The Discriminatory Power of the BCS-Based Biowaiver: A Retrospective With Focus on Essential Medicines

Hofsäss, Martin A.; Dressman, Jennifer B.

doi:10.1016/j.xphs.2019.04.030

Cited by 21 publications

(20 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These aspects were summarized in a recent publication. 6 Two APIs for which the inability of dosage forms to comply with the regulatory criteria has been reported in the literature are amoxicillin and doxycycline (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling–Case Examples Amoxicillin and Doxycycline

Hofsäss

Dressman

2020

Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling–Case Examples Amoxicillin and Doxycycline

Hofsäss

Dressman

2020

Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

“…This difference in permeability highlights the relevance of requiring similar excipients for BCS class III drugs, as the high solubility could allow a similar in vitro dissolution, and even a similar in vivo dissolution, while still other factors may affect their oral fraction from being absorbed. For the BE product, the BCS-based biowaiver dissolution test in 900 mL would have led to a false negative result [3], i.e., differences observed in vitro while BE was observed in vivo. This possibility is not a problem from a regulatory point of view, since the companies always have the possibility to conduct an in vivo BE study, whereas the regulatory problem is to approve the NBE formulation based on in vitro dissolution profiles when the C max is notably different and not able to show equivalence.…”

Section: Discussionmentioning

confidence: 99%

“…For products containing class III (high-solubility, and low-permeability) drugs, which demonstrate very rapid (>85% in 15 min) and similar in vitro dissolutions to that of the reference product at all physiological pHs, it is assumed that test and reference products behave as drug solutions once emptied from the stomach into the duodenum, and consequently their bioavailabilities in rate and extent must be similar if excipients do not alter the drug absorptions. In vitro BE or biowaivers based on the BCS are now included in the main regulatory guidances around the world, with some slight discrepancies on classification boundaries summarized and discussed by Lenic et al [1], Zheng et al [2], and Hoffsäss and Dressman [3].…”

Section: Introductionmentioning

confidence: 99%

Investigation to Explain Bioequivalence Failure in Pravastatin Immediate-Release Products

et al. 2019

View full text Add to dashboard Cite

The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products, where one of them showed bioequivalence (BE) while the other test failed (non-bioequivalence, or NBE), and to explore the reasons for the BE failure. Experimental solubility and permeability data confirmed that pravastatin is a BCS class III compound. The permeability experiments confirmed that the NBE formulation significantly increased pravastatin permeability, and could explain its higher absorption rate and higher Cmax. This finding highlights the relevance of requiring similar excipients for BCS class III drugs. The BCS-based biowaiver dissolution tests at pH 1.2, 4.5, and 6.8, with the paddle apparatus at 50 rpm in 900 mL media, were not able to detect differences in pravastatin products, although the NBE formulation exhibited a more rapid dissolution at earlier sampling times. Dissolution tests conducted in 500 mL did not achieve complete dissolution, and both formulations were dissimilar because the amount dissolved at 15 min was less than 85%. The difference was less than 10% at pH 1.2 and 4.5, while at pH 6.8 f2, results reflected the Cmax rank order.

show abstract

“…It seems in this case (as in many others) the comparative dissolution testing according to the biowaiver guidances might be over-discriminating. 109 It might be interesting to apply physiologically based pharmacokinetic (PBPK) modelling to identify a "safe space" for dissolution in this case.…”

Section: Dissolutionmentioning

confidence: 99%

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate

Plöger

Quizon

Abrahamsson

et al. 2020

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the Food and Drug Administration, World Health Organization and European Medicines Agency, taking the degradation at some pH values into consideration. Together with solubility and permeability data for cephalexin monohydrate from the literature, it was demonstrated to be a Biopharmaceutics Classification System Class 1 drug. The pharmacokinetic behavior, results of bioequivalence studies published in the literature, as well as the therapeutic uses, potential toxicity and potential excipient effects on bioavailability were also assessed. Cephalexin has a wide therapeutic index and no bioequivalence problems have been reported. Dissolution studies were run under Biopharmaceutics Classification Systemebiowaiver conditions for the pure drug and 2 generic formulations available on the German market. Considering all relevant aspects, it was concluded that a biowaiver-based approval for products containing cephalexin monohydrate as the single active pharmaceutical ingredient is scientifically justified, provided that well-established excipients are used in usual amounts and that both test and reference dosage forms meet the guideline criteria of either "rapidly dissolving" or "very rapidly dissolving."

show abstract

The Discriminatory Power of the BCS-Based Biowaiver: A Retrospective With Focus on Essential Medicines

Cited by 21 publications

References 88 publications

Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling–Case Examples Amoxicillin and Doxycycline

Evaluation of Differences in Dosage Form Performance of Generics Using BCS-Based Biowaiver Specifications and Biopharmaceutical Modeling–Case Examples Amoxicillin and Doxycycline

Investigation to Explain Bioequivalence Failure in Pravastatin Immediate-Release Products

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate

Contact Info

Product

Resources

About