The International Regulatory Position

The authors have been successful in achieving regulatory acceptance by a number of Boards of Health within the E.U. for the substitution of a rapid method based on ATP/luciferase for traditional methods. However, this acceptance does not appear to be shared by regulatory authorities worldwide. At an advisory meeting on rapid methods within the FDA in May 2002, concerns were raised about:

• The ability of rapid methods to distinguish between viable and nonviable organisms. Equally, with traditional methods the assumption is made that the media, time and temperature combination selected is suitable for the enumeration of all microorganisms regardless of genera or state of health

• Increased sensitivity such that a rapid method may provide results that are outside compendial limits and would necessitate a relaxation of the limits for certain products. This ignores the fact that rapid methods are simply detecting what has always been there, and which presumably has not given rise to any patient-safety issues. It also ignores the positive benefits that manufacturers armed with this information can more critically evaluate their process but now with the opportunity to do so close to "real time," to see if such counts can be reduced, i.e., an improvement in product quality

Certainly within the U.K., the MHRA recognizes the challenge of rapid and generally more sensitive methods and is on record as stating that "for water used in pharmaceutical production, limits may have to be adjusted to compensate for this increased sensitivity."

The major pharmacopoeias have always recognized that methods other than those specified may be used, always with the caveat that where differences become apparent or in the case of dispute the pharmacopoeial methods will prevail.

The USP states: "Compliance may be determined also by the use of alternative methods, chosen for advantages in accuracy, sensitivity, precision, selectivity or adaptability to automation ... such alternative or automated procedures or methods shall be validated."

The USP also provides some limited guidance on validating microbial recovery methods (<1227>), pointing out the inadequacies of the plate count method in accurately enumerating counts, e.g., for counts of between 1 to 10 per plate, the estimated error of the mean is between 100 to 32%. Both the USP and the PhEur have a process for amending the pharmacopoeia. The USP has tabled at least two so-called "stimuli to the revision process" for rapid methods.

In summary, there still appears to be some reticence in the regulatory authorities to embrace new microbiological methods. In the U.S., this situation will probably resolve as alternative method validation is enshrined in the USP. In the E.U., manufacturers need to use the mechanism already available to them, i.e., the Type 1 marketing authorization process supported by an expert report to gain acceptance of rapid methods.

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