GMP validation slips become theme in recent Lilly audits. (Human drugs).

FDA found validation shortcomings in environmental monitoring (EM) procedures and manufacturing processes for drug giant Lilly's weekly Prozac in a series of inspections covering the first-half of 2002. The inspections underscored continued on-site implementation of GMP improvements at the firm's 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. FDA had not released the EIRs as of deadline.

The first inspection yielding a nine-item 483 focused mainly on 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.

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.

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).

"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 re-inspection, 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. 109325M.

The Checklist--Eli Lilly.

[check] environmental monitoring procedures in validation

[check] process validation

[check] operational procedures not implemented correctly

[check] particle size uniformity