1. NEW DRUG DEVELOPMENT

2. • Once a new compound has been identified in
the laboratory, it undergoes the drug
development process before it can be marketed
for public use.

3. Drug Development Steps
Preclinical testing
Investigational New Drug Application (IND)
Clinical Trials
New Drug Application (NDA)
Approval

5. Preclinical Testing:
• The compound is tested for safety and efficacy
in laboratory and animal studies.
Preclinical testing involves:
Pharmacology
Toxicology
Preformulation
Formulation
Analytical
Pharmacokinetics

6. Toxicology studies in preclinical stage are
conducted to:
Select or reject lead candidate
General Indication of suitability
Dose selection and guidance to clinician

7. The basic studies conducted are
Mutagenicity - In vitro Ames Test
One-week or Two-week Range Finders:
Viz Mouse or Rat, Dog or Primate
Maximum Tolerated Dose
Gross Effects, Clinical Chemistries - What are
the toxicities
Gross Pathology to Indicate Target Organs
Satisfactory Therapeutic Ratio

8. Preformulation
 Characterization of drug molecule is a very important step
at the preformulation phase of product development.
 Solubility determination
 pKa determination
 Partition coefficient
 Chemical stability profile
 Crystal Properties and Polymorphism
 Particle size, shape and surface area

9. Solubility Determination
• The solubility of drug is an important
physicochemical property because it affects the
bioavailability of the drug, the rate of drug
release into the dissolution medium, and
consequently, the therapeutic efficacy of the
pharmaceutical product.
• The solubility of a material is usually determined
by the equilibrium solubility method

10. Chemical stability profile
• Preformulation stability studies are quantitative assessment
of chemical stability of a new drug.
• These studies include both solution and solid state
experiments under conditions typical for the handling,
formulation, storage, and administration of a drug candidate
as well as stability in presence of other excipients
 Solid-State Stability
 Solution-Phase Stability
 Compatibility Studies: Stability in the Presence of
Excipients

11. Solid State Stability
• The primary objectives of this investigation are
identification of stable storage conditions for drug in the
solid state and identification of compatible excipients for
a formulation.
• Solid state studies may be severely affected by changes
in purity and crystallinity, which often result from process
improvements.
Stress conditions utilized
 Elevated temperature Studies
 Stability under High-Humidity Conditions
 Photolytic Stability
 Oxidative Stability

13. Solution Phase Stability
• The primary objective of this phase of
preformulation research is identification of
conditions necessary to form a stable solution.
• These studies should include the effects of pH,
ionic strength, cosolvent, light, temperature and
oxygen.

14. Compatibilty Studies
• In the tablet dosage form the drug is in intimate
contact with one or more excipients; that could
affect the stability of the drug.
• Drug-excipient interactions is very useful to the
formulator in selecting appropriate excipients.
• The three techniques commonly employed in
drug-excipient compatibility screening are:
Thin-layer chromatography
Differential thermal analysis
Diffuse reflectance spectroscopy

17. Crystal Properties and Polymorphism
• Different polymorphs lead to different morphology, tensile
strength and density of powder bed which contribute to
compression characteristics of materials.
• Investigation of polymorphism and crystal habit of a drug
substance in pharmaceutical processing is desirable
during its preformulation evaluation, especially when the
active ingredient is expected to constitute the bulk of the
tablet mass.
• Various techniques are available for the investigation it
include microscopy (including hot-stage microscopy),
infrared spectrophotometry, single-crystal X-ray and X-ray
powder diffraction, thermal analysis, and dilatometry.

19. Particle Size, Shape and Surface Area
• Bulk flow, formulation homogeneity, and surface-area
controlled processes such as dissolution and chemical
reactivity are directly affected by size, shape and surface
morphology of the drug particles.
• Various chemical and physical properties of drug
substances are affected by their particle size distribution
and shapes.

20. Particle Size Determination:
Classical methods for measuring particle size
Microscopy
Sieving or screening
Sedimentation
Surface Area Determination:
Two commonly available methods for determining
surface area are:
Adsorption Method
Air Permeability Method

22. Acceptance Criteria For Drug Product Dissolution
Appropriate type of drug release acceptance
criteria
Appropriate test conditions and acceptance criteria
Appropriate acceptance ranges (extended release)

23. Formulation
• Formulation Developments starts immediately after preformulation
studies
Solid Dosage Form Liquid Dosage Form
Tablets Parenteral
Capsules Emulsions & Suspensions
Suppositories Solutions
Semisolid Dosage Form Special Drug Delivery
Creams Ophthalmic Delivery
Gels Nasal Delivery
Ointments Transdermal Delivery
Microencapsulation

24. Formulation Development chart

25. Analytical
Validation of Chromatographic Methods
Stability testing of Drug Substance & Drug
products (FDA)
Stability testing of New Drugs & Products (ICH)
Validation of Analytical Procedures
Bioanalytical Method Validation for Human Studies

26. Pharmacokinetics
• The primary objective of pharmacokinetics is to
quantify drug absorption, distribution,
biotransformation and excretion of the drug.
Based on pharmacokinetics:
The performance of dosage forms can be
evaluated in terms of rate and amount of drug
delivered to the blood
The dosage regimen of a drug can be adjusted to
produce and maintain therapeutically effective
blood concentrations with little or no toxicity

27. Investigational New Drug Application
(IND)
• After completing preclinical testing, a company
files an IND with the U.S. Food and Drug
Administration (FDA) to begin to test the drug in
people.
• Clinical trials may proceed 30 days after filing
unless the FDA places a hold on the proposal.

29. Clinical Trials involve the following phases:
Number of
Patients Length Purpose Percent of Drugs
Successfully Tested
Phase I 20 - 100 Several
months Mainly safety 70 percent
Phase II Upto several
hundred
Several
months to 2
years
Some short-term
safety, but mainly
effectiveness
33 percent
Phase III
Several
hundred to
several
thousand
1 - 4 years
Safety,
effectiveness,
dosage
25 - 30 percent
Phase IV PMS

30. New Drug Application (NDA)
Following the completion of all three phases of
clinical trials, a company analyzes all of the data
and files an NDA with FDA if the data
successfully demonstrate both safety and
effectiveness.
The NDA contains all of the scientific information
that the company has gathered.
NDAs typically run 100,000 pages or more.
By law, FDA is allowed six months to review an
NDA.
The average NDA review time for new molecular
entities approved in 1997 was 16.2 months.

32. Approval
Once FDA approves an NDA, the new medicine
becomes available for physicians to prescribe.
A company must continue to submit periodic
reports to FDA, including any cases of adverse
reactions and appropriate quality-control
records.
 For some medicines, FDA requires additional
trials (Phase IV) to evaluate long-term effects.
Drug Approval Application Process
Post-Drug Approval Activities
Post Marketing Surveillance Program