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THE ROLE OF DISSOLUTION IN THE DEMONSTRATION OF BIOEQUIVALENCE Prof.Dr.Nevin ÇELEBİ Gazi University Faculty of Pharmacy Department of Pharmaceutical Technology PharmaCon 2007-Dubrovnik

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OUTLINE <ul><li>Definition (Dissolution and Dissolution rate) </li></ul><ul><li>Drug dissolution process </li></ul><ul><li>Dissolution test and dissolution apparatus </li></ul><ul><li>Comparison of dissolution profile </li></ul><ul><li>Dissolution in regulating pharmaceuticals </li></ul>

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Dissolution <ul><li>Dissolution is the process by which a solid substance dissolves. As a fundamental phenomenon, it is controlled by the affinity between the solid and the medium. </li></ul>

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Dissolution rate <ul><li>Dissolution rate may be defined as the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. </li></ul>

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<ul><li>Drug absorption from a solid dosage form after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. </li></ul>

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Effects of factors on dissolution rate of solid dosage forms <ul><li>1.Physicochemical properties of the drug </li></ul><ul><ul><ul><li>Drug solubility </li></ul></ul></ul><ul><ul><ul><li>Crystallinity, salt form, polymorphism </li></ul></ul></ul><ul><ul><ul><li>Particle size </li></ul></ul></ul><ul><li>2.Formulation factors </li></ul><ul><ul><ul><li>Diluents </li></ul></ul></ul><ul><ul><ul><li>Disintegrants </li></ul></ul></ul><ul><ul><ul><li>Lubricants </li></ul></ul></ul><ul><ul><ul><li>Other additives </li></ul></ul></ul><ul><ul><ul><li>Coating components </li></ul></ul></ul>

8.
Effects of factors on dissolution rate of solid dosage forms <ul><li>3.Processing factors on dissolution rates </li></ul><ul><li>of tablets </li></ul><ul><ul><ul><li>Method of granulation </li></ul></ul></ul><ul><ul><ul><li>Compression force </li></ul></ul></ul><ul><ul><li>4.Factors relating to the dissolution </li></ul></ul><ul><ul><li>apparatus </li></ul></ul>

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Effects of factors on dissolution rate of solid dosage forms <ul><li>5.Effects of test parameters </li></ul><ul><ul><ul><li>Agitation </li></ul></ul></ul><ul><ul><ul><li>Stirring rate </li></ul></ul></ul><ul><ul><ul><li>Dissolution fluid </li></ul></ul></ul><ul><ul><ul><li>Influence of pH of dissolution </li></ul></ul></ul><ul><ul><ul><li>Effect of surface tension of the dissolution medium </li></ul></ul></ul><ul><ul><ul><li>Effect of the presence of unreactive and reactive additives in the dissolution medium </li></ul></ul></ul><ul><ul><ul><li>Volume of dissolution medium and sink conditions </li></ul></ul></ul><ul><ul><ul><li>Effect of temperature </li></ul></ul></ul><ul><ul><ul><li>Deaeration of dissolution medium </li></ul></ul></ul>

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Dissolution test <ul><li>The volume of the dissolution medium is generally 500, 900 or 1000mL. </li></ul><ul><li>Sink conditions are desirable </li></ul>

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Dissolution test <ul><li>In vitro dissolution test should be </li></ul><ul><li>simple </li></ul><ul><li>reliable </li></ul><ul><li>reproducible </li></ul><ul><li>able to discriminate between different degrees of product performance </li></ul>

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Dissolution Test Equipment <ul><li>Parameters: Temperature, speed,volume, sampling probe and position </li></ul><ul><li>Apparatus suitability test </li></ul><ul><li>Validation of automated system </li></ul><ul><li>Validation of analytical procedure </li></ul><ul><li>accuracy, precision (reproducibility and repeatability),specificity, linearity </li></ul>

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Official dissolution apparatus <ul><li>USP 28 classification </li></ul><ul><li>Rotating Basket </li></ul><ul><li>Paddle </li></ul><ul><li>Reciprocating Cylinder </li></ul><ul><li>Flow Through Cell </li></ul><ul><li>Paddle Over Disk </li></ul><ul><li>Rotating Cylinder </li></ul><ul><li>Reciprocating Holder </li></ul>

