SUMMARY AND CONCLUSIONS
Contrary to popular belief, the problem with out-of-specification (OOS) test results did not begin with the Barr Decision
in 1993, but existed well before then. The problem was known and understood by quality control laboratory workers since the
1920s,1 but it was not until the 1990s that poor training in mathematics and a lack of statistical thinking combined to make the
problem what it is today.
The US Food and Drug Administration's 1993 draft guidance on investigating OOS test results, and the final guidance issued
in 2006, repeat many of the misconceptions stated in the Barr Decision. These misconceptions relate to the appropriate use
of averages, retesting, outlier tests, and standard deviation. The biggest problem of all, however, is the requirement than
any OOS test result be investigated before any retesting is done to determine whether or not the result arises because of
extreme statistical variation.
The final guidance document restricts its application to chemical tests only, which could lead analysts dealing with biological
tests to breathe a sigh of relief. In fact, this just creates more confusion and leaves a gap in terms of the regulatory expectations
with regard to biological tests.
Given these problems with the existing documents, I believe a revised guidance document may be issued in the future.
Lot release testing is important in the pharmaceutical industry because of the potential for OOS products to harm patients.
FDA often cites this as the basis for its concerns about OOS test results. There are many other industries, however, where
the improper handling of OOS test results could also cause great harm to customers. It is curious that QC workers in the automotive
and aerospace industries are not confronted with equally extensive government regulation of OOS test results. This is an interesting
point that the regulators may wish to ponder.
Steven S. Kuwahara, PhD, is a principal consultant at GXP BioTechnology LLC, Sunnyvale, CA, 408.530.9338. email@example.com
1. United States vs. Barr Laboratories, Inc. Civil Action No. 92-1744, US District Court for the District of New Jersey:
812 F. Supp. 458. 1993 US Dist. Lexis 1932; 4 February 1993, as amended 30 March 1993.
2. Shewhart WA, Economic control of quality of manufactured product. New York: Van Nostrand Company; 1931. 50th Anniversary
Commemorative Reissue, Milwaukee, WI: ASQ Quality Press; 1980.
3. ISPE and GMP Institute. FDA's summary of Judge Wolin's interpretation of GMP issues contained in the court's ruling in
USA vs. Barr Laboratories. 2002 April 16. Available at URL:
4. Kuwahara SS. The Barr Decision, part 1, coping with failing test results. BioPharm 1996 Sept;9(9):24-29.
5. Kuwahara SS. The Barr Decision, part 2, Its impact on outlier tests, averages, and validation studies. BioPharm 1996 Sept;9(9):40–45.
6. CDER, FDA, DHHS. Draft guidance for industry: investigating out of specification (OOS) test results for pharmaceutical
production. Bethesda Md.;1998 September.
7. Kuwahara SS. Outlier testing: its history and application. BioPharm 1997 Feb;10(2):64–67.
8. FDA, DHHS. 21 CFR Parts 210 and 211. Current good manufacturing practice: amendment of certain requirements for finished pharmaceuticals. Proposed
Rule. FR 61, (87):20103–20115; Bethesda Md.; 1966.
9. CDER, FDA, DHHS. Guidance for industry investigating out of specification (OOS) test results for pharmaceutical production.
Bethesda Md.; 2006 Oct.
10. CDER, FDA, DHHS. Guidance for industry: PAC-ATLS: post approval changes -analytical testing laboratory sites. Bethesda
Md.; 1998 April.