FDA advice on Generic Tiotropium DPI: Hello Generic Spiriva HandiHaler !!!

FDA advice on Generic Tiotropium DPI: Hello Generic Spiriva HandiHaler !!!

December 02, 2017

Washington, Oct 2017, the FDA published the draft guidance on “Tiotropium Bromide”.

For those of you familiar with the development of generic dry powder inhalers, the content of the guidance will hardly come as a surprise. The guidance is non-binding as usual, but you would be brave to stray from it. The guidance confirms the Q1/Q2 requirements, the in vitro, PK and PD bio equivalence studies. Yes, all 4 elements are needed.

Here are some highlights:

  • Q1/Q2 equivalence between Test and Reference products required.
  • 3 independent batches of Test products (that does mean 3 batches of devices, APIs, excipients).
  • minimum of 10 samples of Test and 10 of REF needed for the tests.
  • single actuation content at 3 flow rates, 2 actuations, one capsule.

In Vitro BE: Population Bio Equivalence analysis of Impactor-Sized Mass. Full Cascade Impactor data in support.

In Vivo PK BE: Single-dose, two-way crossover. Must breathe in 2 times from the same capsule. Healthy subjects. Equivalence based on: AUC and Cmax for tiotropium. The 90% confidence intervals for the geometric mean T/R ratios of AUC and Cmax should fall within the limits of 80.00-125.00%. Not a surprise, but knowing the variability of the reference products it is a tough goal to achieve: inhalation products are famously “not equivalent to themselves” at the best of time. Plan your PK studies wisely and be prepared for a few repeats. Famous euphenism.

In Vivo PD BE: COPD patients, 2 weeks washout. Those of you aficionados of clinical protocol will enjoy the details listed in the guidance. BE study primary endpoint: area under the serial FEV1-time curve calculated to 24 hours (AUC0-24h) following the treatment. Equivalence based on: T/R ratio for the primary endpoint, 90% confidence intervals for the T/R ratios for the BE study endpoint should fall within 80.00 - 125.00%. Nothing new, just tough and consequently expensive, need a loan for USD 8 M?

The device will be the crucial point in your work. The MRX003 device by Merxin (www.merxin.com) was given the thumbs up for a 505j filing against the Reference product of Tio DPI in February 2017. Trust the best: info@merxin.com.

The guidance says nothing about leachables and extractables, or human factor studies: get in touch with us at Aedestra to learn how to handle these. As they say in French: Bonne Chance. Now you know how to convince the FDA you have a bio-equivalent tiotropium DPI.

Guidance PDF at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581192.pdf

About Aedestra (www.aedestra.com): Aedestra is an inhaled product development company. We develop inhaled dosage forms: DPI, pMDI, Nasal, Nebule and SoftMist: Generics in particular. Aedestra can help you develop the right product in the right way by providing strategic and technical expertise. Get in touch now to expand and develop your inhaled portfolio: www.aedestra.com.