In Vitro Dissolution Testing

1
Dissolution Testing and Pharmaceutical Equivalence
By Assoc. Prof. Dr. Pornsak Sriamornsak BSc(Pharm
), RPh, MSc(Pharm), Ph.D.(Pharmaceutics)
2
Outline

• Introduction
• Biopharmaceutics Classification System (BCS) and
  Bioequivalence Consideration
• Tablet Evaluation
• Dissolution Testing Conditions
• Dissolution Profile Comparisons
• Biowaivers

3
Introduction

• ??????????????????????????????????????????????????
  ??????????????? ??????????????????????????????????
  ????
• ??????????????????????????????????????????????????
  ?? ?????? ???? ?? ????? ????? ???????????????
  ??????????????????????????????????????????????????
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  ????????? ????????????????????????????????????????
  ??????????????????????????????????
  ?????????????????????? ???????????????????????????
  ????????

4
Introduction

• ??????????? ??????????????????????????????????????
  ???????????????? ????????????? ???????????????????
  ???? ???? ?????????????????????? (evaluation)
  ?????? ???????????????????????????????????????????
  ????????????????????????????????????
  (specification) ???????????????????? (quality
  control) ?????????????????????????????????????????
  ??????????????????????????????????????????????????
  ??????????
• ??????????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ???????????????????????

5
Definition

• Bioavailability ?????????????
• ????????????? ??????? ????? ??????????????????????
  ??????????????????????????????????????????????????
  ?????????????????? ???????????????????????????????
  ?????????? ???????? 2 ?????? ??? Absolute
  bioavailability ?????????????????????????????????
  ?????????????????? ????????????????????
  100 ???? ????????????????????????????????????????
  ??? ??? Relative bioavailability
  ??????????????????????????????????
  ??????????????????????????????????????????????????
  ???????????????????? ???? ????????????????????????
  ?????
• The rate and extent to which the active drug
  ingredient or therapeutic moiety is absorbed from
  a drug product and become available at the site
  of drug action

6
Definition

• Bioequivalence ????????
• ?????????????????????????? ???????????????????????
  ??????????????????????????? ????????
  pharmaceutical alternatives ??????????????????????
  ???? (molar dose) ???????? ???????
  ????????????????????????? ????????????????????????
  ??????????????????????????????????
• The absence of a significant difference in the
  rate and extent to which the active ingredient or
  active moiety in pharmaceuticals equivalents or
  pharmaceutical alternatives become available at
  the site of drug action when administered at the
  same molar dose under similar conditions in an
  appropriately designed study

7
Definition

• Pharmaceutical equivalent ???????????????????????
  ??
• ????????????????????????????????????????
  ???????????????????????????????? ???????????
  ???????????????? ?????????????????????????????????
  ?????????????? ???????????????????????????????????
  ???????????????????????????????????
  ??????????????????????????????????
  ????????????????????????? ????????????????????
  ???/?????????????????????????????????
• Pharmaceuticals are pharmaceutical equivalents if
  they contain the same amount of the same active
  ingredient(s) in the same dosage form if they
  meet the same comparable standards and if they
  are intended to be administered by the same
  route. However, pharmaceutical equivalence does
  not necessarily imply therapeutic equivalence as
  differences in the excipients and/or the
  manufacturing process can lead to differences in
  product performance.

8
Definition

• Therapeutic equivalence ??????????????????????
  ???????
• ????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ??????????????????? ??????????????????????????????
  ???????????????? ???????????????
  ???????????????????? ?????????????????????????????
  ??????????????????????????????????????????????????
  ??????????? ??????????????????????????????????????
  ????????????????????????????????????
  ???????????????????????????????????? ?????????
  ???????????????
• A medicinal product is therapeutically equivalent
  with another product if it contains the same
  active substance or therapeutic moiety and,
  clinically, shows the same efficacy and safety as
  that product, whose efficacy and safety has been
  established.

9
Biopharmaceutics Classification System (BCS)

• A guidance for predicting the intestinal drug
  absorption provided by the U.S. FDA
• Used as a basis for setting in vitro dissolution
  specifications
• Can be also provide a basis for predicting the
  likelihood of achieving a successful in vivo-in
  vitro correlation (IVIVC)

10
Biopharmaceutics Classification System (BCS)

• Goals of the BCS Guidance
• Predict in vivo performance of drug products from
  in vitro measurements of permeability and
  solubility
• To improve the efficiency of drug development and
  the review process by recommending a strategy for
  identifying expendable clinical bioequivalence
  tests.
• To recommend a class of immediate-release (IR)
  solid oral dosage forms for which bioequivalence
  may be assessed based on in vitro dissolution
  tests.
• To recommend methods for classification according
  to dosage form dissolution, along with the
  solubility and permeability characteristics of
  the drug substance.

