Manufacturer Cited for Out-of-Spec Operations

Midland Pharmaceutical made significant modifications to critical production parameters for its unapproved version of antibiotic sulfamethoxazole/trimethoprim without evaluating their impact through its change control system, according to a recent warning letter.

The NIH says the drug is used to treat certain infections associated with HIV. It also is used to treat chronic bronchitis, bacterial urinary tract infections, acute otitis media in children and traveler’s diarrhea caused by enterotoxigenic Escherichia coli and Shigella species.

The company recorded tablet-press settings for precompression, compression, fill depth and turret speed that were outside the ranges used during process validation and suggested on the batch record, the March 3 letter said. It was posted recently on the FDA’s website.

Midland had a process validation study that did not have ranges or settings listed for all steps in the protocol for manufacturing the antibiotic, the FDA said, and the corrective action proposed by the firm in its response to the Form 483 observation — to do a retrospective validation of existing drug product — was inadequate for several reasons.

The agency questioned data submitted for the new validation. The firm’s rationale for establishing new tablet settings was not provided, and critical parameters were derived from data on a subset of existing batches used to set retrospective parameters. “This is not a scientifically sound means of conducting a retrospective validation,” the FDA said.

The company reviewed 26 batches but relied on only 10 batches to update the new tablet settings, the FDA said. No rationale for excluding the other batches was given in the validation study, and the retrospective study did not account for the lower of two product strengths made by the company.

The warning letter can be accessed at www.fda.gov/foi/warning_letters/s6769c.pdf.