【文章內(nèi)容簡(jiǎn)介】 g, 250 mg and 125 mg ? Process: Wet granulation and pan coating ? Background – On the market for 20 yrs. – Transfer of manufacturing site from North America to South America due to plant sale ? PAC: Multiple related changes: Site/Composition/Process/Equipment ? Objectives – Understand potential impact on product quality and performance – Justify a biowaiver 14 AAPS/CPA Workshop June 2829, 2022 Case Study 1: A DelayedRelease Tablet ? Summary of Changes – Composition: Ink for printing – Processing/Equipment (SUPAC L3) ? Lowshear plaary mixer/oven drying = highshear Single Pot Processor (SPP) ? Granulation and coating solvents (EtOH = IPA。 grade) ? Slightly different total solids content of coating solution ? 125 mg strength: Perforated coating pan = a conventional pan and the smaller batch size – Site (SUPAC L3) ? Approach – Review of product and manufacturing history ? Product licensed and manufactured in various markets ? Formulation for various markets: Same ? Process: Slightly variable due to local equipment availability ? Specifications, inprocess control and test methods: Same ? Consistent product quality and robust manufacturing for 20 yrs 15 AAPS/CPA Workshop June 2829, 2022 Case Study 1: A DelayedRelease Tablet ? Approach (Cont’d) – Comparison of product performance ? Tablet Characteristics: All tablets met the established acceptance criteria (potency, content uniformity, acid resistance, hardness and physical inspection, etc.) ? In Vitro Drug Release ? Two lots for each of the three strengths from both sites ? Testing at pH , , and to evaluate effective enteric protection and subsequent drug release ? In Vivo Performance ? Evaluate potential impact of the changes: (1) In vivo BE study or (2) In vitroin vivo correlation (IVIVC) ? In vitroin vivo relationship (IVIVR): Distinguish between acceptable and unacceptable drug products or ensure batchtobatch consistency within a range which ensures acceptable in vivo performance ? In the absence of a quantitative IVIVC, a mapping study can be used to define drug release limits of a product that will ensure bioequivalence of batches prepared within the limits 16 AAPS/CPA Workshop June 2829, 2022 Case Study 1: A DelayedRelease Tablet ? In Vivo Performance (Cont’d) – A previous BE study of the US product was used to investigate IVIVR ? A single dose, fasting, 3way crossover study (n=15) ? Mapping in vitro drug release 0 . 02 0 . 04 0 . 06 0 . 08 0 . 01 0 0 . 01 2 0 . 00 20 40 60 80T i m e ( M i n u t e s )% ReleasedC a n a d a ( 1 2 0 2 5 N B 2 )C a n a d a ( 1 5 0 3 2 N B 1 )A r g e n t i n a ( 1 5 7 5 6 Q A )A r g e n t i n a ( 1 8 9 8 6 K I)A ( 7 7 4 4 2 A R ) B ( 7 5 4 3 5 A R )? Tablets studied differ in granulation solvent, ratecontrolling polymer, coating solvent and process parameters (details in backup slides) ? Two different formulations manufactured by varying amounts of ratecontrolling polymer (10% vs. 14%) to provide fastest and slowest drug release are bioequivalent ? Tablets made with changes are expected to be bioequivalent o Near 100% bioavailability o Similar and more rapid drug release than the lower limit of the verified range that offers maximum likelihood of ensuring bioequivalence 17 AAPS/CPA Workshop June 2829, 2022 Case Study 1: A DelayedRelease Tablet ? Justification of a Biowaiver – Drug properties ? Stable, soluble and permeable. 90% BA demonstrated with both DR and ER tablets in multiple biostudies – Formulation ? The tablet core consists of high loading of the soluble active, and hydrophilic excipients, resulting in rapid drug release upon dissolution of the enteric coating ? The enteric polymer has a long history of proven performance. Changes are unlikely to result in changes in functionality of the core position and the enteric coating. ? The in vivo performance remains unaltered when more significant changes in core and coating positions were made with the two formulations tested in the mapping study. – Processing ? Major changes: Low shear to high shear granulation and drying = did not lead to changes in subsequent tablet processing because the inprocess control remain unchanged ? A long history of manufacturing the same product using high shear granulation and fluidbed drying in other markets that showed consistent in vivo performance 18 AAPS/CPA Workshop June 2829, 2022 Case Study 1: A DelayedRelease Tablet ? Justification of a Biowaiver (Cont’d) – Product charact