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WHO Prequalification Programme June 2007
BCS-Based Biowaiver Monographs
Prof. Dr. Jennifer Dressman & Corina Becker
Johann Wolfgang Goethe University
Frankfurt am Main, Germany
Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification
Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification
WHO Prequalification Programme June 2007
The WHO Biowaiver ProcedureThe WHO Biowaiver Procedure
Scope Simplified approval for IR generic solid oral products
AdvantageDemonstration of BE by in vitro instead of in vivo PK
Studies
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
The Biowaiver Monographs I.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 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
lBiowaiver
Criteria
Biowaiver
Criteria
Biowaiver
BCS
Risks Therapeutic Index Indication
Dissolution
Interactions with Food and Excipients BA/BE Studies
WHO Prequalification Programme June 2007
Literature studies on bioequivalence of existing products
Literature and laboratory data comparing dissolution of existing products
Determinations of Permeability e.g. BAabs, urinary excretion, Caco-2 studies
Therapeutic indications, therapeutic index, types and severity of toxic effects observed.
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
The Biowaiver MonographWhat is taken into consideration?The Biowaiver Monograph
What is taken into consideration?
Interactions with food and excipients
WHO Prequalification Programme June 2007
I
Highly permeable
The Biopharmaceutics Classification
System The Biopharmaceutics Classification
System
II
Highly soluble
III IV
Poorly permeable
Poorly soluble
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
WHO Prequalification Programme June 2007
Solubility
BCS Criteria according to WHOBCS Criteria according to WHO
BCS
Dose/Solubility ratio ≤ 250 ml
in 3 aqueous media pH 1.2 – 6.8
37°C
Absorption ≥ 85 %
Human absolute BA or mass balance studies
alternatives are intestinal perfusion and tissue permeation studies
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
]/[
][][/
)(max
mlmgSolubility
mgDmlSD
EMLratio
Permeability
WHO Prequalification Programme June 2007
Case Example: PyrazinamideCase Example: Pyrazinamide
One of the four main APIs used in treatment of Tubercolosis
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.
N
NNH2
O
WHO Prequalification Programme June 2007
Solubility of PyrazinamideSolubility of Pyrazinamide
in compendial buffers pH 1.2 – 6.8 at 37°C,equilibrium solubility after 24 hours
0
2
4
6
8
10
12
14
16
18
20
So
lub
ilit
y [
mg
/ml]
SGFsp pH 1.2 Phosphate buffer pH 4.5 SIFsp pH 6.8
D/S ratio17.6 ml
D/S ratio18.6 ml
D/S ratio18.0 ml
Highlysoluble
WHO Prequalification Programme June 2007
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 SA, Midha KK, Shah VP, Amidon GL 2004. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 1(1):85-96.
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.
Permeability of PyrazinamidePermeability of Pyrazinamide
„Poorlypermeable“
WHO Prequalification Programme June 2007
Dissolution of existing products, literature studies of Bioequivalence
Dissolution of existing products, literature studies of Bioequivalence
No cases of bioINequivalence reported in the literature
Products on German market have similar dissolution profiles
0
20
40
60
80
100
120
0 10 20 30
time [min]
% d
isso
lved
“Very rapidly dissolving” 400 mg pure substance Pyrafat®
Pyrazinamide “Lederle”
WHO Prequalification Programme June 2007
BCS Class (II, III, IV)
narrow therapeutic index
„critical“ indication
Risk of abuse
slow and incomplete dissolution
„Food effects“ or interaction with excipients
published bioinequivalence
Biowaiver
BCS Class I (II, III)
wide therapeutic index
„uncritical“ indication
no risk of abuse
„rapid“ or „very rapid“ dissolution
no reported interaction with food or excipients
BE- Studies
Evaluation of the collected Information
Evaluation of the collected Information
WHO Prequalification Programme June 2007
Biowaiver Recommendation for Pyrazinamide
Biowaiver Recommendation for Pyrazinamide
Biowaiver Only with specific requirements for monitoring hepatic function
Solubility Permeability
Dissolution Risks
0
20
40
60
80
100
120
0 10 20 30
time [min]
% d
isso
lved
Solubility > 20 mg/ml
D/s ratio400mg
< 20 ml
BCS ClassIII
0
2
4
6
8
10
12
14
16
18
20
“Very rapidly dissolving” 400 mg pure substance Pyrafat®
Pyrazinamide “Lederle”
73% Urinary excretion after 72h
no recovery in the feces
Dose-proportional absorption in range 200 – 3600 mg
Indication: Long-term treatment of TB
Toxicity: Hepatoxicity
Monitoring of hepatic function
Inhibition of urate excretion (gout)
WHO Prequalification Programme June 2007
Summary of biowaivers for first line anti-TB drugs
Summary of biowaivers for first line anti-TB drugs
APISolubilityPermeabilityBCSBiowaiverConstraintsBE Test
Isoniazid
(Biowaiver monograph published)
highborderlineIII/IYESOnly if the formulation does not contain reducing sugars.
Otherwise a PK study should be run
In vitro
(in vivo)
Ethambutol • 2 HCl
(Biowaiver monograph published)
highlowIII(YES)Narrow therapeutic index, due to impairment of vision. Should only be biowaived in jurisdictions where visual monitoring can be guaranteed
In vivo
(in vitro)
PyrazinamidehighborderlineIII/I(YES)Narrow therapeutic index, due to impairment of liver function. Should only be biowaived in jurisdictions where liver function monitoring can be guaranteed
In vivo
(in vitro)
RifampicinborderlinehighII/INOInstability, poor wettability, polymorphism, several reported cases of bioinequivalence
In vivo
WHO Prequalification Programme June 2007
Biowaiver Monographs already availableBiowaiver Monographs already available
Acetaminophen (Paracetamol)
Amitriptyline
Atenolol
Chloroquine
Cimetidine
Ethambutol
Ibuprofen
Isoniazid
Prednisolone
Prednisone
Propanolol
Ranitidine
Verapamil
www.fip.org/bcs
WHO Prequalification Programme June 2007
Many thanks to the team of co-authorsMany 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!