Drug Discovery

&
Development
• Drug discovery is a process which aims at identifying a compound therapeutically
useful in curing and treating disease.
• This process involves the identification of candidates, synthesis, characterization,
validation, optimization, screening and assays for therapeutic efficacy.
• Once a compound has shown its significance in these investigations, it will initiate
the process of drug development earlier to clinical trials.
• New drug development process must continue through several stages in order to
make a medicine that is safe, effective, and has approved all regulatory
requirements.
• This process is sufficiently long, complex, and expensive so that many biological
targets must be considered for every new medicine.
• It takes about 12 - 15 years from discovery to the approved medicine.
• On an average, a million molecules screened but only a single is explored in late
stage clinical trials and is finally made obtainable for patients.
• In past drug have been discovered by identifying active ingredients from traditional
medicine of by serendipitous.

• Innovator company synthesises NCE or NBE which can be probably be a cure for a disease.

• Research can be performed by 2 ways

• Basic research
1. Development of lead molecule
2. Starts from cellular level
3. Screening of newly synthesized molecule
4. Time consuming , very complex, highly expensive.

• Applied research work by chemistry on known molecule for its alteration

1. Identification of new drug target
2. Drug design
3. Chemical alteration
4. Screening
5. Biotechnology
• Stages of Drug Discovery and Development Process

1.Target identification
2.Target validation
3.lead identification
4.lead optimization
5.Product characterization
6.Formulation and development
7.Pre- clinical research
8.Investigational New Drug
9.Clinical trials
10.New Drug Application & Approval
Target identification
• The first step in the discovery of a drug is identification of the biological origin of
a disease, and the potential targets for intervention.

• Target identification starts with isolating the function of a possible therapeutic

target (gene/nucleic acid /protein) and its role in the disease.

• Identification of the target is followed by characterization of the molecular

mechanisms addressed by the target.

• An ideal target should be efficacious, safe, meet clinical and commercial

requirements and be druggable.
• The techniques used for target identification may be based principles of
molecular biology, biochemistry, genetics, biophysics, or other disciplines.
Target Validation
• Target validation is the process by which the expected molecular target,

• example gene, protein or nucleic acid of a small molecule is actually involved in a disease process,
and that binding of a drug to the target is likely to have a curative effect.

• Target validation is the process of demonstrating the functional role of the identified target in the
disease phenotype.

• The validation of a drug's efficacy and toxicity in numerous disease-relevant cell models and
animal models is extremely valuable, the ultimate test is whether the drug works in a clinical
setting.
• It involves critical analysis and comparison of various targets and their
association with specific disease
• It discuss ability of target to regulate biological and chemical
compound present in the body
Lead Identification
• Is a substance which have potential to treat or modify the disease or disorder
• A chemical lead is defined as a synthetically stable, feasible, and drug like
molecule active in primary and secondary assays with acceptable specificity,
affinity and selectivity for the target receptor
• Characteristics of a chemical lead are:
• 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
• In order to decrease the number of compounds that fail in the drug
development process, a drug ability assessment is often conducted.
• This assessment is important in transforming a compound from a lead
molecule into a drug.
• For a compound to be considered druggable it should have the
potential to bind to a specific target; however, also important is the
compound‘s pharmacokinetic profile regarding absorption,
distribution, metabolism, and excretion.
• Other assays will evaluate the potential toxicity of the compound in
screens.
Lead Optimization
• Lead optimization is the process by which a drug candidate is
designed after an initial lead compound is identified.
• The process involves iterative series of synthesis and characterization
of a potential drug to build up a representation of in what way
chemical structure and activity are related in terms of interactions
with its targets and its metabolism.
• In initial drug discovery, the resulting leads from hit-to-lead high
throughput screening tests undergo lead optimization, to identify
promising compounds.
• Potential leads are evaluated for a range of properties, including
selectivity and binding mechanisms during lead optimization, as the
final step in early stage drug discovery.
• The purpose of lead optimization is to maintain favorable properties
in lead compounds, while improving on deficiencies in lead structure.

• In order to produce a pre-clinical drug candidate, the chemical

structures of lead compounds (small molecules or biologics) need to
be altered to improve target specificity and selectivity.

