United States of America, Plaintiff, v. Barr Laboratories, Inc., et al., Defendants - Page 3

Civil Action No. 92-1744  OPINION (continued)

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D. Drug Testing Overview

17. 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.  As the Forms 483 suggest, much of this current litigation stems from allegedly defective testing practices.  With the mechanics of test-taking left undefined by the regulations, before discussing the specific allegations against Barr, the Court will outline the CGMP-required parameters which will guide its evaluation.

1. Failures ²

18. In the government's view, a batch failure occurs each time an individual test result does not meet the specifications outline in the USP or the firm's ANDA.   (132:22 to 133:3 (Mulligan)).  In contrast, Barr does not classify initial out-of-specification results as batch failures.  Instead, only after confirming out-of-specification results with additional testing, (1394:1 (Bolton); 1978:18 (Cooper)), pursuant to the firm's predetermined testing procedure, (1979:7 (Cooper)), would Barr conclude that a batch failed.

19. Out-of-specification results obtained in the laboratory fall into three general categories:  (1) laboratory error; (2) nonprocess-related or operator error; and (3) process-related or manufacturing error.  (227:23 (Mulligan)).

20. Laboratory error can result from an analyst's mistake or malfunctioning laboratory equipment.  (923:18 (Gerraughty)).  Examples of analyst error include mistakes in calculations, the use of incorrect standards for comparison, and simple mismeasurement. (923:17 (Gerraughty)).  Those human and mechanical errors which occur during the manufacturing process cause nonprocess-related errors.  For example, manufacturing equipment may malfunction or an operator may fail to add the proper amount of an active ingredient.  In contrast, process-related problems, such as an incorrect mixing time, occur even though the workers and machines function properly.

21. While each type of problem is a matter of great concern which requires some form of corrective action, only nonprocess-related and process-related errors properly are labeled failures.  As Inspector Mulligan acknowledged, all failures are not alike.   (133:20 (Mulligan) (noting if "reason and logic or science" indicate that out-of-specification result is anomaly, batch need not fail)).  An out-of-specification result identified as a laboratory error by a failure investigation or an outlier test, see Ex. 7 at 1503; (202:21, 798:20 (Mulligan)), or overcome by retesting is not a failure.  (225:7-14 (Mulligan)).  Thus, the Court is unwilling to adopt the government's view of failure.

2. Failure Investigations

22. Only with an investigation will a firm be able to identify the cause of an out-of-specification result.  CGMP requires a thorough investigation following:

[a]ny unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications . . . [which] 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 followup.

21 C.F.R. §211.192; see (924:19 (Gerraughty) (violation of CGMP to discard out-of-specification results and pass batch on retesting alone)).

23. The government argues that an adequate failure investigation requires a timely, thorough, and well-documented review of the problem, which yields a written record containing: (1) the reason for the investigation; (2) a summation of process sequences that may have caused the problem; (3) the corrective actions necessary to save the batch and prevent recurrence; (4) a list of other batches and other products possibly affected along with their investigation results; and finally, (5) comments and signatures of production and quality control personnel regarding approval of any material reprocessed after additional testing.  Government Findings ¶ 59.  Barr advocates a sliding-scale approach, claiming that the nature of the failure should govern the intensity of the investigation.

24. In accordance with the CGMP-required for-cause failure investigation, (1027:13 (Mulligan)), the goal of every such inspection is to determine into which of the three failure categories the problems falls.  The degree of inquiry required successfully to complete this task may vary with the object under investigation.  As a result, a full investigation of the type the Government outlined always will not be necessary.

25. The issue of failure investigations first arises when testing produces a single out-of-specification result.  Before proceeding to retest, (924:11 (Gerraughty)), this unhappy occurrence must be met with a step-by-step review of the suspect laboratory tests. (Id.; 1975:12 (Cooper); 1517:1 (Rhodes)).  Specifically, the analyst who performed the test  must report the problem to a supervisor, and the two technicians must conduct an informal laboratory inspection, reviewing the notebook which contained the out-of-specification result, discussing the testing procedure along with any required calculations and examining the instrument used.  (295:20 (Mulligan); 1831:8 (Atwater)).  Thus, the Court requires that a single out-of-specification result be met with more than "a laboratory investigation consisting principally of retesting."  Barr Response to Government Findings ¶ 58-59.

