1996 Proposed GMP Regulations
In 1996—two years before issuing the draft OOS guidance—FDA proposed new good manufacturing practices (GMP) regulations to
cover the OOS problem.8 These regulations were well written and actually served as useful guidance on many GMP subjects in addition to the OOS problem.
A proposed definition of the term out-of-specification was given that would have been consistent with 21 CFR 211.160(b). The regulations would have rewritten 21 CFR 211.192 to clarify the OOS problem, and required investigations and standard operating procedures, just as required later
by the draft guidance document. Unfortunately, these regulations were never finalized and were rescinded before the final
guidance document covering the OOS problem was issued in 2006.
THE 2006 FINAL OOS GUIDANCE DOCUMENT: CHEMICAL TESTS ONLY
In October 2006, 13 years after the Barr Decision and eight years after issuing the draft guidance document, FDA issued the
final guidance document covering the OOS problem.9 The final guidance document is similar to the draft guidance document, and retains many problems from the draft. For example,
the final document retains some of the peculiar statements related to averaging and statistical tests. The confusion between
testing for uniformity and the use of uniform test samples is also maintained.
One significant difference between the draft OOS guidance and the final version, however, is the restriction of the application
of the guidance document to chemical tests. "This guidance applies to chemistry-based laboratory testing of drugs regulated
by CDER," the document says. "It is directed toward traditional drug testing and release methods."
The problem is that the nature of "chemical tests regulated by CDER" and the excluded biological tests have not been clearly
defined. The guidance document mentions in vivo tests and immunoassays as being among the biological assays that the guidance does not cover. A separate 1998 guidance document
(on postapproval changes to analytical testing laboratory sites) notes that "Biological tests include animal, cell culture
or biochemical based testing that measures a biological, biochemical, or physiological response."10
The final guidance document also includes a peculiar reference to microbiological testing and the inherent variability of
biological tests. It refers to microbiological testing and the use of outlier testing with biological tests as given in the
USP, even after insisting that the guidance document does not cover biological tests. These statements create the impression that
the document was written by a committee whose members did not communicate with each other.
One point that the 2006 guidance did clarify is the types of materials subject to these chemical tests. It states that, "These
laboratory tests are performed on active pharmaceutical ingredients, excipients, and other components, in-process materials,
and finished drug products ..." This helps to clarify that the guidance document does not apply to the testing of material
that is not a drug substance or does not contain the drug substance.
This clarification is important because, although the original OOS problem was assumed to arise from the failure to meet final
product specifications, there was disagreement in the industry about whether the problem should be extended to any failure
to meet a specification or if certain types of specifications were not affected. The final guidance document makes it clear
that any chemical-test–related specification mentioned in submissions to the agency, established by the manufacturer, or found
in Drug Master Files and official compendia can produce OOS results that must be reviewed.
The guidance excludes specifications and criteria related to process analytical technology because they do not use single
test results to make batch release decisions. Specifications used for in-process checks and adjustments of process parameters
are also exempted from OOS considerations.
A need for corrective actions and preventive actions (CAPA) is expressed in a footnote. It notes that good manufacturing practices
for devices require CAPA and states that 21 CFR 211.192 contains an implicit requirement for CAPA in response to the OOS result. It suggests that when the draft guidance
for quality systems is finalized, the need for CAPA responses will be explicitly recognized.