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Development of
dissolution test
 in regards to
bioequivalence
   Alex Mirimsky and Sasha Nezlin

          PDA March 2011
2   Development of Dissolution Test
     in regards to Bioequivalence
3   Development of Dissolution Test
     in regards to Bioequivalence
Biopharmaceutics Classification System (BCS)
    High Solubility - High Permeability Drugs
    Low Solubility - High Permeability Drugs
    High Solubility - Low Permeability Drugs
    Low Solubility - Low Permeability Drugs

FDA: This classification can be used as a
basis for setting in vitro dissolution
specifications and can also provide a basis
for predicting the likelihood of achieving a
successful in vivo-in vitro correlation
(IVIVC).

4               Development of Dissolution Test
                 in regards to Bioequivalence
BCS applications
♦ Highly Soluble API should not have any bioavailability
  problems if, in addition, the dosage system is rapidly
  dissolved in the physiological pH-interval expected after
  product administration and the excipients are known not
  to affect the dissolution, stability and absorption
  processes.
  A bioequivalence study may in those situations be waived
  based on similarity of dissolution profiles which are based
  on discriminatory testing, provided that the other
  exemption criteria in Appendix III are met.
♦ Low Soluble API If an active substance is considered to
  have a low solubility, the rate limiting step for absorption
  may be dosage form dissolution. This is also the case
  when one or more of the excipients are controlling the
  release and subsequent dissolution step of the active
  substance. In those cases a variety of test conditions is
  recommended and adequate sampling should be
  performed until either 90% of the drug is dissolved or an
  asymptote is reached.
  5                   Development of Dissolution Test
                       in regards to Bioequivalence
DISSOLUTION STUDIES
    ♦ In vitro dissolution studies are used to
    assess the product quality.
    ♦ In vitro dissolution rate should correlate
    with in vivo bioavailability.
    ♦ A dosage form with a rapid dissolution
    rate is likely to have a rapid rate of drug
    bioavailability in vivo.
    ♦ Bioavailability is not dependent only on
    the dissolution of the drug product, but
    also on the permeability and solubility of
    the drug substance.

6                  Development of Dissolution Test
                    in regards to Bioequivalence
FDA has defined bioequivalence as "the absence of a
significant difference in the rate and extent to
which the active ingredient or active moiety in
pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug
action when administered at the same molar dose
under similar conditions in an appropriately
designed study."

♦ Bioequivalence studies are for determination of
the    therapeutic   equivalence     between    the
pharmaceutically equivalent generic drug product
and a corresponding reference listed drug.
♦ Bioequivalence studies provide information on
product quality and performance when there are
changes in components, composition and method of
manufacture after approval of the drug product.
7                Development of Dissolution Test
                  in regards to Bioequivalence
Testing of product quality
♦ To get information on the test batches used in
  bioavailability/bioequivalence studies and pivotal
  clinical studies:
  - To investigate batch to batch consistency of both
  test and reference products, to be used as basis for
  the selection of appropriate batches for the in vivo
  study.
  - to support setting specifications for quality control.
♦ To be used as a tool in quality control to demonstrate
  consistency in manufacture.
♦ To support the assumption of similarity between
  products provided that the manufacturing process,
  composition and specifications are similar.
♦ To demonstrate similarity between different
  formulations of an API and the reference product
  (biowaivers e.g., variations, formulation changes
  during development and generic products).
  8                 Development of Dissolution Test
                     in regards to Bioequivalence
In-vitro dissolution test complementary to bioequivalence studies

“The results of in-vitro dissolution tests at pH
1.2, 4.5, 6.8 and the media intended for drug
product release (QC media), obtained with the
batches of test and reference products that
were used in the bioequivalence study should
be reported.”

“Unless otherwise justified, the specifications
for the in vitro dissolution to be used for quality
control of the product should be derived from
the dissolution profile of the test product batch
that was found to be bioequivalent to the
reference product.”
9                     Development of Dissolution Test
                       in regards to Bioequivalence
Biowaiver




10          Development of Dissolution Test
             in regards to Bioequivalence
In vitro dissolution test in support
        of biowaiver and/or strengths
♦ pH 1.2, 4.5, 6.8
♦ Particular dosage forms may require
investigations using physiologically relevant
experimental pH conditions.
♦ Similarity of in vitro dissolution should be
demonstrated at all conditions:
     - between strengths used for
     bioequivalence testing,
     - between additional strengths of the
     developed product and corresponding
     strengths of the reference product.
11              Development of Dissolution Test
                 in regards to Bioequivalence
Pharmacopoeial Test or
            Alternative?

