Environmental monitoring, e-mail adherence to Part 11 cited in recent Lilly audits. (Human Drugs).

Eli Lilly, Indianapolis, IN, Detroit District

A series of inspections covering the first-half of 2002 underscored drug giant Lilly's continued on-site implementation of GMP improvements at its Indianapolis parenteral and dry product plants.

Lilly's Quality VP Frank Deane, Ph.D., served as the point person for the three 483s the firm received for two January inspections and an April 8-May 30 inspection, which yielded a hefty 50-item 483. Unnamed investigators from the agency's Detroit District performed the audits, according to FDA records.

The first inspection yielding a nine-item 483 focused mainly on environmental monitoring (EM) deficiencies uncovered by investigators. Two of the observations noted the firm had "not validated the appropriateness of the Environmental Monitoring sampling procedure ... to recover and detect anaerobic microorganisms" and that an anaerobic chamber in one of the EM lab's walk-in incubator was "not set up to the manufacturer's instructions."

To this, Deane replied in a Jan. 25 letter to the agency that the EM program at the plant would be reviewed and that procedural changes and the retraining of analysts would occur "before the next anaerobic monitoring activity scheduled for first quarter 2002."

FDA also cited Lilly for not training lab personnel consistently "in that some routine operational procedures of the firm have not been implemented correctly," and that these "same analysts are used as secondary reviewers for the verification of original laboratory data."

To all the above, Deane replied that besides the firm adding a senior level microbiologist to the EM lab by Jan. 31, Lilly's Parenteral Quality Control Laboratories would create a group by April 1 to "assure the execution of sound scientific laboratory practices and decision making" and "coach and mentor the junior technical staff to ensure consistent training" of lab personnel.

The EM theme continued in the next inspection, which began less than a week later and addressed cross-contamination issues, according to the records.

"Not all of the areas that are touched by Operators A and B are sampled during the environmental monitoring program in order to assure that the work surfaces are not sources for microbial cross contamination," the 483 stated.

In a Feb. 6 reply to the agency, Deane identified eight locations that in-staff QC personnel had identified for sampling to occur "through the end of April 2002." Based on this, changes to the firm's EM program would be made by May 15, Deane stated.

Third 483 is second 50-item 483 in year

The third and most lengthy inspection covered quality and production systems relating to parenteral and dry products, and laboratory control systems of parenteral products.

"In 2002, we focused our corporate GMP improvement plan on site implementation in order to accelerate change at the production floor level, the place where the design and execution of our quality systems converge," Deane wrote.

The 483 stated that the manufacturing process for Prozac weekly capsules (fluoxetine HCl) "lacks documented evidence of validation that it would produce dosage units of a uniform and consistent quality meeting all established specifications."

Specifically, the 483 stated the milling step of fluoxetine "has not been demonstrated to produce the API particles of desired size and characteristics without solubilizing them."

Deane responded in a June 14 letter that the firm had "begun investigations of methods of quantifying" particle size and that the current validation package would be amended to "quantitate the desired reduction" in particle size.

Part 11 figures with e-mails, audit trails

Two citations in the 483 covered electronic archiving of documents.

Noting the firm used e-mail to communicate GMP-related information, FDA noted these were "not necessarily archived as or transcribed into any formalized records."

Referring to the firm's investigation into impurities in the "dirithromycin API resulting from the Dynabac stability failure and subsequent recall in 2001," the agency noted that "extensively documented" daily minutes were kept of the investigation but that "the firm stated that there is no other documentation relating to these activities spanning July 2001 through December 2001."

Deane stated the company e-mail systems were not "intended to be used as an archive or repository for GMP documentation," and that the daily minutes referred to by the investigator would be part of an official report to be completed by July 31.

The 483 continued that Lilly lacked "an adequate procedure for version control and archival of documents prepared electronically." The agency went on to state that Lilly "also lacks a clear policy about when an electronic document becomes an official record and how these records are circulated, archived, and audit-trailed."

Deane remarked that a revision of the SOP covering "Work Product Review and Documentation" ensuring Quality Control Unit approval of relevant GMP information would also be completed by July 31. Deane also referenced a June 19 meeting where the firm would work through issues with the agency.

Other citations involved such Lilly products as Dobutrex (dobutamine injection, USP), Nebcin (tebramycin sulfate injection, USP), Vancocin (vancomycin hydrochloride for injection, USP), and Gemzar (gemcitabine HCl for injection).

FDA had not released EIRs as of deadline.

"Across the inspected Indianapolis sites, the themes of the findings were similar," Lilly Senior VP Pedro Granadillo said in a July 18 company release. "That is, we need to continue to simplify our quality processes, enhance our technical expertise and oversight and improve our ability to identify the root cause of manufacturing deviations."

The exec also commented on the inspections with respect to fared the company's previously-issued 50-item 483 on Nov. 14, 2001 (See June 2002 issue, page 6).

"We accelerated making these changes in Indianapolis late last year following the previous FDA reinspection, but we have not completed implementation and thus the full impact of these changes has not yet been seen," Granadillo commented.

Eli Lilly, Indianapolis, IN, 1/7-11, 17-24, 4/8-5/15, 28, 30/02, Doc. 109321M, $57.50 plus retrieval. A CD-ROM containing 483s and EIRs for Lilly inspections from 1997 to 2002 is available for $70 plus retrieval, Doc. 109324M.