Dow avoids 483 for bulk, but gets some notations.

In two inspections, Dow Chemical of Midland, MI, demonstrated that it is much easier to stay out of hot water with FDA when you only have to keep a tight rein on relatively new facilities.

The contract maker of bulk pharmaceuticals managed to dodge a 483 in each of the two inspections reviewed here, both of which were conducted by members of the Detroit District Office. Dow probably also benefitted from the fact that the firm did no fermenting or sterile processing, according to the EIRs.

In an April-May 1996 inspection, investigators James Mundo and William Tingley and chemist Russel Ayers, all of the Detroit District Office, noted in the EIR that "we found the firm operating in substantial compliance" regarding the company's production of fexofenadine HCL, the only of the three pre-approval items that the company had made a commercial batch of at the time of the inspection.

The FDAers wrote that validation work was then in process for dolasetron mesylate and raniti-dine HCL, both of which were slated for production in 1997. They recommended approval for both of these, although they cited compliance with GMPs in manufacturing, control and laboratory operations. Hence they were able to recommend approval, and suggested that they both "be covered during the next inspection."

According to the EIR, the firm may have done itself a big favor by inviting members of the agency's Detroit office for a "pre-operational design review meeting between Dow" and agency personnel in 1993 and a tour by the local FDA staff in 1994. The latter get-together included a tour of a new pilot plant "where development and clinical BPC (bulk pharmaceutical chemicals) materials are made."

The EIR noted that Dow typically performed "block processing in their multi-production facilities" and that the design of the buildings provided "adequate provision for product protection, either by enclosed equipment, special transfer equipment where product would be exposed, adequate air systems separation or other means." The facilities also permitted considerable segregation of function, depicted in the EIR as rooms for solid preparation, centrifuge, wet cake packaging and drying/final packaging.

Dow's water acquisition was no major trauma either. According to the EIR, the company performed "no further plant treatment" of potable chlorinated water supplied by the city of Midland. The only outside water use described in the EIR was purchased from an outside source for production of dolasetron mesylate.

Dow's cleaning procedures at the time consisted of a "system of verification of cleaning adequacy rather than a strict validation." According to the EIR, Dow personnel conducted the verification between campaigns using "formally-approved cleaning protocols, which described limits, justification, testing and other information." The FDAers commented that the procedure "appears to meet the intent of validation: assuring no carryover of one BPC to the next."

The only hangnail identified in the EIR was that the trio was less than enthused by the firm's storage for dip tubes and transfer hoses in an interchange cabinet in one of the production buildings. The FDAers wrote that they inquired as to the adequacy of circulation in a drying/finishing room in one building, a query prompted by what they felt was a high temperature. However, they noted that the room was not in use at the time of the inspection.

Computer system installed by '98

Investigator Mundo handled the 1998 inspection solo and wrote in the EIR that Dow still was not engaging in any activity calling for sterile production or fermentation.

According to the EIR from this inspection, Dow manufactured sevelamer hydrochloride in a complex in which they set up the equipment to "use gravity as a natural flow in the process" in such a way as to "exclude contaminants." Sevelamer was the only product made in that area.

Mundo noted that production of "dolasetron has been closed and moved to France," but did not explain the firm's motive for doing so.

The establishment report stated that Dow "conducts verification testing for residues after cleaning when switching from one BPC to another" as was the case during the 1996 inspection. Mundo commented that "changes in products (manufactured) usually mean a manual dissemble breakdown of all equipment."

The company had also implemented "a computerized preventative maintenance tracking system" for the entire facility" which "pre-notifies, then alerts all overdue maintenance, calibration or expiration." Mundo wrote that he had checked "several critical pieces of equipment" for which he found an adequate history.

Mundo wrote that "all processes are controlled and monitored with a Dow Chemical Co. [purged] automated computer system," which was installed and qualified by a corporate process control group. The EIR noted that Dow had completed an unspecified number of validation batches of ranitidine HCL, but that the procedure had "moved along slowly" due to litigation. The validation of Dow's manufacture of sevelamer HCL was slated for completion in July 1998.

Mundo wrote that he conducted "no formal discussion" with Dow management at the conclusion of the inspection and that he would recommend approval of the sections of the NDAs that were completed. Dow did not return repeated calls for an update.

Dow Chemical, Midland, MI, 5/18-21/98, 4/30-5/3/96, Doc 108853M, $10.50 plus retrieval.

RELATED ARTICLE: The Checklist - Dow Chemical, Detroit

* Computer, process validation

* Lab controls