THE ROLE OF DISSOLUTION TESTING: AN MCC PERSPECTIVE

THE ROLE OF DISSOLUTION TESTING: AN MCC PERSPECTIVE CM Dangor DISSOLUTION TESTING Dissolution Rate - Act of dissolving of API in unit time amt/time; conc./time Intrinsic Dissolution Rate of API - Pure API Disk (single solid surface) - Controlled Conditions (sink; tempt. stirring rate) Amt/Area/Time ; Conc./Area/ Time 1

In Vitro DISSOLUTION Dissolution of API from dosage form % labelled content of API vs Time or Concentration of API vs Time VARIABLES Physico-chemical properties of API Environmental - Agitation, apparatus geometry - Composition, ph, Temperature, etc - Concentration Gradient Dosage Form Composition and manufacturing process 2

CONTROLLED CONDITIONS Sink, temperature, media, etc VALIDATION Apparatus suitability Assay procedure/s The MCC Dissolution Guideline aims to; Share the current thinking of the regulator Not intended d as an exclusive approach May request additional info in keeping with knowledge current at the times of application Allow use of alternative approaches that are scientifically and technically justified Provide guidance when in vitro instead of in vivo data may be used 3

PURPOSE OF DISSOLUTION STUDIES Research - Elucidate mechanism of drug release - Influence of variables - Selection of Model and specifications Development of D/Formulation - Optimising for clinical studies - Up-scaling, etc Quality Assurance - Monitor Lot to lot variations - Indicate potential problems of bioavail./bioequiv. - Stability studies/shelf life Minor post approval amendments for similarity of quality and performance Predictive Purposes - n vitro/ in vivo correlation - Setting in vitro dissolution specifications - Waiver of biostudies requirements to support surrogate markers i.e.* bioequivalence surrogate inference. 4

In Summary: in vitro dissolution serves: a. as an essential part of drug development b. to obtain info on test batches used in biostudies and pivotal clinical studies to support specs. for quality control c.to demonstrate batch-to-batch and lot-to-lot consistency during manufacture and to indicate potential problems of bioavailability i.e. tool in quality control d. to support a request for waiver of bioequivalence testing PURPOSE A. QUALITY CONTROL B. BIOWAIVER CONSIDERATIONS 5

A. FOR QUALITY CONTROL PURPOSES Compendial Test Methods Available Other Test Methods Special Cases ( poorly soluble APIs) Compendial Product : Dissolution Test Available (i) 6 units (ii) Acceptable monographs (BP,USP,EP or justify others used) (iii) Individual APIs in Combination Product, if not listed under (ii) 6

Indomethacin Capsules USP 30 Medium: 1 vol. ph 7,2 phosphate p buffer + 4 vol. water, 750 ml Apparatus 1: Time: Tolerance: 100 rpm 20 minutes nlt 80 % in 20 minutes. Indomethacin Extended Release Capsules USP 30 Test 1: Medium: Apparatus 1: Times: ph 6,2 phosphate buffer,750ml 75 rpm 1, 2, 4, 6,12, and 24 hours Tolerance: the percentages of the labelled amount dissolved at times specified in the following table 7

time (hrs) Quantity dissolved 1 between 10 % and 25 % 2 between 20 % and 40 % 4 between 35 % and 55 % 6 between 45 % and 65 % 12 between 60 % and 80 % 24 not less than 80 % Compendial Test Method NOT Available Develop an in vitro dissolution method for the product under variety of conditions. Criteria to be considered include: - ph solubility profile of the API -dissolution profiles using different models different agitations e.g App.1 (100 rpm) OR -App 2(75 rpm) different media (ph 1 to 6,8 e.g ph 1.2; 4.5 and 6.8 buffer) Generate comparative profiles on all strengths, media to be discriminating, Method to be justified and validated 8

Special Cases (poorly soluble API) (i) Multipoint profiles or consider (ii) USP Apparatus 4 (flow through cell) for dissolution spec. development. B. FOR BIOWAIVER PURPOSES Specifically used as a bioequivalence surrogate marker To demonstrate similarity between: - RPs from different countries that MCC alligns itself -different product formulations of an API and the RPs To collect info on batch-to-batch consistency of TP and RP used as basis for the selection of appropriate batches for in vivo studies. 9

Concept: For an API to move from the orally administered dosage form to the systemic circulation it must be: completely released from dosage form fully dissolved in GI fluids stable in solution in GI fluids and pass through GI barrier into mesenteric circulation as well as pass through the liver into systemic circulation Therefore: Anything which h adversely affects any of the above will influence the bioavailability exhibited by that API from the dosage form in which it is administered. Factors related to pharmaceutical (i.e. API and dosage form) physiological biological influences, etc 10