♦ The test methodology should be in
  accordance with pharmacopoeial
  requirements unless those requirements
  are shown to be unsatisfactory and/or do
  not reflect the in vivo dissolution (i.e.
  biorelevance).
♦ Alternative methods can be considered
  when justified that these are
  discriminatory and able to differentiate
  between batches with acceptable and non-
  acceptable performance of the product in
  vivo.

12            Development of Dissolution Test
               in regards to Bioequivalence
Dissolution Techniques - Critical Parameters


♦ Knowledge of dissolution properties under
different conditions e.g. pH, agitation, ionic
strength, surfactants, viscosity, osmotic
pressure is important since the behavior of
the solid system in vivo may be critical for
the drug dissolution independent of the
physico-chemical properties of the active
substance.
♦ An appropriate experimental statistical
design may be used to investigate the
critical parameters and for the optimization
of such conditions.


13                 Development of Dissolution Test
                    in regards to Bioequivalence
Similarity Calculation




In this equation ƒ2 is the similarity factor, n is the
number of time points, R (t) is the mean percent
drug dissolved of e.g. a reference product, and T(t)
is the mean percent drug dissolved of e.g. a test
product.


14                Development of Dissolution Test
                   in regards to Bioequivalence
Similarity Factor

     The evaluation of the similarity factor is based on the
     following conditions:

♦ A minimum of three time points (zero excluded): the first
  time point before 15 minutes, the second one at 15
  minutes and the third time point when the release is close
  to 85%.
♦ In general five to eight sampling times within a 0-60
  minutes interval are recommended to achieve meaningful
  dissolution profiles.
♦ The time points should be the same for the two
  formulations.
♦ Twelve individual values for every time point for each
  formulation.
♦ Not more than one mean value of > 85% dissolved for any
  of the formulations.
♦ The relative standard deviation or coefficient of variation of
  any product should be less than 20% for the first point and
  less than 10% from second to last time point.

15                      Development of Dissolution Test
                         in regards to Bioequivalence
Similarity Factor Criteria

An f2 value between 50 and 100 suggests
that the two dissolution profiles are similar.

In cases where more than 85% of the drug
is dissolved within 15 minutes, dissolution
profiles may be accepted as similar without
further mathematical evaluation, except in
the case of gastro-resistant formulations
where the dissolution takes place in the
intestine and the 15 minutes for gastric-
emptying lacks of physiological meaning.


16             Development of Dissolution Test
                in regards to Bioequivalence
Structure of montelukast sodium




 17             Development of Dissolution Test
                 in regards to Bioequivalence
18   Development of Dissolution Test
      in regards to Bioequivalence
19   Development of Dissolution Test
      in regards to Bioequivalence
Solubility of montelukast sodium in blank biorelevant
                media and USP-buffers (Okumu et al)
     A.Okumu et al, “Dynamic Dissolution Testing To Establish In Vitro/In Vivo Correlations
                        for Montelukast Sodium, a Poorly Soluble Drug”,
                       Pharmaceutical Research, 2008, Vol. 25 (12), 2778-2785




20                              Development of Dissolution Test
                                 in regards to Bioequivalence
Bio-relevant dissolution media
♦ USP SGF (simulated gastric fluid)
NaCl 2.0 g
Purified pepsin 3.2 g
HCl 7.0 mL
Purified water qs. 1000 mL
Media has a pH of about 1.2
♦ USP SIF (simulated intestinal fluid)
Monobasic potassium phosphate 6.8 g in Purified water 250 mL
NaOH (0.2 N) 77 mL and Purified water 500 mL
Pancreatin 10.0 g
Adjust with either 0.2 N NaOH or 0.2 N HCl to a pH of 6.8 ± 0.1.
Purified water qs. 1000 mL
♦ FeSSIF (fed state simulated intestinal fluid)
Sodium taurocholate 15 mM
Lecithin 3.75 mM
NaOH (pellets) 4.04 g
Glacial Acetic Acid 8.65 g
NaCl 11.874 g
Purified water qs. 1000 mL
Media has a pH of 5.00 and an osmolality of about 670 mOsmol/kg
♦ FaSSIF (fasted state simulated intestinal fluid)
Sodium taurocholate 3mM
Lecithin 0.75 mM
NaOH (pellets) 0.174 g
NaH2PO4.H2O 1.977 g
NaCl 3.093 g
Purified water qs. 500 mL
Media has a pH of 6.50 and an osmolality of about 270 mOsmol/kg

