'Team Biologics'vaccine letters up, enforcement lax.

Dear Reader,

Each time one of the industries regulated by the Center for Biologics is rolled into "Team Biologics" inspections, warning letters have increased.

Such was the case in 1997 when makers of plasma derivatives had the distinction of undergoing joint CBER/Office of Regulatory Affairs audits. In that year, 10 of 25 fractionators got warning letters and a few wound up operating under court-ordered consent decrees.

This October, it was the vaccine industry's turn at GMP-oriented team inspections, whereby field districts lead inspections that had once been the bailiwick of CBER.

In fiscal 1999 which ran from Oct. 1, 1998-Sept. 30, 1999 -- only two warning letters were issued to vaccine makers. For fiscal 2000 through March 1, three such letters were issued. However, the data through March 1 indicates few letters sent to other CBER-regulated industries; only two apiece to plasma fractionators, allergenics firms and therapeutics manufacturers, and just four to medical device firms. Vaccine makers are the latest CBER-regulated industry to come under Team Biologics audits.

According to data provided at a recent Drug Information Assn. (DIA) meeting in Washington, enforcement actions such as seizures, injunctions and license revocations are few in number so far this fiscal year compared with fiscal 1999.

Cathy Conn, director of the Division of Case Management in CBER's Office of Compliance and Biologics Quality, said inspectors are finding a major problem with vaccine makers that is similar to that which snared many plasma derivatives makers old facilities making old products..

"Companies should have paid attention to this," she told DIA. "But we have to get people into compliance and get them up to speed."

However, it appears FDA may have learned a lesson in its intervention in the plasma industry, which could be one reason the agency is using warning letters more frequently than suspension/revocation of licenses or seizures and injunctions.

"Is our enforcement environment going to create a supply problem, especially if it is a sole manufacturer that makes a product?" Conn asked. "These questions get asked."

In 1998, a shortage of intravenous immune globulin was blamed partially on FDA's crackdown on fractionators, although some reports said the industry was putting more product out for export than for the U.S. market. In any event, FDA bore the blame.

In March, FDA asked Parkedale Pharmaceuticals to stop producing its flue vaccine, Fluogen, but a month later allowed production to resume. On June 9, the firm met with FDA to discuss outstanding compliance issues. According to a June 12 news release, Parkedale, a division of King Pharmaceuticals and one-time Parke-Davis subsidiary, stated that:"The FDA has indicated that it will verify satisfactory implementation of corrective measures. Upon determination that Parkedale is in substantial compliance with the [GMPs], the FDA will issue notification to Parkedale authorizing distribution of Fluogen

"Based on Parkedale's presentation at the June 9 meeting, the FDA stated that it is pleased and encouraged by Parkedale's efforts and progress to date. The FDA officials noted that they would continue to work closely with Parkedale in an attempt to resolve any remaining issues. Further, the FDA officials emphasized the importance of the Influenza Virus Vaccine to the public health."

Inspection trends point to traditional GMP problems that are tripping vaccine makers, Conn said. These include poor record-keeping, microbiological control, insufficient QA/QC training and production and process controls.

Most of the citations referred to drug GMPs 21 CFR Parts 100 and 200 as opposed to biologics GMPs, Part 600.

Sincerely,

The Editors

Conn's presentation, including detailed examples of 483 and warning letter citations and other statistics, is available for $12 plus retrieval, Doc. 8963W