Rationale for using in vitro Dissolution data For most APIs Comparative in vitro Dissolution data of the same API from different dosage forms through the same route, would enable prediction of pharmaceutical equivalence and hence comparative bioavailability in well designed studies. i.e. API must be in solution to be absorbed for systemic effect and dissolution is the rate limiting process Pharmaceutical equivalence bioequivalence The same dissolution methodologies must be used throughout all studies to obtain comparative data/ profiles in each instance for purposes of predicting bioequivalence 11

TYPES OF APPLICATIONS FOR BIOWAIVER CONSIDERATIONS BASED ON IN VITRO DISSOLUTION DATA Immediate Release Oral Solid Dosage forms a) Generic Products b) NCEs Modified Release (Extended Release) Products Foreign RP vs RP (SA) Minor Post Registration Changes METHODOLOGY 12 units (i) () Dissolution data; - in different media (ph 1 to 6,8) - no addition of surfactant, - use of Basket or Paddle (ii) Multipoint profiles (e.g.5, 10, 15, 20, 30, 45, 60 minutes intervals) (iii) Method validation and justification Special Cases (poorly soluble drug) (i) Multipoint profiles or consider (ii) USP Apparatus 4 (flow through cell) for dissolution specification/s development 12

Presentation of Comparative Dissolution Data Provide full report on: Purpose of study Products / batches info e.g batch size and no: with CoA., manufacture / expiry date, packaging Dissolution conditions and method Validated analytical method or reference to it in the dossier Results (%API dissolved d vs Time) per medium Mean and %RSD at each time point/ per medium Tables, graphs, F1 and F2 calculations Dissolution Profile comparison Discussion and Conclusion Dissolution Profile Comparison Model independent approach f 0.5 2 = 50٠log{[1+(1/n) n t=1 (R t -T t ) 2 ] ٠100 } f 1 = {[ n t=1 R t -T t ] / [ n t=1 R t ]} ٠100 Rt and Tt are the cumulative % dissolved at each of the selected n time points f1 is proportional to the average difference between the two profiles. (difference factor) f2 is inversely proportional to the average squared difference between the two profiles and measures the closeness between the two profiles (similarity factor) 13

Procedure: Dtmn. Dissolution profiles of 12 units each of TP and RP Establish Mean data at each time point Use >3 time points Same method for both( dissolution procedure. Collection times e.g.5,10, 15, 20, 30, 45, 60 min.) or until asymptote is reached Only one measurement after 85 % dissolution CV at earlier time point nmt 20 %, others nmt 10 % Calculate f1 and f2 values Assessment: f1 value close to 1 (0 to15) f2 value close to 100 (>50) Ensures sameness/equivalence of the 2 curves. (T) Warfarin sodium tablets 10 mg V/S Warfarin sodium Tablets 10 mg (R) Apparatus: USP Type П, RPM : 50 Dissolution medium: 0,1 N HCl ; Volume 900 ml Method of Analysis : HPLC Time in min Reference Test R -T R - t (R T) 2 No. of time points 0 15 30 45 0 12,81 51,03 68,19 0 75,49 93,03 97,72 0-62,68-42,00-29,53 0 62,68 42,0 29,53 0 3928,78 1764,00 872,02 0 1 1 1 Sigma R 132,03 266,2424-134,21 134,21 6564,80 3 F1 = 101,6511 F2 = 16,49253 14

APPLICATIONS : 1) Immediate Release Oral Solid Dosage Forms Provided that the product contains a a) Class I API s (BCS) ie. High solubility (HS) and high permeability (HP) (i) Criteria: HS API in highest dosage strength is soluble in or 250 ml at 37 0 C Buffer in range ph 1 to 8 and stable in GIT fluids HP - Extent of Absorption >90 % of dose - absence of instability in gastrointestinal tract - Determined experimentally and reported in literature and the b) Product is rapidly Dissolving nlt 85 % of label content of API dissolves (Appar. 1, 100 rpm OR Appar. 2,50 rpm) within 30 mins in: 0,1 N HCl ph 4,5 buffer and ph 6,8 buffer N.B. Bioequivalence data Not required but for an NCEs clinical info is relevant 15

Assessment: Compare profiles (TP vs RP) However : When nlt 85 % of label content of API dissolves (Apparatus 1, 100 rpm OR Apparatus 2, 75 rpm) at 15 minutes then: Assessment: - profile comparison is not required -deemed bioequivalent Time Test-1 Test-2 10 min 92 99 15 min 94 100 20 min 95 100 25 min 94 100 30 min 95 100 45 min 95 100 Comparison of dissolution profile 120 % Cummulative amount 100 80 60 40 20 Test-1 Test-2 0 0 2 4 6 8 Time 16

