1. Waivers 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

2. Waivers 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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3. Waivers 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 :
cave: solubility limitations…
no data available…
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

4. Waivers 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

5. Waivers 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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6. 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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7. 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

8. 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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9. 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)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

10. 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!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

11. BCS-based biowaiver Evaluation of drug substance and drug product
pharmacodynamic/therapeutic aspects
physicochemical aspects
Drug product
in vitro dissolution
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

12. BCS-based biowaiver RISK assessment “critical use medicines”
(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”
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

13. BCS-based biowaiver Biowaiver justification based on ”………
criteria derived from the concepts underlying
the Biopharmaceutics Classification System ”
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

14. simplified mechanistic view of bioavailability
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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

15. BCS-based biowaiver
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

16. Melting point Charge Solubility Size Shape Ionisa-tion H-bonding
Distribution
Lipophilicity
Amphiphilicity
Fig.1: Physicochemical properties that affect absorption (after oral administration)
[H. van de Waterbeemd/ Eur J Pharm Sci 7 (1998), 1-3]
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

17. BCS-based biowaiver Pillars of the BCS
Solubility Permeability Dissolution
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18. BCS-based biowaiver High solubility
the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH (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?
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

19. 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?
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

20. BCS-based biowaiver
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

21. 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?
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

22. 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?
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

23. 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 ….
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

24. in vitro dissolution prerequisites
BCS-based biowaiver
in vitro dissolution prerequisites
reasonable, stability-indicating, validated methods
discriminative methods
reproducible methods
biorelevant methods (?)
……one fits all?!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

25. BCS-based biowaiver in vitro dissolution and BCS concept
meet prerequisites
ensure risk minimization
justify absence of difference
biorelevant?!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

26. BCS-based biowaiver In vitro comparison of immediate release oral
drug 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!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

27. BCS-based biowaiver In vitro comparison of immediate release oral
drug 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!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

28. Experimental conditions:
BCS-based biowaiver
Experimental conditions:
EU guidance – no specific information yet
US-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!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

29. BCS-based biowaiver In vitro comparison of immediate release oral
drug 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/ sect. 9.2 or app. 2 of the EU guidance; note prerequisites)
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

30. 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!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

31. BCS-based biowaiver
Requirement: either very rapid or “similar” in vitro dissolution
how similar is ‘similar’?
discussion of differences usually not appropriate
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

32. BCS-based biowaiver BCS based biowaiver in vitro dissolution
no iviv correlation
no biorelevant conditions (except pH)
concept to justify absence of difference!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

33. 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

34. BCS-based biowaiver
BCS-based Biowaiver for immediate release drug products
containing highly soluble, highly permeable drug
substances.
No BCS-based biowaiver for:
locally applied, systemically acting products
non-oral immediate release forms with systemic action
modified release products
transdermal products
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

35. BCS-based biowaiver drug solubility is high, permeability is limited,
Provided that
drug solubility is high,
permeability is limited,
excipients do not affect kinetics,
excipients do not interact ,.....
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36. BCS-based biowaiver
....then very rapid dissolution (e.g.>85% in 15 min) of test
and reference may ensure similar product characteristics
because...
....absorption process is probably independent from
dissolution and almost not product related…
 limited absorption kinetics due to poor drug
permeability and/or gastric emptying
Biowaiver for BCS class III drugs
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

37. 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]
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

38. BCS-based biowaiver pH-dependent soluble, highly permeable, weak
acidic, ionizable drug compounds may be handled
like 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

39. 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

40. 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
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

41. THANK YOU FOR YOUR ATTENTION!
BCS-based biowaiver
THANK YOU FOR YOUR ATTENTION!
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health