Post on 15-Dec-2015
Federal Institute for Drugsand Medical Devices
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Waivers of in-vivo BE studiesWaivers of in-vivo BE studies
Evaluation of Quality and Interchangeability of Medicinal Products
10 – 14 September 2007
Dar Es Salaam, Tanzania
Dr. Henrike Potthast; Temporary Advisor to WHO
Federal Institute for Drugsand Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
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Waivers of in-vivo BE studiesWaivers of in-vivo BE studies
♦ ‚ 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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Waivers of in-vivo BE studiesWaivers of in-vivo BE studies
…the ‚sensitive‘ strength in case of non-linearity
♦ increase more than proportional:
bioequivalence testing with the highest strength
♦ increase less than proportional :
bioequivalence testing with the highest strength
cave: solubility limitations…
no data available…
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Waivers of in-vivo BE studiesWaivers of in-vivo BE studies
…what to do in case of…
♦ solubility limitations:
bioequivalence testing with the highest strength (or dose) even with linear kinetics
♦ no or inconclusive data on linearity available:
bioequivalence testing with the lowest and highest strength
Federal Institute for Drugsand Medical Devices
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Waivers of in-vivo BE studiesWaivers of in-vivo BE studies
…MR products acc. to 5.1 of EU guidance (e.g.
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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Basis for BCS-based Biowaiver Applications/Decisions
FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000)
WHO – working document on multisource (generic) pharmaceutical products (QAS/04.093)
WHO – working document on a proposal to waive in vivo bioequivalence (QAS/04.109)
EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1
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Definitions
BCS-based ‘Biowaiver’.....
.....is defined as
in vitro instead of in vivo ‘bioequivalence’ testing comparison of test and reference
....is not defined as
no equivalence test
Federal Institute for Drugsand Medical Devices
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Definitions
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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Definitions
acc. to the FDA guidance:
”BCS-based biowaivers are intended only for
bioequivalence studies. They do not apply to
food effect bioavailability studies or other
pharmacokinetic studies.”
(e.g., rel. bioavailability)
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BCS-based biowaiver
In vivo bioequivalence testing is generally required
but
” Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.”
for oral immediate release dosage forms with
systemic action!
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BCS-based biowaiver
Evaluation of drug substance and
drug product
Drug substance pharmacodynamic/therapeutic aspects physicochemical aspects
Drug product in vitro dissolution
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BCS-based biowaiver
RISK assessment (see e.g. WHO QAS/04/093/rev4) sect. 9.2 and 5.1.(a))
♦ “critical use medicines” ♦ “narrow therapeutic index drugs”♦ “documented evidence for BA or BE problems♦ “scientific evidence that API polymorphs, excipients or the
manufacturing process affects BE”
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BCS-based biowaiver
Biowaiver justification
based on
”………
criteria derived from the concepts underlying
the Biopharmaceutics Classification System ......”
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BCS-based biowaiver
Biopharmaceutics Classification System (BCS)
dissolution
drug product drug substance in solution
membrane transport drug substance in the system
simplified mechanistic view of bioavailability
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BCS-based biowaiver
Federal Institute for Drugsand Medical Devices
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Fig.1: Physicochemical properties that affect absorption (after oral administration) [H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3]
Melting point
Charge
Ionisa-tion
H-bonding
Lipophilicity
Size Shape
ChargeDistribution
Amphiphilicity
Solubility
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BCS-based biowaiver
Solubility Permeability Dissolution
Pillars of the BCS
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BCS-based biowaiver
High solubility
the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C)
create a pH-solubility profile
cave: possible stability problems have to be considered
• Discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility • Definition of low solubility?
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BCS-based biowaiver
High permeability♦ EU guidance: ”Linear and complete absorption reduces the possibility of
an IR dosage form influencing the bioavailability”
♦ FDA guidance: absolute BA >90 %♦ WHO guidance: at least 85 % absorption in humans
• Human data are preferred; in vitro data may be submitted if sufficiently justified and valid
• Definition of low permeability?
Federal Institute for Drugsand Medical Devices
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BCS-based biowaiver
Federal Institute for Drugsand Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
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BCS-based biowaiver
♦ ….if the fraction of the dose absorbed is the same, the human body should always do the same with the absorbed compound …Even in a disease state, this argument is still a valid statement.
[Faassen et al. Clin Pharmacokinet 43 (2004)1117]
what does the product do to the drug substance?
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BCS-based biowaiver
When are in vitro results sufficient for bioequivalence evaluation?
When is in vitro instead of in vivo bioequivalence testing scientifically justified (or even more restrictive)?
