Biopharmaceutics Classification System (BCS) Biowaiver Assessment Report

Transcription

1 Biopharmaceutics Classificatio System (BCS) Biowaiver Assessmet Report Bioequivalece Workig Group Versio 1- Feb 10, 2017 Versio Descriptio of Chage Author Effective Date v 1 Origial publicatio BE WG Feb 10, 2017

2 Disclaimer I order to achieve the IGDRPs objective to promote collaboratio ad covergece i geeric drug regulatio, the Bioequivalece Workig Group has developed a series of referece documets coverig a umber of techical ad procedural aspects of Biowaiver assessmet. These documets were developed amog participatig IGDRP members as model documets. The implemetatio of these documets by a give IGDRP member, either as a whole or i part, is ot madatory. Each IGDRP member works withi their ow specific regulatory settig ad some or all aspects of a documet may, for a variety of reasos, ot be applicable. Equally, a give IGDRP member may for practical reasos choose to revise the format or writte laguage of a model documet. IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 2 of 17

3 BCS Biowaiver Assessmet Report <Proposed proprietary ame> <API> <Product stregth(s)> <Product dosage form> <Applicatio/Dossier referece umber> Applicat: <Name of the Applicat> IGDRP Coutry Date of applicatio / Start of assessmet Date of assessmet report Deadlie for commet (if applicable) IGDRP coutries cocered IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 3 of 17

4 Table of Cotets 1 ADMINISTRATIVE INFORMATION GLOSSARY / ABBREVIATIONS SUMMARY: REQUIREMENTS AND OUTCOMES INTRODUCTION APPLICATION OBJECTIVE STATUS OF THE REFERENCE/ORIGINATOR PRODUCT IN OTHER IGDRP/EU COUNTRIES BASIC PHARMACOKINETIC INFORMATION THERAPEUTIC INDICATIONS AND DOSE BCS BIOWAIVER ASSESSMENT SOLUBILITY ABSORPTION (METHODS AND RESULTS) COMPARISON OF TEST AND REFERENCE FORMULATIONS / EXCIPIENTS IN VITRO DISSOLUTION COMPARISON DISSOLUTION TESTING LABORATORY Audit(s) GMP compliace/certificatio ESSENTIAL SIMILARITY / APPROPRIATENESS OF FINAL PRODUCT SPECIFICATIONS LIST OF OUTSTANDING ISSUES / DEFICIENCIES / PROPOSED QUESTIONS CONCLUSIONS AND RECOMMENDATIONS REFERENCES IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 4 of 17

5 1 ADMINISTRATIVE INFORMATION Proposed ame / ame of the medicie i the IGDRP coutry Active Pharmaceutical Igrediet - INN or commo ame of the API(s) Pharmaco-therapeutic group (ATC code/classificatio) Dosage form ad stregth(s) Dose Applicat/Sposor ame ad address, cotact iformatio Fial (test) product maufacturer Name ad address API maufacturer(s) Name ad address Dissolutio (ad solubility if applicable) testig laboratory ame ad address Test product details : batch size ad batch umber Referece product details : ame, HCR, coutry of procuremet Type of applicatio (geeric / formulatio or other variatio(s)) Reviewer(s)/Assessor(s) IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 5 of 17

6 2 GLOSSARY / ABBREVIATIONS API Active pharmaceutical igrediet / Drug Substace Drug Active pharmaceutical igrediet (API) Drug product Pharmaceutical product / medicie/ fial product FC / FDC Fixed combiatio /FDC fixed dose combiatio FPP Fiished pharmaceutical product HCR Holder of certificate of registratio/marketig authorisatio holder NTI Narrow therapeutic idex PHCR Proposed holder of certificate of registratio/marketig authorisatio PK Pharmacokietics SPC Summary of Product Characteristics / Product moograph / Package isert / labellig IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 6 of 17

