1. Assessment of Interchangeable Multisource Medicines
BCS-Biowaivers
Dr. Henrike Potthast
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Basis for BCS-based Biowaiver Applications/Decisions
WHO – Technical Report Series No. 937, May 2006
Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability
Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms
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)
EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1

3. Definitions in vitro instead of in vivo ‘bioequivalence’ testing
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

4. 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)

5. 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

6. 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!

7. BCS-based biowaiver Evaluation of drug substance and drug product
pharmacodynamic/therapeutic aspects
physicochemical aspects
Drug product
in vitro dissolution

8. BCS-based biowaiver RISK assessment “critical use medicines”
(see e.g. WHO guidance; 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”

9. BCS-based biowaiver ”………criteria derived from the concepts underlying
Biowaiver justification
based on
”………criteria derived from the concepts underlying
the Biopharmaceutics Classification System ”

10. 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

11. 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]

12. BCS-based biowaiver Pillars of the BCS
Solubility Permeability Dissolution

13. 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)
generate 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?

14. 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?

15. BCS-based biowaiver

16. 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?

17. 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?

18. 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 ….

19. BCS-based biowaiver in vitro dissolution prerequisites
reasonable, stability-indicating, validated methods
discriminative methods
reproducible methods
biorelevant methods (?)
……one fits all?!

20. BCS-based biowaiver in vitro dissolution and BCS concept
meet prerequisites
ensure risk minimization
justify absence of difference
biorelevant?!

21. BCS-based biowaiver In vitro comparison of immediate release oral
drug products (T and R)
first option: very rapidly 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!

22. BCS-based biowaiver In vitro comparison of immediate release oral
drug products (T and R)
second option: rapidly 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!

23. 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 or less; USP buffer; 37 °C
all: no surfactants!

24. 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 guidance sect. 9.2 or app. 2 of the current EU guidance; note prerequisites)

25. 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!

26. BCS-based biowaiver
Requirement: either “very rapid” or “similar” in vitro dissolution
how similar is ‘similar’?
discussion of differences usually not appropriate

27. BCS-based biowaiver BCS-based biowaiver in-vitro dissolution
no iviv correlation
no biorelevant conditions (except pH)
concept to justify absence of difference!

28. BCS-based biowaiver
Evaluation of excipients (e.g., large amounts, possible interactions....; e.g. Isoniazid J Pharm Sci 96 March 2007: “…permeability changes due to excipient interaction cannot be detected in vitro…”)
Evaluation of manufacturing processes in relation with critical physicochemical properties

29. BCS-based biowaiver
BCS-based Biowaiver for immediate release drug products
containing eligible 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

30. BCS-based biowaiver Provided that ...... drug solubility is high,
permeability is limited,
excipients do not affect kinetics,
excipients do not interact ,.....

31. BCS-based biowaiver
....then very rapid dissolution (at least >85% in 15 min) of test
and reference may ensure similar product characteristics
because...
....absorption process is probably independent from
dissolution and not product related…
 limited absorption kinetics due to poor drug permeability and/or gastric emptying
Biowaiver for BCS class III drugs (see WHO guidance)

32. BCS-class III?!
Fig. 1. Mean in vitro dissolution profiles of metformin for 500mg immediate-release tablet of Glucophage® or Glucofit® in 0.1N HCI (○,●) pH 4.6 (□,■) and pH 6.8 (∆,▲) buffer solution.

