Par hit with 18-item 483 for GMP, validation deficiencies.

New York District investigators Matthew Spataro and Michael Levine found that generic pharmaceutical manufacturer Par Pharmaceuticals failed to qualify critical equipment and lacked developmental data for certain specifications.

According to records from the spring 2001 audit, Par also was cited for SOP deviations, failing to qualify the API vendor and having no established resolution specifications for chromatographic purity methods for stability testing. Other validation deficiencies also were noted in the 483.

The audit covered six assignments for product-specific pre-approval ANDAs. A previous inspection, conducted Aug. 31, 2000, resulted in the voluntary recall of methimazole and benzytropine tablets. Most of the deficiencies noted in that nine-item previous 483 were corrected.

With respect to validation, the EIR stated that "the firm fails to adequately characterize and qualify the impurity standards used for the method validation studies for all the applications." The report also stated that the firm's "chromatographic purity methods for all the applications lack resolution criteria or have no established resolutions specifications, as part of the system suitability tests." It added that the firm "does not have a validated method for residual solvents and did not perform residual solvent testing on [unnamed substance] Active Pharmaceutical Ingredient."

Further review of the submission batch and bio-batch revealed, according to the EIR, that "they were manufactured without a process validation protocol." Spataro wrote in the EIR: "I stated that a process validation protocol is needed prior to manufacturing of the bio-batch/submission batch to validate manufacturing process parameters and specifications."

Additionally, FDA hit the firm with failing to adequately qualify two lots, stating that the "reference material used in accuracy ("recovery") and solutions for stability studies were not qualified as working reference standards."

The audit also revealed that the firm "failed to qualify (IQ, OQ, PQ) a critical piece of equipment, the [name purged] Granulator," which is used in three ANDA applications. Further investigation revealed that the equipment was "not functioning properly during normal operations."

The firm responded to FDA in a letter written by Kenneth Sawyer, chairman and CEO, on April 30, 2001. Concerning the granulator, Sawyer wrote: "The Installation Qualification/Operational Qualification for the [granulator] was completed on 4/3/01. However, the OQ section has been amended to include a more comprehensive examination of the upper and lower operating limits. Execution of the amended OQ indicates that this piece of equipment is operating as designed." Sawyer noted that "[a]n equipment performance qualification will be included as part of each subsequent product's related process validation."

FDA also hit the firm for not following SOPs for "Investigation of Process Deviations, batch Discrepancies and Batch failure," in that this investigation took over 90 days to complete." FDA said Par's SOP states that an incident report should be targeted for no more than 30 days.

The 483 also stated that Par lacked development data for specifications such as hardness (Kp) and thickness (mm) for certain tablets. The EIR stated that research batches defined a hardness range; however, development data was inadequate.

In his response to FDA, Sawyer wrote that the batch records for the 5 mg and 10 mg pilot batches were "developmental batches manufactured for the purpose of defining operational ranges for all critical process parameters. As part of the developmental process, these batches were run under a qualification protocol which included tablet hardness and machine speed challenges."

He also stated that results from these studies "support all operational conditions and tablet specifications utilized for the subsequently manufactured submission batches."

Regarding characterization and method validation, Sawyer responded by stating: "Par accepts non-compendial impurity standards from API manufacturers based on review of certification provided covering structural identity and absolute purity. As part of the Raw Materials Characterization and Impurity Methods Validation processes, the impurities are studied versus manufacturer information on HPLC relative retention times, providing assurance that the materials are in fact the compounds which they are claimed to be."

In addition, the company has updated the SOP to include an additional identification test to provide another level of scrutiny to the process.

Sawyer acknowledged in his letter to FDA that the raw material characterization reports for one product was still in draft form at the time of the pre-approval inspection. He wrote that this has since been corrected "with the review and approval of the final report provided." Sawyer also wrote that formal validation protocols have been completed and approved for [three unnamed] tablets and that before initial commercial distribution.

He added: "Par commits to notifying the New York District Pre-Approval Inspection Monitor when prospective process validation studies have been completed."

Calls into Par seeking an update were not returned. Par Pharmaceuticals, Spring Valley, NY, 3/14, 15, 19, 20, 22, 26-30, 4/2-6, 10/01, Doc. 109382M, $39.50 plus retrieval.

[check] The Checklist--Par Pharmaceuticals

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