11
Biopharmaceutics Classification System (BCS)
Solubility
Case 3 High solubility - Low permeability
Case 1 High solubility- High permeability -Rapid
dissolution drugs
Case 4 Low solubility- Low permeability drugs
Case 2 Low solubility- High permeability drugs
Permeability
12
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14
Biopharmaceutics Classification System (BCS)

• CLASS BOUNDARIES
• HIGHLY SOLUBLE the highest dose strength is
  soluble in 250 ml water over a pH range of 1 to
  7.5 at 37C
• HIGHLY PERMEABLE the extent of absorption
  in humans is determined to be gt 90 of an
  administered dose, based on mass-balance or in
  comparison to an intravenous reference dose.
• RAPIDLY DISSOLVING 85 of the labeled
  amount of drug substance dissolves within 30
  minutes using USP apparatus I or II in a volume
  of 900 ml buffer solutions.

15
Biopharmaceutics Classification System (BCS)

• Case 1 and case 3 drugs 85 dissolution in 0.1N
  HCl in 15 minutes
• Bioavailability of the drug is not limited by
  dissolution

16
Biopharmaceutics Classification System (BCS)

• DISSOLUTION DETERMINATION
• USP apparatus I (basket) at 100 rpm or USP
  apparatus II (paddle) at 50 rpm.
• Dissolution media (900 ml) 0.1 N HCl or
  simulated gastric fluid, pH 4.5 buffer, and pH
  6.8 buffer or simulated intestinal fluid.
• Compare dissolution profiles of test and
  reference products using a similarity factor
  (f2).

17
Quality Control for Tablets

• ???????? (Raw Materials)
• ?????????????? (In-Process)
• ?????? (Granules)
• ?????? (Tablets)
• ?????????????????? (Finished Products)

18
Quality Control for Tablets

• In-process Control for Tablets
• ????????????????????????????????????????
  ?????????????????????????? ???????????????????????
  ??? ??????????????????????????????????????????
  ????????????????????????? ????????????????????????
  ?????????? ?????? ???????????????????? weight
  variation ???????? ??????? ?????????
  ??????????????????????????????????????????????????
  ?????????????????????????
• Finished Products
• ??????????????????????????????????????????????????
  ????????????? ??????????????????????????????????
  ??????????????????????????????????????????????????
  ??????????????????????
• ????????????????????????????????????
  ??????????????????????????? ??????????????????????
  ?????????????????????????? ?????? ?????????????
  weight variation, content uniformity, amount of
  active ingredient, loss on drying ?????????
  ???????????????? ????????????????????
  (bioavailability) ???????

19
Tablet Evaluation

• ?????????????????? (Physical properties)
• ??????????????????????????????????????????????????
  ???? ?????? ??????? ?????? ?? ??????????
  ?????????????????????????????? ???????????????????
  ??????????????????????????????????????????
  ?????????????????????? ??????
• ????????????????????? (weight variation)
• ??????? (thickness)
• ???????? (hardness)
• ????????? (friability)
• ?????????????????? (disintegration)
• ????????????????????? (dissolution)

20
Tablet Evaluation

• ???????????????? (Chemical properties)
• ??????????????????????????????????????????????????
  ?? ????????????????????????????????????
  ??????????????????????????????????? ??????
  ??????????????????? (identification)
  ?????????????????????????????????????????????
  (uniformity of content) ??????????????????????????
  ?? (assay) ???????
• ?????????????????? (Biological properties)
• ??????????????????????????????????????????????????
  ???????? ???? ?? ????? ????????????????? ??????
  ????????????????????? (bioavailability)
  ??????????????????? (toxicity test)
  ????????????????? (clinical test) ???????

21
Weight of Tablets

• Uniformity of dosage unit (USP 27)
• Uniformity of weight or mass (BP)

22
Uniformity of dosage unit

• Uniformity of dosage unit
• ??????????????????????????????????????????????????
  ??????
• ???????????????????????? 2 ????
• ????????????????????? (weight variation)
• ????????????????????????????????? (content
  uniformity)

23
Uniformity of dosage unit

• ????????????????????? (weight variation USP27)
• ??????????????????????????????????????????????????
  ?????????????????????? gt 50 ??.
  ?????????????????????? gt 50 ???????????????????
  (?????????????????????????????????????????????????
  ???????)
• ?????????
• ?????????????????????????????????? 30 ????
• ??????????????????????????????? 10
  ????????????????
• ????????????????????
• ?????????????????????????????????????????? 10
  ???? ?????????????????????? content uniformity
  ????????????????? monograph
• ?????????????????????????????????????????????? 4
  ??????????????????????????????????????????????????
  ????????

