1. Biowaivers Drs. Jan Welink
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, October, 2010

2. Guidance 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 and Bioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1

3. Different approach for establishing equivalence
Bioequivalence
Different approach for
establishing equivalence
Standard:
in vivo BE studies
PD studies
clinical
studies
in vitro
methods

4. Bioequivalence Cases, where the regulatory authorities have to decide
whether a bioequivalence study is mandatory or not:
inside a product:
- scale up processes
- line extensions
- variation after marketing authorisation
between different products:
- application of generics without clinical data

5. Biowaivers based on BCS
low permeability
high
solubility
low
HS/HP
Class I
HS/LP
Class III
LS/HP
Class II
LS/LP
Class IV
high permeability

6. BCS
2 variables:
Solubility
Permeability

7. BCS VIEW of BIOEQUIVALENCE
if two products, containing the same drug, have the same
concentration-time profile at the intestinal membrane surface
then they will have the same rate and extent of absorption
same in vivo dissolution profile under all luminal conditions
- formulation components do not effect the membrane
permeability and/or intestinal transit
(Amidon et al.1995)

8. Biopharmaceutics Classification System (BCS)
dissolution
drug product  drug substance in solution
membrane transport
 drug substance in the system
simplified mechanistic view of bioavailability

9. BCS
Dissolution, solubility, and intestinal permeability are the three major factors that govern the rate and extent of absorption of a drug that is stable in the GI tract
TIME (hours)
Fluid volume pH
hydrodynamics
surface tension
other….
Stomach
Small Intestine (major site for absorption)

10. BCS Class Boundaries: Objectives
Dissolution
(Product)
Very rapid/rapid dissolution - ensure that in vivo dissolution is not likely to be the
“rate determining” step
Solubility (Drug)
High solubility- ensure that solubility
is not likely to limit dissolution and, therefore, absorption
Permeability
(Drug)
High permeability - ensure that drug
is completely absorbed during the limited
transit time through the small intestine

11. Very rapid dissolution:
BCS
Very rapid dissolution:
An IR drug product is considered VERY RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 15 minutes
Rapid dissolution:
An IR drug product is considered RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 30 minutes

12. BCS
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)
250 ml: derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (approximately 250 ml) water

13. pH in the gastro-intestinal tract
BCS
pH in the gastro-intestinal tract

14. BCS
Highly permeable:
A drug substance is considered HIGHLY PERMEABLE when extent of absorption in humans is determined to be > 85% of an administered dose, based on a mass balance determination or in comparison to an intravenous reference dose, in the absence of evidence suggesting instability in the gastrointestinal tract.
Intestinal membrane permeability may be determined by in vitro or in vivo methods that can predict extent of drug absorption in humans.

15. BCS
Highly permeable:
EU guidance: linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailavility (absorption >85%).
FDA guidance: absolute bioavailability >90%.

16. BCS Rapid (and similar) High Dissolution Solubility High Permeability
3 variables:
Rapid (and similar)
Dissolution
High
Solubility
High
Permeability

17. BCS Rapid (and similar) High Dissolution Solubility Candidates for
4 variables:
Rapid (and similar)
Dissolution
High
Solubility
Candidates
for
Biowaivers
Therapeutic
Window
High
Permeability

18. in vitro instead of in vivo ‘bioequivalence’ testing
Biowaivers
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

19. Biowaivers
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)

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

21. 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”

22. 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

23. High solubility BCS-based biowaiver
Class I drugs are candidates for a biowaiver:
but what to be adressed?
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
possible stability problems have to be considered
discussion on ‘intermediate solubility’, i.e., pH-dependent (high) solubility

24. High permeability BCS-based biowaiver
WHO guidance: at least 85 % absorption in humans
Pharmacokinetic studies in humans:
- Mass balance or absolute bioavailability
Intestinal Perfusion Methods
- Humans (In Vivo)
- Animals (In Vivo or In Situ)
In Vitro Methods Using Appropriate Membranes
- Excised intestinal tissue
- Monolayer of functional cultured human intestinal cells

25. Dissolution BCS-based biowaiver in vitro dissolution prerequisites
reasonable, stability-indicating, validated methods
discriminative methods
reproducible methods
biorelevant methods ?

