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Formulating Generic Drug Substances: Overview of FDA Public Meeting

Posted January 22, 2018

Recently, the Food and Drug Administration (FDA) organized two very interactive public workshops. The first, Demonstrating Equivalence of Generic Complex Drug Substances and Formulation (October 5, 2017) will be outlined here.

The FDA public meetings were to provide an overview of:

  • Current scientific regulations related to drug products that are applied to the skin (topical products)
  • New analytical methods and innovative in vitro testing that could provide evidence of drugs that produce the same effect to facilitate the regulatory review process

Demonstrating Equivalence of Generic Complex Drug Substances and Formulations

Ultimately, it is the responsibility of a drug sponsor to develop, justify and validate their own in-vitro release testing (IVRT) method. Reproducibility of an IVRT method must be well established and illustrate how release rate reflects changes over among other aspects.

In general, IVRT has been recommended as part of testing to demonstrate sameness:

  • Between two products that are highly alike
  • In conjunction with in vivo tests to demonstrate sameness between formulations with known differences

Ideally, in-vitro release method should be able to discriminate batches that are not bioequivalent. An IVRT method should determine the effect of variability in the tests.

For this purpose, IVRT should be conducted with drug products that would be sold to the public, compared to drug products that are intentionally altered with meaningful variations in formulation (e.g., particle size, drug loading, etc.).

Drugs that enter the body through the skin are complex and require strict regulation for demonstrating active ingredients an bioequivalence. As part of this workshop, speakers from the FDA, as well as leading researchers from several institutions, shared regulatory perspectives and discussed novel in vitro approaches in developing topical products to characterize them and compare bioavailability.

In general, under the description of complex products, the FDA specifies factors such as a mixture of Active Pharmaceutical Ingredients (APIs), matrix composition, delivery into the body, and specific dosage form. During the meeting, discussions on the development of the regulatory framework of generic versions of complex topically applied drugs have attracted broad attention.

The basic approach as formulated by the FDA and widely adopted by other regulatory agencies considers copies of drug products equivalent to their original products if they are bioequivalent (BE), meaning that their bioavailability after administration in the same dose are comparable.

The goal of the bioequivalence studies is to show that there is no statistically significant difference in the rate and extent of absorption between the test and Reference Listed Product (RLD). Certainly, FDA approved generic drugs are therapeutically equivalent.

Topics discussed during the meeting helped both the FDA and attendees better comprehend current challenges and limitations in IVRT development, and understand the critical quality attributes of complex products and regulatory review. There is still more discussion to be had.


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