24
Uniformity of dosage unit

• ????????????
• ????????????????????????
• ????????????????????????????????????? 10
  ?????????????? 85.0-115.0 ?????????????????????
  ?????? RSD lt 6.0 (RSD 100s / x )
• ??????????? 1 ??????????????? 85.0-115.0
  ??????????????????????????????????????????????????
  ?????? 75.0-125.0 ??????????????????????????
  ???? RSDgt 6.0 ???????? 2 ???? ???????????????????
  ?????? 20 ????
• ?????????????????? 1 ???????????????????? 30
  ??????????????? 85.0-115.0 ??????????????????????
  ??????????????????????????????? 75.0-125.0
  ?????????????????????????? ??? RSD ?????????????
  30 ??????????? 7.8

25
Uniformity of dosage unit

• ????????????????????????????????? (content
  uniformity USP27)
• ??????????????????????????????????????????????????
  ????????????? ????????????????????????????????????
  ??????????????????????????? ??????????????????????
  ??????????????????????????? ??????????????????????
  ??????????????????????????????????????????????????
  ? ??????????????????????????????
• ??????????????????????????????????????????????????
  ?????????????????????????????????? gt 50 ??.
  ?????????????????????? gt 50 ????????????????????
  
• ?????????
• ?????????????????????????????????? 30 ????
• ?????????????????????????????????????????????????
  10 ???? ?????????????????????????? monograph

26
Uniformity of dosage unit

• ????????????
• ????????????????????????
• ????????????????????????????????????? 10
  ?????????????? 85.0-115.0 ???????????????????????
  ?????? RSD lt 6.0
• ??????????? 1 ??????????????? 85.0-115.0
  ??????????????????????? ??????????????????????????
  ??????? 75.0-125.0 ??????????????????????? ????
  RSD gt 6.0 ???????? 2 ???? ???????????????????????
  ?? 20 ????
• ?????????????????? 1 ???????????????????? 30
  ??????????????? 85.0-115.0 ??????????????????????
  ? ?????????????????????????????? 75.0-125.0
  ??????????????????????? ??? RSD ????????????? 30
  ??????????? 7.8

27
???????????????? x 100 ?????????????????????
Assay
28

• RSD 100s / x
• (100 x 7.2624) / 102.3327
• 7.0968 (gt 6.0 )
• ???????????????????????????????????? 20 ????

29
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30

• RSD 100s / x
• (100 x 3.2657) / 100.0208
• 3.2650 (lt 6.0 )
• ????????????????????????????????????

31
Uniformity of weight (BP)

• ????????????????????????????????????????????????
  ????????????? (BP2001) ???????????????????????????
  ???????????????????????????????????????? ????
  ???????? ???????? ????????????????????????????????
  ?? ??????????????? ??????????????????
• ?????????
• ??????????????????????? 20 ????
• ??????????????????????????????????????
• ????????????????????
• ??????????????????????????????????????????????????
  ??????????????????????????????? (?????????????)

32
Uniformity of weight (BP)

• ????????????
• ??????????????????????????????????????? 2
  ??????????????????????????????????????????????????
  ????????????????????????????????
  ??????????????????????????????????????????????????
  2 ????????????????????????????

33
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34
Uniformity of content (BP)

• ????????????????????????????????????????????????
  ? ????????????????????????????????????????????????
  
• ?????????
• ??????????????????????? 10 ????
• ?????????????????????????????????????????????? 10
  ???? ???????????????????? monograph

35
Uniformity of content (BP)

• ????????????
• ????????????????????????
• ???????????????????????????????????????????????
  85.0-115.0 ????????????????????????????
• ??????????? 1 ??????????????? 85.0-115.0
  ????????????????? 75.0-125.0 ????????????????????
  ???????? ???????????????????????? 20 ????
  ??????????????????????????????????????????
  ??????????????????????????????????????? 1
  ???????????????????? 30 ???????????????
  85.0-115.0 ????????????????????????????
  ?????????????????????????????? 75.0-125.0
  ????????????????????????????
• ??????????????????????
• ?????????????????? 1 ?????????????????????????????
  ???? 85.0-115.0 ????????????????????????????
  ??????????????? 1 ??????????????? 75.0-125.0
  ????????????????????????????

