From the Chain Bridge to other Bridges of the Pharmaceu7cal World Biowaiver Applica7ons in the European Scenario

Transcription

1 Bioequivalence, Dissolu0on, Biosimilarity From the Chain Bridge to other Bridges of the Pharmaceu7cal World Biowaiver Applica7ons in the European Scenario Antalya, Turkiye, 24 April,

2 Outline Guidelines and defini7ons Scope and applica0on: BSC based biowaiver and mul0ple strength biowaiver Scien7fic background of biowaiver approach EU guidelines of BCS biowaiver EU requirements for mul7ple strengths waiver Global Harmoniza7on Ini7a7ve 2

3 Guidance for Industry (FDA) Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System index.htm August

4 EMA guidelines 4

5 Defini0ons FDA The term biowaiver is applied to a regulatory drug approval process when the dossier (applica0on) is approved based on evidence of equivalence other than in vivo bioequivalence test. For solid oral dosage forms, Biowaiver(s) is generally based on a dissolu0on test. EMA (CPMP/EWP/QWP/1401/98 Rev. 1) The BCS (Biopharmaceu0cs Classifica0on System)- based biowaiver approach is meant to reduce in vivo bioequivalence studies, i.e., it may represent a surrogate for in vivo bioequivalence, based on sa0sfactory in vitro data (e.g. dissolu0on studies). 5

6 Two different concepts, different requirements!? The concept : for HS drug and rapidly dissolving product, the BA/BE approach is that of an oral solu7on The concern: new product, new raw materials, new manufacturers, different excipients The objec0on: never administered to humans, no in vivo studies The concept: the strengths are inevitably similar being part of the same dossier. In vivo BE data are available. the need to avoid useless BE studies is even more stringent The concern: also possible for LS drugs and slowly dissolving formula7ons The regulatory compliance is based on different requirements 6

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9 Scien0fic background for BCS based biowaiver Class I drugs (HS,HP) Class III drugs (HS, LP) In vivo performance of a rapidly dissolving drug product Complete dissolu0on during gastric residence Prepara0ons emp0ed into intes0ne as a solu0on Drug dissolu0on is not rate limi0ng for absorp0on Complete absorp0on is assured, but ac7ve excipients must be the same BA/BE of such products approach that of an oral solu7ons and is thus, self evident in vivo studies waived In vivo performance of a rapidly dissolving drug product Complete dissolu0on during gastric residence Prepara0ons emp0ed into intes0ne as a solu0on Drug absorp0on problema0c, low and/or erra0c, but dissolu0on not limi0ng in vivo studies waived with restric0ons 9

10 APPENDIX III BCS- based Biowaiver CPMP/EWP/QWP/1401/98 Rev. 1 applicable for an immediate release drug product (same pharmaceu0cal form) if the drug substance has been proven to exhibit high solubility (HS) and complete absorp7on* (HP) and either very rapid (> 85 % within 15 min) or similarly rapid (85 % within 30 min or less) in vitro dissolu7on (RD) with respect to the reference has been demonstrated and ac7ve excipients are qualita7vely and quan7ta7vely the same. In general, the use of the same excipients in similar amounts is preferred If generic is a different salt, BCS biowaiver applies only if both salts have similar status. Not applicable to sublingual, buccal,.. dosage forms *HP = complete absorpgon means extent of absorpgon 85 % (vivo studies) 10

11 APPENDIX III BCS- based Biowaiver CPMP/EWP/QWP/1401/98 Rev. 1 applicable for an immediate release drug product if the drug substance has been proven to exhibit high solubility (HS) besides limited absorp7on (LP) ;and very rapid (> 85 % within 15 min) in vitro dissolugon of the test and reference product has been demonstrated considering specific requirements (VRD) and excipients are qualitagvely the same and quangtagvely very similar 11

12 APPENDIX III BCS- based Biowaiver CPMP/EWP/QWP/1401/98 Rev. 1 Excipients As a general rule, for both BCS- class I and III drug substances well- established excipients in usual amounts should be employed or otherwise jus0fied possible interac0ons affec0ng drug bioavailability and/or solubility characteris0cs should be considered and discussed Excipients (so- called ac7ve) that might affect bioavailability, like e.g. sorbitol, mannitol, sodium lauryl sulfate or other surfactants, should be iden0fied as well as their possible impact on Ø gastrointes7nal mo7lity Ø suscep7bility of interac7ons (e.g. drug complexa0on) Ø Intes0nal drug permeability Ø Interac0on with membrane transporters More restric7ve requirements apply to Class III or if Class I not convincing 12

13 In vitro dissolu7on tests in support of BCS biowaiver CPMP/EWP/QWP/1401/98 Rev. 1(4.2.2) Ø ensure immediate release proper0es Ø prove dissolu7on similarity between test and reference under physiologically relevant experimental ph condi7ons Ø In vitro dissolu0on should be inves0gated within the range of ph 1-8 (at least ph 1.2, 4.5, and 6.8). Addi0onal inves0ga0ons may be required at ph values in which the drug substance has minimum solubility. Otherwise jus0fy. Ø the use of any surfactant is not acceptable Ø Test and reference products should meet certain requirements (as for batch size and number, representa7veness,..) as outlined in sec0on of the main BE guideline text. 13

