Advantage Dose slammed with 38-item report for lack of procedures, unclean conditions.

FDA investigators Marvin Jones and Frances Guidry handed drug manufacturer and repacker Advantage Dose LLC a 483 with a whopping 38 observations following a GMP inspection.

The FDAers found that the company had not established control procedures to validate the performance of manufacturing processes that could cause variability in in-process materials and drug products.

In addition, Advantage Dose "has not validated the computer software system that is used to process drug products, to maintain processing records and to maintain equipment cleaning/use/maintenance records," Jones and Guidry wrote in the 483 following the audit, which occurred Oct. 28-Nov. 12, 2008. "The firm has not performed any installation, operational or performance qualification for the equipment used to process drug products."

The company also had failed to validate the methods used to clean its processing equipment and materials and methods for packaging and shipping repackaged sterile products in glass vials and ampules, the investigators added.

Advantage Dose had not performed stability testing to support the expiration date on any of its finished repackaged liquid, powder and tablet drug products, the 483 noted.

Electronic scales and liquid pumps used during the processing of finished drug products were not calibrated. The inspectors reported that the company's management said "the electronic scales are relocated on a frequent basis with no recalibration associated with these moves."

The inspection further revealed that the company's air handling system for its processing areas did not provide adequate air filtration to avoid contamination of its drug products. Liquids, powders and tablets were being processed in the same areas without the appropriate type of filtration to prevent cross-contamination, the investigators observed.

Advantage Dose also provided insufficient "physical or spatial separation from operations and other drug products to prevent mix-ups and cross-contamination," the FDAers found. They noted that "employees routinely use compressed air from air nozzles located at each work station to blow processing materials off of processing equipment and work benches. This practice is performed while other liquid/powder/tablet processing is occurring in the same processing area." The company also used a hand-held vacuum to clean up drug powders from work benches while other products were being processed in the vicinity, the team added.

Cleaning methods used to clean plastic pump tubings, glassware and utensils used during drug product processing had not been validated. The inspectors observed that plastic pump tubing used to transfer liquid drug products into unit dose containers was cleaned and reused to transfer other liquid drug products. "This 'cleaned' plastic pump tubing was noted to show signs of previous product contamination before being used on another liquid drug product," the investigators reported.

In addition, the cleaned items were stored above and beside the sink used for cleaning without being protected against possible contamination.

Although a number of the drug products Advantage Dose processed were required to be packaged and stored in light resistant packaging, the FDAers found that the company had no information "that supports the packaging material used in their process is light resistant." The firm also had no data to support that the packaging material was moisture resistant, although several of its products were susceptible to moisture, the team added. In addition, they wrote: "The firm only performs a visual inspection for seal integrity testing for container/closure systems."

The inspection further found that the company had not established time limits for processing refrigerated drug products in room temperature conditions. "For example," the FDAers wrote, "during this inspection we observed a liquid drug product requiring refrigeration being processed in room temperature conditions. This product remained at room temperatures for approximately two hours. No testing was performed to determine if this activity affected the strength or quality of this drug product."

Advantage Dose had no written stability records and had not tested any lots of drug product for stability, the team added.

The actual yield and percentages of theoretical yield of liquid drug products were not determined at the end of each appropriate phase of processing, the investigators found. "Also, the firm has no written specifications/ranges for the quantity of liquid drug product contained in each unit dose container," they noted.

The investigators reported that "finished drug product testing is not performed on liquid drug products processed at this facility," and that the firm had also failed to perform any microbial testing on oral liquid drug products. Further, the company retained only one unit of processed drug product, such as one tablet or one dose of a liquid or powder.

Advantage Dose maintained no approved master labeling for its finished drug products, the inspection team stated. "Computer generated labels used by the firm are not accounted for during drug processing. Processing employees can generate any quantity of labels," the inspectors noted.

The company did not perform or document any yield calculation for drugs it processed.

The FDAers found that "members of the firm's quality control unit are not identified in written procedures." Advantage Dose's procedures required that the Receiving Technician must be a member of the Quality Control unit. However, the employee the inspectors observed "checking in and staging drug products to be repackaged" as well as repacking drug products was not identified as a member of the QC unit. "In addition, the labels generated by the processing employee are reviewed by another processing employee and are not reviewed by the firm's quality control unit," the investigators reported.

Further, the company's standard operating procedures were not reviewed and approved by the quality control unit, the team observed.

The investigators also found that the company did not conduct GMP training "with sufficient frequency to assure that employees remain familiar with GMP requirements applicable to them." The team observed one employee asked another how to operate a piece of equipment used to package drug products into labeled plastic pouches. The firm's procedures were not available in the processing rooms for employee reference, as well.

Advantage Dose had not validated its distribution process to ensure that products requiring refrigeration remained in refrigerated conditions throughout distribution, the 483 stated.

The inspection found evidence of "rodent activity at this facility," the investigators wrote. They saw rodent execreta in several locations, including the storage area for packaging materials, the storage area for tubing and syringes, and above the shipping room ceiling. The FDAers also noted "several potential routes of rodent entry" and added that wooden pallets and other items that "could be harborage for rodents and other pests" were stored on the rear loading dock.

The inspectors also observed that "numerous suspended ceiling tiles were noted either damaged or missing," including in the firm's processing rooms, where fiberglass insulation was exposed. "Also, entrance/exit doors to the firm's processing rooms do not have self-closing mechanisms and these doors were noted to remain open during numerous occasions while the firm was processing drug products."

Advantage Dose lacked written procedures describing the storage, handling, sampling and testing of components, drug product containers and closures, and also had no written specifications for its containers and closures. It also had no written procedures describing the use or types of rodenticides and insecticides to prevent the contamination of its drug products with these chemicals, the inspectors added.

The FDAers found that "numerous trash receptacles located in the firm's processing rooms were noted to remain open, exposing their contents to the environment while the firm was processing drug products." Advantage Dose did not perform environmental monitoring for microorganisms or air quality during processing, and had no written specifications for temperature and humidity conditions in its processing rooms.

The company failed to establish written procedures for the distribution of drug products, the preparation of master production and control records, the reprocessing of drug products or the annual review of reserve samples, the inspection team observed. They also noted that the firm had no written finished product specifications for each product processed at its facility. In addition, Advantage Dose's quality control unit did not review or approve the company's written procedures.

The company did not maintain complete labeling including inserts and OTC labels for all of its drug products. The investigators observed that Advantage Dose did not perform testing on receipt of drug product containers and closures, and had no written acceptance specifications for these items. The firm did not trend consumer complaints and had no written procedures addressing the review of "complaints, recalls, returned or salvaged drug products, and the investigations conducted for each drug product."

Jones and Guidry reported that the company did not ensure that all compounding and storage containers used during production were properly labeled and identified. They wrote that during processing "we observed an unidentified/unlabeled glass beaker containing a clear liquid on top of the firm's liquid filling machine. Also, in the firm's sink located in the processing area we observed an unidentified/unlabeled plastic container containing a greenish liquid."

The investigators noted that on several occasions they observed "employees in the processing area not wearing protective head coverings" during production, and also that processing employees with beards and mustaches were not wearing the appropriate protective coverings.