23-item 483 handed to Allergy Labs for inadequate aseptic processing, sanitation procedures.

Allergy Laboratories, Oklahoma City, OK, Dallas, TX, District

Allergy Laboratories, Oklahoma City, OK, was hit with a 23-item 483 of its sterile drug manufacturing facilities because its aseptic processing areas were deficient regarding the system for monitoring environmental conditions. Further, its written procedures for sanitation were not followed.

The firm also received a 20-item 483 following an inspection of its allergenic extract manufacturing facilities (see below). Only the 483s were available as Inspection Monitor went to press.

According to the records from the sterile drugs audit, prepared by FDA investigators Margaret Annes and Lloyd Payne from the Dallas, TX, District Office, Allergy environmental sampling of non-viable and viable particulates in two undisclosed production areas were not adequate to determine the air and surface qualities. Also, "environmental surface monitoring of viable particulates in the [undisclosed] Vial Wash Room and Sterile Gowning Room is performed [at incorrect intervals]."

Concerning written procedures for sanitation, Allergy Labs was cited as follows:

* Production personnel failed to mop all walls and floors of the Vial Fill Suite following the production run;

* Production personnel failed to remove all debris, such as, broken glass and stoppers, from the Vial Fill Suite floor prior to mopping; and

* Production personnel failed to properly clean the walls of the Vial Wash Room on a regular basis, "which resulted in a build-up of airborne lint on the HVAC return air grills on the lower east and west walls being pressure during the production run."

The FDAers also found the firm to be deficient in its written procedures for cleaning and maintenance. For example, "the firm has not validated the procedures used to clean and sanitize the processing equipment and production areas," according to the 483. Also, a finalized validation report for the Ephendrine Sulfate Injection USP drug product was not developed.

Further, the report documented that the cleaning and sanitizing validation report for the Phenylephrine Hydrochloride Injection USP and L Cysteine Hydrochloride Injection USP did not include suitability studies for the use of an undisclosed method for detecting Phenyephrine Hydrochloride and L-Cysteine Hydrocholoride following the cleaning process to ensure that no drug residues were present.

Also, procedures for the cleaning and maintenance of equipment were deficient regarding maintenance and cleaning schedules, including sanitizing schedules. For example, "the firm has not established a written procedure to prevent drug product contamination," the 483 stated. Further, the bulk drug solution mixing tanks were not cleaned and sanitized prior to being placed into the Vial Wash Room from a nonclassified storage area.

Next, "procedures for the cleaning and maintenance of equipment are deficient regarding the protection of clean equipment from contamination prior to use." For example, the bulk drug solution mixing tanks were not covered or held in a manner that would prevent environmental contamination while being stored in a non-classified storage following cleaning. The company also was cited because "equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use and cleaning and maintenance." Specifically, the water for injection system was designed or constructed of a material that could promote microbial contamination of the finished product. Further, there was clear, flexible plastic tubing used to connect an undisclosed part to the water for injection storage tank at one sample port. This resulted in a biofilm on the interior surface of the tubing.

In addition, sampling and testing plans for drug products were not described in written procedures, which included the method of sampling and number of units per batch to be tested. "Specifically, the firm does not have an SOP that addresses out-of-specification (OOS) investigations conducted by contract labs. There is no SOP that allow the firm to retest or re-sample a drug component if the initial tests from the contract lab indicate the product does not conform to specifications."

The next violation in the 483 noted that actual yield and percentages of theoretical yield are not determined at the conclusion of each appropriate phase of manufacturing the drug product. For example, the 483 stated, "the firm is not reconciling the use of the bulk solution during filling operations. The firm does not document the amount of bulk solution left in the carboy after filling operations have been completed." Also, they did not determine the theoretical amount of vials that are to be filled from the bulk solution that was manufactured and did not compare the theoretical vs. actual yields of filled vials to determine if an investigation was required.

Further, FDA documents stated that procedures for the preparation of master production and control records were not followed. "Specifically, the firm's SOP for change control requires that a document action request form be completed when proposing a revision to a current controlled document. SOP also requires that the revision be reviewed and approved." A master batch record was modified for the manufacture of smaller batches than what the approved version of the master batch record called for. "the changes were not made through the firm's formal change control process and were not approved and reviewed by the appropriate personnel."

In the second inspection, Allergy Labs was cited because there was no evidence that trends revealed in annual product reviews were evaluated and that appropriate corrective and preventive actions were implemented to prevent these trends from reoccurring.

For example, a review of the 2003 annual product review revealed that 14 out of 21 batch records reviewed had procedural deviations that were not recorded as deviations. "In addition, six of the 21 batch records were either missing information or were incomplete," the 483 stated.

Also, a review of the 2004 annual product review showed that 19 out of 19 batch records reviewed had discrepancies in the number of vials filled.

Investigators Julie Bringger and Jennifer Bridgewater from the Center for Drugs also found that the firm lacked validation studies to support the current packaging and shipping practices. "Packaging and shipping conditions consist of placing the extracts in uninsulated cardboard boxes wrapped with a thin plastic strip, placing Styrofoam chips throughout the box, and shipping the final container un-refrigerated to the customer," the report noted. There was no assurance by Allergy Labs that this shipping procedure maintained final product at the labeled temperature.

Next, customer product inquiries pertaining to shipping problems are not investigated. Furthermore, these customer inquiries were not deemed product complaints. The FDAer wrote: "For example, product inquiry PE080905596524 was received on Aug. 9, 2005, for a vial that was wet upon receipt. The suspect vial was returned and the examination of the vial revealed a hairline crack within the neck of the vial, causing leakage."

Further, the report noted the following violations relating to clean room practices and conditions: * Personnel performing sterility testing were observed with exposed skin;

* A technician was seen sanitizing hands immediately before touching finger touch plates used for personnel monitoring;

* A technician was observed adjusting clean room clothing;

* There was no assurance that the results obtained from the surface monitoring of the laminar air flow hoods were valid;

* The base of the viable air monitoring devices utilized in the sterile filling area were rusty and exhibited flaking paint;

* Sterility testing personnel were required to sanitize their gloves, but on Oct. 3, 2005, the FDAer noticed that the technician's gloves were so heavily coated with sanitizing solution, that it was dripping off the gloves; and

* Personnel were observed wiping the surface of the LAF hood after filling final product and prior to performing surface monitoring.

In the materials system, the audit noted: "There are no incoming checks or specifications for filters used in sterile filtration and tubing used in the manufacturing of allergenic extracts." Also, there were no incoming checks for Petri dishes utilized in preparation of environmental monitoring plates.

Last, the report stated that there were no maintenance procedures or records for walk-in refrigerators. One of the refrigerators was used to store final product, stability samples and retention samples. The other refrigerator was used to store quarantined bulk product and environmental monitoring plates. Also, there were no equipment logs for both refrigerators.

The firm could not be reached for comment.

Allergy Laboratories, Oklahoma City, OK, 8/9-29/05,10/3-7, 25/05, Doc.109855M, $6 plus retrieval.