Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Biowaivers Based on the BCS –Only for Class I

Dr. Ursula Bonsmann (Abschlußjahr: 2006)

Language: English

Measurements of plasma concentrations of the active substance and demonstration of in vivo bioequivalence to the comparator are well-accepted practices for the authorisation of generics and of medicinal products after variations of the excipients composition or major changes of the manufacturing process.
With the introduction of the BCS a new regulatory tool to use in vitro dissolution testing as surrogate for in vivo bioequivalence studies (often called biowaiver) has been implemented in the authorisation procedures of the FDA.
The BCS and biowaivers are also reflected in the current CPMP-Guideline dealing with appropriate investigations on bioavailability and bioequivalence for the application of generic products or for variations of the formulation or the manufacturing process.
With quite a conservative approach, biowaivers based on the BCS are granted at present only for highly soluble and highly permeable substances (BCS class I) in rapidly dissolving oral medicinal products.
Despite the advantages of using in vitro dissolution testing as surrogate for in vivo bioequivalence studies (avoiding unnecessary time- and cost-consuming clinical studies)) requesting for biowaivers is not very common until now, not least due to the conservative requirements.

The following proposals to lower the criteria for high solubility and high permeability as well as the suggestions of considering biowaivers for BCS class II or III substances are presented in this masterthesis:
  • narrowing the required pH-range for high solubility
  • enlargement of the volume of the media for the solubility estimation
  • supplementation of the media for the solubility classification with surfactants
  • calculation of the required solubility based on usual dosing conditions rather than based on the highest dose strength
  • using the intrinsic dissolution methodology instead of the determination of solubility at equilibrium conditions
  • introduction of an intermediate solubility classification for BCS class II substances with pH-dependent solubility
  • lowering the currently high permeability criterion
  • including BCS class III substances in the possibility of biowaivers based on the BCS


The suggestions of narrowing the required pH-range for high solubility for all substances requesting for biowaivers and of the solubility determination only at neutral pH-conditions for highly permeable weak acidic substances as well as considering biowaivers for BCS class III compounds are implemented in the current proposal for the WHO-Guideline dealing with the interchangeability of multisource (generic) medicinal products.
The presented biowaiver monographs of ibuprofen, acetaminophen, ranitidine HCl and cimetidine support the suggestions to extend the possibility of biowaivers to BCS class II substances with weak acidic properties and to BCS class III compounds.
It is expected that several proposals will be implemented in the authorisation procedures of the FDA as well as in the practices of the European health authorities.


Pages: 57
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