Dissolution and Pharm Equivalence By D Goupale & Dr S Nayak

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Dissolution Testing and Pharmaceutical Equivalence Damodar Goupale Asst. Professor Dr. Satish Nayak Principal & Professor Bansal College of Pharmacy, Bhopal www.bansalpharmacy.com

Outline:

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

Introduction:

Introduction Evaluation of Dosage Specification prescribed in Monograph Quality control of Dosage

Definition:

Definition Bioavailability : 100% “Absolute Bioavailability” “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

Definition:

Definition Bioequivalence : 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

Definition:

Definition Pharmaceutical equivalent: C ontain the same amount of the same active ingredient (s) in the same dosage form; M eet the same comparable standards; I ntended 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.

Definition:

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.

Biopharmaceutics Classification System (BCS):

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)

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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 .

BCS - Classification:

BCS - Classification Solubility Permeability 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

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CLASS BOUNDARIES HIGHLY SOLUBLE the highest dose strength is soluble in ≤ 250 ml water over a pH range of 1 to 7.5 at 37 °C HIGHLY PERMEABLE the extent of absorption in humans is determined to be > 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.

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Case 1 and case 3 drugs + Drugs having > 85% dissolution in 0.1N HCl in 15 minutes Bioavailability of the drug is not limited by dissolution

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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 ( f 2).

Quality Control for Tablets:

Quality Control for Tablets ( Raw Materials) ( In-Process) (Granules) ( Tablets) ( Finished Products )

Quality Control for Tablets:

Quality Control for Tablets Physical properties Weight variation Thickness Hardness Friability Disintegration Dissolution

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Chemical properties Identification Uniformity of content Assay Biological properties Bioavailability Toxicity test Clinical test

Dissolution:

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.

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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).

Dissolution Testing Conditions:

Dissolution Testing Conditions Dissolution apparatus Dissolution medium Agitation Validation

Dissolution Apparatus:

Dissolution Apparatus USP BP apparatus 1 apparatus 2 apparatus 3 apparatus 4 apparatus 5 apparatus 6 apparatus 7 Rotating basket Paddle Reciprocating cylinder Flow-through cell Paddle over disk Rotating cylinder Reciprocating holder Rotating basket Paddle Flow-through cell

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USP Dissolution Apparatus 1 USP Dissolution Apparatus 2 (Basket) (Paddle)

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(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.

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USP Dissolution Apparatus 3 (Reciprocating Cylinder)

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USP Dissolution Apparatus 4 / BP Dissolution Apparatus 3 (Flow-through Cell)

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USP Dissolution Apparatus 5 (Paddle over Disk) USP Dissolution Apparatus 6 (Cylinder)

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USP Dissolution Apparatus 7 (Reciprocating Holder)

Dissolution Medium:

Dissolution Medium Carried out under physiological conditions (37 ±0.5°C) 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

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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

Agitation:

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

Validation:

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

Dissolution Profile:

Dissolution Profile Standard curve Concentration of Paracetamol ( microgram / ml ) Abs 5 0.3493 10 0.6856 15 1.0229 20 1.3479 25 1.6642

Dissolution Profile:

Dissolution Profile

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T ime (min) Abs Concentration (ug/ml) Dilution Concentration (ug/ml) Sampling 3 ml (ug/ml) Cumulative in 3 ml Concentration in 20 ml Release (ug) %Release 5 0.275 3.7781 10 37.7812 113.3435 113.3435 755.6231 755.6231 16.1200 10 0.397 5.6322 10 56.3222 168.9666 282.3100 1126.4438 1239.7872 26.4489 15 0.49 7.0456 10 70.4559 211.3678 493.6778 1409.1185 1691.4286 36.0839 30 0.754 11.0578 10 110.5775 331.7325 825.4103 2211.5502 2705.2280 57.7117 45 0.91 13.4286 10 134.2857 402.8571 1228.2675 2685.7143 3511.1246 74.9043 60 0.959 14.1733 10 141.7325 425.1976 1653.4650 2834.6505 4062.9179 86.6759 Calculate from standard curve Conc x Dilution Drug in sampling Entire drug released Cumulative drug in whole flask Entire drug released x 100 Entire drug in formulation

Dissolution Profile Comparisons:

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

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

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Model-independent approach using a similarity factor Difference factor (f 1 ): calculates % difference between 2 curves at each time point Measurement of the relative error between 2 curves n = number of time point R t = dissolution value of the reference batch at time t T t = dissolution value of the test batch at time t

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

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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 f 1 and f 2 For curves to be considered similar f 1 = close to 0 (0-15) f 2 = greater than 50 (50-100)

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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%

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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

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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

SUPAC-IR Guidance:

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

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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

IVIVC (In-vitro dissolution/in-vivo bioavailability correlations):

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

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Source : V. R. S. Uppoor . (2001), Journal of Controlled Release (72) , 127-132.

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

Level A Correlation:

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

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Source : R. C . Rossi et al (2007), International Journal of Pharmaceutics. (Article In Press)

Level B Correlation:

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

Level C Correlation:

Level C Correlation A single point relationship between a dissolution parameter and a pharmacokinetic parameter Useful in early formulation development

Multiple Level C Correlation:

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. C max versus %dissolved in 2, 6 and 12 hours

Biowaivers:

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

Biowaivers without an IVIVC:

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

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

Biowaivers based on IVIVC:

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 C MAX and AUC between the test and reference product is not more than 20%

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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

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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

Waiver of in vivo bioequivalence based on BCS:

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)

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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

Data To Support a Request for Biowaivers:

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.

European Guidance for an In-Vivo Bioavailability/Bioequivalence Waivers:

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)

European Guidance for an In-Vivo Bioavailability/Bioequivalence Waivers:

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

Canadian Guidance for an In-Vivo Bioavailability/Bioequivalence Waivers:

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

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Damodar Goupale Asst. Professor Dr. Satish Nayak Principal & Professor Bansal College of Pharmacy, Bhopal www.bansalpharmacy.com Thank you

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