7 3 SUMMARY: REQUIREMENTS ad OUTCOMES Outcome Therapeutic rage (ad dose) Solubility Stable Huma absorptio / Permeability: BCS class Dosage form Compariso of excipiets i the formulatios Dissolutio profiles Narrow / No-arrow High / Low Yes / No >85 % / 90 % / < 85 %/90 % : High Low I / II / III / IV Oral, systemic, IR same dosage form Sufficietly similar / Uacceptable differeces Similar ad rapidly dissolvig / similar ad very rapidly dissolvig/ No-similar / Novery rapidly dissolvig / No-rapidly dissolvig CoAs Assays withi 5 % BCS Class I Test ad referece products very rapid or rapid dissolutio Excipiets that may affect BA the same (quatity ad quality) BCS Class III Test ad referece products very rapid dissolutio Excipiets that may affect BA the same Other excipiets very similar Beefit risk summary Coclusio Yes / No Yes /No Yes/No Yes/No Yes/No Acceptable/ Not acceptable Approvable / No-approvable IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 7 of 17

8 4 INTRODUCTION Iclude iter alia the followig as relevat: 4.1 Applicatio objective Reaso or justificatio for applicatio of Biowaiver, BCS Classificatio. Address if maufacturer ad the applied API ad FPP are the same as those employed i the solubility ad dissolutio studies. (If the formulatio proposed for marketig ad those used for comparative dissolutio studies are ot idetical, clear idetificatio ad justificatios should be give by applicat). 4.2 Status of the referece/origiator product i other IGDRP/EU coutries Idicate which is the referece product i each coutry or jurisdictio. Justify that the product applied for has the same dosage form or is a pharmaceutical alterative if acceptable for a particular coutry. Address ideticality / differeces i API: same or differet salts (both BCS class I) for those coutries where a differet salt is acceptable; same ester, ether, isomer, mixture of isomers, complex or derivative as referece product/origiator. If differet salts were accepted by a group of coutries, it is ecessary to show that the literature data justifies that both salts have the same toxicological profile. If data is ot available i the literature the Applicat has to perform toxicological studies. I both cases this is additioal data that eeds to be assessed by other assessors. Cofirm that it is ot subligual, buccal or modified release. If the dosage form is a orodispersible tablet it is essetial to demostrate that the labellig of the referece product states that it is take with water. Some coutries / jurisdictios do ot allow a BCS Biowaiver if the product is take without water. 4.3 Basic pharmacokietic iformatio Liear PK is ecessary to accept mass balace / absolute BA studies with doses differet to the highest. Refereces attached. 4.4 Therapeutic idicatios ad dose Cofirm that the API is ot NTI. Some coutries do ot allow a BCS Biowaiver for NTI APIs, differet coutries may have differet criteria to defie NTI API. Examples from Health Caada guidelie iclude: cyclosporie; digoxi; flecaiide; lithium; pheytoi; sirolimus; tacrolimus; theophyllie; warfari. Europea Uio, o a case-by-case basis the CHMP has agreed the NTID status of cyclosporie ad tacrolimus. WHO TRS 937 Aex 8 also icludes examples. Evidece to support that the API does ot have a NTI, e.g. therapeutic rage or differece betwee miimum effective dose ad miimum toxic dose is required. Reviewer s commets: Discuss iformatio o sectio 4 icludig relevat backgroud, appropriateess of choice of referece as appropriate, etc. IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 8 of 17

9 5 BCS BIOWAIVER ASSESSMENT 5.1 Solubility Bibliographical ad/or experimetal (iclude source of iformatio) Note whether the followig have bee submitted: A complete report A protocol Dates ad site of study Descriptio of solubility method ad coditios. Descriptio ad validatio of the stability-idicatig aalytical method or cross-referece to the Q sectio of the dossier Solubility method Apparatus Volume Time Dose /amout Temperature ph values Buffer compositio Solubility at differet ph values ad replicates Theoretical ph ph 1.2 Itermediate phs ph 4.5 Itermediate phs ph 6.8 Other itermediate ph values ** Repeat Observed ph Adjusted ph ** Other itermediate ph values e.g. pka, pka-1, pka+1 Idividual Cs values Cs (mea) Quatity dissolved i 250 ml Plot of Solubility (Cocetratio at saturatio) vs. ph to idetify the ph of miimum solubility. Add plot IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 9 of 17