• Pharmacodynamic and pharmacokinetic parameters and toxicological

properties are also evaluated. Labs must acquire data on the toxicity,
efficacy, stability and bio-availability of leads, in order to accurately
characterize the compound and establish the route of optimization.
Product Characterization
• When any new drug molecule shows a promising therapeutic activity,
then the molecule is characterized by its size, shape, strength,
weakness, use, toxicity, and biological activity.
• Early stages of pharmacological studies are helpful to characterize the
mechanism of action of the compound.
Formulation and Development
• Pharmaceutical formulation is a stage of drug development during which the physicochemical
properties of active pharmaceutical ingredients (APIs) are characterized to produce a bio-
available, stable and optimal dosage form for a specific administration route.
• During pre-formulation studies the following parameters are evaluated:
Solubility in different media and solvents
Dissolution of the active pharmaceutical ingredient (API)
Accelerated Stability under various conditions
Solid state properties (polymorphs, particle size, particle shape etc.)
Formulation 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
Colloidal drug delivery systems
Sub-micron and nano-emulsions
Pre- clinical Testing

• Pre-clinical research in drug development process involves evaluation of drug‘s safety and
efficacy in animal species that conclude to prospective human outcome.
• The pre- clinical trials also have to acquire approval by corresponding regulatory authorities.
• The regulatory authorities must ensure that trials are conducted in safe and ethical way and would
give approval for only those drugs which are confirm to be safe and effective.
• ICH has established a basic guideline for technical necessities of acceptable preclinical drug
development.
• The pre-clinical trials can be conducted in two ways: General pharmacology and Toxicology.
Pharmacology deals with the pharmacokinetic and pharmacodynamic parameters of drug. It is
essential to explore unwanted pharmacological effects in suitable animal models and monitoring
them in toxicological studies
• Toxicological studies of the drug can be performed by in- vitro and in-vivo test which evaluate the
toxicological effects of the drug.
• In-vivo studies to evaluate pharmacological and toxicological actions, including mode of action,
are often used to support the basis of the proposed use of the product in clinical studies.
The Investigational New Drug Process (IND)
• Drug developers must file an Investigational New Drug application to FDA before
commencement clinical research. In the IND application, developers must include:

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

Clinical Research
• Clinical trials are conducted in people (volunteer) and intended to answer specific
questions about the safety and efficacy
• Clinical trials follow a specific study protocol that is designed by the researcher or
investigator or manufacturer.
• As the developers design the clinical study, they will consider what they want to
complete for each of the different Clinical Research Phases and starts the
Investigational New Drug Process (IND)
• Before a clinical trial begins, researchers review prior information about the drug to
develop research questions and objectives. Then, they decide:
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

1. Implicates investigative, first-in-human (FIH) trials that are conducted according to FDA

guidelines.

2. Phase 0 trials besides termed as human micro dose studies, they have single sub-therapeutic

doses given to 10 to 15 volunteers and give pharmacokinetic data

3. Pharmaceutical industries perform Phase 0 studies to pick which of their drug applicants has the

preeminent pharmacokinetic parameters in humans.

• Phase 1- Safety and dosage
1. Phase I trials are the first tests of a drug with a lesser number of healthy human
volunteers.
2. In most cases, 20 to 80 healthy volunteers with the disease/condition participate in this
3. Patients are generally only used if the mechanism of action of a drug indicates that it will
not be tolerated in healthy people.
4. However, if a new drug is proposed for use in diabetes patients, researchers conduct
Phase 1 trials in patients with that type of diabetes. Phase 1 studies are closely monitored
and collect information about Pharmacodynamics in the human body.
5. Researchers adjust dosage regimen based on animal study data to find out what dose of a
drug can tolerate the body and what are its acute side effects.
6. As a Phase 1 trial continues, researchers find out research mechanism of action, the side
effects accompanying with increase in dosage, and information about effectiveness. This
is imperative to the design of Phase 2 studies. Almost 70% of drugs travel to the next
phase.
• Phase 2- Efficacy and side effects

