THe BIOWaIVer MONOGraPHS - FIP

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uPDaTe ON reGulaTIONS ON in vitro equIValeNce TeSTING Henrike Potthast 1 1 Federal Institute for Drugs and Medical Devices, Bonn, Germany Disclaimer: This text reflects the personal opinions of the author, which do not necessarily represent the views or policies of the German federal Institute for Drugs and Medical Devices (BfarM) Correspondence to: Dr. Henrike Potthast Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany Phone: 049- 228-207-5501 e-mail: henrike.potthast@bfarm.de 34
INTrODucTION Almost two decades have passed since the Biopharmaceutics Classification System (BCS) was published by Amidon et al. 1 and introduced to reduce the need for in vivo bioequivalence studies, in particular for applications of generic drug products. Like bioequivalence studies the BCS concept aims to compare formulation effects. In short, the concept is based on the scientific rationale that rate and extent of drug absorption is assumed not to be dependent on product formulation as long as the drug substance is highly soluble and easily transported and is manufactured in immediate release dosage forms exhibiting similar, rapid in vitro dissolution characteristics. The approach is applicable for generic applications, to compare developmental products with to-be-marketed formulations during the development of new drugs, for certain line extensions and in cases where bioequivalence has to be demonstrated due to product variations. Since its introduction, the BCS based biowaiver has been implemented into guidance documents on bioequivalence in many jurisdictions, since the bioequivalence of oral dosage forms is the primary issue for which the BCS concept can be applied in a regulatory setting. However, differences among the various regulatory requirements are evident and are frequently criticized by pharmaceutical companies. The following brief overview attempts to highlight the main guidance documents, along with their particularities, including more detailed information on the recently revised European guideline on bioequivalence. In addition, the distinction between the BCS based biowaiver approach and other situations is addressed where comparative in vitro dissolution aims to conclude on bioequivalence. The US-FDA guidance The US-FDA was the first jurisdiction that implemented regulatory requirements for BCS based biowaiver applications in a separate, comprehensive guidance document in 2000 2 . The guidance still restricts the eligibility of the BCS based biowaiver approach to BCS Class I drug substances in immediate release formulations and requires in vitro dissolution to be rapid, i.e. at least 85% dissolution of the labelled amount within 30 min or less. In line with common understanding, the US-FDA guidance does not accept BCS based biowaivers for narrow therapeutic range drugs irrespective of their BCS classification. 35
Page 3 and 4: Preface For 100 years, the Federati
Page 5 and 6: 1. Amidon GL, Lennernäs H, Shah VP
Page 7 and 8: Table of Contents BIOWaIVer MONOGra
Page 9 and 10: STarTING POINT Of THe PrOJecT - 200
Page 11 and 12: In this way, users of the FIP Biowa
Page 13 and 14: • Risk of approving a test produc
Page 15 and 16: ethambutol III NTI for ocu- lar tox
Page 17 and 18: quinine I-II Dose-related toxicity
Page 19 and 20: Last but not least, there were thre
Page 21 and 22: For chloroquine phosphate, sulfate
Page 23 and 24: Acetaminophen and lamuvidine are bo
Page 25 and 26: is often difficult to pinpoint whet
Page 27 and 28: product has also been tested for sa
Page 29 and 30: FDCs, as well as products containin
Page 31 and 32: levels are set at 90% and the power
Page 36 and 37: Formulation-wise, products designed
Page 38 and 39: Similar to the US-FDA guidance, the
Page 40 and 41: in other cases the dissolution may
Page 42 and 43: Other Jurisdictions Some countries
Page 44 and 45: dissolution are rather briefly ment
Page 46 and 47: Caco-2 permeability on a regular ba
Page 48 and 49: • In several jurisdictions the re
Page 50: 23. http://www.nihs.go.jp/drug/be-g
Page 53 and 54: INTrODucTION The demonstration of b
Page 55 and 56: Regulations in the European Union I
Page 57 and 58: Table 2. comparison of fDa, eu and
Page 59 and 60: classification of approved drug sub
Page 61 and 62: Table 1. The BcS classification as
Page 63 and 64: It has also been demonstrated that,
Page 65 and 66: 26, 27 , for a rapidly dissolving d
Page 67 and 68: For instance, some metabolic enzyme
Page 69 and 70: 18. NIHS. 2006. Guideline for Bioeq
Page 71 and 72: 51. S Strauch, E Jantratid, JB Dres
Page 73 and 74: INDuSTrIal BeNefITS Of BcS BaSeD BI
Page 75 and 76: an extensive effort going on in par
Page 77 and 78: data, by applying the IVIVC relatio
Page 79 and 80: The most recent development in the
Page 81 and 82: in the pharmaceutical development i
Page 83 and 84:
efereNceS 1. Cook J.A., Davit B.M.,
Page 86 and 87:
BIOWaIVer IMPleMeNTaTION fOr IMMeDI
Page 88 and 89:
Within the BCS, based upon their so
Page 90 and 91:
Very rapidly dissolving: The WHO co
Page 92 and 93:
motility or interactions with trans
Page 94 and 95:
of excipients are considered critic
Page 96 and 97:
Table 4. eligibility for the biowai
Page 98 and 99:
submitted. In such cases an abbrevi
Page 100 and 101:
In case of a rapidly dissolving dru
Page 102 and 103:
The BCS Class category, i.e. Class
Page 104 and 105:
comparator in bioequivalence studie
Page 106 and 107:
efereNceS 1. US, Department of Heal
Page 108 and 109:
lIST Of BIOWaIVer MONOGraPHS aS Of
Page 110:
Silva A, Cristofoletti R, Fernandes
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THe BIOWaIVer MONOGraPHS - FIP

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