Chemistry Reference
In-Depth Information
additional testing that might be necessary, when to go beyond laboratory investiga-
tions, and the final evaluation of test results.
6.11 preventIng oos results
OOS results can come from laboratory, operator, or process/manufacturing errors.
But the best way to minimize the occurrence of OOS results is to prevent them from
happening in the first place, and the best way to do that is to have proper laboratory
controls in place. The integrity of laboratory testing and record keeping is of fun-
damental importance to the FDA in pharmaceutical production and control. Proper
laboratory controls must include
• Standard operating procedures (SOPs)
• Validated analytical methods
• Properly trained and supervised personnel
• Properly qualiied and calibrated instrumentation
SOPs are written for many laboratory activities, including sampling methods, sample
handling, test methods, and calibration and maintenance of instrumentation. They
are written to ensure uniformity, and are necessary for assuring compliance with
regulatory requirements. The SOP covering OOS results must define the responsibil-
ity for the investigation and provide clear direction to laboratory personnel.
By validating an analytical method, documented evidence is obtained that the
method accomplishes or is suitable for its intended purpose. Compendial USP meth-
ods need not be validated, but can simply be verified for suitability under actual
conditions of use. Noncompendial methods must be validated with respect to several
parameters, including accuracy, precision, linearity, limit of quantitation or detec-
tion, robustness, specificity, and range. Both the USP and ICH provide guidelines for
validating noncompendial methods [3,4].
Properly trained and supervised laboratory personnel are needed to effectively
carry out laboratory operations according to established procedures. Having an ade-
quately trained laboratory staff can cut down on the frequency of retests, investiga-
tions, and staff turnover, which are red flags for the FDA.
Similar to a method, an instrument must be suitable for its intended use. Instrument
validation, referred to as qualification, is accomplished by performing installation,
operational, and performance qualifications, along with documented routine cali-
brations. By documenting qualification, calibration, and maintenance procedures,
demonstrating that the instrument can meet a set of predetermined specifications,
one variable (the instrument) can be ruled out in any subsequent investigation. In
addition, all analytical methods have system suitability requirements, and systems
not meeting these requirements should not be used.
6.12 IdentIFyIng And AssessIng oos test results
So, what constitutes an OOS result? For the purposes of this discussion, we can
use the FDA guidance definition: “OOS results include all suspect results that fall
