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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 1| Snehal Khedkar | April 2008 Greetings from Ipca Ipca Laboratories Limited Partnering Healthcare Globally 2| Snehal Khedkar | April 2008 Pharmaceutical Development with Focus on Paediatric formulations Practical problems in developing FDCs & Bilayer tablets Presenter: Snehal Khedkar Email: [email protected] 3| Snehal Khedkar | April 2008 Practical problems in developing FDCs & Bilayer tablets What are Fixed Dose Combinations??? 4| Snehal Khedkar | April 2008 Practical problems in developing FDCs & Bilayer tablets Fixed Dose combination (FDC) “ A combination of two or more actives in a fixed ratio of doses.” Source: WHO Technical report series, No. 929, p.no-107, 2005 Examples of FDCs in WHO’s list of essential drugs Anti- Infective: Sulfamethoxazole + Trimethoprim Anti-Tuberculosis: Rifampicin + Isoniazid 5| Antiviral: Stavidine + Lamivudine + Neviparine Antimalarial : Artesunate + Amodiaquine Snehal Khedkar | April 2008 Rationale…. Reduced Pill Burden Patient Convenience Patient Adherence Monotherapy prevented Least probability of developing drug resistance Validated theory with other infectious diseases like TB, Leprosy, AIDS. 6| Snehal Khedkar | April 2008 Rationale…. Co-morbid Conditions Hypertension Heart Disease Diabetes Obesity Hyperlipidemia 7| Snehal Khedkar | April 2008 Treat different ailments in the same patient (co-morbidity), at the same time and with one pill Allows for synergistic combination Rationale…. POLY -PHARMACY Diabetes Tuberculosis Hypertension Malaria Allergy/Asthma AIDS Ulcers Pain 8| Snehal Khedkar | April 2008 Combination drugs that target the same indication Rationale…. SIDE EFFECTS Weight Gain Reduced by using one drug of the combination for this purpose Stomach Irritation Nausea 9| Snehal Khedkar | April 2008 Amiloride may prevent hypokalemia caused by hydrochlorthiazide Challenges in Development of FDCs “Manufacturing challenges: Product Formulation issues Manufacturing issues 10 | Snehal Khedkar | April 2008 Product Formulation issues …… Problems… Solutions… Disproportionate doses e.g. Metformin + Glibenclamide (400 mg + 2.5 mg) - Content uniformity Dilution for low dose drug Drug loading / Adsorption on excipients - Assay Different release kinetics e.g. Rabeprazole + Domperidone (20 + 30 mg) 11 | Snehal Khedkar | April 2008 IR +SR (Use of OCRS) Bilayer/ Trilayer Product Formulation issues …… Problems… Solutions… Hygroscopicity e.g. Metformin + Glipizide Metformin- Poorly compressible Needs residual moisture Glipizide - Degrades in moisture Separate granulation Coat the Glipizide particles Altered solubility/ stability e.g. Atorvastatin + Ramipril + Aspirin Synergistic action Atorvastatin -is acid labile Aspirin- Undergoes alkaline hydrolysis 12 | Snehal Khedkar | April 2008 Suitable excipients Drug Delivery Systems for FDCs….. Matrix system Multilayered tablets (bi/tri) Compression coated Tab-in-tab In-lay technology 13 | Snehal Khedkar | April 2008 Delivery systems to formulate FDCs….. Multiple unit system Beads / coating Particulate / Coating (MUPS) Multicompartment capsules Capsule within capsule Capsule – coated Mini-tab in capsules 14 | Snehal Khedkar | April 2008 Dual Release Drug Absorption Systems Multi-layered tablets Bilayer, Trilayer & Tab -in -Tab One or more than one drug combination with different release patterns Incompatibility, stability issue can be resolved 15 | Snehal Khedkar | April 2008 Multilayered Tablets….. Bilayer Tabletting + Release of both drugs starts immediately Ease of manufacturing Elegance to the product 16 | Snehal Khedkar | April 2008 Multilayered Tablets….. Trilayer tabletting Inert layer + + Two incompatible drugs Combination of incompatible drugs Combination of different release profiles Elegance to the product 17 | Snehal Khedkar | April 2008 Problems in layered tablets….. Lack of proper bonding of two layers 100,000 tablets several days 200,000 layers Stress due to high compression force degrades certain actives e.g. ramipril 18 | Snehal Khedkar | April 2008 Probable cause of increase in impurities Crystal lattice ruptures 19 | Snehal Khedkar | April 2008 Tablet-in- Tablet Technology….. Tab-in-Tab Elegance to the product Improved product stability Minimal incompatibility 