QA takes rap for cooling tunnel, autoclave missteps.

Paddock Labs, New Hope, MN, Minneapolis District

Investigators Marie Fadden and Fannie Harrell scrutinized Paddock Labs' New Hope, MN, plant in January and February 2001, and kicked out a three-page 483 that rang up 25 deviations (the EIR was not released). These included validation citations, some of which the firm managed to quickly get a handle on.

The firm's president, Bruce Paddock, issued a 483 reply 16 days later on March 2, but FDA seemed to need little time evaluating the reply, rebutting with a March 6 warning letter (Doc. 10070W). Acting Minneapolis District Director Cheryl Bigham made no reference to Paddock's response to the 483, but still listed only a trio of multi-part deviations compared to the 25 appearing on the 483.

Fadden and Harrell commenced the 483 with a citation for lack of a temperature-recording device for an autoclave used to sterilize media, glassware and buffers. Paddock responded by informing FDA the firm had qualified and performed a validation of the load patterns for the autoclave, including validation of "time required to achieve required temperature." Bruce Paddock added, however, that his company had purchased and installed an unspecified temperature-recording device.

Bigham was not impressed, citing this deviation twice on the warning letter. On first mention, she wrote it up as part of a four-item citation that ran under the headline of failure to have lab controls to assure strength, quality and purity. The autoclave temperature recording device was also the lead sub-issue in an identical four-parter that hammered the quality control unit for failure to provide the "necessary oversight in the microbiology lab."

Fadden and Harrell made a similar comment on the 483, writing on the tenth deviation that the autoclave temperature recorder was one of six items that indicated lack of quality assurance oversight in the microbiology lab.

Bigham took aim at roughly the same target in the last paragraph of the warning letter,writing that Paddock had "a long history of GMP violations" and recommending that the firm's management meet with FDA on March 15 to discuss corrective actions.

Fadden and Harrell wrote that only one lot of bulk Nystop (nystatin) was placed on stability to evaluate a holding time for bulk. The FDAers followed this citation up with one for failure to put Nystop revalidation lots into stability. The 483 indicated the revalidation was prompted by a switch in the firm's supplier of talc, but no dates were given in regard to either of these events.

Warning letter cites stability problems

Paddock's letter indicated his firm had stability data for three lots with a hold time FDA purged from the letter. As to the revalidation, the company's president admitted that none of the revalidation lots found their way into a stability program, but stated that the second lot after validation was placed on stability and that Paddock had drawn from five additional lots for the stability program.

The warning letter mentioned both these hangups but did not comment on them, listing them together as a failure to test adequate numbers of batches to determine expiration dates.

The firm managed to sweep away a substantial number of miscues before the warning letter made it to print. FDA purged some data from a section citing the validation for Compro (prochloperazine) because Paddock did not take samples at start-up of the fill run at the beginning of each day's production or "after prolonged shutdowns to demonstrate" product uniformity.

The firm replied that it had followed the protocol, which called call for interval sampling based on batch size and that assays came backwithin specifications, according to FDA records. The letter added that tanks of a batch were mixed continuously overnight and the compound was circulated through a filling head for an unspecified number of minutes before each filling day.

Fadden and Harrell alleged further that the firm did not come up with information regarding "tunnel temperature and its relationship to tunnel speed" and that the validation did not include shut-down and start-up procedures for multiple-day packaging runs.

Paddock's letter stated that shut-down and start-up procedures were part of the validation and that the information had been incorporated into the master control batch record.

Regarding tunnel speed/temperature, the firm stated that validation data provided sufficient information to determine appropriate temperature and fill speed ranges in the cooling tunnel and that such information had been posted on the master control batch record along with information on the relationship between tunnel temperature and speed. Paddock wrote further that the company had generated worksheets to record such data.

Some of the firm's paperwork problems ran across product lines. FDA zapped the 1999 validation for Colocort (hydrocortisone) because of absent shut-down and startup procedures and for lack of documentation that samples were pulled from two lots.

Paddock wrote that future validations would describe shut-down and startup work. He also said the batch record for one of the two batches cited by FDA indicated the existence of "extra samples." Paddock stated that the firm would promulgate "chain of custody" forms to assure retention of samples.

Paddock also found a way to deal with the sole computer-related finding, which was that data for gas chromatographs was at risk due to the posting of a password on the "computer controller." In one of only three annotations to the 483, Paddock nailed down a corrected-not verified description of this deviation.

In an interview, Bruce Paddock said he had met with FDA and that as of June 26, "all issues have been resolved to the mutual satisfaction" of the agency and his company.

Paddock Labs, New Hope, MN, 12, 13, 14, 18-21, 1/2-5, 10, 17/01, Doc. 109103M, $7.00 plus retrieval.