10 Notes for cosideratio: Is the maximum/highest dose (or stregth i some jurisdictios) that ca be take i a sigle admiistratio accordig to the SPC, soluble i 250 ml i at least three buffers (preferably 1.2; 4.5; 6.8/7.5) i rage ph 1 to 6.8/7.5 buffers ad at the pka if withi specified rage; at 37 C +/- 1 C? Replicate determiatios are required to achieve uequivocal solubility classificatio (shake flask method or other justified method). Solutio ph should be verified prior ad after additio of API to buffer. Note whether the drug is stable i the buffers ad whether the aalytical method is stabilityidicatig. For example acetylsalicilic acid or capecitabie are highly soluble but ustable ad the BCS biowaiver is ot allowed i the Europea Uio. Capecitabie ca however be waived i the USA based o their recommedatios for capecitabie. I some jurisdictios the cocetratio at saturatio is ecessary ad the demostratio of solubility i 250 ml does ot suffice. Reviewer s commets: Discuss iformatio o sectio Absorptio (methods ad results) Iclude source of absorptio data, literature data or experimetal data Huma Absolute BA referece (give literature citatio) Oral Dose Itraveous Number of subjects Result Mass balace referece (give literature citatio) Dose Number of subjects Result I vivo or i vitro permeability Test system Cocetratios Result Other iformatio Ifluece of the trasporters to absorptio Notes for cosideratio Complete absorptio measured extet of absorptio is 85 % / 90 % geerally related to high permeability, based o reliable ivestigatios i huma. Discussio of the literature: mass balace ad absolute BA studies. Supportive iformatio (e. g. Caco-2 moolayers, aimal data) IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 10 of 17

11 Has complete absorptio bee show for the highest dose i case the PK is o-liear (less tha proportioal due to saturatio of absorptio, e.g. gabapeti has complete absorptio at low doses, but icomplete whe the trasporter is saturated)? Dose liearity of pharmacokietics. Absorptio should be ivestigated at the highest dose if PK is ot liear. Reviewer s commets: Discuss iformatio o sectio Compariso of Test ad Referece formulatios / Excipiets Compoet Fuctio Test Referece Notes for cosideratio: BCS I Similar quatities of the same excipiets advisable BCS III Very similar qualitatively ad quatitatively to exclude differet effects o membrae trasporters Well established excipiets i usual/ormal quatities. Descriptio of fuctio of each. The test ad referece product quatities of excipiets that might affect bioavailability should be qualitatively ad quatitatively the same, e.g. sorbitol, maitol, sodium lauryl sulphate or other surfactats (e.g. PS80, Cremophors, Pluroics), ad cyclodextri. Fixed combiatios (FCs): All APIs/drug substaces either BCS I or III ad fulfil all the requiremets of the correspodig BCS class. Reviewer s commets: Discuss iformatio o sectio I vitro Dissolutio compariso Complete documetatio submitted study report, study protocol, batch iformatio o test ad referece batches icludig CoAs, admiistrative details of the dissolutio studies: perso resposible, cetre, dates, etc., detailed experimetal coditios, validatio of experimetal aalytical methods, idividual ad mea results ad respective summary statistics. Summary of dissolutio test method parameters Apparatus Rate of Operatio Dissolutio Media Volume IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 11 of 17

12 Temperature Samplig times Number of Dosage Uits Samplig Filtratio methods De-aeratio method (i-lie filtratio) Usual experimetal coditios are e.g.: Apparatus: paddle or basket Number of Dosage uits: 12 Volume of dissolutio medium: 900 ml or less Temperature of the dissolutio medium: 37±1 C Agitatio: paddle apparatus - usually 50 or 75 rpm as applicable; basket apparatus - usually 100 rpm (specify for coutry) Samplig schedule: e.g. 10, 15, 20, 30 ad 45 mi Buffer: ph (usually 0.1 N HCl or SGF without ezymes), ph 4.5, ad ph 6.8 (or SIF without ezymes); (ph should be esured throughout the experimet; USP/Ph.Eur. buffers recommeded) Other coditios: o surfactat; i case of gelatie capsules or tablets with gelatie coatigs the use of ezymes may be acceptable. Notes o CoA compariso: The differece betwee test ad referece product i the assay of the CoA must be less tha 5 %. The objective is to use products with comparable quatities so that a potecy correctio is ot ecessary. IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 12 of 17