14 Example of biowaivers granted for IR product (selec0ve histamine H1 receptor antagonist, dihydrochloride salt) 10 mg IR coated tablets Same excipients as originator (lactose, MMC, colloidal silica, Mg stearate, Opadry II) BE not accepted (non compliant site) Biowaiver not immediately acceptable (belonging to Class I not supported, solubility data insufficient) Class I belonging not convincing Original solubility studies provided Class III accepted more restric0ve requirements applied Dissolu0on comparability data on full scale batches at 3 ph levels and with QC rou0ne test 14

15 Example of biowaiver granted (IR fixed combina0on product, analgesic) 500 mg (drug 1) + 30 mg (drug 2) tablets Composi0on quali/ quan0ta0ve different Drug 1 assigned to class I BCS classifica0on of drug 2 not presented Dissolu0on similarity only on experimental batches Ini7ally biowaiver denied Drug 2 ini0ally assigned to Class III due to 50% systemic absorp0on Based on literature data (extensive first pass effect, metabolite mass balance accoun0ng for complete absorp0on) reassigned to Class I Dissolu0on similarity data provided on 3 commercial batches of test and reference Biowaiver granted 15

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17 Biowaiver of strengths (CPMP/EWP/QWP/1401/98 Rev ) a) the different strengths are manufactured by the same manufacturing process b) Same qualita7ve composi0on in excipients of the different strengths c) Propor0onal composi0on in excipients (dose propor0onality) d) except if the 5% rule applies, excipients constant (diluent compensa0on of drug substance) e) Similar dissolu7on profile: QC media, ph 1.2, 4.5, and 6.8 f) PK linearity If linear: BE study with the most sensi0ve strength, normally the highest strength If non- linear : the most sensi0ve strength might be lowest and/or the highest. g) Bracke7ng admiied if BE assessment is performed for more than two strengths 17

18 Biowaiver of strengths (CPMP/EWP/QWP/1401/98 Rev ) dissolu0on should be inves0gated at different ph values (normally ph 1.2, 4.5 and 6.8) and in QC media unless otherwise jus0fied Similarity of in vitro dissolu0on should be demonstrated at all condi0ons within the applied product series, i.e. between addi0onal strengths and the strength (biobatch) used for bioequivalence tes0ng At ph values where sink condi7ons may not be achievable for all strengths in vitro dissolu0on may differ between different strengths. However, the comparison with the respec7ve strength of the reference medicinal product should then confirm that this finding is drug substance rather than formula7on related In addi0on, the applicant could show similar profiles at the same dose (e.g. as a possibility two tablets of 5 mg versus one tablet of 10 mg could be compared) 18

19 Example (cox- 2 inhibitor, acidic) of biowaiver of strengths two strengths capsules (100 and 200 mg) BE study on higher strength (200 mg) very low solubility drug (0.1 mg/l at ph 6.8) surfactant addi7on needed to get dissolu0on at physiological ph Dissolu0on similarity proved at ph 4.5 and 6.8, failed at acidic ph (no sink condi0on even with surfactant ) In these cases, addi0onal dissolu0on data required Dissolu0on comparison required between test and reference strengths (disregard sink condi0ons) and eventually with QC method If similarity is achieved in all cases biowaiver is accepted 19

20 Example (an0pertensive drugs) of biowaiver of strengths fixed combina0on, mul0ple strengths (five) Dose similarity of strengths 1, 2 and 3 Dose similarity of strengths 4 and 5 two BE studies (higher dose strenghts vs originators) One LS drug (but low dose number ) rapid dissolu0on in 3 media biowaiver applicable and auspicable dissolu0on similarity proved in 3 media between strengths 1, 2 and 3 and between strengths 4 and 5 on representa0ve batches Biowaiver granted 20

21 In summary Applicable to class I and III, same ac0ve, no esters, complexes, different salts only if jus0fied IR formula0ons, same dosage form, no sublingual, buccal, orodispersible?... No narrow therapeu0c index drugs In vivo data or peer- reviewed literature for absorp0on In vitro permeability studies only suppor0ve generic medicinal products, extensions of innovator products, varia0ons, bridging studies No BCS restric0ons In vivo data available, extrapola0on less risky Dose propor0onality required Some flexibility on dose propor0onality (bracke0ng admiied) and use of dissolu0on aid Representa0ve batches always required Topic s0ll under discussion 21

22 Biowaiver Global differences (EU, USA, JP, Canada..) BCS biowaiver: Class I vs class III, higher dose vs higher strength, dissolu0on requirements, permeability data.. Mul0ple strengths biowaiver: devia0on from dose propor0onality, fixed combina0on products, bracke0ng approach, modified release formula0ons,.. 22

23 Harmonisa7on conferences Interna0onal Workshop (AAPS, EUFEPS, FIP) New Orleans (November 2010) 23

24 THANKS FOR THE ATTENTION 24