26. Such an investigation, along with any conclusions reached, must be preserved with written documentation that enumerates each step of the review, (1519:10 (Rhodes)), in the form of a "computer generated flow sheet" (1517:19 (Rhodes)), or a check-list.   (1974:25 (Cooper)).   This writing should be preserved in an investigation or failure report, (1517:1 (Rhodes)), and placed in a central file.   (1519:19 Rhodes)).  In order to enhance this review process, each analyst conducting a test should follow a written procedure, checking off each step as it is completed.  (1974:25 (Cooper)).

27. Any easily identified analyst errors, such as calculation mistakes, should be specified with particularity and supported by evidence.  (925:20 (Gerraughty)).   In some instances, however, "the subtle influences which can result in test variability are not apparent when such an assay or test investigation is carried out."  (1954:13 (Cooper)).  Thus, because it can be difficult to pin down the exact cause of a problem (1833:13 (Atwater)), it is unrealistic to expect that the cause of analyst error always will be determined and documented. (1416:22 (Bolton)).

28. In recognizing the existence of less readily identifiable mistakes and the influence of variables unrelated to the purity or potency of the drug under scrutiny, the Court does not intend to create a means for firms to avoid the performance and documentation of an informal laboratory investigation.  The inability to identify an error's cause with confidence affects retesting procedures, see ¶¶ 38-39 infra, but does not affect the failure inquiry for initial out-of-specification results.

29. Other problems more serious than single out-of-specification results, from multiple out-of-specification results to product mixups and contamination, require full-scale inquiries involving quality control and assurance personnel in addition to laboratory workers in order to identify the exact process or nonprocess-related errors.

30. Extending beyond the laboratory and often labeled formal investigations, (1563:25 Rhodes)), these inquiries should follow the outline the Government provided, with firms paying particular attention to any necessary corrective action, whether reprimanding, retraining, or firing employees, remixing batches, or adjusting processes.  Thus, in the failure report firms must: (1) state the reason for the investigation; (2) provide a summation of the process sequences that may have caused the problem; (3) outline the corrective actions necessary to save the batch and prevent a similar recurrence; (4) list other batches and products possibly affected, the results of their investigations, and any required corrective action; and finally, (5) preserve the comments and signatures of all production and quality control personnel who conducted the investigation and approved any reprocessed material after additional testing.

31. The outcome of the failure investigation will determine whether additional batches of the same product and related products also require remedial measures. (1709:10 (Rhodes)).  Process-related errors suggest the need to examine other batches of the problem product as well as other products made according to similar procedures.   Addressing nonprocess-related errors requires an examination of other batches or products the trouble-making employee or machine may have handled.

32. Thus, the elements of a "thorough" investigation necessarily will vary with the nature of the problem identified.  However, all failure investigations must be performed promptly, within thirty business days of the problem's occurrence, and recorded in written investigation or failure reports.

3. Outliers

33. The outlier test provides an alternative means of invalidating an initial out-of-specification result.  If the failure investigation of an initial out-of-specification result proves inconclusive, firms searching for a better explanation can utilize this method.

34. Significant limits accompany the outlier test, however.  The USP specifically warns against using outlier tests too often, and thus, as a general rule,³ firms must be careful not to reject results frequently on this basis. (2036:9 Baldassarra)).

