NEW DRUG DEVELOPMENT

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

Drug Development Steps

Preclinical testing Investigational New Drug Application (IND) Clinical Trials New Drug Application (NDA) Approval

Preclinical Testing:• The compound is tested for safety and efficacy

in laboratory and animal studies.

Preclinical testing involves: Pharmacology Toxicology Preformulation Formulation Analytical Pharmacokinetics

Toxicology studies in preclinical stage are conducted to:

Select or reject lead candidate General Indication of suitability Dose selection and guidance to clinician

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

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

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

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

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

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. 

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

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.

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.

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

Acceptance Criteria For Drug Product Dissolution Appropriate type of drug release acceptance

criteria Appropriate test conditions and acceptance criteria Appropriate acceptance ranges (extended release)

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

Formulation Development chart

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

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

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.

 Number of

PatientsLength Purpose

Percent of Drugs Successfully Tested

Phase I 20 - 100Several months

Mainly safety 70 percent

Phase IIUpto 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 yearsSafety, effectiveness, dosage

25 - 30 percent

Phase IV PMS

Clinical Trials involve the following phases:

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.

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