Corrective actions lacking at First Priority.(Human Drugs)

During her Oct. 24-Nov. 9, 2006, inspection of veterinary drug manufacturer First Priority of Elgin, IL, Susan Bruederle found a number of violations, even after the firm had corrected deviations observed in its 2004 inspection. According to Bruederle, the company's corrective actions were not effective in preventing recurrence of those earlier deviations.

The 2006 inspection resulted in Bruederle issuing a substantial 25-item 483 and FDA following up with a warning letter to the company.

First Priority makes a variety of veterinary drug dosage forms, including liquids, ointments, pastes, powders, tablets and boluses, as well as one human product, an antibacterial hand soap.

Bruederle wrote in the 483 resulting from the inspection that the company did not thoroughly review unexplained discrepancies or failures of a batch of its product to meet specifications. She found that the firm did not investigate the reason that testing of a one-year inverted stability sample of Pyrantel Pamoate Suspension Canine (2.27mg/mL) showed a discrepancy between actual potency and the label claim.

First Priority also had no documentation that it investigated defective seals on bottles of Ivermectin Equine Oral Liquid 200 mL or leaking bottles of Povidone Iodine Shampoo; lots of both these products were released. Further, the inspector found that the firm's investigation of a customer complaint about a possible reaction of two dogs to Pyrantel Pamoate Suspension Canine-2X "was not thorough and/or completely documented."

The FDAer observed that First Priority's procedures "do not assure that all reports of product defects are documented as complaints, reviewed by quality control and investigated, if needed."

Although the company submitted reports to FDA reporting that a number of bottles from multiple lots of Copper Naphthenate Solution were returned because of leaking containers, missing labels or missing caps, these "reports of product defects were not recorded and handled as complaints," Bruederle wrote. Other products returned by customers for problems such as leaks and odors also were not documented or investigated as complaints, she added.

The inspection revealed that while "production and control records for the compounding, filling, testing and labeling (if performed during filling operations) are viewed by the quality control (QC) unit prior to the release of a batch," any labeling or packing that occurs after a batch release is not reviewed by QC before the work order is shipped.

Further, QC responsibilities and procedures were not in writing and fully followed, the investigator wrote. In-house reference standards used to test finished product samples were not being retested annually as company procedures required. Procedure governing validation was not followed when First Priority made a change to the manufacturing process for Pyrantel Pamoate Suspension Canine-2X, Bruederle added.

"The Validation Department did not determine if the modification was major or minor," as procedures called for, nor did the department "address the need to do additional testing to assure the product was equivalent to that made by the validated process."

The firm had no written procedure describing how to conduct visual examination of reserve samples of finished drug products for deterioration or that defined the pass/fail criteria, the inspector indicated.

First Priority also had no written procedures that described the receipt, documentation, storage, examination, testing, approval for return to stock or reprocessing/reworking of returned drug products, the 483 stated. Some drug products that were returned because they were damaged in shipment were returned to stock for distribution, without documentation to show that the products had been examined, tested if necessary and approved for return by QC.

Further, Bruederle noted that records of returned products did not always include the reason for return, date of disposition or ultimate disposition of the products.

The company's procedures and forms for annual evaluation of quality standards did not assure that complaints, recalls, returns and stability data were included.

Bruederle cited First Priority for failing to establish control procedures to monitor the output and validate performance of manufacturing processes that could cause variability in in-process materials and drugs. She noted that the company had no process validation data for Levoxine Powder, a prescription drug product, that demonstrated the ingredients, formula and manufacturing process consistently produced a powder that met the density requirements. Further, process validation data for Chlorhexidine Antiseptic Ointment did not demonstrate that the manufacturing process consistently produced a uniform product that met all finished product specifications.

The FDAer observed the reworking of several bottles of a lot of one finished product that was performed to remove leaking bottles. The reworking consisted of pouring the contents of leaking bottles into new bottles and capping them by hand. Bruederle noted that none of these steps was documented in the batch production record, nor were there any records of controls used to assure that the correct containers and closures were used for the reworked product.

The investigator also stated that the firm's written procedures did not describe or reference the controls needed to assure that reworked product met the same standards as the initial batch. "The SOP does not address the need for specific instruction for the rework operations," she wrote. For example, a rework of Povidone Iodine Shampoo involved a change in the container size, but there were "no instructions for how this should be done. The descriptions and lot numbers of the containers and caps used are not recorded. The rework record does not identify the location where the rework was performed."

The equipment and lines used to label drug products were not recorded in batch records, the inspector continued. Further, finished product release testing of some products was not done on representative samples but rather "on samples of bulk material collected from compounding tanks, kettles and blenders." First Priority also lacked written procedures describing the method to be used to collect samples of bulk material used for final release testing of drug products.

Where established test procedures existed, they were not always followed, the 483 reported. The chromatographic system suitability checks were not performed when testing samples of certain products for finished product release. Not all of these checks specified in assay procedures were done when testing samples of Pyrantel Pamoate Suspension for finished product release, the inspector found. Identify tests were not performed on all drug products before release.

Checklist: First Priority

* Unexplained testing inconsistencies

* Deficient complaint documentation

* Deviation from test procedures

Laboratory controls did not include the appropriate, scientifically sound specifications, test procedures and standards required to ensure that the components, in-process materials and drug products conformed to standards of identity, strength, quality and purity, Bruederle wrote. First Priority based its determination of the relative standard deviation (RSD) on "replicate injections of the standard preparation," which is not in accordance with USP's discussion of system suitability. Further, in-house reference standards used to conduct HPLC assays of finished products were not dried before use, although USP "provides specific instructions for drying reference standards before using," the report stated.

Many laboratory records the investigator reviewed did not include sufficient data to assure compliance with established test methods, specifications and standards, Bruederle reported. Some reference standards used to conduct assay and identity tests were not identified in lab records; certain characteristics of chromatographic systems used in assays were not documented; and sample preparation information and weights were also not fully documented in laboratory records.

Some lab records did not include a statement of each method used to test a sample, the 483 continued. In addition, the source from which a sample was obtained, the sample quantity, the date it was taken and the date it was tested were not routinely documented.

The FDAer also observed that labeled products were not periodically examined during bright stock labeling operations. Samples of representative units were not collected and visually examined for correct labeling at the completion of finishing operations. The inspector also observed that "there is no reconciliation of the number of labels issued, used and returned for some types of labeling material, such as tubes and cartons."

First Priority's batch production records did not include a statement of the actual yield after labeling operations were completed for a finished batch lot, the investigator added. "There is no comparison of the number of units labeled and the number of units filled," she wrote.

Finally, Bruederle observed that equipment maintenance activities were not documented in individual equipment cleaning and use logs, and there were no such logs for equipment used in labeling First Priority's drug products.

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