Rheology for generic equivalence assessments

Rapid rheology profiling for generic formulation submissions

Handling properties of topical products now make up one of the criteria for regulatory submissionsIf you are looking to satisfy regulatory requirements for the submission of a generic topical pharmaceutical, we provide a fast, highly effective profiling service to assess and demonstrate structural equivalence of your development formulations to the innovator reference product. The testing provided is as described by regulatory bodies such as the FDA and EMA including viscosity shear rate sweep curves, thixotropic profiles, measurements of yield stress and oscillation frequency sweeps, for the measurement of G’ and G” as a function of oscillatory frequency.

Our lab follows GLP guidelines and has plenty of experience in dealing with generating reports for regulatory submission. On completion of the testing we provide a full report detailing the test methods, graphical and numerical results and observations. We also set up a web meeting for us to present the results and answer any questions on methodology, results and observations. Following the testing we can provide all the support you need to help you with any challenging rheology-related questions that may arise.

Contact us to discuss your requirements for testing.

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In an effort to accelerate development and improve quality of new drug submissions, regulatory bodies such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are asking for more sophisticated testing to demonstrate Q3/physicochemical/structural equivalence:

Microstructure / Physical Properties

Evidence should be provided to characterise the microstructure/physical properties in terms of bulk physical CQAs that influence bioavailability, usability or indicate variability in the manufacturing process and product instability.

e.g. for solutions and suspensions – pH, buffering capacity, viscosity, density, surface tension, osmolality.

e.g. for semisolid formulations – pH, density, rheological behaviour.

Non-Newtonian rheological behaviour should be characterised using an appropriate absolute rheometer and include:

    • A complete flow curve of shear stress (or viscosity) versus shear rate, comprising multiple data points across the range of increasing and decreasing shear rates so that any linear portions of the up-curves or down-curves are clearly identified. The resulting curves should be characterised by fitting to (modified) power law equations so that numerical data can be produced.
    • Yield stress and creep testing
    • The linear viscoelastic response (storage and loss modulus vs. frequency)

Excerpt from “Draft guideline on quality and equivalence of topical products” from the European Medicines Agency.

Analysis of the rheological behavior which may be characterized using a rheometer that is appropriate for monitoring the non-Newtonian flow behavior of semi-solid dosage forms. The following evaluations are recommended:

  • A complete flow curve of shear stress (or viscosity) vs. shear rate should consist of multiple data points across the range of attainable shear rates, until low or high shear plateaus are identified.
  • Yield stress values should be reported if the material tested exhibits plastic flow behavior.
  • The linear viscoelastic response (storage and loss modulus vs. frequency) should be measured and reported.

Excerpt from “Draft Guidance on Acyclovir” from the US Food and Drug Administration.

…an applicant should consider the following attributes:

  • For adhesive polymer(s) as raw material(s): molecular weight, polydispersity, spectroscopic analysis (e.g., infrared radiation (IR) absorption), thermal analysis, intrinsic or complex viscosity, and measurement of residual monomers, dimers, solvents, heavy metals, catalysts, and initiators.
  • For adhesive as a laminate (in the absence of the active ingredient and other excipients):residual solvents, peel, tack, shear, and adhesion.
  • For adhesive in the final product (along with drug substance and other excipients and components): identification, residual monomers, dimers, and solvents; impurities; loss on drying; and uniformity. Other properties to be considered include the viscoelastic
    properties (such as elastic modulus (G’), viscous modulus (G”), and creep compliance (J)), and functional properties including, but not limited to, peel, shear, adhesion, tack, in vitro drug release, and in vitro drug permeation.

Excerpt from “Transdermal and Topical Delivery Systems – Product Development and Quality Considerations” from the US Food and Drug Administration.

The reality of performing this testing is that it’s tough! You have to deal with:

  • Equipment cost
  • Lead time to get the equipment and train the users
  • Experimental parameters / which versions of the methods to run
  • Sample handling and conditioning
  • Experimental artifacts
  • Results interpretation and presentation
  • Confidently communicating findings and conclusions
  • Supporting your statements in the face of tough technical questions.

Our lab has years of experience in working with and characterising soft materials, having supported many companies through the regulatory submissions process.

Contact us to discuss your challenges and how we might best be able to help.

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