35. In addition, the utility of the outlier test varies with the type of assay performed.⁴  The USP expressly allows firms to apply this test to biological and antibiotic assays, see Ex. 7 at 1503; (202:21, 798:20 (Mulligan)), but is silent on its use with chemical tests.  (1239:8 (Mulligan)). Although some experts advocated use of the outlier method for chemical assays, (1395:1 Bolton)), other testimony suggested that firms generally do not rely on outlier tests to invalidate chemical test results.  (1238:21 (Mulligan)).  In the Court's view the silence of the USP with respect to chemical testing and outliers is prohibitory.

36. The substantial innate variability of microbiological assays, (1916:1 (Cooper)), supports this distinction.  (1238:11 (Mulligan)).  Chemical assays are considerably more precise than biological and microbiological assays, (1915:12 (Cooper)), since only the latter testing is "subject to whims of microorganisms." (1915:18 (Cooper)).

4. Retesting

37. In addition to triggering a failure investigation, out-of-specification results also generate the need for retesting.  A retest is defined as additional testing on the same sample, and thus it necessarily follows an initial test.  An analyst performing a retest takes the second aliquot from either: (1) the sample that was the source of the first aliquot (1022:5 (Bolton), 1533:21 (Rhodes)); or (2) the larger sample previously collected for laboratory purposes.⁵ (1534:8 (Rhodes)).   These procedures are equivalent.  (1839:17, 1840:16 (Atwater)).  Thus, whether retesting is performed at the finished product or blend stage, such testing should be performed from the same bottle of tablets or capsules and the same drum or mixer, respectively.  (661:2 (Mulligan); 1423:3 (Bolton)).

38. Retesting is proper only after a failure investigation is underway, (235:1, 661:2 (Mulligan)), since the outcome of the failure investigation itself, in part, determines when retesting is appropriate.⁶ Retesting is necessary if a failure investigation indicates that analyst error caused an initial out-of-specification result. (144:1, 1023:18 (Mulligan)).  A retest is similarly acceptable when review of the analyst's work is inconclusive.  (664:12 (Mulligan)).  In these instances, retesting substitutes for or supplements the original tests which have been rejected or questioned, respectively.  In the case of nonprocess and process-related errors, however, retesting is suspect.⁷ (1024:10 (Gerraughty)).  Because the initial tests are genuine, in these circumstances, additional testing alone cannot infuse the product with quality.  (1024:15 (Gerraughty)).

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Footnotes

2What's in a name?  Would a "failure" by any other name smell sweet?  The Court will use the term "out-of-specification result" when referring to an individual test value that does not meet predetermined   specifications.  Investigations that follow such results are labeled "failure investigations."  The Court has attempted to avoid the use of "failure" when discussing non-passing results.

3 The Court chooses not to rely on the phrase "rule of thumb."  Although apparently a common and useful phrase, as evidenced by the frequency with which it appears in the hearing transcript, this expression is derived from the historical common law right of the husband to beat his wife with a switch, provided it was " no thicker than his thumb."  Caitlin E. Borgman, Note, Battered Women's Substantive Due Process Claims:  Can Orders of Protection Defeat DeShaney?, 65 N.Y.U.L. Rev. 1280, 1281 n.3.

4 Outlier tests should not be used to invalidate content uniformity test results, since variability among test values may indicate nonuniformity in the blend.   See Hammerstrom Declaration, ¶¶ 10-12.

5 Although there is a possibility that any two 20-tablet grinds taken from the same laboratory sample will not be identical (1676:10 (Rhodes)), this risk is small and this procedure properly is termed a retest and not a resample. (1677:1 (Rhodes)).  Any variation in the batch should be detected through content uniformity testing. (1677:14 (Rhodes)).

6 The line between a failure investigation and retesting is difficult, if not impossible, to draw.  Although a single out-of-specification result alerts the firm to a possible problem, and the need to investigate, one test does not allow conclusive judgments about the batch. (1394:13 (Bolton)).  Thus, repeat testing on the same sample is an appropriate part of the failure investigation. (1261:18-1262:2 (Mulligan); 1419:3 (Bolton)).

7 The Court acknowledges that some retesting may precede a finding of nonprocess or process-based errors.  Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable.

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