1. Phase II trials are conducted on larger groups of patients (few hundreds) and are
aimed to evaluate the efficacy of the drug and to endure the Phase I safety
assessments.
2. These trials aren‘t sufficient to confirm whether the drug will be therapeutic.
3. Phase 2 studies provide with additional safety data to the researchers.
4. Researchers use these data to refine research questions, develop research
methods, and design new Phase 3 research protocols.
5. Around 33% of drugs travel to the next phase.
• Phase 3- Efficacy and adverse drug reactions monitoring
1. Phase III of a clinical trial usually involves up to 3,000 participants who have the
condition that the new medication is meant to treat. Trials in this phase can last for
several years.
2. The purpose of phase III is to evaluate how the new medication works in comparison
to existing medications for the same condition.
3. To move forward with the trial, investigators need to demonstrate that the medication
is at least as safe and effective as existing treatment options. To do this, investigators
use a process called randomization.
4. This involves randomly choosing some participants to receive the new medication
and others to receive an existing medication.
5. The FDA usually requires a phase III clinical trial before approving a new
medication. Due to the larger number of participants and longer duration or phase Ill,
rare and long-term side effects are more likely to show up during this phase.
6. If investigators demonstrate that the medication is at least as safe and effective as
others already on the market, the FDA will usually approve the medication.
• Phase 4- Post-Market Drug Safety Monitoring
1. Phase 4 trials are conducted when the drug or device has been approved by
FDA.
2. These trials are also recognized as post-marketing surveillance involving
pharmacovigilance and continuing technical support after approval.
3. There are numerous observational strategies and assessment patterns used in
Phase 4 trials to evaluate the efficacy, cost- effectiveness, and safety of an
involvement in real-world settings.
4. Phase IV studies may be required by regulatory authorities (e.g. change in
labelling, risk management/minimization action plan) or may be undertaken by
the sponsoring company for competitive purposes or other reasons.
5. FDA reviews reports of complications with prescription and OTC drugs, and
can decide to add precautions to the dosage or practice information, as well as
other events for more serious adverse drug reactions.
New Drug Application

• A New Drug Application (NDA) expresses the full story of a drug

molecule.

• Its purpose is to verify that a drug is safe and effective for its proposed
use in the people studied.

• A drug developer must include all about a drug starting from

preclinical data to Phase 3 trial data in the NDA.
INNOVATOR & GENERICS
1. Innovator
• An innovator drug is the first drugs created containing its specific active
ingredient to receive approval for use.
• It is usually the product for which efficacy, safety and quality have been
fully established.
• When a new drug is first made, drug patent usually will be acquired by
the founding company.
• Most drug patents are protected up to 20 years. During the patent period,
other companies cannot make or sell the same drug until the patent
expires.
GENERIC
• A generic drug is made of the same active ingredient as its innovator drug.
• An active ingredient is the chemical contained inside a drug that makes it work.
• In other words, the pharmacological effect of a generic drug is exactly the same as
those of its innovator counterpart.
• Other companies can manufactures the generic drugs when patent expires.
• There are similarities between generic and innovator drug, such as:
1. Active ingredient
2. Strength (dose)
3. Therapeutic effect
4. Side effects
5. How to take
CONCEPT OF GENERICS
• On September 24, 1984, in the 98th U.S. Congress, the Act named 'The Drug Price
Competition and Patent Term Restoration Act' was passed, also known as the Hatch-
Waxman Act.
• The objective of this act was to encourage the manufacturing of generic drugs by the
pharmaceutical industries and to establish the modern system of government generic
drug regulation in the USA.
• The requirement for this was to submit an Abbreviated New Drug Application
(ANDA by the pharmaceutical companies to the regulatory authorities for getting the
approval to market a generic drug.
• Generics are formulated, developed, and manufactured by other companies when
patent and other exclusivity rights of the innovator have expired.
• As generic drug development does not involve large investment for drug discovery
and preclinical and clinical trials, they are available at a lower cost and provide an
opportunity for savings in drug expenditure of a country.
ACCORDING TO WHO
• "Generic drug is a pharmaceutical product which is usually intended to
be interchangeable with an innovator product, is manufactured without a
license from the innovator company, and is marketed after the expiry
date of the patent or other exclusive rights".
• In generic pharmaceutical products, there is no standard categorization as
it does not cover the specifics of this industry.
• Thus, the new generic products can be defined as:
 Line extensions: Line extensions are small adaptations of an
existing product, which is normally already available on the market.
 Retargeting: Retargeting refers to existing products registered,
launched, and marketed in a new market.
 New product: A new product is a completely new product for the
company and for the market int h e generics segment.
• A generic drug is approved by the regulatory agency if it is
1. Pharmaceutically equivalent to an approved safe and effective reference product in
that it:
a) Contains identical amounts of the same active drug ingredient in the same
dosage form and route of administration and
b) Meets compendial or other applicable standards of strength, quality, purity,
and identity.
2. Bioequivalent to the reference product in that it:
a) Does not present a known or potential bioequivalence problem and it meets
an acceptable in vitro standard (usually dissolution testing) or
b) If it does present such a known or potential problem, it is shown to meet an
appropriate bioequivalence standard.
3. Adequately labeled.
4. Manufactured in compliance with CGMP regulations.
GENERIC DRUG PRODUCT DEVELOPMENT
• Drug product development is a creative and multidisciplinary process that
turns a technological innovation and a market Opportunity in products
with economic profitability for the company.

