Biogen slapped with 12-item 483 for inadequate complaint procedures, Part 11 issues.

Biogen Idec, Inc., Research Triangle Park, NC, Center for Biologics

For complaint procedures not assuring full investigation and an inadequate deviation reporting system that, among other flaws, was not compliant with 21 CFR Part 11, Biogen Idec, Inc., received a 12-item 483.

The Team Biologics inspection of the Research Triangle Park, NC, firm was conducted by Investigators Sidney Priesmeyer and Robert Jennings from CBER.

The EIR noted that Biogen is a biotechnology company that develops drugs through genetic engineering. The firm manufactures Avonex (interferon beta1a), which is used in the treatment of multiple sclerosis. According to the firm's website, the company was renamed Biogen Idec, Inc., in November 2003, after Biogen merged with IDEC Pharmaceuticals Corporation.

According to the report, the investigators reviewed 15 of approximately 2,400 complaints in Biogen's database from June 2000 to January 2002. "Complaint SOP 198.2 fails to provide instructions for both classifying a complaint as valid after investigation/testing and follow-up action to assure correction," the 483 stated.

In addition, during review of the firm's master validation plan, "it was determined the plans are actually procedures," the EIR noted. The FDAers informed management that they did not have a master validation plan that showed what had been accomplished and when.

"Brief lists of executed RTP studies for process validation and software validation were provided ... management asserted that all equipment, processes, software and methods had been validated and as such, there was no need for remedial plans," the EIR continued. "The firm designed and implemented a very prescriptive set of procedures for validation of individual pieces of equipment and processes. These procedures act essentially as permanent validation protocols."

The EIR also noted that at the time of the inspection, Biogen was in the process of implementing Part 11 controls, and that the firm's deviation system was not Part 11-compliant. "An extensive portion of a future inspection could cover the firm's software-driven automated processes and ancillary systems, as well as Part 11 controls," the report stated.

Biogen QA process manager Donovan Rocha responded during the inspection that the firm was in the process of revising the SOPs for handling deviations, and that the FDAers' observations related to incidents more than two years old. "I reminded Rocha that [the revised SOPs] are currently in draft form, adding it is in the best interest of his firm to finalize the document ...," the EIR stated.

Next, "written complaint files do not contain complaint-type investigation results." Per SOP, certain assigned complaint-type files, such as, atypical appearance, did not require additional investigation or review, as well as approval by a second individual, the report noted.

The EIR reported that deviation report deficiencies included DEV-R-2000-091, which related to excessive filter pressure that was experienced during an undisclosed procedure. "This report fails to identify the possible root causes for excessive filter pressure; reference that a previous formal investigation and a critical work order had earlier addressed this problem; and provide supporting documentation that the process deviation did not adversely impact the product, process or materials," Priesmeyer and Jennings wrote in the report.

Next, the 483 stated that Biogen did not properly conduct CIP cleaning of bioreactors. "Cleaning validation study 21-BR-2301 evaluated the removal of detergents and product residues based on pH and TOC levels in final rinse samples. Prior to this inspection, no correlation was made between the study's acceptance criteria and the potential carryover of total detergent and protein residues with respect to maximum daily therapeutic dose limits."

Also, the report noted that the firm's routine and end-of-campaign cleaning evaluate bioburden and endotoxin levels for final rinse samples. But, the EIR stated, "prior to this inspection, no acceptance criteria have been established, as bioburden and endotoxin results are [designated] 'FYI'."

Further, the investigators discovered that Biogen had no documentation showing that the QA unit reviews environmental monitoring data, which "is collected during cell culture activities and filling of the final bulk product, prior to batch release," the 483 stated.

The EIR noted Rocha's response: "This observation was an oversight that will be corrected."

Monitoring of steam-in-place (SIP) cycles for bioreactors was also deficient, the report noted. "No documentation is generated (e.g., computer printouts, temperature recording charts) to record time/temperature profiles, as well as alarms during SIP of bioreactors and transfer lines," according to the EIR.

Next, the company stored microfilters and ultrafilters for up to an undisclosed number of days. However, the 483 noted, Biogen conducted no studies to determine the microbial effectiveness or the concentration of these solutions after an undisclosed number of days of storage.

Finally, Biogen determined protein yields during final purification and after ultrafiltration. "However, yield specifications have not been established to ensure process limits are met or to alert production managers when yields may be extended," the 483 noted.

The FDAers also reviewed the firm's environmental-monitoring data, and noted in the EIR that "controls appeared to be effective and there was little reported evidence of product impact from environmental contaminants." They also noted that "water monitoring data showed controls that appeared to be effective and monitoring appropriate."

Biogen did not respond to requests for comment before deadline.

Biogen Idec Inc., Research Triangle Park, NC, 1/23-31/02, Doc. 109718M, $15 plus retrieval.