13 Test Batches Dissolutio Profiles for Lot #: = o. of uits/ ph medium ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility Dissolutio Profiles for Lot # = o. of uits/ ph medium ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility dissolutio profiles of 2 batches (24 tablets) ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 13 of 17

14 Referece Batches: Coutry 1 Dissolutio Profiles for Lot #: = o. of uits/ ph medium ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility Dissolutio Profiles for Lot # = o. of uits/ ph medium ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility dissolutio profiles of 2 batches (24 tablets) ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 14 of 17

15 Referece Batches: Coutry 2 (add as may coutries as ecessary) Dissolutio Profiles for Lot #: = o. of uits/ ph medium ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility Dissolutio Profiles for Lot # = o. of uits/ ph medium ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility dissolutio profiles of 2 batches (24 tablets) ph of medium x Mi x Mi x Mi x Mi x Mi ph of miimum solubility IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 15 of 17

16 Dissolutio profile compariso Test product (batch umber) vs. referece product (batch umber, coutry 1): Poits cosidered for f2 calculatio: f 2 : Test product (batch umber) vs. referece product (batch umber, coutry 2): Poits cosidered for f2 calculatio: f 2 : Very rapidly dissolvig: more tha 85 % at 15 miutes Rapid dissolvig: more tha 85 % at 30 miutes - calculatio of similarity ƒ2 factor Discussio of dissolutio profile differeces i terms of cliical/therapeutical relevace cosidered iappropriate (o i vitro i vivo correlatio) Sice most coutries do ot accept the referece from aother jurisdictio, two differet tables are required for the referece products. Duplicate tables as ecessary tables for test should be o oe page (two tables per page) ad the referece tables o oe page to facilitate compariso. The results of the test will be the same for all jurisdictios (but more tha oe batch of test ad referece may be required i some regios). The, 24 values will be available for each product. If oly oe batch is ecessary, the additioal tables ca be deleted. Dissolutio studies at the ph of miimum solubility may ot be ecessary i certai coutries. I other coutries they are ecessary if that ph is differet to the specified dissolutio media. Reviewer s commets: Discuss iformatio o sectio 5.4: Sufficiet/adequate umber of batches, low eough variability, adequate umber of poits to calculate f2, correct selectio of poits to calculate f2, similar, rapid eough, ot more tha 5 % differece i CoA assay values, etc. 5.5 Dissolutio testig laboratory Audit(s) Describe if the QA uit of the cetre has audited the study coductace ad the data GMP compliace/certificatio Describe if GMP ispectios have bee performed i the facilities where these studies have bee coducted, idicate the level of the fidigs ad the regulatory authorities that coducted the studies. Reviewer s commets: Discuss iformatio o sectio 5.5 IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 16 of 17

17 6 ESSENTIAL SIMILARITY / APPROPRIATENESS OF FINAL PRODUCT SPECIFICATIONS (if applicable) Notes for cosideratio: If the approval is based o very rapid dissolutio or rapid dissolutio the specificatios should ot be at loger times, 15 ad 30 mi respectively. Iclude dissolutio specificatio ad actual profile characteristics, e.g. very rapid / rapid. Reviewer s commets: Discuss iformatio o sectio.6 7 LIST OF OUTSTANDING ISSUES / DEFICIENCIES / PROPOSED QUESTIONS 8 CONCLUSIONS AND RECOMMENDATIONS 9 REFERENCES Relevat regulatory guidelies ad scietific papers. IGDRP BCS Biowaiver Assessmet Report <Drug Product ame> Page 17 of 17