26. In vitro comparison of immediate release oral drug products (T and R):
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!

27. In vitro comparison of immediate release oral drug products (T and R):
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!

28. In vitro comparison of immediate release oral drug products (T and R):
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 EU guidance; note prerequisites)
f2 = 50 x log {[ 1 + (1/n) t=1n (Rt – Tt)2 ]-0.5 x 100
inversely proportional to the average squared difference between the R and T profile and measures the closeness between the two profiles (similarity factor)

29. f2-test: BCS-based biowaiver
Acceptance value based on 10 % difference between profiles
„identical“ profiles: f2 =100
„similar“ profiles: f2 between 50 and 100

30. BCS-based biowaiver Additional issues to be addressed
Pharmacokinetics
Excipients
Linear..
BA problems..
Well know/established..
Acceptable quantities..
No interaction PK active substance..
(surfactants, absorption enhancers,
GIT transit time)..

31. BCS-based biowaiver And the other classes? need for BE study LS/LP
risk for differences
LS/LP
LS/HP
HS/LP
HS/HP

32. aqueous solubility at 25°C
BCS-based biowaiver
Class II (LS/HP):
- critical parameter solubility
- due to pH, may be acceptable
solubility (mg/ml) pH 1 2 3 4 5 6 7 8 9 20 40 60 80
100
Verapamil HCl
aqueous solubility at 25°C

33. BCS-based biowaiver
Example of a dissolution profile of an ibuprofen (Class II) tablet formulation at different pH levels: X O pH 2 4 6 8
dissolution (%) 50
100
time (min) 30 60
ibuprofen

34. Class III (HS/LP): BCS-based biowaiver
critical parameter permeability;
but to which extent?
less dependent on formulation
often exhibit site-dependent absorption
(transit time may be critical:
dissolution criteria!!)

35. Experience BCS-based biowaiver
Biowaivers accepted by FDA
Cefadroxil
Galantamine HBr
Labetalol
Levetiracetam
Levofloxin
Memantine HCl
Metoprolol
Ofloxacin
Pramipexole dihydrochloride
Pregabalin
Propanolol
Ramelteon
Rivastigmine HCl
Sotalol HCl
Tiagabine HCl
Timolol
Venafaxine HCl
Presentation LX Yu, January 2006,
SODD workshop, Lake Tahoe

36. Experience BCS-based biowaiver
Biowaivers accepted by Sweden
Phenoxymethylpenicillin
Prednisolone
Transexamic acid
Acetaminophen and codeine
Ibuprofen Presentation of C. Graffner, “Practical Applications of MPA”, Lisboa, April, 2003.

37. Experience BCS-based biowaiver
Biowaivers accepted by The Netherlands
Amoxicillin
Dextromethorfan
Doxycycline
Phenoxymethylpenicillin
Flunarizine
Indomethacin
Isosorbide-5-mononitrate
Lorazepam
Salbutamol
Lormetazepam
Metoprolol
Naproxen
Nitrazepam
Oxprenolol
Acetaminophen
Pindolol
Piroxicam
Temazepam

38. Current situation WHO biowaivers
Based upon this information (Programme experience and applied biowaivers by other NRAs) decision made to select drug substances.
The following drug substances have been identified as eligible for a BCS-based biowaiver application as either monocomponent or fixed-dose combination (FDC) products
Monocomponent or FDC products containing other drug substances must be supported with in vivo BE data

39. World Health Organization
Current situation WHO biowaivers
19 April, 2017
Medicines for HIV/AIDS and related diseases
Lamivudine (Class I)
Stavudine (Class I)
Zidovudine (Class I)
Anti-tuberculosis medicines
Ethambutol (Class III/I)
Isoniazid (Class III/I)
Levofloxacin (Class I)
Ofloxacin (Class I)
Pyrazinamide (Class III/I)