• Generic drug products are proven therapeutically equivalent to the

corresponding innovator's product, and hence can be substituted in
clinical practice.

• The objective of generic drug product development is to develop a stable

and bioequivalent generic drug product with desirable properties.
• The process of development includes three sequential stages essential for
successful generic drug development.

1. First, a predevelopment stage involves collecting and evaluating data and

information related to a drug such as its physicochemical properties and critical
quality attributes, before implementing any development activities.
2. Second, development stages begin with a thorough characterization of
the innovator's product, followed by an initial compatibility study between the
drug and proposed excipients to be used in the formulation, suitable selection of
method for formulation development, and suitable selection of manufacturing
process.
3. Third, Once a pilot batch of the generic product is obtained, an in vivo
bioequivalent test is conducted in accordance with the GCP to assure that the
generic drug product is therapeutically equivalent to the innovator's product.
• Generic drug product development is the process that completely covers a series
of stages required to bring a generic drug product to the market.
1. Drug candidate selection
This phase covers the broad selection of potential drug candidates. A team
decides which drug candidates should be selected to proceed into the preliminary
assessment phase.
2. Candidate drug screening
In this phase drug candidates selected in the earlier phase is carefully
screened to roughly assess the potential drug candidates. The simple strategy
followed is to accept the best and eliminate the poor. Development proceeds with
only one or two candidates for the next phase.
3. Concept development
It is an exercise in which the screened candidate drug is translated into the
product concept. The product concept is a detailed version of the product idea. The
needs of the target market are identified, alternative product concepts are generated
and evaluated, and a single development is selected for further development.
• System-level design
The final formulation scheme for the production system is usually defined during
this phase. A preliminary process flow diagram for the final manufacturing.
• Detail design
This phase includes the complete specification of the materials and limits of all
the components in the product and the identification of all the probable suppliers.
• Concept testing
This phase is the laboratory development of a generic product. This
phase starts with experimental and accelerated stability study work, the
development based on a laboratory scale, including the (pilot) bio-equivalent-
study and development of the primary packaging.
• Business analysis
Landmarks and milestones of the product development process and time
required for the completion should are fixed. Also, in this phase, the impacts of
delays and time of product arrival in the market are analyzed carefully.
• Development of a prototype
This phase is also called production ramp-up. It also describes the period from
completed initial product development to maximum capacity utilization, characterized
by product and process experimentation and improvements.
• Development of technology
This phase includes the transfer to the industry measure and the preparation of
registration documentation. It includes clinical studies, toxicological studies, bio-
equivalent studies, and completed stability studies.
• Registration
Registration is a phase of filing of registration dossiers at regulatory authorities,
It finishes when the product is registered and the registration documentation and
marketing authorization is obtained.
• Launch
The launch phase includes all final pre-launch activities such as ordering of
materials, production of launch stock, ordering of raw materials, packaging materials
etc. including the launch of the product on the selected market.