OOS Guidance

1. OOSGuidance SOCMA September 6, 2007 L. Torbeck

2. Overview • CGMP’s 21 211.192 • U.S.A. vs. Barr Laboratories, Inc. • Able Laboratories • Reportable Results • Specifications • OOS flowchart • Specific OOS topics L. Torbeck

3. Specific Topics • OOS definition • Initial and full investigations • Testing and retesting • Sampling and resampling • Averaging and Outliers L. Torbeck

4. CGMP’s 21 CFR 211.192 • “Any unexplained discrepancy of the failure of a batch or any of its contents to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed.” L. Torbeck

5. CGMP’s 21 CFR 211.192 • “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 or discrepancy. • A written record of the investigation shall be made and shall include the conclusions and follow-up.” L. Torbeck

6. Barr Court Case • Civil action by FDA, June 12, 1992. • Judge Alfred M. Wolin • Can the FDA expand the CGMP’s interpretation into the statistical areas of outliers, retesting, resampling, averaging and sample size and other areas of failure investigations, …” L. Torbeck

7. Barr Background • “The current conflict surrounding these rules is best characterized as a confrontation between a humorless warden and his uncooperative prisoner. … These witnesses revealed an industry mired in uncertainty and conflict, guided by vague regulations which produce tugs-of-war of varying intensity.” L. Torbeck

8. Able Laboratories • On May 23, 2005, Able labs issued a Class II recall of all of its 46 drug products • The company immediately suspended operations and laid off 200 employees. • The stock price in the last two weeks of May dropped by more than 90%. • The company went out of business. L. Torbeck

9. OOS Philosophy • “Testing lies at the heart of a drug manufacturer’s successful operation. Through testing companies validate their processes and ensure the quality of batches for release.” Judge Wolin • If we can’t trust our measurements, we don’t have anything. L. Torbeck

10. Draft Version • 30 September 1998 • “Guidance for Industry – Investigating Out of Specification (OOS) Test Results for Pharmaceutical Production” • Submitted comments by 30 November 1998 • These comments can be inspected by going to the FDA offices. L. Torbeck

11. Final Guidance • 12 October 2006 in the Federal Register • FDA authors include: • Richard Friedman – Director of the Division of Manufacturing & Product Quality • Paul Haynie is responsible for the Guidance • (301) 827-9020 • Hayniep@cder.fda.gov L. Torbeck

12. Controversial Topics • Definition of reportable values? • Use of averaging? • Number of retests? • Second analyst? • Use of outlier testing? • What specification limits? • Defining testing into compliance? L. Torbeck

13. OOS Definition • “… the term OOS results includes all test results that fall outside the specification or acceptance criteria established in drug applications, drug master files, official compendia, or by the manufacturer. • Two Major Issues: • What test results? • What specifications? L. Torbeck

14. Scope • “These laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials and finished drug products. • “Laboratory testing … is necessary to confirm that components, container and closures, in-process materials and finished products conform to specifications, including stability specifications. L. Torbeck

15. Scope • This guidance applies to chemistry-based laboratory testing of drugs regulated by CDER. • “The term also applies to all in-process laboratory tests ….” • “… applies to in-house testing of drug product components that are purchased …” L. Torbeck

16. Reportable Valuesfor Out-of-SpecificationTest results Lynn Torbeck Pharmaceutical Technology Vol. 23, No. 2, February 1999 Special Supplement L. Torbeck

17. FDA Definition • “It should be noted that a test might consist of replicates to arrive at a result. For instance, an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation.The assay result would be calculated using the peak response average.” L. Torbeck

18. FDA Definition • “This determination is considered one test and one result.” L. Torbeck

19. Implied Definition • A reportable value is the end result of the complete measurement method as documented. • It is the value compared to the specifications. • It is the value used for official reports. • It is the value used for statistical analysis. L. Torbeck

20. Figure 1 L. Torbeck

21. Figure 2 L. Torbeck

22. Figure 3 L. Torbeck

23. Interpretation • The individual determinations do not have to meet the specification. • Determinations are not reported out of the lab. • The variability of determinations is like a system suitability issue. • Set an upper limit on the standard deviation or %RSD. L. Torbeck

24. Interpretation • All reportable values must be documented • Do not average OOS with in spec to get an in spec results to release with. • Do not average reportable values for QA to make a decision. QA must see all R.V. • If after QA makes a decision, and a value is needed for a COA, then average them. L. Torbeck

25. Specifications • Types of Limits? • Regulatory specifications (External) • Accept/reject limits (Includes stability) • Action (Cpk=1.33 ?) • Alert or Trend (Cpk=1.0 ?) • In-process adjustment limits ? L. Torbeck

26. Phase I Investigations • An investigation is required for an OOS. • The purpose is to find the cause of the OOS. • Is it measurement or manufacturing? • “Batch rejection does not negate the need to perform the investigation.” • The first phase should include an assessment of the accuracy of results. L. Torbeck

