Firm operated without approved applications.(Human Drugs)

April 10--New York District

In addition to GMP violations, Time-Cap Laboratories manufactured a number of prescription drugs without approved applications, FDA inspectors found during a Oct. 28-Dec. 5 inspection.

The Farmingdale, NY, company also produces OTC products and a prescription veterinary drug.

Time-Cap failed to establish reliable, meaningful and specific test methods as part of a written testing program designed to assess the stability characteristics of its drug products to determine appropriate storage conditions and expiration dates, the agency wrote. "For example, your firm's analytical methods have not been validated to demonstrate that they are stability-indicating," the letter stated.

The firm's response stated that it was reviewing all of its analytical methods to assess their validation status and suitability for determining the stability of its drug products. Time-Cap committed to conduct any validation studies necessary to demonstrate that its analytical methods were stability-indicating. However, the proposed validation studies did not have specific timeframes for completion, FDA noted.

This was a repeat observation from the October 2006 inspection.

The company also failed to establish scientifically sound and appropriate specifications, standards, sampling plans and test procedures designed to assure each drug product satisfactorily conformed to appropriate standards of identity, strength, quality and purity. The warning letter noted that Time-Cap failed to perform residual solvent testing on drug products that were manufactured using solvents that are required to be limited in drug products.

The company committed to completing the residual solvent testing within the next nine months. "However your response does not include any plans for future periodic residual solvent (RS) testing of these drug products to ensure the RS specifications of these drug products remains below the required levels. Further, your corrective action did not address products that have been distributed that were not tested for RS," FDA wrote.

Time limits for completion of each phase of production had not been established in a written procedure or in master production records for all drug products, the letter continued. For example, investigators noted that a lot of Thyroid Tablets 65mg was blended on May 13 but tablet compression for the finished product was not started until Sept. 1.

Time-Cap replied that it had stability data extending to 48 months. However, FDA stated, "you have not established a correlation between the extended stability data test results and the extended product hold times. Finished product release testing is not a substitute for GMP controls."

The firm also failed to establish test procedures or other laboratory control mechanisms to assure that drug products conformed to appropriate standards and to assure that any deviation from the written test procedures or laboratory control mechanisms were recorded and justified. Investigators observed that analysts did not follow the firm's established method on four dissolution drug release tests for Aspirin Delayed Release Tablets, the letter noted, and there was no documented justification for these deviations.

Time-Cap also failed to follow its written procedures for qualification of raw materials as in-house reference standards. The laboratory assay testing method for preparing Thyroid Tablets USP did not include instructions to protect standard laboratory solutions from light exposure, per USP requirement.

The company's response to these observations included revised procedures and eliminating inadequate sampling methods and use of glassware by analysts. FDA requested the rationale for the distribution of products with standards that were characterized incorrectly and justification regarding the use of test results obtained using inadequate glassware for standard solutions sensitive to light.

Time-Cap did not maintain laboratory records with complete data from all tests necessary to assure compliance with established specifications and standards, the warning letter charged. The firm's "system suitability testing under the nine-month time point for the CRT stability assay and dissolution analysis of Nitroglycerin Extended Release Capsules Lot M041S is inadequate," the agency stated. "Your firm's analyst discarded data from a total of seven standard injections for system suitability and standard average calculations. The analyst failed to provide any justification for discarding the selected data. Further, the analyst and supervisor failed to review this discarded data."

Time-Cap contended that the data were legitimately discarded because they did not meet system suitability requirements. However, FDA wrote: "Not meeting system suitability requirements alone it is not adequate justification to discard data." The agency found the company's procedure deficient, noting that "it only requires the analyst to explain why an injection was eliminated from a calculation. A decision to discard data should be based on a detailed assessment of the steps taken during the test. In addition, adequate corrective action should include training for the analysts and supervisor on the proper handling of OOS results."

Time-Cap was also cited for failing to conduct calibration of instruments, apparatus, gauges and recording devices at suitable intervals in accordance with an established written program. The baskets used for dissolution testing were severely warped, resulting in significant wobble-an observation the firm's director of quality control agreed with. However, wobbling was not checked during apparatus calibration and set up.

FDA acknowledged the company's corrective action to replace the baskets, but noted that company procedure was inadequate because it did not describe how to use a wobble meter; failed to define unacceptable wobbling; and did not describe what is considered a physical defect for baskets and paddles.

Time-Cap failed to follow its procedure for annual calibration of the QC laboratory's HPLC units, when its analyst instead re-injected a standard solution and proceeded to calculate the carryover incorrectly. The company replied that it conducted a training session with the analyst involved with the calibration protocol for HPLC Unit. However, the record revealed training for two analysts and did not include training documentation for the additional analysts and the Director of QC that reviewed and approved these incorrect test results.

The company did not establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture of drug products. The investigators observed that the disintegration apparatus basket-rack assemblies were unclean and contained excessive residue from previous analysis. Disks that were available for use did not all have smooth surfaces free from chips as required by the USP, and were discolored.

The firm's response was inadequate because the revised SOP failed to indicate if these physical defects and unclean basket-racks or disks should be discarded or removed from use when observed.

Time-Cap also failed to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport to possess. For example, the firm failed to complete the process validation study report for Thyroid Tablets, USP. Data were collected for this product in July 1999 and July 2004, but the documentation was not evaluated to show that product performance was consistent and reproducible from batch-to-batch.

The firm committed to review the process validation studies and issue a summary report on each.

The company did not maintain separate or defined areas necessary to prevent mix-ups during manufacturing and processing operations. Specifically, adjacent tablet compression areas were separated by pass-through clear plastic curtains. Although Time-Cap contended that the interleaved six- inch strips act as a solid barrier, FDA disagreed with this assessment.

In addition to the GMP violations discussed above, this inspection also revealed that Time-Cap manufactured and marketed unapproved new drugs, the letter added. The firm did not have any FDA-approved applications on file for the products Thyroid 1/2 gr. (32.5 mg) tablets; Thyroid l gr. (65 mg) tablets; Thyroid 2 gr. (130 mg) tablets; and Thyroid 3 gr. (195 mg) tablets.

FDA acknowledged the firm's commitment to discontinue manufacturing the following unapproved drugs and other unapproved extended release products:

* Papaverine HCl 150 mg/Chlorpheniramine Maleate 8 mg E.R. capsules

* Chlorpheniramine Maleate 4 mg/Phenylephrine 20 mg capsules

* Chlorpheniramine Maleate 8 mg/Pseudoephedrine HCl 120 mg capsules

* Chlorpheniramine Maleate 12 mg/Pseudoephedrine HCl 100 mg capsules

The agency also requested that Time-Cap outline the actions it would be taking to cease distribution of these or any other unapproved drug products, and provide an inventory of all unapproved drugs at the firm and disposition of these unapproved drugs. Cal; NDA; OOS; QC/QS; Stab; Val

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