Drug Development Process

Presented
by
Dr. Shaheen Sultana
Professor
Galgotias College of Pharmacy
Drug discovery is defined as the process of designing and
developing new chemical moieties for the treatment of diseases.

The association of chemistry, biology and pharmacology has

worked miracles in the field of medicines.

The discovery of new molecules started back from the olden times
that include extraction of medicinal components from natural
sources.
• Drug discovery and development is complex, time-
consuming, costly process which carries commercial risk.
• Drug discovery and development is broadly divide into three
main components-
 drug discovery,
 Pre-clinical evaluation and
 clinical trials

The process of new drug discovery and development is required

on an average of 12 to 15 years at a cost of US 1 Billion dollors
(over 5000 crore rupees) to produce a new drug into the market.
STAGES OF DRUG DEVELOPMENT:
1. Drug Discovery
a. Target Identification
b. Target Validation
c. Lead Compound Identification
d. Lead Optimization
2. Drug development process
(A) Preclinical Testing
a. Toxicological studies
b. Pharmacodyanamic studies
c. Pharmacokinetics studies
(B) Clinical testing
Drug Development Process: Phases
Step 1: Drug Discovery
(a) Target Identification: Identification of Target for the Drug: Drug can
be therapeutically efficient after it binds to the body proteins. Hence, it
is essential to determine the binding target of the drug. These targets
include gene or a protein that is responsible for the particular disease.
However, it is important, for the researchers to select an appropriate
target that will interact with drug molecule and produce the therapeutic
effect.
(b) Target Validation:
Confirm the Role of Target on the Disease: After the selection
of target, the researchers must confirm that the targets are the
potential cause of disease. This stage is considered essential as it
saves the times and avoids unproductive results.
Reproducibility: The targets can be identified by literature
review or by specific technique. However, it is considered almost
essential to repeat the experiments again to confirm the targets
are the cause of disease.
 (c) Lead Compound Identification: Lead compounds are the
ones with desired pharmacological and the therapeutic effect. After
ensuring the target, the scientist and researchers work on selecting
the compound that can bind to the desired target. Lead compound
is the tested compound with known drug whose effect is known.
The sources of lead compound include:
Natural Sources: Nature has been source of lead compound from
earlier days. Although it is difficult to extract the desired
compound from natural resources, however it motivates the
researchers to replicate the similar structure and produce the lead
compound. Natural products include; plants, animals and
microorganisms. Chemical Libraries: Chemical libraries contain
large number of compounds with varying sizes from hundreds to
millions. These libraries are developed via combinatorial
chemistry. The molecules in libraries are screened through high
throughput screening methods to identify the lead compound.
Computational Medicinal Chemistry: It includes Computer
Aided Drug Discovery and Designing. The 3D structure of the
target protein is resolved by X- ray crystallography, and the
binding site of the compound is determined.

(d) Lead Optimization: After the identification of lead

compound, efforts have been made to increase the potency,
binding and pharmacokinetic properties of the drug followed by
decreasing the toxicity. This phase involves the analysis of
Structure Activity Relationship (SAR) and various analogues are
developed. The developed analogues are tested by the biologics
and the chemists. The biologics are concerned about the effect of
analogues on the biological systems.
2. Drug development process
Once lead optimization is completed, the drug development process
starts which is further divided into 2 types ie. Preclinical and
clinical studies.
(A) Preclinical Testing: Safety of the drug is determined by testing
on lab animals. Scientist carries out in-vitro and in-vivo tests to
estimate its safety. It is a study to defined pharmacological profile
of lead molecule using suitable animal model. In this the screening
is either diseases oriented or organ oriented which is further
extended to cellular or molecular level.
Preclinical evaluation mainly consist of:
a. Toxicological studies: To evaluate the toxicity of lead molecule to a
particular organ, system or whole body with respect to duration and
dose of a compound. It is divided into:
(1) Acute Studies: Acute toxicity studies look at the effects of one or
more doses administered over a period of up to 24 hours. The goal is
to determine toxic dose levels and observe clinical indications.
Usually, at least two mammalian species are tested. Data from acute
toxicity studies helps to determine doses for repeated dose studies in
animals and Phase 1 clinical studies.
(2) Repeated Dose Studies: Depending on the duration of the
studies, repeated dose, studies may be referred to as sub acute
(identify toxicity on longer use, ie 1-3 months), or chronic
(identify toxicity on long term use ie more than 6 months).
Again, two species are typically required.
(3) Genetic Toxicity Studies: These studies assess the chances
that the drug compound is mutagenic or carcinogenic.
Procedures such as: the Ames test (conducted in bacteria) detect
genetic changes. DNA damage is assessed in tests using
mammalian cells such as: the Mouse Micronucleus Test. The
Chromosomal Aberration Test and similar procedures detect
damage at the chromosomal level.
(4) Reproductive Toxicity Studies: Segment I reproductive
toxicity studies look at the effects of the drug on fertility.
Segment II and III studies detect effects on embryonic and post-
natal development. In general, reproductive toxicity studies must
be completed before a drug can be administered to women of
child-bearing age.

