Early CMC submission speeds pre-approval audit.

Pharmacia & Upjohn, Kalamazoo, MI, Detroit District.

A pre-approval audit of Pharmacia & Upjohn for irinotecan HCl injection, an active phar-maceutical ingredient, ended after just two days, thanks in part to the prior submission of the chem-istry, manufacturing and controls (CMC) section of the application and "additional justification docu-mentation," according to the newly released EIR.

Investigator Timothy Hillary, Kalamazoo resident post, credited the early submission of the documents with giving him enough review time for the May 1996 audit, reporting in the EIR that this "shortened in-plant time considerably."

Hillary reviewed technology transfer, sta-bility, sterility, potency, impurity levels, cleaning and capping validation, lab controls and depyro-genation of vials, among other areas, but found no reportable observations, the EIR stated.

This was a step up from a pre-approval check for Colestid (colestipol hydrochloride) tablets in February 1994, in which investigators Cheryl Fuhs and D. Michael Erspamer and Chem-ist Kay Ogger found unexpected variability in some stability time-point samples.

In its written response, Pharmacia-Upjohn acknowledged the variation and promised an inves-tigation of the stability database for water-soluble resin substances at the data points in question.

Ogger also used the inspection to follow up on findings involving ibuprofen and erythromycin from an audit two years earlier. Her observations in the 483 faulted the firm for some deviations from the most current USP stability and release test methods.

The EIR indicated that FDA had three questions in this area:

* Whether an annual report stating that the firm was updating its potency assay for ibuprofen to match the latest USP method meant that it would adopt any later pharmacopeia revisions.

* Whether the USP XI assay in use was as accurate an indicator as the method in USP XII.

* Whether weight variation was a suitable sub-stitute for content uniformity testing for coated ibuprofen and delayed-release erythromycin.

The firm's response defended the reliability of its methods and noted that the USP General Notices section permitted alternative methods.

Nevertheless, in the case of the potency issue, the company promised to develop a new method incorporating an increased number of tablets.

The firm also planned to develop content uniformity testing -- but "with the intent of sup-plementing ... existing data to demonstrate that weight variation testing on the core tablet is an adequate means of assuring dose uniformity," the response stated.

Pharmacia & Upjohn, Kalamazoo, MI, 5/7-8/96, Doc. 108167M, $1.50 plus handling; 2/28-3/4/94, Doc. 107846M, $15.50 plus handling.