Drug Development by Government Pharmaceutical Organization Dr. Rachaneekorn Jevprasesphant The Government Pharmaceutical Organization (GPO) Thailand 20August 2012
GPO s Profile GPO was established in 1966. GPO is a state enterprise under the Ministry of Public Health At present, GPO manufactures and sells more than 300 items of pharmaceutical products including biological products, with more than 2,500 staff.
Vision To be a leader in pharmaceutical products and medical supplies beneficial and essential to the Thai society and fairness
Mission To manufacture, sell and supply pharmaceutical products and medical supplies with a aim to achieve world-class standard To develop business to ensure competitiveness and selfsustainability To maintain price level of pharmaceutical products and medical supplies for the Thai society to ensure people s accessibility To research and develop new pharmaceutical products, and medical supplies to respond to the need and necessity of the Thai society
Drug Development Product Formulation Overview
Preformulation Physicochemical characteristics of the drug Pharmaceutical factors Physiological factors
1. Physicochemical characteristics of the drug Molecular structure Solubility Organoleptic property Purity Crystalline and Polymorph Hygroscopic Bulk density Particle size and shape Melting point Surface properties (charge) Drug pka Partition coefficient (Log P) Chemical degradation Powder flow property
Particle size analysis X-ray diffractometry Differential scanning calorimetry
2. Pharmaceutical factors Factors related to formulation (excipients) i.e. Lactose, Microcrytalline cellulose Dosage form Compatibility study Manufacturing process
Compatibility study Initial 30 days 30º C,75%RH 40º C, 75%RH Drug +Diluent (1:1) Drug+Binder (1:1) or (10:1) Drug +Disintegrant (1:1) or (10:1) Drug +Lubricant (1:1) or (15:1) Drug +Coloring agent (1:1) or (20:1) Powder characteristics (i.e. Color and Impurity) Powder characteristics (i.e. Color and Impurity) Powder characteristics (i.e. Color and Impurity) Powder characteristics (i.e. Color and Impurity) Powder characteristics (i.e. Color and Impurity)
Pharmaceutical Equipments For Solid dosage form i.e. Powder, Tablet, Capsule, Lozenge, Suppository Liquid dosage form i.e. Solution, Syrup, Tincture, Emulsion, Suspension Semi-solid dosage from i.e. Cream, Paste, Ointment
Cube mixer V-shape mixer
Double Cone Mixer (for powder blending)
Wet Granulation Hobart mixer Horizontal mixer
Wet Granulation High speed mixer
Dryer Tray dryer Fluidized bed dryer
Compression Machine Rotary tablet compression machine
Film coater
Pelletization Extruder and Spheronizer Fluidized bed coater
Demonstrations on different types of extruders ZSE 18 HP-PH Pelletizer (configuration of vacuum conveyor according to pressure requirements)
Semisolid dosage form Vacuum Homogenizer Homogenizer
2. Physiological factors Protein and tissue binding Regional ph Intestinal permeation Hepatic metabolism Mucus Gastric and intestinal transit Presence of food Individual variation (gender, race, age and disease state)
Physical and Chemical Studies 1. Disintegration test 2. Dissolution test 3. Stability studies
Dissolution Profile Levofloxacin 500 mg tablet dissolution profiles Percent labeled amount dissolved 120 100 80 60 40 20 0 Reference product S510260 0 20 40 60 80 100 120 Time (mins)
Stability studies Container Closure System 1. Primary packaging HDPE bottle Strip pack (Nylon/Al/PVC) Alu/Alu pack (Nylon/Al/PVC) Blister pack - Duplex (PVC/PVDC) - Triplex (PVC/PE/PVDC ) - PVC/ACLAR 2. Secondary packaging (Boxes)
Stability study a) Evaluated temperature study b) Stability under high humidity condition c) Photolytic stability d) Stability to oxidation
Stability study Accelerated Stability Study (40ºC, 75%RH) Pass 6 months Long term Stability Study (30ºC, 75%RH) Pass 12 months (Estimation shelf-life 2 years) Real time study up to 60 months Long term Stability Study (25ºC, 60%RH) Real time study up to 60 months
Stability Chamber
Pilot batch Scale up batch (at least 2 pilot batches) Stability data generation for registration Bioequivalence study Pharmacokinetic and Clinical studies