(5) Carcinogenicity Studies: Carcinogenicity studies are

performed to determine the oncogenic potential of a test article in
animals in order to assess the potential cancer risk for humans.
Pharmaceutical agents that are to be continuously administered
for at least 6 months must be tested for carcinogenicity.
b. Pharmacodyanamic studies: In this study, evaluation of
action of lead molecule is determined that is related to the
proposed therapeutic effect. The normal course of study is
targeted to particular generalized condition (eg arrythmia by
reporting heart rate, ECG etc) followed by organ specific ex vivo
or in-vitro studies (e.g isolated heart, aortic strip, in vitro cultures
cells etc). Finally the study is extended to molecular level like
receptor recording affinity, receptor binding studies on cell
membrane fraction from organs or cultured cells.
c. Pharmacokinetics studies
• It is used to determine the pharmacokinetic evaluation
(absorption, distribution, metabolism, excretion) in different
animal model.
• PK studies yield parameters such as; AUC (Area Under the
Curve), Cmax (maximum concentration of the Drug in
Blood), and Tmax (Time at which Cmax is reached).
• Later on, this data from animal PK studies is compared to
data from early stage clinical trials to check the predictive
power of animal models.
• Beside ADME, bioavailability and bioequivalence are also
recorded.
B. Clinical tests: Upon satisfactory completion of preclinical
studies, the new compound is subjected to clinical studies
through proper application known as Investigational New Drug
(IND) application to respective regulatory authorities. In US, it is
Food and drug administration (FDA), whereas in India it is Drug
Controller General, Govt. of India (DCGI).
IND application consist of preclinical data, chemical structure,
source, manufacturing details, specification of dosage form,
investigational protocol, details of investigators involved,
informed consent of participants, other various agreements etc.
Different phases of clinical trials:
1. Phase I: During Phase 1 studies, researchers test a new drug
in normal volunteers (healthy people). In most cases, 20 to 80
healthy volunteers or people with the disease/condition (eg in
cancer) participate in Phase 1. Phase 1 studies are closely
monitored and gather information about how a drug interacts
with the human body. The entire study complete within 6-9
months.
2. Phase II: This phase is used to determine the safety and
effectiveness of the drug in patients with target disease.
Duration range between 6 months to 3 years. Usually
conducted on few hundred patients. Researchers use these
data to refine research questions, develop research methods,
and design new Phase 3 research protocols.
3. Phase III: These studies are conducted to further establish
the safety and efficacy of drug. These studies involve 300 to
3,000 participants. Phase 3 studies provide most of the safety
data. The duration of this phase is 1-4 years.

