1. John R. MurphyACPS 10/2003 1 Zero Tolerance Criteria Do Not Assure Product Quality John R. Murphy, Ph.D. Meeting of the Advisory Committee for Pharmaceutical Science 21 October 2003

2. John R. MurphyACPS 10/2003 2 Is a Zero Tolerance necessary or required? If not required, is ZT a good thing to have anyway? What is a Zero Tolerance criterion?

3. John R. MurphyACPS 10/2003 3 A Zero Tolerance criterion as an element of final product testing cannot eliminate nonconforming product. A Zero Tolerance criterion is not inherently better than any other acceptance criterion, and for DDU testing is probably a poor choice amongst many available alternatives.

4. John R. MurphyACPS 10/2003 4 What Is a “ZT Criterion”? A Zero Tolerance (ZT) criterion requires that none of the test results can be outside certain fixed limits.

5. John R. MurphyACPS 10/2003 5 Is a “ZT Criterion” Necessary or Required? The ZT criterion appears to have been borrowed from the current USP Uniformity of Dosage Units test. While USP methods are referee methods, batch release tests may be performed using alternate methods.

6. John R. MurphyACPS 10/2003 6 If not Required, is a ZT Criterion a Good Thing Anyway? If not Required, is a ZT Criterion a Good Thing Anyway? A Zero Tolerance criterion as an element of final product testing cannot eliminate nonconforming product. A Zero Tolerance criterion is not inherently better than any other acceptance criterion, and for DDU testing is probably a poor choice amongst many available alternatives. Not Necessarily, because:

7. John R. MurphyACPS 10/2003 7 Perfection is not achieved even with 100% screening. (Consider Airport Security Screening) It cannot be guaranteed that batches are free from nonconforming product. You cannot change the laws of probability. Zero Tolerance Criterion in the Context of Sampling and Acceptance

8. John R. MurphyACPS 10/2003 8 About a 10% chance of passing a batch containing as high as 7.5% nonconforming units. Slightly more than a 10% chance of failing a batch containing only 0.4% nonconforming units. Example: Sampling and Acceptance Plan is to inspect a random sample of 30 units and to accept the batch if zero nonconforming units are found.

9. John R. MurphyACPS 10/2003 9

10. John R. MurphyACPS 10/2003 10 You cannot eliminate nonconformances, no matter how hard you try, not even with 100% screening. When you can test only a sample (due to destructive testing), what is observed in the sample does not provide certainty regarding the untested units. Finding zero nonconforming units in the sample tested does not mean that the batch is free from nonconforming units. To summarize: Therefore: A Zero Tolerance criterion as an element of final product testing cannot eliminate nonconforming product.

11. John R. MurphyACPS 10/2003 11 A zero accept criterion is only one of several available options – often the least desirable. Zero accept criteria apply to sampling and acceptance for attributes. Zero accept criteria remove flexibility and lead to minimalist strategies. Zero Tolerance Criterion in the Context of Zero Accept criteria for Sampling and Acceptance Plans

12. John R. MurphyACPS 10/2003 12 A zero accept criterion is only one of several available options – often the least desirable. Zero accept criteria apply to sampling and acceptance for attributes. Zero accept criteria removes flexibility and leads to minimalist strategies. Zero Tolerance Criterion in the Context of Zero Accept criteria for Sampling and Acceptance Plans

13. John R. MurphyACPS 10/2003 13

14. John R. MurphyACPS 10/2003 14 A zero accept criterion is only one of several available options – often the least desirable. Zero accept criteria apply to sampling and acceptance for attributes. Zero accept criteria removes flexibility and leads to minimalist strategies. Zero Tolerance Criterion in the Context of Zero Accept criteria for Sampling and Acceptance Plans

15. John R. MurphyACPS 10/2003 15 Where to draw the line. Risks of misclassification may be high if the measurement process cannot distinguish Disregards much, if not most, of the useful information. Sampling and Acceptance for Attributes (yes-no, black- white).. Attribute can be clearly counted or classified without error. Example: Try to classify beads as black or white in a container where the beads range continuously from dark gray to light gray.

16. John R. MurphyACPS 10/2003 16 A zero accept criterion is only one of several available options – often the least desirable. Zero accept criteria apply to sampling and acceptance for attributes. Zero accept criteria removes flexibility and leads to minimalistic strategies. Zero Tolerance Criterion in the Context of Zero Accept criteria for Sampling and Acceptance Plans

17. John R. MurphyACPS 10/2003 17

18. John R. MurphyACPS 10/2003 18 Two Important Negative Consequences of Forcing a Minimalistic Strategy Stability Testing Risk of a “stability failure” increases as the number of tests are performed (even for cases where the characteristic does not actually change over time). Validation Often want more data than for routine testing. Cannot do without increasing the risk of failing the validation. Can force validation to be little more than a “roll of the dice”

19. John R. MurphyACPS 10/2003 19 A Zero Tolerance (zero accept) criterion is only one of several options one might consider when designing a plan. A yes-no criterion applied to continuous data: –Discards information, retaining only counts or classifications (much less powerful) –Causes argument and uncertainty about the boundary point –Raises the potential for significant misclassification A Zero Tolerance criterion can force a minimalistic strategy in order to cope with an untenable situation. To summarize; In the context of Attribute Sampling: Therefore: Zero Tolerance for DDU testing is a very poor choice from the available options.

20. John R. MurphyACPS 10/2003 20 If not Required, is a ZT Criterion a Good Thing to Use in DDU Testing Anyway? C annot eliminate nonconforming product. Poor choice from many alternatives Major drawbacks that render it inapplicable to DDU testing Is a ZT Criterion Required? No - appears to be borrowed from a USP test criterion for uniformity of Dosage Units.