 21                                  Development of Dissolution Test
                                      in regards to Bioequivalence
Dissolution data in various
                                            bio-relevant media




 Pharmacokinetics (“Observed”)
 overlayed with “GastroPlus”
 models obtained from
 dissolution data




22                   Development of Dissolution Test
                      in regards to Bioequivalence
Flow-Through Cell Dissolution - equipment




23             Development of Dissolution Test
                in regards to Bioequivalence
Example of flow through cell equipment for dynamic dissolution

     M.McAllister “Dynamic Dissolution: A Step Closer to Predictive Dissolution Testing?”
                         Mol. Pharmaceutics, 2010, 7 (5), pp 1374–1387




24                            Development of Dissolution Test
                               in regards to Bioequivalence
Guidances
♦ USP <711> Dissolution: Description of Apparatus 1, 2, 3, 4 . Procedures for
Immediate-Release Dosage Forms and for Extended-Release Dosage Forms
♦ USP <724> Drug Release: Description of Apparatus 5, 6, 7 for Transdermal
Delivery Systems
♦ USP <1088> In Vitro and In Vivo Evaluation of Dosage Forms
Dissolution Testing for Immediate and Modified-Release Dosage Forms.
♦ USP <1092> The Dissolution Procedure: Development and Validation
Medium, Volume, Deaeration, Enzymes, IVIVC (Biorelevant medium),
Apparatus, Sinkers, Agitation, Time Points, Observations, Sampling, Filters,
Centrifugation, Assay.
♦ FDA Guidance for Industry: Dissolution Testing of Immediate – Release
Solid Oral Dosage Forms, August 1997
♦ FDA Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage
Forms, September 1997
♦ FDA Guidance for Industry: Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms
Based on a Biopharmaceutics Classification System, August 2000
♦ BP Appendix XII B. Dissolution and Ph.Eur. method 2.9.3
♦ EMEA. Note for Guidance on the Investigation of Bioavailability and
Bioequivalence London, 26 July 2001, CPMP/EWP/QWP/1401/98
♦ EMEA. Guidance on the Investigation of Bioequivalence DRAFT,
London, 24 July 2008, CPMP/EWP/QWP/1401/98 Rev. 1

25                       Development of Dissolution Test
                          in regards to Bioequivalence
26   Development of Dissolution Test
      in regards to Bioequivalence
27   Development of Dissolution Test
      in regards to Bioequivalence

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Dissolution Test development in regard to bioequivalence