Once phase III studies are completed, the sponsor files New
Drug application (NDA) with respective regulatory authorities
to market this drug. The NDA consist of complete monograph
of the product, proposed brand name, package insert, detailed
drug development data etc. This application is then thoroughly
reviewed by the regulatory department. Once NDA is
acceptable then drug enter in the market with new Drug status
ie available for controlled marketing.
4. Phase IV: Phase IV trials are carried out once the drug is
marketed. It is called post marketing post surveillance. It don’t
have any specific time. It is mainly focused on identification of
rare side effects, previously unknown side effects and even
therapeutic applications. During new drug status, it is expected
that manufacturers should gather and report such new information
to respective regulatory authorities until it is released to
unrestricted marketing.
Innovator and Generics
Drug
Any substance or pharmaceutical product for human use that is
intended to modify or explore physiological systems or pathological
states for the benefit of the recipient
Innovator product
The innovator product is generally that which was first authorized
for marketing (normally as a patented product)
When a substance has been available for many years, it may not be
possible to identify an innovator pharmaceutical product.
Generic drug
• A generic drug product is essentially identical to the brand
name(reference) drug product in terms of active ingredient,
dosage form ,route of administration, quality, safety, efficacy,
performance characteristics and therapeutic indication.
• EX- PHENYTOIN is the generic drug and DILANTIN is the
brand name for the same drug.
• Brand drugs are the drugs which are protected by the patent.
In 2002 about 47%of prescription drug product are generic
versions while 53% innovator product.
• Generic products growth is 19% in 1984 and 50% in 2004.
Every year about 4 billions dollars business potential exists
for next 4 years due to patent expiry
Concept of Generics and Generic Drug Product Development
• A pharmaceutical product usually intended to be
interchangeable with the originator brand product,
manufactured without a license from the originator
manufacturer and marketed after the expiry of patent or other
exclusivity rights.
• Generic medicines are marketed either under a non-proprietary
name, for example diazepam or occasionally another approved
name, rather than under a proprietary or brand name.
• However, they are also quite frequently marketed under brand
names, often called ‘branded generics. Many different branded
generic products of the same medicine can be on the market in
a country along with the originator brand product.
• Generic drug product manufacturers must formulate a drug
product that will have the same therapeutic efficacy and clinical
performance as their brand-name counterpart.
• The FDA’s office of Generic Drugs is responsible for reviewing
• the ANDA and approving the drug products marketing.
• FDA is responsible for the quality, safety, and efficacy of
generic drug products prior to the approval for marketing.
• Generic drug application reviewers focus on bioequivalence
data, chemistry and manufacture quality, microbiology data
where relevant, requests for plant inspection, and drug labeling
information
• The ANDA for generic drug product approval is based on
bioequivalence to the brand name product, appropriate
chemistry and manufacturing information, and appropriate
labeling.
• Generic drug sponsors do not have to perform the nonclinical
animal toxicity studies or expensive clinical efficacy and safety
studies that are included in the new drug application.
• NDA which is submitted to the FDA for market approval of the
brand name drug product.
• The ANDA contains data which is then submitted to FDA’s
Center for drug evaluation and research for the generic drugs.
• FDA approved generic drugs must meet the same rigid
standards as the innovator drug.
• To obtain FDA approval, a generic drug product must contain
same active ingredient as an approved drug product the
inactive ingredients may vary.
Originator pharmaceutical product/originator brand
• Generally the product that was first authorized worldwide for
marketing, normally as a patented product, on the basis of the
documentation of its efficacy, safety and quality, according to
requirements at the time of authorization, e.g. Valium.
• Some substances (e.g. prednisolone and isoniazid) are so old
that no originator can be identified and the patent was probably
never claimed.
SELECTION OF GENERIC DRUGS FOR MANUFACTURE:
• The main driving force for the selection of generic drug
products for manufacture is the estimated sales volume for the
branded product.
• And the potential market share that the firm expects to have
once the generic drug product is manufactured and approved for
marketing.
• In addition to the expiration date of the patent for the active
ingredient, the generic firm must consider any other patent
claims and exclusivities that the innovator firm has filed.
The generic drug manufacturer needs to consider:
• The lead time that is needed to make the product and
submission of an Abbreviated New Drug Application (ANDA)
to the U.S.FDA for approval.
• Moreover, there is a financial incentive to being the first
generic drug product filed and approved by FDA.
• 180-days exclusivity, is given under certain conditions, for the
generic manufacturer who is to file first.
Para IV filing and 180 Days exclusivity procedure:
• When patent is not expired and ANDA applicant wants to make
its generic version, prior t expiration of the patent, ANDA
applicant files the application with P-IV certification.
• While making P-IV certification, ANDA applicant claims one
of the following:

Infringe: No one can making, use or selling the other invention)

