How will recent FDA In Vitro Drug Release Testing (IVRT) observations affect your topical semi-solid product submission?

Posted April 16, 2015

Since the May 1997 U.S. Food and Drug Administration (FDA) release of the guideline entitled, Scale Up and Post Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Release Testing and In vivo Bioequivalence Documentation for Non-Sterile Semi-solid Dosage Form (SUPAC-SS), In Vitro Release Testing (IVRT) has become an increasingly popular, cost-effective, time-saving testing practice most often used during two significant phases of drug development: determining product sameness after post-approval changes; and formulation optimization and screening.

However, recent observations and deficiencies identified by the FDA with regards to New Drug Applications (NDA)/Abbreviated New Drug Applications (ANDA) submissions for semi-solid drug products specifically related to IVRT have caught many pharmaceutical companies by surprise.

Some of the confusion may be due in part to the limited guidance published on the topic or by the fact that there is a wide spectrum of approaches to conducting IVRT studies following the general chapter <1724> of the current USP for IVRT as a performance test for semi-solid drug products.  These are approaches that have been used successfully for submission purposes over the last 8 years, but are now being questioned or found to be deficient by the FDA.

Some of the recent FDA observations identified include, but are not limited to, the lack of mass balance and dose depletion information during the testing, the lack of IVRT method robustness or greater method robustness experimentation and proofs, longer study release profiles of no less than 4-6 hours (regardless of fast release formulations), or even the total omission of IVRT as part of the submission.

If your company has been given a deficiency letter related to IVRT recently, you have topical products requiring IVRT, or you just have some questions in this regard, please contact us at Diteba to discuss possible solutions.  We can help.

Our science team has superior scientific experience and expertise dedicated to IVRT method development and validation of release rate studies for topical formulations, including creams, lotions, ointments, gels, pastes, less viscous solutions and suspensions and transdermal patches for both product development and regulatory purposes.

The members of our science team possess in-depth expertise in operating Franz Cell and Enhanced Cell systems for semi-solid, pulmonary and rectal/vaginal formulations and routinely work with synthetic, biomimetic tissue membranes, including cadaver skin. As well, our expertise extends to paddle over disk apparatus for transdermal patches. As a result, we can meet the challenges of the most complex in vitro release tasks while keeping to strict timelines in a cost-effective manner.

Our services include:

  • In-process testing for formulation optimization
  • Quality control, lot to lot variability
  • Skin penetration, depth profiling and absorption studies for Bioequivalence or Bioavailability evaluation
  • In Vitro and analytical method development and validation in full compliance with SUPAC-SS and FDA requirements
  • In Vitro release comparison testing for pre and post-changes formulations
  • In Vitro-In Vivo (IVIVC) Correlation
  • OECD Test Method 428 – In Vitro Skin Absorption Studies
  • Data interpretation and FDA submission for approval of SUPAC-related changes

Diteba's testing services are performed in accordance with the requirements of the U.S. FDA, Health Canada and the International Conference on Harmonization (ICH). Diteba is licensed by Health Canada as a GMP drug establishment and registered as a drug establishment with the FDA. Diteba is also licensed by Health Canada to handle controlled drugs and substances.

Do you have further questions about IVRT or do you want to learn more about Diteba’s analytical and bioanalytical testing services?  Contact Neil Holman, VP of Business Development, today at, or click here to submit a quote request.

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