27. Phase I Investigations • “For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s quality control unit who should then initiate the full scale investigation.? L. Torbeck

28. Responsibility of the Analysts • “The first responsibility for achieving accurate laboratory results lies with the analysts who is performing the test.” • “The analysts should be aware of potential problems that could occur …” L. Torbeck

29. Responsibility of the Analysts • “Analysts should check the data for compliance with test specifications before discarding test preparations or standard preparations.” • An assessment of the accuracy of the results should be started immediately. L. Torbeck

30. Responsibility of the Supervisor • Supervisors assessment should be: • Objective • Timely • No preconceived assumptions • Prompt assessment of data • Laboratory or manufacturing? L. Torbeck

31. Supervisors Steps • Discuss the method with analysts • Examine raw data • Verify calculations • Confirm performance of instruments. • Confirm reference standards, reagents • Evaluate performance of method • Document, document, document L. Torbeck

32. Phase II Investigations • Unconfirmed OOS requires a full scale OOS investigation with predefined procedure. • Find the root cause and do CAPA • Review production and sampling procedures • Investigations given the highest priority L. Torbeck

33. Review of Production • Quality Control Unit conducts the investigation. • Other departments participate: • Manufacturing • Process Development • Maintenance • Engineering L. Torbeck

34. Review of Production • “In cases where manufacturing occurs off-site (i.e., performed by a contract manufacturer or at multiple manufacturing sites), all sites potentially involved should be included in the investigation.” • Review all documents and records of the manufacturing process. L. Torbeck

35. Full Scale Investigation • A written record of the review includes: • A clear statement of the reason • Summary of manufacturing process aspects that could cause the problem • Results of documentation review with probable cause. • Results of previous reviews • Description of corrective actions to be taken. L. Torbeck

36. Retesting • A retest is another test of a portion of the original sample brought into the lab. • FDA prefers a second analysts do the retest. • Don’t “test into compliance.” • Specify the number of retests. • Prepare a protocol before retesting. • If the error is found the retest substitutes. L. Torbeck

37. How Big the Retest Sample? • This is still and unresolved issue and the statisticians are still publishing journal articles and discussing it. • Bar case n=7 not fully supported by statistics • Could be too much or not enough • Currently n= 3 to n=9 L. Torbeck

38. Testing Into Compliance • Testing into compliance is the practice of ignoring valid information that should be used to make decisions. • Such a practice is at best not scientific and at worst is fraudulent, illegal, and immoral. • Such practices must be found and stopped. • See Torbeck, Pharm Tech, Oct 2002 L. Torbeck

39. Testing Into Compliance • Averaging OOS with in specification results to get an in specification result. • Physically averaging powers, granulations and liquids to get in specifications results. • Not recording data until is known to be in specification. • Missing samples L. Torbeck

40. Not Testing Into Compliance • Large initial sample sizes are acceptable if all data generated is reported. • Large number of retests are acceptable if all data generated is reported. • Failing system suitability is not an OOS • Out of limits for an in-process adjustment is not an OOS L. Torbeck

41. Resampling • “Resampling involves analyzing a specimen from any additional units collected as part of the original sampling procedure or from a new sample collected from the batch. • Original should be large enough for retests • Original sample must representative • Resampling should be a rare event. L. Torbeck

42. Averaging • We can average determinations to get the reportable value. • We do not average reportable values. • QA must see all of the reportable values. • Don’t average OOS with in spec results. L. Torbeck

43. Outliers • "In a sample of n observations it is possible for a limited number to be so far separated in value from the remainder that they give rise to the question whether they are not from a different population, or that the sampling technique is at fault. Such values are called outliers. Tests are available to ascertain whether they can be accepted as homogeneous with the rest of the sample." Marriott, 1990. L. Torbeck

44. Outliers • "The USP expressly allows firms to apply this test to biological and antibiotic assays, ..., but is silent on its use with chemical tests." • "In the Court's view the silence of the USP with respect to chemical testing and outliers is prohibitory." L. Torbeck

45. Outlier Tests • Use of outlier tests is determined in advance • Specify the test and the sample size. • Can reject biological data but not chemical. • The outlier can be omitted. • Outlier tests to be used sparingly. • No application variability or homogeneity is being assessed. L. Torbeck

46. Concluding the Investigation • If a cause is found, invalidate the initial result and use the retest value(s) in its place. • If the OOS is confirmed the batch is rejected. • If the OOS is inconclusive and the retests are within specification, then QA may be able to justify releasing the batch. L. Torbeck

47. Field Alerts • “For those product that are the subject of approved full and abbreviated new drug applications, regulation require submitting within 3 working days a field alert report of information concerning any failure of a distributed batch to meet any of the specifications ….” L. Torbeck

48. Conclusion L. Torbeck