Dissolution, Pharmaceutical Product Interchangeability
and Biopharmaceutics Classification
BCS-Based Biowaiver Monographs
Prof. Dr. Jennifer Dressman & Corina Becker
Johann Wolfgang Goethe University
Frankfurt am Main, Germany
WHO Prequalification Programme June 2007
The WHO Biowaiver Procedure
Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms.
Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations
Scope Simplified approval for IR generic solid oral products
Demonstration of BE by in vitro instead of in vivo PK
Advantage
Studies
WHO Prequalification Programme June 2007
The Biowaiver Monographs I.
An initiative of the Federation Internationale Pharmaceutique
(FIP).
The aim is to summarize all data from the literature relevant to
the decision as to whether dissolution can be used as a
surrogate for PK to show bioequivalance.
The biowaiver procedure can be used to demonstrate
bioequivalence after a product has been scaled-up, in the
approval of a new, multisource product of an existing API, and
in continued approval of products for which there has been a
change in composition and/or manufacturing procedure.
WHO Prequalification Programme June 2007
The Biowaiver Monographs II.
The approach includes all factors considered in the WHO
Document: „Proposal to waive in vivo bioequivalence
requirements for WHO Model List of Essential Medicines
immediate-release, solid oral dosage forms.” Technical Report
Series, No 937, 40th Report, Annex 8 of WHO Expert committee on
specifications for pharmaceutical preparations
Where criteria vary among various regions (US, EU), these are
also addressed.
A recommendation is given about whether the biowaiver
procedure can be utilized, or if bioequivalence should rather be
tested with a pharmacokinetic comparison.
WHO Prequalification Programme June 2007
Biowaiver l
BCS
Criteria
Risks
Therapeutic
Dissolution Biowaiver
Index
Indication
Interactions with
Food and
Excipients
BA/BE Studies
WHO Prequalification Programme June 2007
The Biowaiver Monograph
What is taken into consideration?
Physicochemical properties, especially solubility at 37°C between pH 1.2
and 6.8, but also pKa, logP, polymorphism, solvates and saltsIf necessary,
additionaly solubility and dissolution studies are run with the pure API
Determinations of Permeability
e.g. BAabs, urinary excretion, Caco-2 studies
Literature studies on bioequivalence of existing products
Interactions with food and excipients
Literature and laboratory data comparing dissolution of existing
products
Therapeutic indications, therapeutic index, types and severity of
toxic effects observed.
WHO Prequalification Programme June 2007
The Biopharmaceutics Classification System
U.S. Department of Health and Human Services Food and Drug Administration Center for Evaluation and Research (CDER). 2000. Guidances for industry: Waiver of in vivo bioavailability
and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System
Highly permeable
I II
Highly Poorly
soluble soluble
III IV
Poorly permeable
WHO Prequalification Programme June 2007
BCS Criteria according to WHO
Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms.
Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations
Solubility Permeability
Dose/Solubility ratio Absorption ≥ 85 %
≤ 250 ml
Human absolute BA
D / Sratio [ml ]
D m ax( EML) [mg ] or mass balance
Solubility [mg / ml ] studies
BCS
alternatives are
in 3 aqueous media intestinal perfusion
pH 1.2 – 6.8 and tissue permeation
37°C studies
WHO Prequalification Programme June 2007
Case Example: Pyrazinamide
One of the four main APIs used in treatment of Tubercolosis
O
N
NH2
N
Its highly specific action against mycobacterium tuberculosis in an
acid environment contributes important sterilizing activity to the
standard chemotherapy
The most common, serious adverse effect is liver damage, which
occurs in 15% of patients at doses just above the therapeutic
range.
WHO Prequalification Programme June 2007
Solubility of Pyrazinamide
in compendial buffers pH 1.2 – 6.8 at 37°C,equilibrium solubility after 24 hours
20
18
16
14
Solubility [mg/ml]
12
10 Highly
8 soluble
6
4
2
D/S ratio D/S ratio D/S ratio
17.6 ml 18.6 ml 18.0 ml
0
SGFsp pH 1.2 Phosphate buffer pH 4.5 SIFsp pH 6.8
WHO Prequalification Programme June 2007
Permeability of Pyrazinamide
34% Urinary recovery of a oral dose after 24 h,
40% after 48 h
Ellard GA 1969. Absorption, metabolism and excretion of pyrazinamide in man. Tubercle 50(2):144-158.