  • 1. Development of dissolution test in regards to bioequivalence Alex Mirimsky and Sasha Nezlin PDA March 2011
  • 2. 2 Development of Dissolution Test in regards to Bioequivalence
  • 3. 3 Development of Dissolution Test in regards to Bioequivalence
  • 4. Biopharmaceutics Classification System (BCS) High Solubility - High Permeability Drugs Low Solubility - High Permeability Drugs High Solubility - Low Permeability Drugs Low Solubility - Low Permeability Drugs FDA: This classification can be used as a basis for setting in vitro dissolution specifications and can also provide a basis for predicting the likelihood of achieving a successful in vivo-in vitro correlation (IVIVC). 4 Development of Dissolution Test in regards to Bioequivalence
  • 5. BCS applications ♦ Highly Soluble API should not have any bioavailability problems if, in addition, the dosage system is rapidly dissolved in the physiological pH-interval expected after product administration and the excipients are known not to affect the dissolution, stability and absorption processes. A bioequivalence study may in those situations be waived based on similarity of dissolution profiles which are based on discriminatory testing, provided that the other exemption criteria in Appendix III are met. ♦ Low Soluble API If an active substance is considered to have a low solubility, the rate limiting step for absorption may be dosage form dissolution. This is also the case when one or more of the excipients are controlling the release and subsequent dissolution step of the active substance. In those cases a variety of test conditions is recommended and adequate sampling should be performed until either 90% of the drug is dissolved or an asymptote is reached. 5 Development of Dissolution Test in regards to Bioequivalence
  • 6. DISSOLUTION STUDIES ♦ In vitro dissolution studies are used to assess the product quality. ♦ In vitro dissolution rate should correlate with in vivo bioavailability. ♦ A dosage form with a rapid dissolution rate is likely to have a rapid rate of drug bioavailability in vivo. ♦ Bioavailability is not dependent only on the dissolution of the drug product, but also on the permeability and solubility of the drug substance. 6 Development of Dissolution Test in regards to Bioequivalence
  • 7. FDA has defined bioequivalence as "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." ♦ Bioequivalence studies are for determination of the therapeutic equivalence between the pharmaceutically equivalent generic drug product and a corresponding reference listed drug. ♦ Bioequivalence studies provide information on product quality and performance when there are changes in components, composition and method of manufacture after approval of the drug product. 7 Development of Dissolution Test in regards to Bioequivalence
  • 8. Testing of product quality ♦ To get information on the test batches used in bioavailability/bioequivalence studies and pivotal clinical studies: - To investigate batch to batch consistency of both test and reference products, to be used as basis for the selection of appropriate batches for the in vivo study. - to support setting specifications for quality control. ♦ To be used as a tool in quality control to demonstrate consistency in manufacture. ♦ To support the assumption of similarity between products provided that the manufacturing process, composition and specifications are similar. ♦ To demonstrate similarity between different formulations of an API and the reference product (biowaivers e.g., variations, formulation changes during development and generic products). 8 Development of Dissolution Test in regards to Bioequivalence
  • 9. In-vitro dissolution test complementary to bioequivalence studies “The results of in-vitro dissolution tests at pH 1.2, 4.5, 6.8 and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported.” “Unless otherwise justified, the specifications for the in vitro dissolution to be used for quality control of the product should be derived from the dissolution profile of the test product batch that was found to be bioequivalent to the reference product.” 9 Development of Dissolution Test in regards to Bioequivalence
  • 10. Biowaiver 10 Development of Dissolution Test in regards to Bioequivalence
  • 11. In vitro dissolution test in support of biowaiver and/or strengths ♦ pH 1.2, 4.5, 6.8 ♦ Particular dosage forms may require investigations using physiologically relevant experimental pH conditions. ♦ Similarity of in vitro dissolution should be demonstrated at all conditions: - between strengths used for bioequivalence testing, - between additional strengths of the developed product and corresponding strengths of the reference product. 11 Development of Dissolution Test in regards to Bioequivalence
  • 12. Pharmacopoeial Test or Alternative? ♦ The test methodology should be in accordance with pharmacopoeial requirements unless those requirements are shown to be unsatisfactory and/or do not reflect the in vivo dissolution (i.e. biorelevance). ♦ Alternative methods can be considered when justified that these are discriminatory and able to differentiate between batches with acceptable and non- acceptable performance of the product in vivo. 12 Development of Dissolution Test in regards to Bioequivalence
