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