2) Proportionally Similar Dosage Forms Definition: (i) APIs and excipients i are in exactly the same proportion between different d/forms. If not, then (ii) Ratios of excipients to total mass of d/form are within limits defined under "Major and Minor Changes guideline" OR For highly potent APIs containing products, the masses of different d/forms are similar although APIs amounts differ. Clinical trial unit formulation : 10, 5, 2,5 mg are proportionally equivalent. The different strengths are manufactured by the same manufacturer, at the same site, with API (s) sourced from the same manufacturer. Same indication of use. APPROVED NAME A Sodium equivalent to A Hydroxypropyl cellulose (Klucel LF) Pregelatinized Starch (Starch 1500) Lactose Monohydrate ( PharmatoseDCL-11) QUANTITY PER QUANTITY PER QUANTITY PER DOSE UNIT 10 mg DOSE UNIT 5 mg DOSE UNIT 2,5 mg (mg/tablet) t) (mg/tablet) t) (mg/tablet) t) 10,90 mg 10,00 mg 5,45 mg 5,00 mg 2,720 mg 2,50 mg 4,00 4,00 4,00 15,00 15,00 10,00 168,60 173,85 181,678 Magnesium Stearate 1,50 1,50 1,50 FD & C Yellow No. 6 Aluminium Lake (CI 15895) ----- 0,20 0,096 Total tablet Mass 200,00 mg 200,00 mg 200,00 mg 17

FORMULATION OF THE TEST PRODUCT : 12,5 mg ; 25 mg and 50 mg are dose proportional. The different strengths are manufactured by the same manufacturer, at the same site, with API (s) sourced from the same manufacturer. FORMULATION 12,5 mg TABLET 25 mg TABLET 50 mg TABLET CORE A.P.I 12,50 mg 25,00 mg 50,00 mg Microcystralline cellulose ( Vivapur 102) Lactose Monohydrate (Tablettose 80) 12,600 mg 25,20 mg 50,40 mg 5,850 mg 11,70 mg 23,40 mg Pregelatinised Maize Starch 5,2375 mg 10,475 mg 20,95 mg Sodium Starch glycolate (Type A) 0,750 mg 1,50 mg 3,00 mg Magnesium Stearate 0,5625 mg 1,125 mg 2,25 mg Total mass 37,500 mg 75,00 mg 150,00 mg (a) Generic Products (TP vs RP) Bioequivalence of higher strength is MCC compliant (i) Lower Strength Assessment Comparable profile in 3 media Calculate f1 and f2 values F2 value must be 50 for equivalence acceptance 18

(Test Product 1) Name Ropinirole Hydrochloride Tablets 0,25 mg Mfg.By A PHARMACEUTICALS LTD., INDIA B.No. Avg. Mass G0981 154 mg Time 10 min 15 min 20 min 25 min 30 min 45 min % Avg. 92 94 95 94 95 95 % RSD 2,86 2,00 2,06 1,50 2,23 2,61 Min 87 91 91 91 91 90 Max 96 98 98 97 99 99 (Test Product 2) Biostudy Batch Name Ropinirole Hydrochloride Tablets 5 mg Mfg.By A PHARMACEUTICALS LTD., INDIA B.No. G1152 Avg. Mass 318 mg Time 10 min 15 min 20 min 25 min 30 min 45 min % Avg. 99 100 100 100 100 100 % RSD 2,38 1,45 1,35 1,36 1,29 1,39 Min 94 98 98 98 98 98 Max 101 103 103 103 103 103 19

NCE (H vs L) only Due to its toxicity, the in vitro data of higher strengths would be considered Proviso : MCC accepts Biostudy on Lower strength Clinical safety and/or efficacy studies including dose desirability of higher strength Linear kinetics over therapeutic range Assessment Comparable profiles in 3 media Calculate f1 and f2 values F2 must 50 Modified Release (Extended Release) Products (i) Beaded Capsules (Lower strength) Proviso: Single dose, fasting BE study on Higher Sstrength is MCC acceptable Number of beads containing API differentiates the different strengths Same dosage form and proportionally similar 20

REFERENCE PRODUCT (RP) An MCC approved innovator product and procured (and available) in South Africa OR An "Old Medicine" still available in SA (Use Market Leader, if more than one) OR Registration Authority including SADC acceptable to MCC [FDA,MHRA, MPA,TGA, Canada,EMEA, Japan]. Members of PIC/S for quality matters relating to GMP only. If marketed in country of Origin-include: Documents on licensing arrangements (same innovator/api/product; same company/corporate entity, etc with SA counterpart Copies of Labels, PI and PIL and CoAs for both RPs (SA and outside) OR Product on the WHO Comparator List of acceptance OR If no innovator is identified in context of above, the choice must be carefully made and comprehensively justified 21

Post Registration Amendment If changes in formulation, site and manufacture. method impact on: Quality only dissolution data as per original submission- single point study Quality and performance- multipoint dissolution profiles in medium as per original Quality, formulation and performance- multipoint dissolution in 3 media. Bioavail. Studies required unless otherwise justified. Biowaivers possible if in vitro/ in vivo correlations have been established. Provide Comparative data in all three instances i.e. Original vs amended product viz. Pre-changed vs post- change product THANK YOU I acknowledge the contributions of all who have participated and contributed to the compilation of the Guidelines. In addition, the assistance and support of colleagues in the refinement of the powerpoint presentation is sincerely appreciated. 22