36
???????????????? x 100 ?????????????????????
Assay
37
Disintegration

• ??????????????????????????????? (solution)
  ?????????????????????????????????
  (disintegration) ???? ????????????????????????????
  ????????????????????????????????????
  (dissolution) ????????????????????????????????????
  ???????????????????
• ??????????????????????????????????????????????????
  ?????????????????????????????????????????
• ??????????????????????????????????????????????????
  ????????????????????????????????????
  ???????????????????????????????????????????????

38
Disintegration

• ?????????????? USP ??? BP ????????????????????????
  ?????????????????????? ??????????????
• ?????????????? (lozenges) ?????? (chewable
  tablets) ???? sustained-release tablets
  ?????????????????????

39
Dissolution

• ????????????????????????????? ????????????????????
  ???????????????????????????????
  ?????????????????????????????????????????????
  ??????????????????????????????????????????????????
  ??????????????????????????????????
• ?????????????????????????????? (Tablet
  Dissolution) ?????????????????????????????????????
  ?????????????????????? ???????????????????????????
  ??????????????????????????????????????????????????
  ????
• ??????????????????????????????????????????????????
  ?????????????????????????????????????????????????
  ?????????????????????????????????????????????

40
Dissolution

• Tablet Dissolution is a standardized method for
  measuring the rate of drug release from a dosage
  form. The principle function of the dissolution
  test may be summarized as follows
• Optimization of therapeutic effectiveness during
  product development and stability assessment.
• Routine assessment of production quality to
  ensure uniformity between production lots.

41
Dissolution

• Assessment of bioequivalence, that is to say,
  production of the same biological availability
  from discrete batches of products from one or
  different manufacturers.
• Prediction of in-vivo availability, i.e.
  bioavailability (where applicable).

42
Dissolution Testing Conditions

• Dissolution apparatus
• Dissolution medium
• Agitation
• Validation

43
Dissolution Apparatus
44
Dissolution Apparatus
USP Dissolution Apparatus 1 USP Dissolution
Apparatus 2 (Basket) (Paddle)
45
Dissolution Apparatus
(a) (b) (c)
(d) Baskets for dissolution apparatus 1 (a)
standard 40-mesh basket, (b) 20-mesh basket, (c)
10-mesh basket and (d) suppository basket.
(a) (b) Paddles for dissolution
apparatus 2 (a) PTFE coated paddle and (b) solid
PTFE paddle.
46
Dissolution Apparatus
USP Dissolution Apparatus 3 (Reciprocating
Cylinder)
47
Dissolution Apparatus
USP Dissolution Apparatus 4 / BP Dissolution
Apparatus 3 (Flow-through Cell)
48
Dissolution Apparatus
USP Dissolution Apparatus 5 (Paddle over Disk)
USP Dissolution Apparatus 6 (Cylinder)
49
Dissolution Apparatus
USP Dissolution Apparatus 7 (Reciprocating Holder)
50
Dissolution Medium

• Carried out under physiological conditions
  (370.5C) or based on physicochemical
  characteristics of the drug substance and the
  environmental conditions the dosage form might be
  exposed
• Allow interpretation with regard to in vivo
  performance of the product

51
Dissolution Medium

• Volume generally 500, 900 or 1,000 ml
• Simulate gastric fluid (SGF) pH 1.2
• Simulate intestinal fluid (SIF) pH 6.8 (not
  exceed pH 8.0)
• The need for enzymes should be evaluated
  case-by-case (pepsin with SGF and pancreatin with
  SIF)
• Use of a surfactant is recommended for water
  insoluble or sparingly soluble drug products

52
Agitation

• Mild agitation conditions should be maintained
  during dissolution testing
• Basket method 50-100 rpm
• Paddle method 50-75 rpm

53
Validation

• The system suitability test using calibrators
• Deaeration (if necessary)
• Validation between manual and automated
  procedures
• Validation of a determinative step

54
Dissolution Profile

• Standard curve

55
Dissolution Profile
56
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57
Dissolution Profile
58
Dissolution Profile Comparisons

• To ensure batch-to-batch consistency
• To signal potential problems with in vivo
  bioavailability
• For accepting product sameness under
  SUPAC-related changes
• To waive bioequivalence requirements for lower
  strengths of a dosage form
• To support waivers for other bioequivalence
  requirements

