Process control is required in sections 211.100 and 211.110(a). The latter requires us to"monitor the output and to validate
the performance of those manufacturing processes that may be responsible for causing variability...." Moreover, section 211.165(d)
says, "to assure that batches ... meet ... appropriate statistical quality control criteria ...." Thus, we should look for
data and techniques used to control the process. These could include statistical control charts and process capability studies.
Ideally, critical sources of variation would be identified and controlled.
Setting specifications is addressed in section 211.110(b), where it states:
Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall
be derived from previous acceptable process average and process variability estimates where possible and determined by the
application of suitable statistical procedures where appropriate.
Clearly, we should look for evidence that the specifications were set using real data, averages, and standard deviations and
not just wishful thinking.
Labeling discrepancies, 211.125(c) says, are to be compared with "narrow preset limits based on historical operating data."
This would imply trending and summary statistics to set those limits.
A statistical basis for stability is required in section 211.166(a)(1), where "sample size and test intervals based on statistical
criteria..." are to be in the written program. Furthermore, sections 211.137(a) and 211.137(b) expect expiry dates to be determined
by "... appropriate stability testing..." and "... related to any storage conditions...." ICH Q1 addresses stability in considerable
Method validation, of course, is required in section 211.165(e) where "The accuracy, sensitivity, specificity, and reproducibility
of test methods ... shall be established and documented." Section 211.166(a)(3) requires "reliable, meaningful, and specific
test methods." Note that there have never been operational definitions in the literature for reliable and meaningful in this context. Section 211.194(a)(2) also requires "... that the methods used in the testing of the sample meet proper
standards of accuracy and reliability..." and that "the suitability of all testing methods uses shall be verified under actual
condition of use." The standards for method validation are given in USP <1225> and the ICH Q2 documents (8, 9).
Out-of-specifications investigations are required in section 211.192:
Any 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
shall be thoroughly investigated, whether or not the batch has already been distributed. 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
Based on this, FDA issued in final form its Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for
Pharmaceutical Production (10). Many of the issues in OOS are statistical, including defining the reportable results, retesting,
resampling, sample size, averaging, outliers, testing into compliance, and specification limits.
Finally, it should be emphasized that these statistical topics are of a specialized nature and require that personnel be qualified
to perform these tasks. As stated in section 211.25:
Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have the education, training,
and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in
particular operations that the employee performs ....
Another paragraph requires the same for supervisors. Clearly, personnel must be trained in the statistical topics and techniques
and must have practical experience in their application.