  • 13. Dissolution Techniques - Critical Parameters ♦ Knowledge of dissolution properties under different conditions e.g. pH, agitation, ionic strength, surfactants, viscosity, osmotic pressure is important since the behavior of the solid system in vivo may be critical for the drug dissolution independent of the physico-chemical properties of the active substance. ♦ An appropriate experimental statistical design may be used to investigate the critical parameters and for the optimization of such conditions. 13 Development of Dissolution Test in regards to Bioequivalence
  • 14. Similarity Calculation In this equation ƒ2 is the similarity factor, n is the number of time points, R (t) is the mean percent drug dissolved of e.g. a reference product, and T(t) is the mean percent drug dissolved of e.g. a test product. 14 Development of Dissolution Test in regards to Bioequivalence
  • 15. Similarity Factor The evaluation of the similarity factor is based on the following conditions: ♦ A minimum of three time points (zero excluded): the first time point before 15 minutes, the second one at 15 minutes and the third time point when the release is close to 85%. ♦ In general five to eight sampling times within a 0-60 minutes interval are recommended to achieve meaningful dissolution profiles. ♦ The time points should be the same for the two formulations. ♦ Twelve individual values for every time point for each formulation. ♦ Not more than one mean value of > 85% dissolved for any of the formulations. ♦ The relative standard deviation or coefficient of variation of any product should be less than 20% for the first point and less than 10% from second to last time point. 15 Development of Dissolution Test in regards to Bioequivalence
  • 16. Similarity Factor Criteria An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. In cases where more than 85% of the drug is dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation, except in the case of gastro-resistant formulations where the dissolution takes place in the intestine and the 15 minutes for gastric- emptying lacks of physiological meaning. 16 Development of Dissolution Test in regards to Bioequivalence
  • 17. Structure of montelukast sodium 17 Development of Dissolution Test in regards to Bioequivalence
  • 18. 18 Development of Dissolution Test in regards to Bioequivalence
  • 19. 19 Development of Dissolution Test in regards to Bioequivalence
  • 20. Solubility of montelukast sodium in blank biorelevant media and USP-buffers (Okumu et al) A.Okumu et al, “Dynamic Dissolution Testing To Establish In Vitro/In Vivo Correlations for Montelukast Sodium, a Poorly Soluble Drug”, Pharmaceutical Research, 2008, Vol. 25 (12), 2778-2785 20 Development of Dissolution Test in regards to Bioequivalence
  • 21. Bio-relevant dissolution media ♦ USP SGF (simulated gastric fluid) NaCl 2.0 g Purified pepsin 3.2 g HCl 7.0 mL Purified water qs. 1000 mL Media has a pH of about 1.2 ♦ USP SIF (simulated intestinal fluid) Monobasic potassium phosphate 6.8 g in Purified water 250 mL NaOH (0.2 N) 77 mL and Purified water 500 mL Pancreatin 10.0 g Adjust with either 0.2 N NaOH or 0.2 N HCl to a pH of 6.8 ± 0.1. Purified water qs. 1000 mL ♦ FeSSIF (fed state simulated intestinal fluid) Sodium taurocholate 15 mM Lecithin 3.75 mM NaOH (pellets) 4.04 g Glacial Acetic Acid 8.65 g NaCl 11.874 g Purified water qs. 1000 mL Media has a pH of 5.00 and an osmolality of about 670 mOsmol/kg ♦ FaSSIF (fasted state simulated intestinal fluid) Sodium taurocholate 3mM Lecithin 0.75 mM NaOH (pellets) 0.174 g NaH2PO4.H2O 1.977 g NaCl 3.093 g Purified water qs. 500 mL Media has a pH of 6.50 and an osmolality of about 270 mOsmol/kg 21 Development of Dissolution Test in regards to Bioequivalence
  • 22. Dissolution data in various bio-relevant media Pharmacokinetics (“Observed”) overlayed with “GastroPlus” models obtained from dissolution data 22 Development of Dissolution Test in regards to Bioequivalence
  • 23. Flow-Through Cell Dissolution - equipment 23 Development of Dissolution Test in regards to Bioequivalence
  • 24. Example of flow through cell equipment for dynamic dissolution M.McAllister “Dynamic Dissolution: A Step Closer to Predictive Dissolution Testing?” Mol. Pharmaceutics, 2010, 7 (5), pp 1374–1387 24 Development of Dissolution Test in regards to Bioequivalence
  • 25. Guidances ♦ USP <711> Dissolution: Description of Apparatus 1, 2, 3, 4 . Procedures for Immediate-Release Dosage Forms and for Extended-Release Dosage Forms ♦ USP <724> Drug Release: Description of Apparatus 5, 6, 7 for Transdermal Delivery Systems ♦ USP <1088> In Vitro and In Vivo Evaluation of Dosage Forms Dissolution Testing for Immediate and Modified-Release Dosage Forms. ♦ USP <1092> The Dissolution Procedure: Development and Validation Medium, Volume, Deaeration, Enzymes, IVIVC (Biorelevant medium), Apparatus, Sinkers, Agitation, Time Points, Observations, Sampling, Filters, Centrifugation, Assay. ♦ FDA Guidance for Industry: Dissolution Testing of Immediate – Release Solid Oral Dosage Forms, August 1997 ♦ FDA Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms, September 1997 ♦ FDA Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, August 2000 ♦ BP Appendix XII B. Dissolution and Ph.Eur. method 2.9.3 ♦ EMEA. Note for Guidance on the Investigation of Bioavailability and Bioequivalence London, 26 July 2001, CPMP/EWP/QWP/1401/98 ♦ EMEA. Guidance on the Investigation of Bioequivalence DRAFT, London, 24 July 2008, CPMP/EWP/QWP/1401/98 Rev. 1 25 Development of Dissolution Test in regards to Bioequivalence
  • 26. 26 Development of Dissolution Test in regards to Bioequivalence
  • 27. 27 Development of Dissolution Test in regards to Bioequivalence