Minimizing risk by means of ‘worst case’ investigation?
Which in vitro investigations may be sufficient?
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BCS-based biowaiver
in vitro dissolution objectives
quality control justification of minor variations iviv-correlation (e.g. major variations; bridging) additional to BE studies proportionality based biowaiver BCS based biowaiver ….
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BCS-based biowaiver
in vitro dissolution prerequisites
reasonable, stability-indicating, validated methods discriminative methods reproducible methods biorelevant methods (?)
……one fits all?!
Federal Institute for Drugsand Medical Devices
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BCS-based biowaiver
in vitro dissolution and BCS concept
meet prerequisites ensure risk minimization justify absence of difference
biorelevant?!0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20
time
%
Federal Institute for Drugsand Medical Devices
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BCS-based biowaiver
In vitro comparison of immediate release oraldrug products (T and R)
first option: very rapidely dissolving products Not less than 85 % of labeled amount are dissolved within
15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required
reasonable, validated experimental conditions/methods are strongly recommended!
Federal Institute for Drugsand Medical Devices
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BCS-based biowaiver
In vitro comparison of immediate release oraldrug products (T and R)
second option: rapidely dissolving products Not less than 85 % of labeled amount are dissolved within
30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer)
reasonable, validated experimental conditions/methods are strongly recommended!
Federal Institute for Drugsand Medical Devices
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BCS-based biowaiver
Experimental conditions:EU guidance – no specific information yetUS-FDA guidance – ‚USP‘-conditions
50 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C
WHO – 75 rpm (paddle) or 100 rpm (basket); 900 ml; USP buffer; 37 °C
no surfactants!
Federal Institute for Drugsand Medical Devices
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BCS-based biowaiver
In vitro comparison of immediate release oraldrug products (T and R)
Proving similarity of dissolution profiles of T and R
e.g., using f2-test, unless similarity is obvious
(see e.g. WHO QAS/04.093 sect. 9.2 or app. 2 of the EU guidance; note prerequisites)
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BCS-based biowaiver
f2-test
acceptance value based on 10 % difference between profiles
„identical“ profiles: f2 =100
„similar“ profiles: f2 between 50 and 100 (?!)
any other reasonable/justified test possible!
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BCS-based biowaiver
Requirement: either very rapid or “similar” in vitro dissolution
how similar is ‘similar’? discussion of differences usually not appropriate
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BCS-based biowaiver
BCS based biowaiver in vitro dissolution
no iviv correlation
no biorelevant conditions (except pH)
concept to justify absence of difference!
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BCS-based biowaiver
Evaluation of excipients (e.g., large amounts, possible interactions....; e.g. Isoniazid J Pharm Sci 96 March
07: “…permeability changes due to excipient interaction cannot be detected in vitro…”)
Evaluation of manufacturing processes in relation with critical physicochemical properties
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BCS-based biowaiver
BCS-based Biowaiver for immediate release drug products containing highly soluble, highly permeable drugsubstances.
No BCS-based biowaiver for:
locally applied, systemically acting products non-oral immediate release forms with systemic action modified release products transdermal products
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BCS-based biowaiver
Provided that ......
drug solubility is high, permeability is limited, excipients do not affect kinetics, excipients do not interact ,.....
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BCS-based biowaiver
....then very rapid dissolution (e.g.>85% in 15 min) of testand reference may ensure similar product characteristics because.......absorption process is probably independent fromdissolution and almost not product related…
limited absorption kinetics due to poor drug permeability and/or gastric emptying
Biowaiver for BCS class III drugs
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BCS-based biowaiver
For drugs showing ....
‘very’ high permeability
pH-dependent solubility within the physiologically relevant pH range
.....an ‘intermediate solubility’ class is suggested
[Polli et al. J Pharm Sci 93 (2004) 1375]
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BCS-based biowaiver
pH-dependent soluble, highly permeable, weakacidic, ionizable drug compounds may be handledlike BCS class I drugs (e.g. chpt 8 in: Drug Bioavailability, van de
Waterbeemd, Lennernäs, Artursson (edts) 2003 Wiley-VCH)
in vitro dissolution requirements acc. to WHO doc at least 85% within 30 min at pH 6.8 and
f2 testing for pH 1.2 and 4.5 profiles
but no biowaiver for weak basic drugs
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BCS-based biowaiver
meaningful literature data may be used for drug substance characteristics (and excipients)
product related data must always be actually generated for the particular product
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BCS-based biowaiver
BCS-based biowaiver are not just in-vitro dissolution, but in-vitro dissolution is meant to be an important part of BCS-based biowaiver applications