groups/is-insp/documents/websiteresources/con100182.pdf) 3. MHRA Out of specification (OOS) FAQs (http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/FAQ/OOSFA Qs/index.htm) 4. Jenny Hantzinikolas, GMP Inspector, Office of Manufacturing Quality Laboratory, TGA “Investigations - A Regulatory Perspective” 2008 5. United States of America, Plaintiff V. Barr Laboratories Inc., Defendants, Civil Suite 92-1744 (http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM216425.pdf) (http://www.navigategmp.com/pdf/BarrLabs.pdf) 6. Lynn Torbeck “Preventing the practice of testing into compliance. A practical solutions guide”, Pharmaceutical Technology, October 2002 7. Jeffrey D. Hofer “Considerations When Determining a Routine Sample Size for a Retest Procedure”, Pharmaceutical Technology, November 2003 Handling an OOS in a QC Lab 20 04 Sept 2012
- 21. Questions? Handling an OOS in a QC Lab 21 04 Sept 2012