40. World Health Organization
Current situation WHO biowaivers
19 April, 2017
The identified comparators:
HIV/AIDS:
Lamivudine: Epivir 150 and 300 mg tablet
Stavudine: Zerit 30 mg capsule
Zidovudine: Retrovir 300 mg tablet, 100 and 250 mg capsule
 combination: lamivudine/zidovudine: Combivir (150/300 mg)
Anti-tuberculosis medicines
Ethambutol: Myambutol 400 mg tablet
Isoniazid: Isozid (100 mg tablet)/Isoniazid 100 and 300 mg (US RLD)
Levofloxacin: Tavanic and Levaquin (US RLD)
Ofloxacin: Tarivid and Ofloxacin (US RLD)
Pyrazinamide: Pyrazinamide Lederle

41. World Health Organization
19 April, 2017
Class I Drug Substances
Selection of comparator product
Biobatch reflective of proposed commercial product
Comparison of products
Should employ well known excipients in usual amounts
Beneficial to contain similar amounts of the same excipients
Critical excipients (e.g., mannitol, sorbitol, surfactants), if present, should not differ qualitatively or quantitatively

42. World Health Organization
19 April, 2017
Class I Drug Substances
Comparative in vitro dissolution
Comparative testing should ensure the similarity of the test and comparator product in three different pH media considered relevant for absorption from the GI tract
Comparative in vitro dissolution testing should be conducted in at least three media of pH 1.2, 4.5, and 6.8
12 units
Paddle apparatus at 75 rpm or basket apparatus at 100 rpm
Use of surfactants strongly discouraged

43. World Health Organization
19 April, 2017
Class I Drug Substances
‘Very rapidly’ dissolving products
At least 85% of the labelled amount is released within 15 minutes or less from the test and comparator product
In this case, profile comparison is not needed
‘Rapidly’ dissolving products
At least 85% of the labelled amount is released within 30 minutes or less from the test and comparator product
Profile comparison (e.g., f2 testing) required

44. World Health Organization
19 April, 2017
Class III/I Drug Substances
Drug substances are highly soluble but limitations to absorption due to various reasons
Comparison of products (test vs. comparator)
Qualitatively the same excipients
Quantitatively very similar (as per Level 1 change according to SUPAC)
Comparative in vitro dissolution
At least 85% dissolved within 15 minutes for both products
At least 85% dissolved within 30 minutes is acceptable if dissolution profiles are similar and product compositions are very similar

45. World Health Organization
19 April, 2017
Guidance:
Biowaiver application form, identifying clearly what should be submitted.
Detailed information on Test product (generic)
Detailed Information on comparator/reference product (identification).
Comparability between Test and comparator
In vitro dissolution data
Quality assurance

46. Report Format report 1. Purpose of study dissolution test:
2. Products / batch information
• Batch numbers, manufacturing and expiry dates, batch size of the test product, Certificates of Analysis (CoAs) and packaging of the batches used in the study
• Batch manufacturing record(s) for the batch of the test product used in the comparative dissolution study.
3. Full dissolution conditions and method, as well as the number of units (tablets, capsules, etc) per study. It should be indicated how and when the samples were filtered. Any problems with pH related stability of samples should be indicated and discussed in terms of preventive handling measures, analysis and interpretation of data.
4. Analytical method including validation, or reference to the quality part of the dossier.
5. Results (% API dissolved)
• Tabulated (individual results, mean and %CV)
• Graphically
• Similarity determination / f2 calculation if necessary and applicable
6. Conclusion/recommendation.

