Swiss firm skips 483 despite retrospective validation.

FDA's review of Micro-Macinazione SA, located in Lugano, Switzerland, resulted in no 483 although the contract processor informed the inspecting personnel that prospective validation was not feasible. The inspections also disclosed unanticipated new traffic for the contract micronizer handling human and veterinary drugs.

Chemist Cynthia Lee of FDA's Pacific Northwest Regional Lab and investigator Charles Edwards of the Philadelphia district combed through the company's operations in June 1999 accompanied by an inspector from the Swiss Health Ministry.

According to the EIR, Micro management was unaware their firm was mentioned in another firm's abbreviated new animal drug application (ANADA) for micronization work. The firm testified they had performed such work for other customers but never for the ANADA filer, who was described as a regular customer, according to FDA records.

Micro personnel insisted they could not prospectively validate their operations because it could not anticipate the types of products it might contract to process. Still, the EIR indicated that between January and June 1999, Micro validated the operation of their mills, noting that "the final particle size range of any of their micronized substances is that specified by the customer."

FDA records also stated the firm validated the milling equipment "within individual lots for uniformity of particle size as well as" an undisclosed number of lots per campaign for each of an unspecified number of campaigns.

According to the EIR, a 1996 audit reviewed undescribed aspects of the firm's cleaning validation and the FDAers from that inspection "made some recommendations for improve-ment" that Micro apparently took to heart. The EIR indicated the firm has since revalidated its cleaning operations annually. Micro was said to have employed "a scientifically-based matrix system," but additional details were purged.

According to the EIR, product testing was examined for two unnamed products at both in-process and finished product stages. The products in question passed for odor, color and melting point. Raw materials tests likewise passed regulatory muster.

The investigators looked at Micro's procedure for investigation into out-of-specification (OOS) outcomes. This part of the firm's operation also got a passing grade with the exception of the paradigm for retests, although the difference of opinion apparently did not warrant a 483.

According to FDA records, Micro's procedure passed a batch if the retest came back within specifications, but the inspectors insisted the retest should be accorded no more credibility than the failing outcome. The firm's management initially held ground, commenting they retested from the same sample as the original and that they felt the OOS result was due to instrument error. Micro insisted that under this regime, no finished product ever failed tests when in-process tests passed.

Still, Micro agreed to take the matter under consideration, but the issue was not discussed further in the EIR. FDA issued an Aug. 19, 1999, letter informing the firm that the agency deemed Micro-Macinazione "an acceptable micronizer" of the pharmaceutical substances covered during the inspection. Micro-Macinazione SA, Lugano, Switzerland, 6/21-22/99, Doc. 109110M, $10.00 plus retrieval.

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