Laboratory Notebook

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PRESENTED BY BRAHMABHATT BANSARI K. M.
PHARM DEPARTMENT OF PHARMACEUTICS AND
PHARMACEUTICAL TECHNOLGY L. M. COLLEGE OF PHARMACY
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Contents of Presentation
Drug products for which BA/BE can be waived
Biowaivers for solid oral dosage form based
on BCS Biowaiver extensions Data to support
biowaivers
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Drug Products for which bioavailability or
bioequivalence can be waived
Bioavailability is self evident IVIVC BCS based
biowaivers
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Biowaivers for immediate release solid oral
dosage form based on BCS (FDA Guidance for
Industry)

• Recommendations provided by guidance

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BCS pillars
Solubility
Permeability
Dissolution
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BCS drug substance are classified as below

• Class 1 High Solubility, High Permeability
• Class 2 Low Solubility, High Permeability
• Class 3 High Solubility, Low Permeability
• Class 4 Low Solubility, Low Permeability

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Biopharmaceutics Classification System

• Solubility
• Easy to determine
• Permeability
• Harder to determine

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Solubility

• Objective to determine equilibrium solubility of
  a
• drug substance under physiological pH conditions.
• pH-solubility profile of test drug at 37oC in
  aqueous media with a pH range of 1 to 7.5
• Shake-flask or titration method
• Analysis by validated stability-indicating assay

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Permeability

• Extent of absorption in humans determined by
• Pharmacokinetic studies in humans
• Mass-balance studies
• Absolute bioavailability studies
• Intestinal permeability methods
• In vivo intestinal perfusions studies in humans
• In vivo or in situ intestinal perfusion studies
  in animals
• In vitro permeation experiments with excised
  human or animal intestinal tissue
• In vitro permeation experiments across epithelial
  cell monolayers
• Instability in the Gastrointestinal Tract
• Accounts for extent of degradation of a drug in
  the GI fluid prior to intestinal membrane
  permeability.

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Permeability Standards
IS Internal standard for Permeability studies ES
Efflux pump substrates
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DISSOLUTION DETERMINATION

• USP apparatus I (basket) at 100 rpm or USP
  apparatus II (paddle) at 50 rpm.
• Dissolution media (900 ml)
• 0.1 N HCl or simulated gastric fluid USP,
• A pH 4.5 buffer,
• A pH 6.8 buffer or simulated intestinal fluid
  USP.
• Compare dissolution profiles of test and
  reference products
• Using a similarity factor f2.

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BCS BIOWAIVER (no in vivo BA/BE needed)

• Rapid dissolution relative to gastric emptying
• Class 1 High solubility, High permeability
• Wide therapeutic window
• Excipients used in dosage form should be used
  previously in FDA approved Immediate Release (IR)
  solid dosage forms
• Prodrugs buccal absorption

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No biowaiver for

• locally applied, systemically acting products
• non-oral immediate release forms with systemic
  action
• modified release products
• transdermal products

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Biowaiver Extensions ?!

• Provided that ......
• drug solubility is high,
• permeability is limited,
• excipients do not affect kinetics,
• excipients do not interact ,.....

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Biowaiver Extensions ?!

• ....then very rapid dissolution (e.g.gt85 in 15
  min) of test and reference may ensure similar
  product characteristics
• because...
• ....absorption process is probably independent
  from
• dissolution and not product related
• limited absorption kinetics due to poor drug
• permeability and/or gastric emptying
• Biowaiver for BCS class III drugs (e.g.
  Atenolol)?!

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Biowaiver Extensions ?!

• For drugs showing ....
• very high permeability
• pH-dependent solubility within the
  physiologically relevant pH range
• .....an intermediate solubility class is
  suggested

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Data to support Biowaivers

• Data supporting
• High solubility
• High permeability
• Rapid and similar dissolution

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• Write note on drug products for which BA/BE
• studies can be waived. (5 marks)
• Write note on BCS based biowaivers. (5 marks)
• Enlist the methods to determine the permeability
• of drug substance. (2 marks)
• Comment on Biowaiver extensions. (2 marks)

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REFERENCES

• http//ikev.org/haber/bioav/Barends_Istanbul2004-
  1_korr.pdf
• http//www.absorption.com/site/Services/BCS.aspx
• http//ikev.org/haber/bioav/BA-BE20Intro-01-30-co
  lor.pdf
• http//medicine.iupui.edu/clinical/F813_spring2006
  /S_ClinicalPKF813Lecture1709March2006Bioavailabili
  tyandBioequivalencerevised.pdf
• http//www.sfbci.com/SFBC/upload/sfbc/Generateur/L
  eonShargel.pdf

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