Urinary recovery of 73% after 72 h
0- 4% fecal recovery
Lacroix C, Hoang TP, Nouveau J, Guyonnaud C, Laine G, Duwoos H, Lafont O 1989. Pharmacokinetics of
pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol 36(4):395-400.
Pyrazinamide is actively reabsorbed in the kidney
Weiner IM, Tinker JP 1972. Pharmacology of pyrazinamide: metabolic and renal function studies related to
the mechanism of drug-induced urate retention. J Pharmacol Exp Ther 180(2):411-434.
Kasim et al. BCS III
Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS, Junginger HE, Stavchansky
„Poorly
SA, Midha KK, Shah VP, Amidon GL 2004. Molecular properties of WHO essential drugs and provisional
biopharmaceutical classification. Mol Pharm 1(1):85-96. permeable“
Lindenberg et al. BCS III
Lindenberg M, Kopp S, Dressman JB 2004. Classification of orally administered drugs on the World Health
Organization Model list of Essential Medicines according to the biopharmaceutics classification system.
Eur J Pharm Biopharm 58(2):265-278.
WHO Guideline für bioequivalence BCS III/I
WHO 2006. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines
immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of
WHO Expert committee on specifications for pharmaceutical preparations.
WHO Prequalification Programme June 2007
Dissolution of existing products, literature
studies of Bioequivalence
No cases of bioINequivalence reported in the literature
Products on German market have similar dissolution
profiles 120
100
80
“Very rapidly
60
dissolving”
% dissolved
400 mg pure substance
40 Pyrafat®
Pyrazinamide “Lederle”
20
0
0 10 20 30
time [min]
WHO Prequalification Programme June 2007
Evaluation of the collected
Information
BCS Class (II, III, IV)
narrow therapeutic index
BCS Class I (II, III)
„critical“ indication
wide therapeutic index
Risk of abuse
„uncritical“ indication
slow and incomplete dissolution
no risk of abuse
„Food effects“ or interaction
Biowaiver
with excipients „rapid“ or „very rapid“
dissolution
published bioinequivalence
no reported interaction with
food or excipients
BE- Studies
WHO Prequalification Programme June 2007
Biowaiver Recommendation for
Pyrazinamide
BCS Class
Solubility III
Permeability
20
18
16
Solubility > 20 mg/ml 73% Urinary excretion after
72h
14
D/s ratio < 20 ml
12 400mg
10
no recovery in the feces
8
Dose-proportional absorption
6
4
2 in range 200 – 3600 mg
0
Biowaiver
120
Only with specific requirements
100 for monitoring hepatic function Indication: Long-term
80
treatment of TB
% dissolved
60
“Very rapidly Toxicity: Hepatoxicity
dissolving”
40
Monitoring of hepatic function
400 mg pure substance
20
Inhibition of urate excretion
Pyrafat®
0
0 10 20 30
time [min]
Pyrazinamide “Lederle” (gout)
Dissolution Risks
WHO Prequalification Programme June 2007
Summary of biowaivers for
first line anti-TB drugs
API Solubility Permeability BCS Biowaiver Constraints BE Test
Isoniazid high borderline III/I YES Only if the formulation does not In vitro
contain reducing sugars.
(Biowaiver Otherwise a PK study should
(in vivo)
monograph be run
published)
Ethambutol • 2 HCl high low III (YES) Narrow therapeutic index, due In vivo
to impairment of vision. Should
(Biowaiver only be biowaived in (in vitro)
jurisdictions where visual
monograph monitoring can be guaranteed
published)
Pyrazinamide high borderline III/I (YES) Narrow therapeutic index, due In vivo
to impairment of liver function.
Should only be biowaived in (in vitro)
jurisdictions where liver
function monitoring can be
guaranteed
Rifampicin borderline high II/I NO Instability, poor wettability, In vivo
polymorphism, several reported
cases of bioinequivalence
WHO Prequalification Programme June 2007
Biowaiver Monographs already available
Acetaminophen (Paracetamol) Isoniazid
Amitriptyline Prednisolone
Atenolol Prednisone
Chloroquine Propanolol
Cimetidine Ranitidine
Ethambutol Verapamil
Ibuprofen www.fip.org/bcs
WHO Prequalification Programme June 2007
Many thanks to the team of co-authors
Dirk Barends (rivm Holland), Chief Editor
Jennifer Dressman (University of Frankfurt), Co-Editor
Gordon Amidon
Vinod Shah
Kamal Midha
Solomon Stavchansky
Sabine Kopp (WHO)
Hans Junginger…………………………and the many first authors
who give their time and
expertise to the project!
WHO Prequalification Programme June 2007