Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
Evaluation of Quality and
Interchangeability of Medicinal Products
10 – 14 September 2007
Dar Es Salaam, Tanzania
Dr. Henrike Potthast; Temporary Advisor to WHO
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 EU “Note for Guidance on the Investigation of
Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98
 FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies
for Orally Administered Drug Products – General Considerations” (Oct.
2000) – and related guidances
 WHO – Multisource (generic) pharmaceutical products: Guidelines on
registration requirements to establish interchangeability (2005)
 CN – Guidance for Industry; Conduct and analysis of bioavailability and
bioequivalence studies – Part A: Oral dosage formulations used for
systemic effects (1992)
 ….and others
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
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Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Bioavailability – rate and extent at which a drug
substance... becomes available in the general system
(product characteristic!)
 Bioequivalence – equivalent bioavailability within pre-set
acceptance ranges
 Pharmaceutical equivalence  Bioequivalence
 Bioequivalence  Therapeutic equivalence
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Bioequivalence Studies
 in vivo comparison of products by means of volunteers
serving as “in-vivo dissolution model”
 ‘biological quality control’
comparison of product characteristics in order to ensure
therapeutic equivalence
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Immediate and Modified Release Dosage
Forms
BE is generally required and can be investigated by
means of
♦
♦
♦
♦
pharmacokinetic (BE) studies (preferred as most sensitive)
comparative pharmacodynamic studies
comparative clinical trials
comparative in vitro trials
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Immediate Release (IR) Dosage Forms
 possible BE exemptions
♦ aqueous solution (incl. syrups, elixirs, but no suspensions)
♦ gases
♦ aqueous otic or ophthalmic products (contg. the same actives and
excipients)
♦ nebulizer inhalation products or nasal sprays (contg. the same actives
and excipients)
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
Particularity for IR dosage forms
‘BCS-based Biowaiver’.....
.....which is defined as
 in vitro instead of in vivo bioequivalence testing
 comparison of test and reference
....is not defined as
 no equivalence testing
cave: different recommendations in WHO, EU, and FDA!
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Bioequivalence for Immediate Release Dosage Forms
by means of…
 …the ‘parent’ drug substance within a single dose 2-period
crossover design is usually appropriate
 note – special cases
♦
♦
♦
♦
♦
dose- or time-dependent kinetics
specific food recommendations in the SPC
active metabolites
pro-drugs
enantiomers……
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Modified Release (MR) Dosage Forms
 controlled (extended, sustained) release
 delayed release
♦ single unit formulations
♦ multiple unit formulations
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Modified Release (MR) Dosage Forms
generally BE under specific conditions
♦ single dose study (fasting)
♦ multiple dose study (steady state conditions – EU, not FDA)
♦ food-effect study (“dose-dumping” under high-fat
conditions; note: FDA guidance on ‘Food-Effect Bioavailability and
Fed Bioequivalence Studies’, CDER; December 2002)
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
♦ ‚ If a product concerns several strengths…‘
(see e.g. 5.4 EU guidance)
♦
♦
♦
♦
♦
bioequivalence proven for one strength
same manufacturer and manufacturing process
linear drug input (if this is not the case…..)
same qualitative composition of different strengths (WHO)
same ratio between active substance and excipients, or same excipients
in case of low concentration (less than 5 % API)
♦ similar in vitro dissolution (WHO)
 see also guidance for MR products, 5.1 of EU guidance
CPMP/EWP/280/96…
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 …MR products acc. to 5.1 of EU guidance
(CPMP/EWP/280/96)…however, there is a possibility for
♦ single-unit forms:
single dose study in the fasted state for every
strength, multiple dose study may be waived for lower
strengths
♦ multiple-unit forms:
single and multiple dose studies may be waived for
lower strengths in case of identical beeds or pellets
cave: in vitro dissolution studies……..
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
♦ Comparative in vitro dissolution ….
♦ complementary to BE studies (see e.g. 3.7 EU guidance)
♦ comparison of reference products
♦ in vitro/in vivo correlation (only level A for BE decision)
♦ ‚biowaiver‘ – dose proportionality
♦ ‚biowaiver‘ – BCS concept
♦ batch release and other ‚quality issues‘….
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Fixed combination products
 in vivo comparison vs appropriate comparator combination
(or separate comparator products in specific cases)
 general testing criteria apply to all active components
bioequivalence criteria apply to all active components
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Bioequivalence for transdermal therapeutic systems
(TTS)
 BE by means of single and multiple dose studies
 performing a replicate design study is advisable (investigation
of subject by formulation interaction)
 ‘BE’ regarding local tolerability
 dose proportionality issue: thorough in vitro release testing
and exact proportionality (partial effective surface area!)
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
 Bioequivalence for topical dosage forms
without systemic action
EU/WHO  usually therapeutic studies necessary
(therapeutic equivalence, safety and tolerability usually not possible by means
of blood sampling and PK data)
FDA  usually therapeutic studies necessary (specific
FDA guidance for corticosteroids…..)
 possibilities are e.g. skin stripping, microdialysis, NIR…
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
♦ ..inhalatives… metered dose inhalers…(locally
acting)
♦ usually therapeutic studies necessary
♦ in some cases PK studies for safety reasons
♦ in some cases PK studies in addition to in-vitro (‚quality‘ -
deposition characteristics e.g. FPD)
♦ usually in patients
 EU guidances: CPMP/EWP/4151/00 ref. to 75/318/EEC – Council Regulation No
594/91), CPMP/EWP/2922/01, and CPMP/EWP/239/95
 FDA: ‚Critical Path Opportunities for Generic Drugs‘ May 1, 2007
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
Regulatory Requirements for BE
THANK YOU FOR YOUR
ATTENTION
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health