Out of Specification OOS Test Results

1. Out of Specification (OOS) Test Results ????? ????? ? ?? 2003? 8? 25?

2. OOS (Out of Specification) The failure of a batch or any of its components to meet any of its specifications OOS indicates non-compliance with specifications

3. Outliers Statistically invalid individual test result Can be eliminated

4. OOS – General Principles How should we handle OOS results? OOS cannot be ignored or discounted without basis When does testing stop (accept the result) First test failure? Second test failure? Tenth test failure?

5. Barr Decision (1993) cGMP regulations are vague about exactly how to handle OOS 1993? Barr Laboratories, Inc United States District Court for the District of New Jersey Jurdge Wolin made it clear what is acceptable and what is not acceptable in handling OOS

6. What does the cGMP Regulation say about Handling OOS Results?

7. cGMP Part 211.192 The failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated… The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure of discrepancy…

8. cGMP Part 211.194 A written record of the investigation shall include the conclusions and follow-up… A complete record of all data secured in the course of each test… Complete records shall be maintained of all stability testing performed…

9. Barr Decision Failure investigation is central Failure investigation Immediate Timely follow-up Appropriate resolution Documented

10. FDA: Interpretation of investigation results Batch acceptance or rejection must be based on scientific justification Overall body of data must be considered in judging the batch

11. Essence of Barr Labs Decision Include all suspect results that fall outside established specifications Drug testing Drug companies must Validate their processes and Ensure the quality of the batch for release Out-of-Specification Better word than “failure” for non-passing results

12. Essence of Barr Labs Decision (continued) Failure investigation: Elements include Reason for investigation Summation of process sequences List of other batches and results All comments and signatures

13. Key Points: Essence of Barr Labs Decision Release of batch Testing must show satisfactory conformance to specifications, including ID/Strength of each active ingredient Context and history of product and batches inform the final conclusion

14. Averaging Assay results should never be averaged because averaging hides individual variability: e.g. 89, 89, 92 (x=90) Individual content uniformity tests should not be averaged to obtain passing value Microbiology averaging is acceptable due to biological variability

15. Averaging (continued) Relying on the average of OOS results and in-spec results is usually misleading and unacceptable Should not be used to hide variation in individual test results As a general rule, avoid averaging Preferred only when it is originally designed as part of test

16. Averaging of Results: FDA Caution with product release at either end of limits

17. Avoid “Testing into Compliance” Retesting: Additional test should be for the same sample, only after a failure investigation is underway “Testing into compliance” is not acceptable Retest only by predetermined written SOP

18. Retesting In accordance with SOPs Re-test done by a second analyst Number of retests predetermined Results substitute for original Investigation ? Remove all bias ? Retest If the retest is pass, it is pass.

19. Resampling: Controversial Cannot be relied upon when testing and retesting have failed Appropriate for USP content uniformity and dissolution testing and for limited circumstances when initial sample is unrepresentative Never do resampling

20. Resampling Never do resampling Justification for resampling Not representative of batch Sample preparation error Sample consumed in analysis Only for homogeneous material

21. Reprocessing/Reworking Reprocessing Repeat of the validated process Reworking Repeat of the unvalidated process

22. Reprocessing/Reworking (continued) cGMP is vague in allowing reprocessing and reworking cGMP allows reworking if the batches conform to all established standards, specifications and characteristics at CFR211.115

23. OOS Investigations: FDA Expectations Written SOPs Responsibility Methodology – Handling of OOS Results Documentation

24. Is the First Result Real? Are the first results true and accurate? Validated methods? Changes in validated methods? Qualified and calibrated laboratory equipment? Correct instrumentation parameters? Correct sample and standard weights? Reference standards dried properly?

25. Lab Error Evaluation System suitability before and during run? Incomplete Dissolution of active? Dilution, shaking, extraction times? Proper Glassware/solution storage? Trained personnel? Documentation problems? Transcription errors?

26. Qualification Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Maintenance Procedures (MP)

27. Installation Qualification (IQ) Verify receipt of software and hardware product Identify all component of software and hardware product Connect Fluid Electrical power Communications Document

28. Operational Qualification (OQ) Verify equipment performance (each component, in case of HPLC) Pump Flow rate accuracy test Gradient proportioning valve test Auto sampler Injection accuracy test Heater/cooler test Column heater test

29. Operational Qualification (OQ, continued) Detector Wavelength accuracy test Linearity test Software Internal or external standard and unknown samples Actual vs. expected output testing

30. Performance Qualification (PQ) Documented verification of system (hardware & software) performance Verify total system control integrity Analytical system Reproducibility test Peak area Peak height Retention time Injection linearity test (5, 10, 20, 50 ?l)