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USP apparatus 1 - Basket <ul><li>Useful for </li></ul><ul><ul><li>capsules </li></ul></ul><ul><ul><li>beads </li></ul></ul><ul><ul><li>delayed release / enteric coated dosage forms </li></ul></ul><ul><ul><li>floating dosage forms </li></ul></ul><ul><ul><li>surfactants in media </li></ul></ul><ul><li>Standard volume </li></ul><ul><ul><li>900 ml </li></ul></ul><ul><ul><li>1, 2, 4 liter vessels </li></ul></ul>Klein S., Hands-on-Dissollution workshop,İstanbul,2005

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USP apparatus 1 - Basket <ul><li>Advantages </li></ul><ul><ul><li>breadth of experience (more than 200 monographs) </li></ul></ul><ul><ul><li>full pH change during the test </li></ul></ul><ul><ul><li>can be easily automated which is important for routine investigations </li></ul></ul><ul><li>Klein S., Hands-on-Dissollution workshop,İstanbul,2005 </li></ul>

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USP apparatus 2 - Paddle <ul><li>Useful for </li></ul><ul><ul><li>tablets </li></ul></ul><ul><ul><li>capsules </li></ul></ul><ul><ul><li>beads </li></ul></ul><ul><ul><li>delayed release / enteric coated dosage forms </li></ul></ul><ul><li>Standard volume </li></ul><ul><ul><li>900 ml </li></ul></ul><ul><li>Method of first choice !!! </li></ul><ul><li>Klein S., Hands-on-Dissollution workshop,İstanbul,2005 </li></ul>

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USP apparatus 3 – Reciprocating cylinder <ul><li>Useful for </li></ul><ul><ul><li>tablets </li></ul></ul><ul><ul><li>beads </li></ul></ul><ul><ul><li>controlled release formulations </li></ul></ul><ul><li>Standard volume </li></ul><ul><ul><li>200-250 ml per station </li></ul></ul>

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USP apparatus 4 – Flow-Through Cell <ul><li>Useful for </li></ul><ul><ul><li>low solubility drugs </li></ul></ul><ul><ul><li>microparticulates </li></ul></ul><ul><ul><li>implants </li></ul></ul><ul><ul><li>suppositories </li></ul></ul><ul><ul><li>controlled release </li></ul></ul><ul><ul><li>formulations </li></ul></ul><ul><li>Variations </li></ul><ul><ul><li>open system </li></ul></ul><ul><ul><li>closed system </li></ul></ul>

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USP apparatus 5 – Paddle over disk <ul><li>Useful for </li></ul><ul><li>transdermal patches </li></ul><ul><li>Standard volume </li></ul><ul><ul><li>900 ml </li></ul></ul>

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<ul><li>Dissolution test has been extensively used as a quality control tool for drug products. </li></ul><ul><li>In vitro dissolution may be relevant to the prediction of in vivo performance. </li></ul>

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<ul><li>The dissolution test is important </li></ul><ul><li>in terms of the revealing of in </li></ul><ul><li>vitro/in vivo correlation (IVIVC). </li></ul>

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Dissolution/In vitro Release Testing-Important Tool <ul><ul><li>Assess batch to batch quality of the product </li></ul></ul><ul><ul><li>Determine product stability/shelf life </li></ul></ul><ul><ul><li>Guide in the development and/or process control of formulations </li></ul></ul><ul><ul><li>Ensure quality and performance after changes in the formulation,the manufacturing process, the site of manufacture and the scale-up of manufacturing process </li></ul></ul><ul><ul><li>Bioequivalency Test: Biowaivers </li></ul></ul>

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Role of Dissolution Testing in Regulating Pharmaceuticals <ul><li>I n vitro dissolution testing is relied on to assure product performance. </li></ul><ul><li>An appropriate dissolution test procedure is a simple and economical method that can be utilized effectively to assure acceptable drug product quality. </li></ul><ul><li>Appropriate dissolution test can be used as a s urrogate marker for BA/BE. </li></ul>

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Policy Related Dissolution BA/BE Guidances <ul><li>IR Dissolution Guidance </li></ul><ul><li>ER (IVIVC) Dissolution Guidance </li></ul><ul><li>BCS (Waiver) Guidance </li></ul><ul><li>General BA/BE Guidance </li></ul>http://www.fda.gov/cder/guidance/index.htm