59
Dissolution Profile Comparisons

• May be considered similar by virtue of
• Over all profile similarity
• Similarity at every dissolution sample time point

60
Dissolution Profile Comparisons

• Statistical methods based in the analysis of
  variance or in t-student tests
• Single time point dissolution
• Multiple time point dissolution
• Model-independent methods
• Similarity factor
• Multivariate confidence region procedure
• Model-dependent methods

61
Dissolution profile comparison

• Model-independent approach using a similarity
  factor
• Difference factor (f1) calculates difference
  between 2 curves at each time point
• Measurement of the relative error between 2
  curves
• n number of time point
• Rt dissolution value of the reference batch at
  time t
• Tt dissolution value of the test batch at time
  t

62
Dissolution profile comparison

• Model-independent approach using a similarity
  factor
• Similarity factor (f2) a logarithmic reciprocal
  square root transformation off the sum of square
  error
• Measurement of the similarity in the
  dissolution between 2 curves

63
Model independent approach using a similarity
factor

• Determine the dissolution profile of two products
  (12 units each) of the test and reference
  products
• Using the mean dissolution values from both the
  curves at each time interval, calculate f1 and f2
• For curves to be considered similar
• f1 close to 0 (0-15)
• f2 greater than 50 (50-100)

64
Model independent approach using a similarity
factor

• This model method is most suitable when 3-4 or
  more dissolution time points are available
• The dissolution measurements of the test and
  reference batches should be made under exactly
  the same conditions
• Only one measurement should be considered after
  85 dissolution of both the products
• The percent coefficient of variation at the
  earlier time point should not be more than 20
  and at other time points should not be more than
  10

65
Model independent multivariate confidence region
procedure

• Suitable when batch variation is more than 15 CV
• The following steps are suggested
• Determine the similarity limits in terms of
  multivariate statistical distance (MSD) based on
  interbatch differences in dissolution from
  reference batch
• Estimate the MSD between the test and reference
  mean dissolution
• Estimate 90 confidence interval of true MSD
  between the test and reference batches
• Compare upper limit of the confidence with the
  similarity limit

66
Model dependent approaches

• Select most appropriate mathematical model for
  the standard batches (linear, quadratic,
  logistic, and Weibull models)
• Using data for the profile generated for each
  unit, fit the data to model
• A similarity region is set based on variation of
  parameters of the fitted model for test units
  from the standard approved batches
• Calculate the MSD in model parameters between
  test and reference batches
• Estimate the 90 confidence region of the true
  difference between the two batches
• Compare the limits of the confidence region with
  the similarity region

67
SUPAC-IR Guidance

• Defines the levels of changes, recommend tests
  and filling document to ensure product quality
  and performance of reference with post approval
  changes in
• Component and composition
• Site of manufacturing
• The scale of manufacturing
• Process and equipment changes in the manufacturing

68
SUPAC-IR Guidance

• Recommend dissolution profile comparisons for
  approving difference level of changes and
  documenting product sameness between the test and
  reference product
• Using a model independent approach and the
  similarity factor to compare dissolution profile

69
IVIVC (In vitro dissolution/in vivo
bioavailability correlations)
Source V. R. S. Uppoor . (2001), Journal of
Controlled Release (72), 127-132.
70
IVIVC (In vitro dissolution/in vivo
bioavailability correlations)
Source V. R. S. Uppoor . (2001), Journal of
Controlled Release (72), 127-132.
71
IVIVC (In vitro dissolution/in vivo
bioavailability correlations)

• Levels of correlation
• Level A
• Level B
• Level C
• Multiple level C

72
Level A Correlation

• Represent a point-to-point relationship between
  in vitro dissolution and in vivo input rate
• Refer to a predictive mathematical model for the
  relationship between the entire in vitro
  dissolution time course and the entire in vivo
  response time course
• Linear, but nonlinear correlations are also
  acceptable

73
Level A Correlation
Source R. C. Rossi et al (2007), International
Journal of Pharmaceutics. (Article In Press)
74
Level B Correlation

• Predictive mathematical model for the
  relationship between summary parameters that
  characterize the in vitro and in vivo time
  courses e.g.
• Mean in vitro dissolution time versus mean in
  vivo dissolution time
• Mean in vitro dissolution time versus mean
  resident time in vivo
• Not very useful because of many different
  dissolution and plasma concentration profiles and
  shapes can give the same mean summary parameters

75
Level C Correlation

• A single point relationship between a dissolution
  parameter and a pharmacokinetic parameter
• Useful in early formulation development

76
Multiple Level C Correlation

• One or several pharmacokinetic parameters of
  interest to the amount of drug dissolved at
  several time points of the dissolution profile
  e.g.
• Cmax versus dissolved in 2, 6 and 12 hours

77
Biowaivers

• Bioequivalence study may be replaced by in
  vitro dissolution testing. When such a
  substitution is allowed by registration
  authorities this is referred to as a "biowaiver".

