Drug Development by Government Pharmaceutical...
Transcript of Drug Development by Government Pharmaceutical...
Drug Development by Government Pharmaceutical Organization
20August 2012
Dr. Rachaneekorn Jevprasesphant
The Government Pharmaceutical Organization (GPO) Thailand
• 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.
GPO’s Profile
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 self-sustainability
• 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
Powder flow property
Particle size and shape
Melting point
Surface properties (charge)
Drug pKa
Partition coefficient
(Log P)
Chemical degradation
Particle size analysis
Differential scanning calorimetry
X-ray diffractometry
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)
Powder characteristics (i.e. Color and Impurity)
Drug+Binder
(1:1) or (10:1)
Powder characteristics (i.e. Color and Impurity)
Drug +Disintegrant
(1:1) or (10:1)
Powder characteristics (i.e. Color and Impurity)
Drug +Lubricant
(1:1) or (15:1)
Powder characteristics (i.e. Color and Impurity)
Drug +Coloring agent (1:1) or (20:1)
Powder characteristics (i.e. Color and Impurity)
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
Pharmaceutical Equipments
Cube mixer V-shape mixer
Double Cone Mixer (for powder blending)
Hobart mixer Horizontal mixer
Wet Granulation
High speed mixer
Wet Granulation
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
Pelletizer (configuration of vacuum conveyor according to pressure requirements)
ZSE 18 HP-PH
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
0
20
40
60
80
100
120
0 20 40 60 80 100 120
Time (mins)
Perc
ent l
abel
ed a
mou
nt d
isso
lved
Reference product
S510260
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
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)
Direct mixing
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)
Rapid Mixer Granulator (250 & 600 L)
Planetary Mixer (2 - 4L)
Planetary Mixer (60 L & 120 L)
B. Top Spray Granulator
Fluid Bed Processor (5 L)
Fluid Bed Processor (125 & 500 L)
Technological Capabilities - Tablets
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
Faculty of Medicine
Siriraj Hospital
Mahidol University
2. Clinical, virological and immunological response of HIV-
infected children to highly active antiretroviral treatment
Faculty of Medicine
Chiangmai University
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
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
Faculty of Medicine
Siriraj Hospital
Mahidol University
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
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
Faculty of Medicine
Siriraj Hospital
Mahidol University
7. Therapeutic drug monitoring safety and efficacy of the
generic lopinavi/ritonavir tablets 200/50 mg in Thai HIV-
infected Patient
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 HIV-
infected 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
Timelines
Stage I
2 months
Stage II
4 – 6 months
Stage III
1 – 2 months
Stage IV
12 months
Stage V
R & D
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
Pilot Plant BE Study Stability data generation
Manufacturing
New ARV Rungsit Plant
• Total area : 20,000 Sq.mt.
• Capacity around : 2,335 million tablets and capsule/year
• Apply for WHO pre-qualification
THANK YOU AND ANY QUESTIONS
Please visit us at www.gpo.or.th