Riset dan Pengembangan

dalam Farmasi Industri

Dr. apt. Linda Margata, S.Farm
Drug Development
• Objective: initiated because there is a disease or clinical condition
without suitable pharmacotherapeutic products available
• Testing is done in cells (in vitro) and in animals (in vivo) to study the
metabolism and to produce a product that is safe and has passed all
regulatory requirements.
• Two main reasons of drug failure in clinical practice:
1. The drug is not working properly
2. The drug is not safe
Definition of API
"active pharmaceutical ingredient (API)
Any substance or combination of substances used in a
finished pharmaceutical product (FPP), intended to furnish
pharmacological activity or to otherwise have direct effect in
the diagnosis, cure, mitigation, treatment or prevention of
disease, or to have direct effect in restoring, correcting or
modifying physiological functions in human beings."

(WHO TRS 961)

• API production is a highly sophisticated, technically demanding chemical
and biochemical fermentation and/or synthesis process
• APIs constitute a significant portion of the total cost for a drug: on average,
40-50% of the cost of goods sold for generic oral solids comes from APIs
• Commodity API manufacturing tends to be a high-volume, low-margin
business where economies of scale play an important role.
• The average commodity API profit margin is less than 10%
• In fact, many large bulk API exporters from India work with a 3% margin on
exported products
• Profit margins for final formulations average 20-30%
Stages of Drug Development
1. Drug Invention
2. Product Characterization
3. Formulation & Development
4. Preclinical Testing
5. IND Application
6. Clinical Trials
7. Regulatory Review
8. Marketing the product or drug
9. Post-marketing monitoring (phase-IV) trials
1. Drug Invention
A. Target identification
B. Target validation
C. Lead identification
D. Lead optimization
Target Identification:
• biological origin of the disease & potential targets
• based on principles of molecular biology, biochemistry, genetics,
biophysics, or other disciplines
Target validation:
• is the process of demonstrating the functional role of the identified
target in the disease phenotype
• Can be broken down into 2 steps:
1. Reproducibility : repeat the experiment to confirm that it can be
successfully reproduced.
2. Introduce variation to the ligand (drug)-target environment
Identification of Lead:
• SAR defined
• Drug ability (preliminary toxicity)
• Synthetic feasibility
• Select mechanistic assays
• In vitro assessment of drug resistance and efflux potential
• Evidence of in vivo efficacy of chemical class
• PK/Toxicity of chemical class known based on preliminary toxicity or in
silico studies
Lead Optimization:
• iterative series of synthesis and characterization of a potential drug
• to improve target specificity and selectivity
2. Product Characterization
• Size
• Shape
• Strength
• Weakness
• Use
• Toxicity
• Biological activity
• Mechanism of action
3. Formulation and Development
• Physicochemical properties of Active Pharmaceutical Ingredients (APIs) are characterized to produce a
bioavailable, stable and optimal dosage form for a specific administration route.
• Evaluation of parameters:
• Solubility in different media and solvents
• Dissolution of the active pharmaceutical ingredient (API)
• Accelerated Stability Services under various conditions
• Solid state properties (polymorphs, particle size, particle shape etc.)
• Formulation Services and Capabilities
• Formulation development of new chemical entities (NCE)
• Optimization of existing formulations
• Process development for selected dosage forms
• Novel formulations for improved delivery of existing dosage forms
• Controlled release and sustained release formulations
• Self-emulsifying drug delivery systems
• Colloidal drug delivery systems
• Sub-micron and nano-emulsions
4. Preclinical Testing
• Observed by:
1. studying the accidental exposure to a substance
2. in vitro studies using cells
3. in vivo exposure to experimental animals
• Toxicology profile consists of:
1. safety pharmacology
2. genetic toxicology
3. acute and subchronic toxicology
4. absorption, distribution, metabolism, and excretion (ADME) studies
5. reproductive and developmental toxicity
6. evaluation of carcinogenic potential
5. IND Application
• Preclinical and toxicity study data
• Drug manufacturing information
• Clinical research protocols for studies to be conducted
• Previous clinical research data (if any)
• Information about the investigator/ developer
6. Clinical Trials
• Selection criteria for participants
• Number of people take part of the study
• Duration of study
• Dose and route of administration of dosage form
• Assessment of parameters
• Data collection and analysis
Phase 0 clinical trial:
• single sub-therapeutic doses
• 10 to 15 volunteers
• give pharmacokinetic data
Phase 1: Safety and dosage
• 20 to 80 healthy volunteers (sometimes with the disease/condition)
• acute side effects / the side effects accompanying with increase in
dosage
• mechanism of action
• information about effectiveness
• Almost 70% of drugs travel to the next phase.
Phase 2: Efficacy and side effects
• larger groups of patients (few hundreds)
• to evaluate the efficacy
• to endure the Phase I safety assessments / provide with additional
safety data
• Around 33% of drugs travel to the next phase
• Phase II clinical studies aid to found therapeutic doses for the large-
scale Phase III studies
Phase 3: Efficacy and adverse drug reactions monitoring
• to prove whether a product deals an action benefit to a specific
people or not
• 300 to 3,000 volunteers
• deliver most of the safety data
• longer in duration
• Around 25-30% of drugs travel to the next phase of clinical research.
7. Regulatory review
• After completion of clinical trials data
• data collected is submitted to the relevant regulatory authorities to obtain
approval to market the drug in their jurisdictions.
• New Drug Application:
• Clinical trial outcomes
• Proposed labeling
• Safety updates
• Drug abuse information
• Patent information
• Institutional review board compliance information
• Directions for use
9. Marketing the product
• The last stage in the drug development process
10. Post-marketing monitoring (phase-IV)
trials
• to assess the safety of the drug in the market place
• pharmacovigilance
• Include:
1. reporting and investigation of the incidence and severity of rare adverse
reactions
2. cost-effectiveness analyzes comparative trials
3. quality of life studies
Global API Industry
Pharmaceutical production in developing
countries
Two types of
markets for
pharmaceuticals: On-patent originator drugs