78
Biowaivers

• Biowaivers without an IVIVC
• Biowaivers based on IVIVC
• Waiver of in vivo bioequivalence based on BCS

79
Biowaivers without an IVIVC

• New drug application of immediate-release drug
  products
• Clinical safety and/or efficacy studies including
  data on the dose and the desirability of the
  higher strength
• Linear elimination kinetics over the therapeutic
  dose range
• The higher strength being proportionally similar
  to the lower strength
• The same dissolution procedures being used, and
  similar result obtained in the approved medium

80
Biowaivers without an IVIVC

• Modified-release drug products
• Beaded capsules-lower strength
• Tablets-lower strength

81
Biowaivers based on IVIVC

• In vivo bioequivalence studies for extended
  release products could be waived If the sponsor
  has developed a correlationwhose predictability
  has been evaluated
• The waiver is granted if the difference in the
  predicted mean CMAX and AUC between the test and
  reference product is not more than 20

82
Biowaivers based on IVIVC

• For generic products to qualify for this
  biowaiver, one of the following situations should
  exist
• Bioequivalece has been established for all
  strengths of the reference-listed product
• Dose propositionally has been established for the
  reference-listed product, and all reference
  product strengths are compositionally
  proportional or qualitatively the same, have the
  same release mechanism, and the in vitro
  dissolution profiles of all strength are similar

83
Biowaivers based on IVIVC

• Bioequivalence is established between the generic
  product and the reference-listed product at the
  highest and lowest strengths and for the
  reference-listed product, all strengths are
  compositionally proportional or qualitatively the
  same, have the same release mechanism, and the in
  vitro dissolution profiles are similar

84
Waiver of in vivo bioequivalence based on BCS

• Applicable to immediate release products only
• Not applicable to narrow therapeutic range drugs
• The drug substance should be highly soluble and
  highly permeable and the drug product should be
  rapidly dissolving (BCS case 1)

85
Waiver of in vivo bioequivalence based on BCS

• When requesting a BCS-based waiver for in vivo
  BA/BE studies for IR solid oral dosage forms,
  applicants should note that the following factors
  can affect their request or the documentation of
  their request
• Excipients
• Prodrugs
• Exceptions
• Narrow Therapeutic Range Drugs
• Products Designed to be Absorbed in the Oral
  Cavity

86
Data To Support a Request for Biowaivers

• Data Supporting High Solubility
• Data Supporting High Permeability
• Data Supporting Rapid and Similar Dissolution
• Additional Information
• The manufacturing process used to make the test
  product should be described briefly to provide
  information on the method of manufacture (e.g.,
  wet granulation vs. direct compression). A list
  of excipients used, the amount used, and their
  intended functions should be provided. Excipients
  used in the test product should have been used
  previously in FDA-approved IR solid oral dosage
  forms.

87
European Guidance for an In Vivo
Bioavailability/Bioequivalence Waivers

• If a new application concerns several strengths
  of the active substance, a bioequivalence study
  investigating only 1 strength may be
  acceptable(the choice of the strength used should
  be justified on analytical, pharmacokinetic, and
  safety grounds)

88
European Guidance for an In Vivo
Bioavailability/Bioequivalence Waivers

• All of the following conditions should be
  fulfilled
• The pharmaceutical products are manufactured by
  the same manufacturer and process
• The drug input has been shown to be linear over
  the therapeutic dose range
• The qualitative composition of the different
  strengths should be the same
• The ratio between amounts of active substance and
  excipients is the same
• The dissolution profile should be similar under
  identical conditions for the additional strengths
  and the strength of the batch used in the
  bioequivalency study

89
Canadian Guidance for an In Vivo
Bioavailability/Bioequivalence Waivers

• Uncomplicated drug in which the proportions of
  excipients to the drug and the dissolution
  characteristics are the same, it is sufficient to
  establish the bioavailability of one strength
• For some of complicate drugs such as those with
  narrow therapeutic range, steep dose response
  characteristics, or nonlinear kinetics, a single
  dose bioavailability study should be conducted on
  each strength