Analysis of 483s/EIRs for GMP validation issues.

Human Drugs

Focus on water, calibration in ChemCentral inspection

Investigator Vicky Stoakes of the Atlanta District Office needed little ink and paper to document her inspection of ChemCentral/Atlanta. The June 1999 inspection produced a three-page EIR and a one-page 483.

The 483 stated that the company was using normal butyl acetate instead of distilled water to determine specific gravity. One of the firm's chemists, Karen Edge, stated that the butyl acetate "was obtained from a bold material received by the firm" and that if the specific gravity of the material was within the range specified by the certificate of analysis, the instrument was deemed calibrated.

The Checklist

ChemCentral, Atlanta

Calibration

Stoakes wrote that she found the change in procedure unacceptable because it deviated from documented procedures and the manufacturer's constructs, but also expressed concern that the change in procedure made use of the known value (the specific gravity of the butyl acetate) "to determine the unknown specific gravity of the sample." The firm's general manager, John McQuillan, stated that procedure had been changed because the firm had no access to distilled water at the site. The firm promised to correct the situation by July 1, 1999.

The 483 stated that ChemCentral had not conducted gas chromatography testing of propylene glycol USP, which was required by its own SOPs. The EIR noted that "the record used for recording test results (has) no space for the GC tests." McQuillan was quoted as saying that he was unaware of the problem, but then promised immediate resolution. The EIR had been annotated to indicate the situation had been corrected and verified. Attempts to contact the company for comment were unsuccessful.

Chemcentral/Atlanta, Doraville, GA, 6/21 & 25/99, Doc. 108827M, $2.00 plus retrieval.

Cleaning, process validation cited at Hi-Tech Pharmacal

FDA conducted two inspections of Hi-Tech Pharmacal of Amityville, NY, last year and compressed both 483s into a single warning letter dated July 23, 1999 (Doc. 7879W) issued from the New York District Office. The agency zapped the firm for poor record-keeping and cleaning and process validation problems.

FDA scientist Gary Greco and investigator James Liubicich handled the January-March inspection and wrote in the 483 that the validation of the cleaning procedure "was performed on only four products," including one lot of each of the four, in 1993 and 1994 (the EIR from this inspection was not made available by FDA).

Cleaning validation difficult, firm says

The March 31 letter from the firm's president, David Seltzer, stated that "we agree with the investigator's observation" in stating that selection of the four drugs was "based on a matrixing approach." Seltzer explaint this as involving a suspension product, a viscous syrup, a concentrated solution and a concentrated syrup.

Seltzer offered that "these products represented the most difficult to clean" in stating the firm was "aggressively working on a contemporary cleaning validation based on the newly-written protocol," which he stated had been presented to Greco and Liubicich during the audit.

The 483 from this first inspection stated that the firm had not tested to determine what sort of residues would be left by detergents during the validation.

In the March 31 letter, Seltzer stated that Hi-Tech had developed a validation protocol for this purpose using ultraviolet analysis and that this validation was "being performed concurrently" with the contemporary cleaning validation study.

This observation was addressed in the warning letter along with an observation about cleaning validation for only four products. The warning letter, however, goes into little detail.

In his Aug. 9 letter, Seltzer responded to the warning letter observation by stating that "the remedial action plan will include a formal program for the evaluation of cleaning validation" and that cleaning validation for three products had been completed while that for three others were in progress.

The first item appearing on the 483 from the June-July inspection, conducted by investigator Tej Poonai, was that the manufacturing method used to produce calcionate syrup had not been validated and that, during the production of one lot, "excess amount of sorbitol 70 percent solution was used in the formulation resulting in the precipitation of the active ingredient."

Hi-Tech's executive vice president for operations, Elan Bar-Giora, wrote the June 24 letter in response to the finding. Giora wrote that the firm had completed the process validation protocol on March 3 and issued the validation summary report on May 25. He also stated that prior to validation, "the product was reformulated to prevent precipitation" and that the validation report had been presented to Poonai during the summer inspection.

Nonetheless, the observation made its way into the fourth citation on the warning letter, which acknowledged the firm's validation effort. FDA rebutted that "the procedures and formulations, and their validations, are required to be established and completed prior to marketing."

The Checklist

Hi-Tech Pharmacal, New York District

Cleaning validation

Process Validation

In his Aug. 9 letter, Seltzer stated that the company had implemented "a program to evaluate and upgrade as necessary the validation status of its products." He wrote further that the remedial action plan called for evaluation of product validations "to determine if any products aside from calcionate syrup were marketed prior to the completion of validation."

In his Oct. 14 letter, Seltzer informed the agency that the firm had retained the services of an entity as a regulatory consultant, whose identity was not disclosed. FDA's letter dated Sept. 10 stated that the agency had received the Aug. 24 letter and that "it appears that your response is adequate; however, we will assess the impact of your corrective actions in a future inspection."

Hi-Tech Pharmacal's executive vice president of operations, Elan Bar- Giora, stated that FDA had reinspected the facility between November 1999 and this past February. He commented that, in spite of receiving a 483 for this inspection, he felt that "the reinspection went very well." Bar-Giora also stated that the company was waiting to hear from the New York District Office.

Hi-Tech Pharmacal, Amityville, NY, 1/5-3/19/99, Doc. 108826M, $25.00 plus retrieval.