20 | Snehal Khedkar | April 2008 Inlay Technology….. A new platform technology for decreasing the mechanical shear on double compressed products which can lead to decrease in unknown/process related impurities. Release of both drugs starts immediately 21 | Snehal Khedkar | April 2008 Case study……Artemisinin based FDCs Artesunate + Amodiaquine HCl Dosing regimen based on weight to age data Optimised dose ratio i.e. 1 : 3 Rationale: To ensure that patients take both drugs together in the right dose, with a particular attention paid to paediatric needs (dose ratio, age-adapted strengths, optimized pharmaceutical formulation) Ref: WHO Bulletin, Vol 84, No. 12 Dec. 2006, 921-1000 22 | Snehal Khedkar | April 2008 Chemical incompatibility….. ACID –DEGRADED ARTESUNATE AMODIAQUINE. HCl 23 | Snehal Khedkar | April 2008 ARTESUNATE Technology Used …… A’sunate (Optionally coated) A’quine Bilayer technology Limited contact Degradation problem solved 24 | Snehal Khedkar | April 2008 Critical Process Parameters …… Sr. No. Parameters 1 API 25 | Remark i. Particle size distribution Increase in effective surface area ii. Storage Protect Artesunate from moisture 2 Granulation Point Wet mass (mixing time)= Improved wetability 3 Moisture Content Less than 1%w/w (Measured on IR moisture balance at 65ºC) Improvement in compaction properties 4 Hardness of Tablets Low High Snehal Khedkar | April 2008 Layer separation Decrease in Solubility/ Dissolution Evaluation studies …… Stability Indicating Assay Related Compounds Dissolution Profile Content Uniformity OVI / Residual Solvents Impurity profile study Drug : Excipients compatibility study 26 | Snehal Khedkar | April 2008 Characterization of impurities Some of IPCA’s Unique Products*….. Physical and /or chemical incompatible drugs Artesunate + Amodiaquine Drugs with different biological half lives Loratidine + Pseudoephedrine Multiple release formulations Bilayer Antidiabetic drug combinations Inlay Zolpidem tartarte ER Trilayer Metformin ER +Glicazide MR + Pioglitizone IR To prevent side effects Lamotrigene MR tablets Mumps – multiple unit particulate system Filled in hard gelatin capsule Compressed within a tablet (Metoprolol Succinate XL) *For Indian Market 27 | Snehal Khedkar | April 2008 The starting formulation may be based on INTUITION but the ending formulation must be based on SCIENCE Science means: There will be no weak eye in the pharmaceutical development chain 28 | Snehal Khedkar | April 2008 Research & Development (Formulations)….. New Product Introduction Pharmacology Evaluation Regulatory Affairs R&D Analytical Research Divisions Medical Marketing Identification Product Development Developm ent Evaluation 29 | Snehal Khedkar | April 2008 R&D Production Q.A. R&D Production Validation team Validation Tech. Transfer Regulatory Development Program Timelines….. Stages Months Activities 4 Pre-formulation Establish Drug : Excipients compatibility 3 Development lots Mini experimental trials to decide the formula / process 2 Process optimization Fine tuning to avoid scale-up problem Process qualification (Scale-up batch) To define critical processing steps and test parameters usually mimics production conditions Stability Studies Pivotal batch 4 2 Product development report & Submission Samples are used to perform the bioequivalence study / clinical trials. For PAI visit ~ 15 Months for Product Development, by Following ICH Guidelines 30 | Snehal Khedkar | April 2008 Technology Transfer….. 100 R&D Development More effective as we move point of intersection to the left Manufacturing & Quality 0 Early Development 31 | Snehal Khedkar | April 2008 Launch / Commercialization • Master Manufacturing Document • Development Report • Specifications • Validation Protocols/SOPs • Onsite training & technical Presentation Product Quality Design….. Knowledge space DESIGN SPACE CONTROL STRATEGIES Existing knowledge & new scientific data generated in the process Design space Interaction of input variables & process parameters that provides Quality Product Control strategy Includes Input material controls, Process controls & FPP control tests Development of ‘ASSURED QUALITY PRODUCT’ 32 | Snehal Khedkar | April 2008 BECAUSE Knowledge space & resulting design space & process understanding CONSTANTLY EVOLVES……!! 33 | Snehal Khedkar | April 2008