31. Maintenance Procedures (MP) Periodic procedures To minimize the risk of losing raw data and analytical results Inspection/replacement of normal wear and maintenance items File back-up and recovery Data archival and retrieval Security Lan administration

32. System Suitability Test H/W, S/W and analysis checks to provide assurance of system integrity Before, during and following analysis of unknown samples System precision Separation parameters System suitability testing alone is not sufficient, qualification is still required

33. Precision (Repeatability) Retention time (RT) Area Height % RSD ? 1% for N ? 5

34. Separation Parameters Tailing factor (T) T = W/2f W = width of the peak determined at 5% from the baseline of the peak height f = Distance between peak maximum and peak front at W T ? 2

35. Separation Parameters (continued) Theoretical plate number (N) N = 16 (tR/tW)2 tR: Retention time of the analyte tW: Peak width measured at the baseline

36. Analytical Methods Validation or verification Finished dose form API Intermediates Ruggedness and robustness Transferability Person-to-person Equipment-to-equipment Site-to-site

37. Chromatography Chromatography HPLC GC TLC Inspection Column (Medium) Mobile phase (pH, buffer, etc.) Expiration date (change with time) Detector (wavelength) Flow rate Injection volume Cleaning and regeneration

38. Chromatography Inspection Identification of equipment and materials Status Reagent mfg by Mfg date & expiration date Cautionary statements on label Expiration date RH (relative humidity) Light Temperature Cleaning: Lab, table, equipment

39. Chromatography: Impurities 0.1% individual impurities Identify known impurities 1% total Impurity profile

40. HPLC Consistency Peak areas Retention times Unusual peak shapes Poor chromatography Unexplained peaks Shoulders Poor separation Qualification/System suitability

41. UV/Vis Spectrophotometers No filters (UV region 200 to 380 nm) Internal calibration only Old-outdated standard spectra Generally poor quality spectra No baseline Point readings Scanning

42. IR Spectrophotometers Reference standard missing Polystyrene film Old standard spectra library Poor quality spectra Follow SOP for “fingerprint” scan Poor peak comparison for fingerprint region Fast vs slow scan speed (follow specification) Varying scan speeds - problem

43. Balances Equipment not identified Not checked or calibrated each day of use Linearity test Zero plus 2 weight points (3 points) Weights missing No periodic checks by manufacturer Faulty room design Air flow directly onto balance Table stability

44. pH Meters Buffer No in-house manufacturing record for buffer One point calibration? Linearity Lot number missing Temperature compensating check?

45. Stability Test Temperature recording Controlled temperature vs monitored Actual product packaging Method validation – missing? Stability indicating methods Impurities Protocol discrepancies Missing time points Late time points

46. OOS Investigations: FDA Focus Pre-established protocol for investigating OOS results Summary of specific investigation steps: Evaluation of other batches Conclusion and follow-up Action necessary to prevent similar recurrences

47. OOS Investigations: FDA Focus (continued) Timely investigation must be performed within 30 business days Investigate before retest Well documented Scientifically sound

48. Investigations If the investigation has an attributable cause, then corrective action must be instituted Cause: Incomplete capsule dissolution Corrective action: “A 15 minute sonication step will be added to the assay prep procedure”

49. Expectation of FDA OOS results will be generated Comprehensive, honest approach to investigation of OOS results Evaluation using scientifically valid principles Learn from the experience Permanent solution to the problem

50. Documentation Document reasons for investigation Report the set of events that may have caused the problem Report results (actual or probable cause) Review of other batches and products Document corrective action

51. Warning Letters In FY 1997, about 30% of GMP Warning Letters sent to firms referenced deficient OOS failure investigations… Failure to conduct an investigation Inadequate follow-up

52. Inspectional Observations on FDA 483s “Laboratory Investigations for OOS Results”, SOP# xxx does not specify the number of retests which can be performed. For lot# xxxx, the product was retested 6 times by 3 different analysts

53. Inspectional Observations on FDA 483s (continued) 22 out of 37 failure investigation reports reviewed did not include corrective actions. There is no procedure in place to assure that corrective actions are actually made For report # xxxx, 14 months had elapsed before the corrective action was actually implemented

54. Inspectional Observations on FDA 483s (continued) The laboratory does not have procedures in place for tracking and trending laboratory investigations. The investigations do not include The corrective actions necessary, nor do they include a review of batches with similar OOS results, or other products affected

55. Inspectional Observations on FDA 483s (continued) The firm does not conduct failure investigations for every product failure During the failure investigation, it was determined that the analytical method used was not stability indicating, and therefore the analytical results were not valid. No follow-up, changes or corrective actions were instituted regarding the analytical method.

56. FDA Out of Specifications Guidance Draft issued in September 1998