Hi-Tech, FDA still hashing out January '99 inspection.

Hi-Tech Pharmacal, Amityville, NY, New York District

FDA visited the Amityville, NY, plant of Hi-Tech Pharmacal twice during 1999 and, despite extensive documentary response to the 483s, issued a warning letter (Doc. 7879W) dated July 23, 1999. The first of the two inspections, commencing in January, was a pre-approval audit for four products that were documented in 29 observations on the 483 (the EIR for that inspection was not released). Investigator James Liubicich and scientist Gary Greco of the New York district conducted this inspection.

The second inspection, which took four days between May and June, resulted in a one-page 483 with only two observations. The EIR from that inspection, penned by investigator Tej Poonai of the New York district, stated that Hi-Tech had not caught up on all the GMP deviations documented in the first inspection.

Test dating, chromatogram rework records eyed

The opening observation from the first inspection was that the firm's equipment allowed for "changing of internal conditions and reprinting of chromatograms" and that such reprocessing of chromatograms could only be detected by evaluation at the time of sequence of multiple injections.

In a letter to FDA dated March 31, 1999, the firm's President, David Seltzer, stated that he agreed "with the inspector's observations regarding reprocessing of chromatograms." He insisted, however, that the data system in question did not overwrite results but saved the reprocessing as new files.

According to the documents, Seltzer promised that the firm would change procedures to indicate whether a chromatogram was an original or a reprocessed specimen and that justification for reprocessing would have to be approved by a supervisor.

The warning letter acknowledged Seltzer's response, but averred that "data obtained from assays conducted in May 1997 were replaced by data from assays conducted months later and not all of your records adequately recorded the correct assay dates."

The EIR noted problems with the firm's files for stability testing. The 483 stated that paperwork for one of the pending applications indicated that the stability tests were conducted on Aug. 22, 1996, but that the firm's internal records indicated that only the benzalkonium chloride assay was conducted on that date. Other assays were described as having been conducted between July 9 and Aug. 2 of that year.

In two other pending applications, the names of which were likewise redacted from the 483, similar observations were made for microbiological tests conducted in 1997. These observations regarding stability tests dates were addressed in the same section as the chromatogram reprocessing observation in the warning letter.

In his letter to the agency, Seltzer stated that his firm had been using the last test date when recording the results of stability tests. He stated that files for any new products would be appropriately dated and that the company would "revisit this issue on currently approved products as their respective stations come up for testing."

FDA apparently was not persuaded, stating in the warning letter that "your commitments are unclear" and that the dating discrepancies were of particular concern "because they could represent a pattern."

The agency also expressed concern with regard to whether paperwork filed for the drugs would be amended to reflect the correct test dates.

Seltzer's Aug. 9, 1999, response to the warning letter stated that the firm had "reorganized its documentation control system to assure the accuracy of current documentation" and that a quality assurance representative had been assigned to verify the accuracy of information.

Seltzer also promised that the firm was developing a program to update paperwork it had filed with FDA as part of the drug applications.

Validation, complaints focus of 2nd audit

The first observation on the 483 from the May-June inspection stated that the manufacturing methods used in production of calcionate syrup had not been validated. This observation was triggered by a recall of the product which was attributable to calcium precipitates.

According to the EIR, the complaint centered on a cloudy appearance and the calcium precipitate.

The firm's investigation pointed the finger at a high percentage of sorbitol as the culprit. The EIR went into no further detail except to state that a "second batch was made with [redacted] of sorbitol solution" and that "the batch was also [redacted]."

In a June 24 letter to the agency, Seltzer stated that the firm had developed a validation protocol in March 1999 and had a summary report by the end of May. He wrote that prior to the full validation, the product had been reformulated and that validation had been performed on three lots. Seltzer stated that this validation report had been presented to Poonai during the summer inspection.

The warning letter acknowledged the completed validation effort but reminded Seltzer that such efforts were required to be completed prior to marketing.

The second observation from the May-June inspection cited Hi-Tech for an inadequate complaint-handling procedures. The basis of this observation was that there were "no reported results" for retained samples as a follow-up to the action plan.

In the EIR, Poonai wrote that the procedural inadequacy was based on the fact that there was no indication as to "how samples are taken, the amount of samples taken, the type of analysis conducted and the results of the analysis."

In the June 24 letter, Seltzer referred to the retains sample evaluation form that provided for the information referred to by Poonai. This observation was not referred to in the warning letter.

In a telephone interview, Elan Bar-Giora, Hi-Tech's executive vice-president of operations, stated that FDA had revisited the plant between November 1999 and February. Although another 483 was issued, Bar-Giora noted that he felt that "the reinspection went very well" and that Hi-Tech was waiting to hear back from the New York district.

Hi-Tech Pharmacal, Amityville, NY, 1/5-3/19/99 and 5/25, 27, 28 and 6/9 & 15/99, Doc. 108826M, $25.00 plus retrieval.