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Setting Dissolution Specification (FDA) <ul><li>In vitro dissolution specifications are established to ensure batch-to-batch consistency and to signal potential problems with in vivo bioavailability. </li></ul><ul><li>For NDAs, the dissolution specifications should based on acceptable clinical, pivotal bioavailability, and/or bioequivalence batches. </li></ul><ul><li>For ANDAs/AADAs, the dissolution specifications should be based on the performance of acceptable bioequivalence batches of the drug product. </li></ul>

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Setting Dissolution Specification(FDA) <ul><li>The NDA dissolution specifications should be based on experience gained during the drug development process and the in vitro performance of appropriate test batches. </li></ul><ul><li>In the case of generic drug product, the dissolution specifications are generally the same as the reference listed drug (RLD) </li></ul><ul><li>Once a dissolution specification is set, the drug product should comply with that specification throughout its shelf life </li></ul>

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Guidance of BY/BE (EMEA2001) <ul><li>Dissolution studies can serve several purposes: </li></ul><ul><li>I-Quality assurance </li></ul><ul><ul><li>To get information on the test batches used in BY/BE studies and pivotal clinical studies to support specifications for quality control </li></ul></ul><ul><ul><li>To be used a tool in quality control to demonstrate consistency in manufacture </li></ul></ul><ul><ul><li>To get information on the reference product used in BY/BE studies and pivotal clinical studies </li></ul></ul>

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Guidance of BY/BE (EMEA2001) <ul><li>II.Bioequivalence surrogate interface </li></ul><ul><ul><li>To demonstrate similarity between different formulations of an active substance (variations and new, essentially similar products included) and the reference medicinal product. </li></ul></ul><ul><ul><li>To collect information on batch to batch consistency of the products (test and reference) to be used as basis for the selection of appropriate batches for in vivo study. </li></ul></ul><ul><ul><li>To demonstrate similarity between reference products from different Member States. </li></ul></ul>

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Dissolution-Based Biowavers <ul><li>In vitro dissolution test can also be used to waive for lower strenghts of immediate release and extended release drug products under certain conditions (dose proportional formulation and similar release mechanism) </li></ul>

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Dissolution-Based Biowavers <ul><li>IR Products </li></ul><ul><li>Lower strenghts-Formulation Proportionality </li></ul><ul><ul><li>Dissolution Profile f 2 </li></ul></ul><ul><li>BCS Class I:HS/HP/RD </li></ul><ul><li>Post-approval changes </li></ul><ul><ul><li>Dissolution profile f 2 </li></ul></ul>

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Dissolution-Based Biowavers <ul><li>ER Products </li></ul><ul><li>Lower Strenghts-tablet dosage form </li></ul><ul><ul><ul><li>Compositionally proportional </li></ul></ul></ul><ul><ul><ul><li>Same release mechanism </li></ul></ul></ul><ul><ul><ul><li>Similar dissolution profile in pH 1.2,4.5 and 6.8 buffer media, f 2 </li></ul></ul></ul>

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Dissolution Specifications (FDA) <ul><li>Three catogories of dissolution test specifications for immediate release drug products are described in the guidance. </li></ul><ul><ul><ul><li>Single point specifications </li></ul></ul></ul><ul><ul><ul><li>Two-point specifications </li></ul></ul></ul><ul><ul><ul><li>Dissolution profile comparison </li></ul></ul></ul>

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Dissolution Specifications (FDA) <ul><li>Single Point </li></ul><ul><ul><ul><ul><li>For routine quality control test </li></ul></ul></ul></ul><ul><li>Two Points F or characterizing the quality of the drug p roduct </li></ul><ul><ul><ul><ul><li>As a routine quality control test for certain types of drug products (e.g., slow dissolving or poorly water soluble drug product like carbamazepine ) </li></ul></ul></ul></ul>

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The comparison of dissolution profiles <ul><li>The dissolution profiles similarity may be compared by; </li></ul><ul><ul><li>Model independent </li></ul></ul><ul><ul><li>Model dependent </li></ul></ul><ul><ul><li>Linear regression of the percentage dissolved at specified time points </li></ul></ul><ul><ul><li>Statistical comparison of the parameters of the Weibull function </li></ul></ul><ul><ul><li>Calculating a similarity factor </li></ul></ul>

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The comparison of dissolution profiles <ul><li>Model independent approach using a similarity factor </li></ul><ul><li>A simple model independent approach uses a difference factor (f 1 ) and a similarity factor (f 2 ) to compare dissolution profiles. </li></ul>

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Difference factor (f 1 ) n is the number of time points R t is the dissolution value of the reference batch at time t, and T t is the dissolution value of the test batch at time t.

