Guidelines
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Pharmaceutical Development with Focus on Paediatric Formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008 Industry Perspective on practical approaches and experiences in Development Pharmaceutics 1| Ashish Gogia 30th April 2008 Industry Perspective on practical approaches and experiences in Development Pharmaceutics Name: Ashish Gogia E mail ashishgogia@macleodspharma.com Industry Perspective on practical approaches and experiences in Development Pharmaceutics 2| Ashish Gogia 30th April 2008 Industry Perspective on practical approaches and experiences in Development Pharmaceutics 3| Ashish Gogia 30th April 2008 Drug Development - Opportunities Industry Perspective on practical approaches and experiences in Development Pharmaceutics 4| Ashish Gogia 30th April 2008 Drug Discovery and Development DRUG NCE GENERIC BIOTECH CC/HTS Macro Molecules Small Molecules Permeability Solubility Class III Permeability All Classes Industry Perspective on practical approaches and experiences in Development Pharmaceutics 5| Ashish Gogia 30th April 2008 BCS Class I Class III Class II Class IV Factors Influencing Development of Drug Delivery Systems PHARMACEUTICAL PHARMACOLOGY PATHOLOGY ECONOMICS Drug polarity Therapeutic index Acute/chronic treatment Cost of goods Drug size Onset/duration Preferred route Time to market Drug stability Pharmacodynamics Patient acceptability Regulatory hurdles Quality/Quantity to be delivered Pharmacokinetics First pass metabolism Industry Perspective on practical approaches and experiences in Development Pharmaceutics 6| Ashish Gogia 30th April 2008 Factors Influencing Development of Drug Delivery Systems PHARMACEUTICAL Drug polarity In vitro Dissolution Drug size Drug stability IVIVC Quality/Quantity to be delivered In vivo BA/BE First pass metabolism Industry Perspective on practical approaches and experiences in Development Pharmaceutics 7| Ashish Gogia 30th April 2008 Drug Dissolution and Absorption Industry Perspective on practical approaches and experiences in Development Pharmaceutics 8| Ashish Gogia 30th April 2008 Dosage Form Strategies - Paediatrics Delivery Systems Generics New Drug Applications - 505(b)2 Industry Perspective on practical approaches and experiences in Development Pharmaceutics 9| Ashish Gogia 30th April 2008 Generics Applicability - ANDA 505(j) 21 CFR 314.92 Abbreviated applications may be submitted for: Drug products that are the same as a listed drug Identical in active ingredient (s) Identical in form Identical in strength Identical in route of administration Identical in conditions of use (non exclusive uses) Industry Perspective on practical approaches and experiences in Development Pharmaceutics 10 | Ashish Gogia 30th April 2008 NDA 505(b)(2) Applicability 21 CFR 314.54 Contains Reports of Safety and Effectiveness wherein some investigations are not conducted by applicant and for which the applicant has no right of reference Types of products 21 CFR 314.54 New Chemical or New Molecular Entity Info from studies not conducted by applicant Info where applicant lacks the right of reference Changes to Previously Approved Drugs (RLD) New Dosage Form, Strength, Route of Administration Substitution of an Active Ingredient in Combo Product Formulation changes outside 505(j) limits Industry Perspective on practical approaches and experiences in Development Pharmaceutics 11 | Ashish Gogia 30th April 2008 NDA 505(b)(2) Applicability – Changes to Previously Approved Drugs (RLD) …..contd Dosage Regimen API change - salt, ester, complex, chelate, racemate, enantiomer New Indication Rx/OTC switch May or may not be bioequivalent to existing RLD but n Excluded Products Excluded Products Product covered by 505(J) Only difference is lower extent than RLD Only difference is unintended lower rate than RLD Only difference is unintended lower rate than RLD Industry Perspective on practical approaches and experiences in Development Pharmaceutics 12 | Ashish Gogia 30th April 2008 Examples of 505(b)(2) applications • Dosage form • Combo. of individually approved products • Strength • Indication • Rx/OTC Switch Substituted active ingredient in combo. • OTC monograph • Formulation • • Naturally derived or recombinant active ingredient Dosing regimen • NME • • Route of administration • Active ingredient • Intentional bio-inequivalence Industry Perspective on practical approaches and experiences in Development Pharmaceutics 13 | Ashish Gogia 30th April 2008 New Dosage forms - Paediatrics Existing adult dosage forms No benchmarking Paediatric Reference Product BA/BE against existing adult dosage form Creation of Paediatric Reference Product Industry Perspective on practical approaches and experiences in Development Pharmaceutics 14 | Ashish Gogia 30th April 2008 New Dosage forms – Paediatrics Case Study 1 Metformin Liquid Formulation (Riomet) Reference Product – Glucophage Tablet Approval of Citizen petition for liquid formulation Grant of US Patent Creation of new Paediatric Reference Product Relative BA Comparable to Reference !! Marketing of Branded Paediatric Product in US Industry Perspective on practical approaches and experiences in Development Pharmaceutics 15 | Ashish Gogia 30th April 2008 New Dosage forms – Paediatrics Case Study 2 Cefalexin Tabs for Oral Suspension (Panixine) Reference Product – Powder for Oral Suspension Approval of Citizen petition for ODT Grant of US Patent Grant of USP monograph (Tablets for oral suspension) Creation of new convenient Paediatric Reference