Generic off-patent drugs

• Two thirds of the total value of medicines produced globally in 1999
($327.2 billion) is accounted for by firms in the United States, Japan,
Germany, France and the United Kingdom
• Driven by lower costs, API manufacturing has slowly been shifting
from the historical leaders in Western countries to newer firms in
India and China.
Indian and Chinese advantages typically come from:

• Lower labor, infrastructure, transportation and equipment costs

• Fewer environmental regulations
• Larger scale manufacturing
• Lower barriers to market entry
New Drug Research in Indonesia
https://www.fiercepharma.com/
National Agency of Drug and Food Control – Republic of
Pre-requisite and attracting investment in the
pharmaceutical sector
• Critical mass of skilled human resources:
Pharmacists, graduates from universities with chemistry and biochemistry
degrees, technicians, engineers, business manager
Countries that have been able to attract investors in the pharmaceutical
sector all have a relatively strong pharmacy faculty at their leading national
universities
• Basic infrastructure:
reliable source of electricity
access to clean water
set up special industrial zones
• A functioning national drug regulatory authority
Assuring safety and quality
providing relevant information for local pharmaceutical firms
need for qualified human resource
builds confidence among exporting countries
• Government support is important
Investment in the pharmaceutical sector will not come on its own
Seeking to attract foreign direct investment and technology transfer is
necessary
Government can also be a potential investor
Conclusion
• The manufacture and distribution of pharmaceuticals is a complex
process
• Pharmaceutical industries in Indonesia are still highly dependent to
imported APIs, therefore attempts to produce APIs are needed.
• Support can come only through sustained efforts, including foreign
direct investment and technology transfer
• The availability of good human resources, basic infrastructure and a
functioning drug regulatory authority are prerequisites in attracting
the desired investment and related technology transfer.
Daftar Pustaka
• Bumpas, J., Betsch, E. (2009). Exploratory Study on Active Pharmaceutical Ingredient
Manufacturing for Essential Medicines. Washington DC: Health, Nutrition and Population (HNP)
Discussion Paper.
• CpHI North America. (2020). Global API industry snapshot: Pharma demands and evolving
markets. www.cphinorthamerica.com
• Deore, A.B., Dhumane, J.R., Wagh, H.V., Sonowane, R.B. (2019). The Stages of Drug Discovery and
Development Process. Asian Journal of Pharmaceutical Research and Development. 7(6): 62-7.
• Elhassa, G.O., Alfarouk, K.O. (2015). Drug Development: Stages of Drug Development. Journal of
Pharmacovigilance. 3: e141. doi: 10.4172/2329-6887.1000e141
• UNCTAD. (2011). Investment in Pharmaceutical Production in the Least Developed Countries.
Geneva: United Nations.