Technological Capabilities - Tablets Direct mixing Unit operation Equipment R&D Pilot Plant Manufacturing Screening Vibratory sifter Vibratory sifter Vibratory sifter Comil (Lab Model) Quadro, Canada Comil Quadro, Canada Comil Quadro, Canada Blending Bin Blender (10 /20L ) Bin Blender (75/165 L) Bin Blender (300/600L)
Technological Capabilities - Tablets Wet granulation Unit operation Equipment R&D Pilot Plant Manufacturing A. High Shear Granulator Rapid Mixer Granulator (5-25 L) Rapid Mixer Granulator (40 L) Planetary Mixer (2-4L) Rapid Mixer Granulator (250 & 600 L) Planetary Mixer (60 L & 120 L) B. Top Spray Granulator Fluid Bed Processor (5 L) Fluid Bed Processor (125 & 500 L)
Pharmacokinetic and Clinical Study No Projects Organization 1. 152 Weeks Study of Safety and Efficacy of a Simplified Fixed-Dose Combination of Stavudine, Lamivudine and Nevirapine (GPO-VIR ) for the Treatment of Advanced HIV-Infected Patients 2. Clinical, virological and immunological response of HIVinfected children to highly active antiretroviral treatment 3. A 48 week, randomized, open-label, 2 arm study to compare the efficacy, safety and tolerability of HAART containing nevirapine 400 mg/day versus nevirapine 600 mg/day in HIV-1 infected patients started at 2-6 weeks after initiating rifampin containing antituberculous therapy Faculty of Medicine Siriraj Hospital Mahidol University Faculty of Medicine Chiangmai University HIV-NAT, Thai Red Cross AIDS Research Centre
Pharmacokinetic and Clinical Study (cont.) No Projects Organization 4. A Phase I/II comparative Pharmacokinetic study of the fixed-dose combination (FDC) of stavudine (d4t), lamivudine (3TC) and nevirapine (NVP) as GPO-VIR S7 pediatric chewable tablets versus the individual liquid formulation in HIV-infected children 6 months to < 13 years of age in Thailand 5. A 72-week randomized clinical trial comparing the safety and efficacy of three initial antiretroviral regimens-gpo- VIR S30 (D4T/3TC/NVP) for 24 weeks followed by GPO- VIR Z250 (AZT/3TC/NVP) vs GPO-VIR Z250 vs TDF/FTC/NVP Faculty of Medicine Siriraj Hospital Mahidol University HIV-NAT, Thai Red Cross AIDS Research Centre
Pharmacokinetic and Clinical Study (cont) No Projects Organization 6. A Phase I/II comparative Pharmacokinetic study of the fixed-dose combination (FDC) of zidovudine (AZT), lamivudine (3TC) and nevirapine (NVP) as GPO-VIR Z30 pediatric tablets versus the individual liquid formulation in HIV-infected children 5 months to < 13 years of age in Thailand 7. Therapeutic drug monitoring safety and efficacy of the generic lopinavi/ritonavir tablets 200/50 mg in Thai HIVinfected Patient Faculty of Medicine Siriraj Hospital Mahidol University HIV-NAT, Thai Red Cross AIDS Research Centre
Pharmacokinetic and Clinical Study (cont) No Projects Organization 8. Treatment outcome and safety of zidovudine/lamivudine/nevirapine fixed-dose combination in HIV-infected Thai patients HIV-NAT, Thai Red Cross AIDS Research Centre 9. Pharmacokinetic study and safety monitoring of tenofovir including once daily antiretroviral regimen in HIVinfected children with viral suppression Faculty of Medicine Siriraj Hospital Mahidol University
Pharmacokinetic and Clinical Study (cont) No Projects Organization 10. Initiation of a once daily regimen of tenofovir, lamivudine and efavirenz after 4 weeks versus 12 weeks of tuberculosis treatment in HIV-1 infected patients Bamrasnaradura Infectious Diseases Institute 11. Comparative study between entecavir and tenofovir in the treatment of chronic hepatitis B infection in Thai patients Chulabhorn Hospital
R & D Pilot Plant BE Study Stability data generation Manufacturing Stage I 2 months Stage II 4 6 months Stage III 1 2 months Stage IV 12 months Stage V Product Preformulations Prototype & lab-scale Scale-up & Stability data Tech. transfer Identification Development Exhibit Batch generation for to Mfg & Process & Allocation registration Validation Development Timelines ( upto Stage III ) Simple Products : 7 10 Months Complex Products : 12 15 Months Timelines
New ARV Rungsit Plant Total area : 20,000 Sq.mt. Capacity around : 2,335 million tablets and capsule/year Apply for WHO pre-qualification
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