Product Bio equivalent to RLD Marketing of Branded Paediatric Product in US Industry Perspective on practical approaches and experiences in Development Pharmaceutics 16 | Ashish Gogia 30th April 2008 What information can an applicant rely on? Published literature specific to the approval sought in the NDA FDA’s finding of safety and effectiveness for an RLD Industry Perspective on practical approaches and experiences in Development Pharmaceutics 17 | Ashish Gogia 30th April 2008 NDA 505(b)(2) type WHO filings Paediatrics Paediatric Formulations proposals for Anti HIV – New Dosage Forms for FDC/Single ingredient Liquid syrup – e.g LA/LZ/LZA Aqueous ready made Liquid Suspensions - e.g Efavirenz Dispersible Tablets - e.g LA/LZ/LZA Industry Perspective on practical approaches and experiences in Development Pharmaceutics 18 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective Literature Search Pharmacopoeial Electronic databases, FDA documents (www.fda.gov/cder/guidance) WHO medicines program (http://www.who.int/medicines/en/) ICH website (http://www.ich.org ) European guidelines for human medicines (http://www.emea.europa.eu/htms/human/humanguidelines/background.htm) International Pharmaceutical federation: Pharmaceutical sciences section (http://www.fip.org/www2/sceinces/index.php) Dissolution methods for drug products (http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm) Patent & exclusivity evaluation (www.wipo.int), (www.uspto.org), (www.esp@cenet.in) etc. Industry Perspective on practical approaches and experiences in Development Pharmaceutics 19 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective API Sourcing & Evaluation International suppliers, supplier evaluation DMF availability and Patent non-infringement Compliance with USP, BP, Ph. Eur and other international pharmacopoeias Impurity profile, stability data, polymorphic forms Analytical testing of API Physical characterization – polymorphism, BET, PSD and bulk density Chemical characterization - Assay, Stress analysis, degradants, enantiomeric purity and residual solvents testing. Industry Perspective on practical approaches and experiences in Development Pharmaceutics 20 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective Innovators Product Selection/ testing Various pack types, evaluation of physical parameters (weight, thickness, hardness, LOD, disintegration and friability) Evaluation of innovator formula ingredients and microscopic testing Evaluation of biostudy parameters Dissolution profile Excipients Suitable excipients selection – compatibility and Stability and tolerance in paediatric population Industry Perspective on practical approaches and experiences in Development Pharmaceutics 21 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective Container Closure System Material composition, thermoplastic resin, liner and seals, cotton, desiccants DMF availability and access letters Analytical method validation API – Impurity Profile, Assay, Residual Solvents, PSD Formulation - Impurity Profile, Assay, Dissolution Industry Perspective on practical approaches and experiences in Development Pharmaceutics 22 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective Manufacturing Process Solid dosage forms Direct compression - Granulation - wet or dry - aqueous or non aqueous, high shear mixing/low shear mixing, order of mixing, premixing, fluid addition, granulation time, torque end point value, drying parameters and LOD limits Granulate flow properties, density, PSD and compressibility, Compression – weight, thickness, hardness, friability and disintegration Assessment of final formulation and stability profile (1-3 months) Industry Perspective on practical approaches and experiences in Development Pharmaceutics 23 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective Liquid Dosage Forms Solutions Solubility of API and dependence on pH Choice of Co solvents for poorly soluble drug, selection of excipients (Sweetening agents, Viscosity control, Coloring Agent etc) Suspensions Solubility of API, Particle Size, Propensity for crystal growth Viscosity of vehicle, Rate of sedimentation or settling, Chemical stability Emulsions Stability w.r.t pH, Freeze Thaw Cycles, Creaming Flocculation, Coalescence or breaking Industry Perspective on practical approaches and experiences in Development Pharmaceutics 24 | Ashish Gogia 30th April 2008 Pharmaceutical Developmental Activities – Industry Perspective Process Optimization/Evaluation Granulation, drying, blending and compression parameters Process Qualification/Pilot Scale/Submission/Exhibit Batch Simulation of production/Laboratory Facilities Manufacturing under cGMP conditions Minimum 100, 000 units API and Excipients sourcing from qualified suppliers Master Formula and manufacturing instructions Packaging order and packaging instructions Different pack types on stability Bioequivalence Study Usually Higher strength - Fasting/Fed as applicable Other strengths – In-vitro dissolution (3 pH media) Industry Perspective on practical approaches and experiences in Development Pharmaceutics 25 | Ashish Gogia 30th April 2008 Summary Create new convenient paediatric dosage formulation Rely on published literature for safety & efficacy No additional Clinical Trials BA/BE vs adult formulations !! Usual pharmaceutical development curriculum (in line with Q –8 addendum) Strength identification Organoleptic acceptability Industry Perspective on practical approaches and experiences in Development Pharmaceutics 26 | Ashish Gogia 30th April 2008
