The term Out-of-specification is used so often in pharmaceutical industry, but many of us are still unaware of its meaning. Well, when a drug undergoes stability testing or release testing and the tests results aren’t within the limits of pre-defined specifications, it is said to be Out-of-Specification result that may trigger an OOS investigation.
Laboratories sometimes follow a practice called ‘testing into compliance’ where they respond to an OOS outcome only by performing additional tests until they somehow obtain the passing results. FDA’s response to such activities is:
“This practice of retesting without proper investigation is completely unscientific and objectionable under the cGMP regulations. The OOS results may sometimes legitimately reflect the batch quality.”
But the real question is – when should an OOS result be reported? What should be the acceptance criteria for triggering the OOS investigation?
What is Reportable Value to Trigger a GMP OOS Investigation?
In pharmaceutical laboratories, the results are generally arrived at by averaging the replicates of the same preparation. For example, let’s say the results of HPLC assay are determined by averaging the four consecutive responses of the same preparation. If the acceptance criterion for HPLC assay is ≥99.00%, and the individual values obtained by a validated method are - 99.70, 99.36, 99.83, 98.89%. Should it be considered an Out-of-specification result? According to FDA guidance, since all the values are close to one another and only one value is slightly below the acceptance criterion, the results are acceptable and there is no need to warrant an investigation.
However, when the variations are much greater than the expected variation for that method, it should trigger an investigation. For example, if the acceptance criterion for a test is 95%, and the two results are 98% and 87.4%, there is no meaning in averaging the values. An instant investigation should be initiated in such cases.
How to Establish Acceptance Criteria that Doesn’t Lead to Unwarranted GMP OOS Results?
Determining the acceptance criteria poses a big challenge as it must ensure the safety of patients. The residual solvents, impurities and degraded compounds should be limited in the product to a level that doesn’t harm patients in any circumstances.
Another thing worth considering is the efficacy of products. Impurities are acceptable to a level that doesn’t affect the effectiveness of drug. You should evaluate all the statistical figures, procedures, development history and clinical trials when deciding upon the acceptance criteria.
How Else Can You Limit the GMP Out-of-Specification Results
Qualification of the laboratory equipments and quality analysts is one of the most important factors that can limit unnecessary OOS results. A trained analyst better knows the critical calibration requirements for the instruments to perform tests. Well, think who can more effectively conduct a laboratory analysis – an analyst who has received training on general HPLC or the one who has received specific training on each of the individual HPLC techniques?
A majority of FDA inspectors say that careful transfer of technology from development laboratory to quality control laboratory also plays crucial role in putting a check on Out-of-specification investigations.
FDA has been helping pharmaceutical companies to increase their efficiency by developing sound and cGMP-compliant OOS procedures.