Valid: Novel and non-obvious
Enforceable: Not Expired
If company get 180 days exclusive right to sale their generic products, along with
branded drug in the market, the generic company takes the market share from the
branded drug company by setting the price of their product slightly lower than the
branded drug.
Formulation considerations for generic drugs include:
• The availability of raw materials, chemical purity, polymorphic
form.
• Particle size of the active pharmaceutical ingredient.
• Any patents that the innovator company has filed, including
patents for the synthesis of the active pharmaceutical ingredient
and composition of the dosage form.
 GENERIC DRUG APPROVAL PROCESS:
The FDA’s office of Generic Drugs is responsible for reviewing
the ANDA and approving the drugs products marketing.
The FDA’s Office of Generic drugs has a website
http//www.fda.gov.org that provides additional information for
manufactures of generic drug products that includes flow chart
presentation of ANDA review process.
And it also describes how FDA determines the quality, safety,
and efficacy of generic drug products prior to the approval for
marketing.
Generic drug application reviewers focus on bioequivalence
data, chemistry and manufacture quality, microbiology data
where relevant, requests for plant inspection, and drug labeling
information.
• The ANDA for generic drug product approval is based on
bioequivalence to the brand name product, appropriate
chemistry and manufacturing information, and appropriate
labeling. Generic drug sponsors do not have to perform the
nonclinical animal toxicity studies or expensive clinical
efficacy and safety studies that are included in the new drug
application.
• NDA which is submitted to the FDA for market approval of
the brand name drug product.
• The ANDA contains data which is then submitted to FDA’s
Center for drug evaluation and research for the generic drugs.
• FDA approved generic drugs must meet the same rigid
standards as the innovator drug.
• To obtain FDA approval, a generic drug product must- contain
same active ingredient as an approved drug product the inactive
ingredients may vary.
• Be identical strength, dosage form, route of administration,
same indications, bioequivalent, meet the batch requirements.
STEPS IN GENERIC DRUG PRODUCT DEVELOPMENT
PROCESS:
1. CONCEPT DEVELOPMENT- The needs of the target
market are identified, alternative product concepts are generated
and evaluated, and a single concept is selected for further
development.
2. Prior to Development
A product for development must be selected. In order to properly
select a product, information is needed from a variety of disciplines
including:
- R&D
- Regulatory Affairs
- Legal
- Marketing & Sales
- Finance, etc.
Once selected, details of the selected product should be recorded
into some kind of document to include information such as:
- Innovator Product Description and Dosage Form
- Innovator Product Packaging Description
- Innovator Product Sales
- Generic Product Description and Dosage Form
- Generic Product Packaging Description
- Generic Sales Forecasts
- Intended Manufacturing Site
- Intended Production Batch Size
- Any other relevant information

Based on patent expiry, product exclusivity, forecasts,

availability of the active ingredient etc., the project needs to be
scheduled and its’ progress tracked and managed with the goal
of being the first generic drug manufacturer (for that particular
product) on the market.
3. Pre-formulation
Prior to preparing actual trial formulations, “pre-formulation” work
must be performed to obtain as much information about the
reference product and drug substance as possible.
Common pre-formulation activities include the following:
• Review of the product selection document
• Review of any related patent information
• Obtain samples of reference product and packaging
• Evaluate physical characteristics of the reference product
• Determine reference drug release characteristics through “in-
vitro” dissolution profiling.
• Characterize drug substance to determine drug form (i.e.
crystalline, powder, amorphous), drug solubility, polymorphism,
particle size, bulk density, flow characteristics, chemistry (i.e.
pKa, functional groups), drug absorption characteristics
(pharmacokinetics), incompatibilities, sensitivities (light, heat,
moisture), etc.
Following these “pre-formulation” activities, decisions can be
made as to the type of formulation and process to be considered
for development.

4. Formulation Development
Once pre-formulation work and a development strategy are
completed, a series of small-scale trials are prepared. These trials
involve processing the drug substance with excipients using the
selected process to produce a dosage form with the desired
strength and appearance dictated in the product selection
document. The dosage form is then physically and chemically
evaluated to determine its acceptability relative to the reference
product.
Physical Testing: Appearance, average weight and weight
variation, disintegration time
Chemical Testing: Dissolution profiles vs. reference product,
assay, content uniformity, chemical identification, impurities and
related substance, ICH Stability
Development trials continue until a formulation with a matching
dissolution profile, relative to the reference product, is obtained in
one or more dissolution media.
5. Formulation scale up: This formulation should then be scaled-
up to a slightly larger size and the resulting dosage form packaged,
and placed on accelerated stability stations for monitoring. In the
meantime, additional trials should be prepared to optimize various
formulation and process parameters.
6.Bioequivalence studies: If the product retains acceptable physical
and chemical characteristics, it is further scaled-up under GMP
conditions to serve as the “test batch” for “in-vivo bioequivalency
testing” vs. the reference product. If the product proves to be “non-
bioequivalent” to the reference product, reformulation is required,
assuming that the continued development of this product remains
economically viable due to this delay.
If the product proves to be “bioequivalent” to the reference product,
a submission package is assembled and submitted to the respective
Government Regulatory Agency for review and eventual approval.
A truly successful generic product is a product that can be made
repeatedly, by any trained operator, on any qualified piece of
equipment, at any time of the year, without any problems.

Generic Drug Product Development