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Similarity factor (f 2 ) n is the number of time points Rt is the mean percent drug dissolved of e.g a reference product, Tt is the mean percent drug dissolved of e.g a test product

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Similarity factor (f 2 ) <ul><li>The evaluation of similarity is based on the conditions of </li></ul><ul><ul><li>a minumum of three time points (zero excluded) </li></ul></ul><ul><ul><li>12 individual values for every time point for each formulation </li></ul></ul><ul><ul><li>not more than one mean value of <85 % dissolved for each formulation </li></ul></ul><ul><ul><li>That the standard deviation of the mean of any product should be less than 10 % from second to last time point. </li></ul></ul>

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Similarity factor (f 2 ) <ul><li>An f 2 value between 50 and 100 suggests that the two dissolution profiles are similar. </li></ul>

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<ul><li>In cases where more than 85% of the drug are dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation. </li></ul>

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Biopharmaceutics Classification System(BCS) <ul><li>The BCS is a scientific framework for classifying a drug substance based on its aqueous solubility and intestinal permeability. </li></ul><ul><li>The FDA issued a guidance for industry on waivers in vivo for IR solid oral dosage forms based on the BCS in A u gust 2000. </li></ul>

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According to BCS,drug substances are classified as follows: <ul><li>Based on in vitro solubility and in vivo permeability dru g s can be divided into four groups: </li></ul>BCS for Immediate Release (IR) products Case by case Low Low IV Permeability Low High III Dissolution High Low II Gastric Emptying High High I Absorption rate control Permeability Solubility Class

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BCS (Cont’d) <ul><li>The BCS guidance recommends that sponsors may request biowaivers for highly soluble and highly permeable drug substances (Class I) in IR solid dosage forms that exhibit rapid in vitro dissolution, provided the following conditions are met: </li></ul><ul><li>the drug must be stable in the gastrointestinal tract, </li></ul>

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BCS (Cont’d) <ul><li>excipients used in the IR solid oral dosage forms have no significant effect on the rate and extent of oral drug absorption, </li></ul><ul><li>the drug must not have a narrow therapeutic index, </li></ul><ul><li>the product is designed to not be absorbed in the oral cavity </li></ul>

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BCS (Cont’d) <ul><li>According to the tenets of the BCS, certain drug products can be considered for biowaivers, i.e. Approving the product based on in vitro dissolution test rather than bioequivalence studies in human subjects. </li></ul>

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Regulation aspects of drug dissolution from a European perspective (Con’t) <ul><li>The qulity assessors of the virtual agency of EU,EMEA, pay strong attention to how well the composition of the dosage forms and the different steps of manufacturing process are chosen and uderstood. </li></ul>

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Regulation aspects of drug dissolution from a European perspective (Con’t) <ul><li>In addition , the ability of the dissolution test to detect deviations in those formulation factors that are defined to be critical in respect to drug absorption is emphasised (EMEA,1998,2005) </li></ul>

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Reference product-EU origin <ul><li>Another situation where a dissolution test might be a valuable tool is when the reference product used in a bioequivalence study is taken from another EU market than the one aimed for the applied generic product. </li></ul>

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Reference product-EU origin <ul><li>Still there are medicinal products with different compositions available from innovator company on the different member states markets of EU and it is therefore, up to the generic company to prove that the reference product chosen in the bioequivalence study is approprate. </li></ul>

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Graffner C., Eur.Pharm.Sci.,29,288-298 (2006)

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Summary <ul><li>In vitro dissolution testing is a powerful and useful method for determining product quality and sometimes to evaluate the clinical performance of dosage forms. </li></ul>

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<ul><li>Thank You…. </li></ul><ul><li>e-mail: nevin@ tr.net </li></ul>

