development of dissolution test wrt be

Development of dissolution test in regards to bioequivalence

Alex Mirimsky and Sasha Nezlin

PDA March 2011

Development of Dissolution Test

in regards to Bioequivalence

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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).

Biopharmaceutics Classification System (BCS)

High Solubility - High Permeability Drugs

Low Solubility - High Permeability Drugs

High Solubility - Low Permeability Drugs

Low Solubility - Low Permeability Drugs



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♦ 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.

BCS applications



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♦ 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.

DISSOLUTION STUDIES



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♦ 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.

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."



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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 vivostudy.- 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).



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“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.”

In-vitro dissolution test complementary to bioequivalence studies



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Biowaiver



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♦ 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.

In vitro dissolution test in support

of biowaiver and/or strengths



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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.



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Critical Parameters-Dissolution Techniques

♦ 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.



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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.



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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 anyof 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.



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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.



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Structure of montelukast sodium



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Solubility of montelukast sodium in blank biorelevantmedia 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



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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 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 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 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



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

Dissolution data in various bio-relevant media



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Flow-Through Cell Dissolution - equipment



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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



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♦ 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 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 – 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

Guidances



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development of dissolution test wrt be

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