Cody Labs, Cody, WY, April 7 (Denver).

An FDA investigation March 7-17, 2005, found deviations from the current Good Manufacturing Practice (GMP) requirements that caused Cody's active pharmaceutical ingredient (API) product hydromorphone HCI and finished drug product morphine sulfate concentrate oral solution to be adulterated by the methods, and the facilities or controls, used for the manufacturing, processing, packing, storage and holding of the products.

Since the close of the inspection, FDA acknowledged that it had received several rebuttal letters from the company--dated May 26, 2005, and Jan. 6 and 17, 2006--but found the responses did not adequately address the deficiencies indicated by FDA's inspection observations.

According to the warning letter, current GMP deviations included failure to ensure that automatic, mechanical or electrical equipment, or other types of equipment, performed satisfactorily.

For example, the reverse osmosis (RO) water system used in the manufacture of finished dosage forms did not have complete installation qualification; and, the operational qualification did not include backflow prevention, nor flush times or maximum hold time in the storage tank. Furthermore, the RO water system validation protocol did not list specific acceptance standards for volatile organic compounds, including nitrogen, sulfates and metals in Phase I testing, and for heterotrophic plate count in Phase I, II or III testing.

Additionally, FDA noted a failure to follow procedures. For example, Cody did not follow its own standard operating procedure (SOP) for the RO water system in that purge ports, backflush, ultraviolet lamp check and pressure readings had not been maintained since April 2004.

The firm also was hit with failure to assure that the air filtration system, including prefilters, were working correctly when used on air supplies to the production areas for both finished dosage forms and APIs. For example, API products sold as dry powders were manufactured in a suite with solution drug product. "There have been no studies showing whether contamination of the solution drug product by the dry powders cannot occur when doors to the manufacturing suites are opened at the same time," the agency noted.

Moreover, the air handling system, including the air filters and filter combinations, were not qualified to demonstrate that the drug product did not become contaminated with the dry powders. There also were no diagrams showing the flow of air through the rooftop vents, fans and air return units, FDA added.

Other violations included a lack of written procedures for cleaning and maintaining equipment used in the manufacture, processing, packing or holding of a drug product. For example, Cody's Used Equipment Cleaning Form did not address what agents were used to clean the equipment. Also, there was no indication if the final rinse verification by QC was still visual, or if there was a rinse analysis to ensure that the equipment was clean.

Cody also failed to investigate a batch that did not meet specifications. FDA said the company failed to meet the acceptable ranges listed on the batch production record, and an investigation into this discrepancy was not conducted.

Finally, Cody failed to date and sign the Master Production and Control record and failed to include statements of theoretical yield and a specimen or a copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling, as required. E-M, Lab, OOS, QC/QS, Ster, Val; Doc. 13764W