BRIEFING

 Tiotropium Inhalation Spray. Because there is no existing USP monograph for this drug product, a new monograph based on validated methods of analysis is proposed.

1. The liquid chromatographic procedure used in the Assay was validated using the LiChrospher 60 RP-select B brand of column with L7 packing. The typical retention time for tiotropium is about 3 min.

2. The liquid chromatographic procedure used in the Content of Benzalkonium Chloride test was validated using the Inertsil ODS-3 brand of column with L1 packing. The typical retention times for C12 and C14 benzalkonium homologs are about 5 and 13 min, respectively.

3. The Organic Impurities test is based on the liquid chromatographic procedure validated using the LiChrospher 60 RP-Select B brand of column with L7 packing. Tiotropium related compound A is quantified at 240 nm while tiotropium related compound F is monitored at 320 nm. The typical retention times for tiotropium related compound A and tiotropium related compound F are about 4.5 and 14.5 min, respectively.

4. The Limit of Tiotropium Related Compound G and Tiotropium Related Compound H test is based on the liquid chromatographic procedure with mass spectrometric detection. The procedure was validated using the Zorbax 300-SCX brand of column with L9 packing and single quadrupole mass spectrometric detector (Waters ACQUITY QDa Mass Detector) using selected ion monitoring mode. The analyses were performed with the detector set to monitor ion with m/z of 170.1 daltons. The typical retention times for tiotropium related compound H and tiotropium related compound G are about 8 and 10 min, respectively.

 Performance tests for this inhalation product monograph have not been included at this time to address the stakeholders' concern that the inclusion of detailed performance tests in inhalation drug product monographs adds a regulatory burden that potentially impedes the approval of generic drug products already in development. This is because manufacturers are required to demonstrate their product’s conformance (or to address non-conformance) to the performance test requirements in the public standard. It should not be interpreted to imply that performance quality tests are unnecessary for inhalation drug products. These tests remain a critical aspect of the overall quality controls for these complex dosage forms. The importance of performance quality tests is specifically addressed in Inhalation and Nasal Drug Products—General Information and Product Quality Tests 〈5〉. Additionally, standardized apparatus and procedures for the execution of these tests are described in Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—Performance Quality Tests 〈601〉. USP is engaged with stakeholders to explore new ways of addressing these important performance quality tests for inhalation drug products within the public standard in a manner that will not impede generic development.

 (SM5: S. Shivaprasad)

 Case ID—SUB-1098