54.
Dissolution <ul><li>Dissolution can be considered as a specific type of certain heterogenous reaction in which a mass transfer results as a net effect between the escape and deposition of solute molecules at a solid surface. </li></ul>

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Dissolution <ul><li>These heterogeneous reactions can be classified into three main categories: </li></ul><ul><li>1. The reaction or interaction at the interface is much faster than the transport of reactants to and products from the interface. In this case, the rate is controlled by transport process. For dissolution, this would be the diffusion or convective transport of solute from the interfacial bondaries to the bulk of the solution. </li></ul>

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Dissolution <ul><li>2. The reaction at the interface proceeds at a significantly slower speed than the transport process, and hence, it becomes the rate controlling step. In case of dissolution, this would occur if the process of releasing and depositing the solute molecules at the interface is the rate determining step. </li></ul>

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Dissolution <ul><li>3. The rate constants of both processes are approximately equivalent, and in this case, the rate of dissolution would be a fraction of both the rate of the reaction at the interface as well as the rate of the transport process. </li></ul>

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Dissolution test <ul><li>The dissolution studies should be carry out under different conditions; </li></ul><ul><li>e.g., pH agitation, ionic strenght, surfactants, viscosity, osmotic pressure is important since the behaviour of the solid system in vivo may be critical for the drug dissolution independent of the physicochemical properties of the active substance. </li></ul>

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Dissolution Guidance <ul><li>Provides methods for dissolution recommendations on the development of dissolution test methodology, approaches for setting specifications and the regulatory applications </li></ul><ul><li>profile comparison and indications as to when dissolution is sufficient for biowaivers </li></ul>

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Dissolution-Based Biowavers <ul><li>ER Products </li></ul><ul><li>Lower Strenghts-beads in a capsule </li></ul><ul><ul><ul><li>In vivo BE on highest strenght </li></ul></ul></ul><ul><ul><ul><li>Strengths differ only in number/amount of active beads (same release mechanism), linear PK </li></ul></ul></ul><ul><ul><ul><li>Dissolution profile comparison, f 2 </li></ul></ul></ul>

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<ul><li>Profile Profile comparison for granting biowaivers </li></ul><ul><li>For accepting product “sameness” under scale-up and post-approval changes </li></ul>

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Regulation aspects of drug dissolution from a European perspective <ul><li>During the development of a dosage form, it is therefore, important for the pharmaceutical companies to have a tool, a dissolution test, which makes it possible to evaluate the combined effects of different formulation factors, such as physicochemical properties of the active substance, properties of different excipients and different steps in the manufacturing process, on the rate and extent of drug absorption </li></ul><ul><li>Graffner C.,Eur.J.Pharm.Sci.,29,288-293(2006) </li></ul>

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Regulation aspects of drug dissolution from a European perspective (Con’t) <ul><li>An application dossier contains documentation on evidence of the effect, safety and pharmaceutical quality of a potential medicinal product and the role of regulatory authority is to ensure the appropriateness of the candidate product based on a scrutiny of scientific documentation submitted. </li></ul><ul><li>Graffner C.,Eur.J.Pharm.Sci.,29,288-293(2006) </li></ul>

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Regulation aspects of drug dissolution from a European perspective (Con’t) <ul><li>If the dissolution rate is not critical an appropriate test is still requested,e.g. For oral dosage forms, for controlling that the dissolution properties are consistent both within a manufactured batch and between batches. </li></ul>

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Regulation aspects of drug dissolution from a European perspective (Con’t) <ul><li>If the potential medicinal product is a modified-release dosage form, the discriminatory power of the dissolution test is expected, to be discussed based on an in vitro-in vivo correlation, i.e. a predictive mathematical model describing the relationship between in vitro dissolution properties and a relevant in vivo response (EMEA, 1999) </li></ul>

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Regulation aspects of drug dissolution from a European perspective (Con’t) <ul><li>By establishing a meaningful correlation between in vitro release characteristics an in vivo bioavailability parameters, the in vitro dissolution test can serve as a surrogate marker for in vivo behaviour. </li></ul>

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<ul><li>By applying the present mutual recognition approval systems of EU, such differences in the properties of product of a company product are, of course, not expected in the future. </li></ul>

68.
Graffner C., Eur.Pharm.Sci.,29,288-298 (2006)