Breakout Session G Focus on MR dosage forms - PQRI

1. How can IVIVC help during MRformulation development?• Formulation optimization is not possible withoutbiorelevant dissolution method• If dissolution is not discriminating, scale up of aformulation using in pilot PK studies may be afailure• BA/BE studies are important before scale up• Use pilot study and pilot lots to determine IVIVR;formal IVIVC may be done later in formulationdevelopment3

1. How can IVIVC help during MRformulation development?• Mapping with Level C can be helpful• Pilot BE studies don’t have to be statisticallypowered• If pilot study doesn’t meet BE criteria, can weuse it to develop IVIVR? The answer is yes. Weshould use all available information• All lots including pilot lots should be made underGMP4

2. Can a previously establishedIVIVC model help in thedevelopment of similar MRformulations with different drugs?• No• In principle, it could be useful• Previous experience can be starting point• IVIVR should be developed within formulation5

2. Can a previously establishedIVIVC model help in thedevelopment of similar MRformulations with different drugs?• Formulation excipients may have large range inspecs which may alter drug release• A polymer in USP may have a narrow range butchemical suppliers don’t guarantee range• Functional excipient should have a narrow rangein specs to get good reproducibility6

2. Can a previously establishedIVIVC model help in thedevelopment of similar MRformulations with different drugs?• Do not even try.7

3.What steps are necessary tooptimize IVIVC development forMR products?• Pilot study should be appropriate, ideally withthree formulations and at least one reference• Use Cmax and AUC to get rank order• Tmax can be a helpful parameter to estimateabsorption rate and compare to dissolution8

3.1 What steps are necessary tooptimize IVIVC development forMR products?• Perfusion studies for site specific absorptionshould be used for new drugs.• Dog has similar absorption process to humans,but can not assume one-to-one relationship.• Dog studies can be used to characterize thedrug absorption and find the right dissolutionmethods.9

3.2 What steps are necessary tooptimize MR products using IVIVC?• Develop an IVIVrelationship early.• Define the goal to be achieved.• For a generic, use RLD, faster and slowerformulations to find the release mechanism andappropriate dissolution method.10

4. What are some of the reasonsfor failing to establish IVIVC withMR formulations?• Having an inappropriate dissolution method• Dissolution time should not be too short, shouldbe validated• Dissolution method should be predictive• Inappropriate PK study design: sampling time,role of metabolites11

4. What are some of the reasonsfor failing to establish IVIVC with• Food effectsMR formulations?• Tmax in foreign study is shorter than in US study(probably due to GI transit time)• RLD variability in different lots12

4. What are some of the reasonsfor failing to establish IVIVC withMR formulations?• Site specific drug not predicted. Targeted thewrong site for drug release from MR.• A tablet may stay in stomach for 10 hours asseen with some hydrogel products.• An example: metabolism was not obtained. Firstpass create active metabolite• Slow drug release leads to a greater first-passeffect.13

4. What are some of the reasonsfor failing to establish IVIVC withMR formulations?• Active transport may play a role. Slow drugrelease may provide a more efficient activetransport.• Slow gastric empting may play a role.• Parallel group study for long half life drugs willcomplicate developing an IVIVC.14