【正文】 ellets is a copolymer of acrylic and methacrylic acid esters with a content of ammonium groups. – 8. A onceaday controlled release diltiazem formulation as defined in claim 1 which exhibits in HCl, a release rate profile which is initially a zero order release rate of diltiazem that continues for up to about 1214 hours and thereafter exhibits a increase in the rate of release of diltiazem. Formulation and Process Development of Oral ER Dosage Forms in Generic Industry ? Generic Formulation Development – An once daily ER capsule containing two different coated pellets: – Enteric coated pellets containing active drug ? Coating formulation: methacrylic acid copolymer and acetyltributyl citrate – Delayed pulse polymer coated pellets containing active drug ? Coating formulation: copolymer of acrylic and methacrylic acid esters with a content of ammonium groups and acetyltributyl citrate Formulation and Process Development of Oral ER Dosage Forms in Generic Industry ? Process Development – Manufacturing Active Pellets – Drug layering process in a fluid bed – Enteric coating on active pellets in a fluid bed ? Possibly a seal coat ? Methacrylic acid copolymer and acetyltributyl citrate – Delayed pulse polymer coating on acive pellets in a fluid bed ? Possibly a seal coat ? Copolymer of acrylic and methacrylic acid esters with a content of ammonium groups and acetyltributyl citrate Formulation and Process Development of Oral ER Dosage Forms in Generic Industry ? Defining Process Parameters – A – Surface Area for drug diffusion (size and density of pellets) – h – Coating thickness (coating efficiency, size and density of pellets, and etc.) – D – Diffusivity (plasticizer, curling, and etc.) )( CCsAhDdtdMQ ???FDA Regulations to Approve ANDA for Oral Controlled Release Dosage Forms ? Bioequivalence Requirement – Single Dose Two Way Crossover BE Study with Fasting Conditions – Single Dose Two Way Crossover BE Study with NonFasting Conditions – Additional Sprinkle single Two Way Crossover BE Study with Apple Juice for CR Capsules – All Require – % at 95% Confidence Intervals Regulatory Requirements for Filling ANDA by FDA ? Drug Product – Description and Composition of the Drug Product – Pharmaceutical Development – Manufacture – Control of Excipient – Control of Drug Product – Reference Standard and Materials – Container Closure System – Stability Intellectual Property Related Issues – Challenges in Developing Oral ER Dosage Forms ? Paragraph III Fillings – Request approval after the Orange Book listed patents expire, or – No any patent(s) listed by brand pany in Orange Book – Patent search with legal opinion preferred ? Paragraph IV Filings – Patent(s) listed by Brand pany in Orange Book – Certification of Patent Infringement Status by Patent holder – 30 months stay – Court Decision in 30 months – 180 days exclusivity periods ANDA Filing ? Chemistry, Manufacturing and Control (CMC) Section – Executed Manufacturing Batch Records and Packaging Records ( 100,000 Units) Preferred same batch size with intended mercial batch size. – Commercial Blank Master Batch Records – Manufacturing InProcess Controls – All Valid DMFs for Active and Ingredients – Commitment for cGMP Regulations – Development Report – The Quality Overall Summary (QOS) ANDA Filing ? Chemistry, Manufacturing and Control (CMC) Section (Cont’d) – All Release Data of Active, Ingredients and Packaging Components for Executed Manufacturing Batch – Analytical Method Validation Reports ? Assay for API, InProcess Control and Finished Product ? Assay for Impurities and Degradants ? Stability Indicating Methods ? Dissolution – All Release Data for InProcess Control Samples – All Release Data for Finished Product for the Executed Batch – Stability Results from 3 Months of Storage at AC and RT – Specifications for Quality Controls Acknowledgement Conference Organizer Novast Holdings Attendees