47. World Health Organization
19 April, 2017
Problems identified:
Wrong comparator
Failing comparability regarding excipients
Failing excluding/including critical excipients
Failing dissolution tests

48. World Health Organization
19 April, 2017
Example: 1.

49. World Health Organization
19 April, 2017
Example: 2.

50. World Health Organization
19 April, 2017
Good news:
Successful BCS-based biowaiver applications have been submitted for HIV/AIDS and anti-tuberculosis products
Successful BCS-based biowaiver applications for FDCs have been submitted
BCS-based biowaiver approach for certain drug substances introduced in 2009
Approaches employed by regulatory authorities considered carefully
Drug substances on Expressions of Interest being reviewed
Potential additions to list of eligible drug substances

51. Biowaivers normally accepted in BE
Immediate release (IR) oral dosage forms:
Possible BE exemptions:
aqueous solution (incl. syrups, elixirs, but no suspensions)
gases
aqueous otic or opthalmic products (containing the same actives and excipients)
nebulizer inhalation products or nasal sprays (containing the same actives and excipients)

52. Biowaivers and dose proportionality
Immediate release (IR) oral dosage forms:
If a product concerns several strengths (EU):
Bioequivalence proven for one strength
Same manufacturer and manufacturing process
Linear pharmacokinetics
Same qualitative composition of different strengths (WHO)
Same ratio between active substance and excipients, or same excipients in case of low concentration active substance (less than 5%)
Similar dissolution profiles (WHO)

53. Dose proportionality

54. Experience

55. Bioanalytical part Critical deviations in %
GCP overview
Bioanalytical part Critical deviations in %

56. Bioanalytical part Major deviations in %
GCP overview
Bioanalytical part Major deviations in %

57. Deficiencies
Overall:
GLP/GCP
no bio-study submitted
insufficient clinical data
Test and Reference product
outside the 90% confidence intervals
Inadequate validation method of the bioanalysis
no submission of dissolution test
study design
outliers

58. subjects Examples Subjects included:
- subjects: normal healthy volunteers, male, years
* report all demographic data
* report all withdrawals from study and reasons why
* protocol: handling!
Exclusion only when:
- subject had vomited shortly after intake of product
- analytical problem

59. Examples
subjects
Case: Report stated that 32 subjects were selected and included in the study.

60. subjects Examples Case: Exclusion of subjects (1).
- protocol 28 subjects enrolled
PK data 24 subjects used as defined by protocol
two drop-outs (for personal reason)
26 subjects completed the study
selection procedure replacements not defined!!
replacements subjects 25 and 27

61. Examples
subjects
Case: Exclusion of subjects (1).
Subject 26:

62. subjects Examples Case: Exclusion of subjects (2).
- number of subjects: 36
used for statistical analysis: 35
reason: low drug plasma levels in one subject
calculated 90% CI: AUC0-t 0.83 – 1.07
Cmax – 1.04
Conclusion: Bioequivalent!

63. Examples
subjects
Case: Exclusion of subjects (2).
subject excluded!

64. subjects Examples Case: Exclusion of subjects (2).
- number of subjects: 36
used for statistical analysis: 36
calculated 90% CI: AUC0-t 0.76 – 1.03
Cmax – 1.02
Conclusion: not bioequivalent!

65. Examples
Blood
sampling
Adequate sampling times and period.
- reliable estimation of Cmax
- reliable estimation of extent of absorption (AUC)
AUC0-t / AUCinf > 80%

66. Examples Blood sampling
Case: sampling scheme.
Drug: literature reported tmax 2 – 7 hours

67. Blood
sampling
Case: tmax.

68. Examples
Test
product
Case: formulation.
Application:
Studied:

69. Examples
Analytical
method
Specificity/selectivity:

70. Results: Pharmacokinetic data
Examples
PK data
Results: Pharmacokinetic data
- check PK results; also C-t curves
- in line with to be expected
- normal variability

71. PK data
Case: Cmax.

72. Examples
PK data
Case: C-t curves.

73. criteria local market ≠ world market GLP fraud
Examples
GCP/GLP
criteria local market ≠ world market
GLP
fraud
original data/documents not available

74. Examples
GCP/GLP
Case: manipulation

75. Example
GCP/GLP
Case: remarkable data

76. Example
GCP/GLP
Case: integration (1)

77. Example
GCP/GLP
Case: integration (2)

78. Example
GCP/GLP
Case: falsified data

79. Example
GCP/GLP
Case: falsified data

80. Thank you for your attention
End
Thank you for your attention