Dissolution Test development in regard to bioequivalence

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Dissolution Test development in regard to bioequivalence

  1. 1. Development ofdissolution test in regards tobioequivalence Alex Mirimsky and Sasha Nezlin PDA March 2011
  2. 2. 2 Development of Dissolution Test in regards to Bioequivalence
  3. 3. 3 Development of Dissolution Test in regards to Bioequivalence
  4. 4. Biopharmaceutics Classification System (BCS) High Solubility - High Permeability Drugs Low Solubility - High Permeability Drugs High Solubility - Low Permeability Drugs Low Solubility - Low Permeability DrugsFDA: This classification can be used as abasis for setting in vitro dissolutionspecifications and can also provide a basisfor predicting the likelihood of achieving asuccessful in vivo-in vitro correlation(IVIVC).4 Development of Dissolution Test in regards to Bioequivalence
  5. 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. 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. 7. FDA has defined bioequivalence as "the absence of asignificant difference in the rate and extent towhich the active ingredient or active moiety inpharmaceutical equivalents or pharmaceuticalalternatives becomes available at the site of drugaction when administered at the same molar doseunder similar conditions in an appropriatelydesigned study."♦ Bioequivalence studies are for determination ofthe therapeutic equivalence between thepharmaceutically equivalent generic drug productand a corresponding reference listed drug.♦ Bioequivalence studies provide information onproduct quality and performance when there arechanges in components, composition and method ofmanufacture after approval of the drug product.7 Development of Dissolution Test in regards to Bioequivalence
  8. 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. 9. In-vitro dissolution test complementary to bioequivalence studies“The results of in-vitro dissolution tests at pH1.2, 4.5, 6.8 and the media intended for drugproduct release (QC media), obtained with thebatches of test and reference products thatwere used in the bioequivalence study shouldbe reported.”“Unless otherwise justified, the specificationsfor the in vitro dissolution to be used for qualitycontrol of the product should be derived fromthe dissolution profile of the test product batchthat was found to be bioequivalent to thereference product.”9 Development of Dissolution Test in regards to Bioequivalence
  10. 10. Biowaiver10 Development of Dissolution Test in regards to Bioequivalence
  11. 11. In vitro dissolution test in support of biowaiver and/or strengths♦ pH 1.2, 4.5, 6.8♦ Particular dosage forms may requireinvestigations using physiologically relevantexperimental pH conditions.♦ Similarity of in vitro dissolution should bedemonstrated 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. 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. 13. Dissolution Techniques - Critical Parameters♦ Knowledge of dissolution properties underdifferent conditions e.g. pH, agitation, ionicstrength, surfactants, viscosity, osmoticpressure is important since the behavior ofthe solid system in vivo may be critical forthe drug dissolution independent of thephysico-chemical properties of the activesubstance.♦ An appropriate experimental statisticaldesign may be used to investigate thecritical parameters and for the optimizationof such conditions.13 Development of Dissolution Test in regards to Bioequivalence
  14. 14. Similarity CalculationIn this equation ƒ2 is the similarity factor, n is thenumber of time points, R (t) is the mean percentdrug dissolved of e.g. a reference product, and T(t)is the mean percent drug dissolved of e.g. a testproduct.14 Development of Dissolution Test in regards to Bioequivalence
  15. 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. 16. Similarity Factor CriteriaAn f2 value between 50 and 100 suggeststhat the two dissolution profiles are similar.In cases where more than 85% of the drugis dissolved within 15 minutes, dissolutionprofiles may be accepted as similar withoutfurther mathematical evaluation, except inthe case of gastro-resistant formulationswhere the dissolution takes place in theintestine and the 15 minutes for gastric-emptying lacks of physiological meaning.16 Development of Dissolution Test in regards to Bioequivalence
  17. 17. Structure of montelukast sodium 17 Development of Dissolution Test in regards to Bioequivalence
  18. 18. 18 Development of Dissolution Test in regards to Bioequivalence
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  20. 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), 2778-278520 Development of Dissolution Test in regards to Bioequivalence
  21. 21. Bio-relevant dissolution media♦ USP SGF (simulated gastric fluid)NaCl 2.0 gPurified pepsin 3.2 gHCl 7.0 mLPurified water qs. 1000 mLMedia has a pH of about 1.2♦ USP SIF (simulated intestinal fluid)Monobasic potassium phosphate 6.8 g in Purified water 250 mLNaOH (0.2 N) 77 mL and Purified water 500 mLPancreatin 10.0 gAdjust 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 mMLecithin 3.75 mMNaOH (pellets) 4.04 gGlacial Acetic Acid 8.65 gNaCl 11.874 gPurified water qs. 1000 mLMedia has a pH of 5.00 and an osmolality of about 670 mOsmol/kg♦ FaSSIF (fasted state simulated intestinal fluid)Sodium taurocholate 3mMLecithin 0.75 mMNaOH (pellets) 0.174 gNaH2PO4.H2O 1.977 gNaCl 3.093 gPurified water qs. 500 mLMedia has a pH of 6.50 and an osmolality of about 270 mOsmol/kg 21 Development of Dissolution Test in regards to Bioequivalence
  22. 22. Dissolution data in various bio-relevant media Pharmacokinetics (“Observed”) overlayed with “GastroPlus” models obtained from dissolution data22 Development of Dissolution Test in regards to Bioequivalence
  23. 23. Flow-Through Cell Dissolution - equipment23 Development of Dissolution Test in regards to Bioequivalence
  24. 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 1374–138724 Development of Dissolution Test in regards to Bioequivalence
  25. 25. Guidances♦ USP <711> Dissolution: Description of Apparatus 1, 2, 3, 4 . Procedures forImmediate-Release Dosage Forms and for Extended-Release Dosage Forms♦ USP <724> Drug Release: Description of Apparatus 5, 6, 7 for TransdermalDelivery Systems♦ USP <1088> In Vitro and In Vivo Evaluation of Dosage FormsDissolution Testing for Immediate and Modified-Release Dosage Forms.♦ USP <1092> The Dissolution Procedure: Development and ValidationMedium, Volume, Deaeration, Enzymes, IVIVC (Biorelevant medium),Apparatus, Sinkers, Agitation, Time Points, Observations, Sampling, Filters,Centrifugation, Assay.♦ FDA Guidance for Industry: Dissolution Testing of Immediate – ReleaseSolid Oral Dosage Forms, August 1997♦ FDA Guidance for Industry: SUPAC-MR: Modified Release Solid Oral DosageForms, September 1997♦ FDA Guidance for Industry: Waiver of In Vivo Bioavailability andBioequivalence Studies for Immediate-Release Solid Oral Dosage FormsBased 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 andBioequivalence 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. 125 Development of Dissolution Test in regards to Bioequivalence
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  27. 27. 27 Development of Dissolution Test in regards to Bioequivalence

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