33. BCS-class III?!
Fig.
Fig. 2. Mean in vivo plasma conentration-time profiles of metformin in 12 healthy Chinese subjects after oral administration of a 500mg immediate-release tablet of Glucophage (○) or Glucofit (●).
Fig. 2

34. BCS-class III?! Clin Pharmacokinet. Jantratid et al 2006
Fig. 1. Comparison of mean cimetidine released-time profiles obtained from dissolution testing of cimetidine tablets containing methacrylate copolymer and Tagamet® tablets in different media. Each value is the mean of six observations. Data for the Tagamet® tablet were obtained from dissolution testing in 0.01N hydrovhloric acid (HCI) and simulated intestinal fluid without pancreatin (SIFsp): (a) 0.01N HCI, pH 2; (b) phosphate buffer, pH 4.5; (c) SIFsp, pH 6.8; and (d) fasted-state simulated intestinal fluid, pH 6.5 pancreatin.
Clin Pharmacokinet. Jantratid et al 2006

35. BCS-class III?!
Fig. 2. Comparison of mean plasma cimetidine concentration-time profiles obtained after
administration of a singel oral dose of cimetidine tablets containing methacrylyte copolymer or
Tagamet® tablets. Each point represents the mean plasma cimetidine concentration (standard
error) from 12 subjects.
Clin Pharmacokinet. Jantratid et al 2006

36. BCS-based biowaiver
♦ biopharmaceutics assessment (with necessary underlying PK background!!) ≠ pure PK assessment
♦ differentiation between solubility (API) and dissolution (product performance)
♦ volume of dissolution medium (900 vs 500 ml) not relevant (no concerns regarding hydrodynamics; recent findings); sink conditions!
♦ in-vitro/in-vivo relationship rather than correlation!!
♦ slow absorption… intestinal transit about 3hs!!

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; see WHO guidance]

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 guidance
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

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

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

41. BCS-based biowaiver no BCS-based biowaiver for RMP
Current recommendation for TB drugs
no BCS-based biowaiver for RMP
‘regular’ BCS-based biowaiver possible for levofloxacin and ofloxacin (“rapid dissolution”)
currently a BCS-based biowaiver is possible for isoniazid (cave: excipients!), ethambutol and pyrazinamide if the same “very rapid” dissolution (T and R) is demonstrated
see specific, currently published WHO guidance documents at:

42. BCS-based biowaiver ex.: Pyrazinamide [Dressman et al., 2008, unpubl.]

43. BCS-based biowaiver ex.: Pyrazinamide [Dressman et al., 2008, unpubl.]

44. BCS-based biowaiver ex.:Pyrazinamide [Dressman et al., 2008, unpubl.]

45. BCS-based biowaiver ex.: Isoniazid [Dressman et al., 2008, unpubl.]

46. BCS-based biowaiver ex.: Isoniazid [Dressman et al., 2008, unpubl.]

47. BCS-based biowaiver ex.: Isoniazid [Dressman et al., 2008, unpubl.]

48. BCS-based biowaiver ex.: Ethambutol [Dressman et al., 2008, unpubl.]

49. BCS-based biowaiver ex.: Ethambutol [Dressman et al., 2008, unpubl.]

50. BCS-based biowaiver ex.: Ethambutol [Dressman et al., 2008, unpubl.]

51. BCS-based biowaiver
Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide; J Pharm Sci Feb 12; [Epub ahead of print]
Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride; J Pharm Sci Apr;97(4):
Vogt M, Derendorf H, Krämer J, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: prednisone; J Pharm Sci Jun;96(6):
Becker C, Dressman JB, Amidon GL, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Barends DM; International Pharmaceutical Federation, Groupe BCS: Biowaiver monographs for immediate release solid oral dosage forms: isoniazid; J Pharm Sci Mar;96(3):
Kalantzi L, Reppas C, Dressman JB, Amidon GL, Junginger HE, Midha KK, Shah VP, Stavchansky SA, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol); J Pharm Sci Jan;95(1):4-14.
Potthast H, Dressman JB, Junginger HE, Midha KK, Oeser H, Shah VP, Vogelpoel H, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen; J Pharm Sci Oct;94(10):
Kortejärvi H, Yliperttula M, Dressman JB, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride; J Pharm Sci Aug;94(8):
Verbeeck RK, Junginger HE, Midha KK, Shah VP, Barends DM: Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride; J Pharm Sci Jul;94(7):
……….

52. THANK YOU FOR YOUR ATTENTION!
BCS-based biowaiver
THANK YOU FOR YOUR ATTENTION!