Download An Overview of the Pharmaceutical Development Process

Discovering New Medicinal
Drugs
Freddie Arocho-Perez, Ph.D.
Senior Research Scientist
Inhalation Products and Medical Devices Development
Pharmaceutical Product Development, Inc. (PPDI)
Terminology
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FDA – U.S. Food and Drug Administration
API – Active Pharmaceutical Ingredient
NCE – New Chemical Entity
IND – Investigational New Drug
IRB – Institutional Review Board
NDA – New Drug Application
GLP – Good Laboratory Practices
GMP – Good Manufacturing Practices
NCE/API Discovery
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Medicinal chemists develop compounds based on related
substances.
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Aspirin developed as synthetic form of willow bark extract (Salicin).
Willow bark is found primarily on moist soils in cold and temperate regions
of the Northern Hemisphere.
Ibuprofen: a based-off aspirin.
Salicin
Aspirin
(Bayer)
Ibuprofen
(Advil, Motrin)
NCE/API Discovery
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Ibuprofen:
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It is a non-steroidal anti-inflammatory drug (NSAID).
It is used as an anti-inflammatory agent and as analgesic
(painkiller).
NCE/API Discovery
Pharmacology
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Most drugs:
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Enter the body (by mouth, injection, etc.).
Are distributed by the blood to the site of action;
distribution affects concentration at site of action,
sites of excretion, and bio-transformation.
Are bio-transformed to several different compounds
by enzymes; this event may change drug actions.
Are excreted (by kidney or …???) which removes
them and/or their metabolites from the body.
Pharmacokinetics is the quantification of these
processes.
Product Development Cycle
Pre
Clinical
Phase I
Phase II
Phase III
NDA
Review
Years
2-6
0.5-1
1-2
1.5-3
1-3
Test
Subjects
Animal
20 100
100 1000
1000 10,000
Purpose
Safety/
Efficacy
Safety/
Dose in
Healthy
Safety/
Effect
on
Disease
Safety/
Effect/
Side
Effects
Review
Process
and
Approval
Success
Rate
5,000
5 into Human trials
Overall process takes 6-15+ years
1
Phase I Studies
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Determine tolerable dose.
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Determine potential side effects profile.
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Dose ranging on healthy individuals.
Side effects on healthy individuals help determine
impact on patients with disease.
Discover human pharmacology and drug
distribution.
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Analysis of patient’s blood, urine and feces to
determine metabolites, API half-life, and route of
elimination.
Phase I Studies
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Limited number of test
subjects used (20-100).
These studies use healthy,
male volunteers to determine
the safety of the product
through dose-ranging studies.
Phase I Studies: Side Effects
Before
After
Phase II Studies
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Actual product development for
commercial style product.
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Tablets, creams, liquids, injectables.
These studies use test subjects with the
target disease to confirm the safety, dose,
and efficacy of the drug product.
Number of test subjects (both sexes)
increases for determination of efficacy
(100-1000).
These studies will determine whether the
selected drug product actually works on
the target disease.
Phase III Studies
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Final product developed for commercial sale.
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Assessment of API on disease state.
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Final components, excipients, formulation.
Main focus is to confirm efficacy and provide chronic
use side effects profile.
These studies use test subjects with the target
disease to further confirm the safety, efficacy, and
comparability of the drug product.
Phase III Studies
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Number of test subjects (both sexes) increases for further
determination of safety, efficacy, and comparator studies
(1000-10,000).
Also will track chronic, long-term use side-effects.
NDA Submission
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NDA has 2 major sections:
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Chemistry, Manufacturing and Controls
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Discusses means of manufacturing and testing of API and
drug product.
Outlines performance and stability of drug product.
Clinical Studies
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Discusses studies performed, outcomes, and statistical
analysis.
Outlines safety and effectiveness of product.
Overall Development Process
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The pharmaceutical development process is a
long (6-15+ years) and complicated procedure.
Research and Development has 4 basic parts:
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API development
Product development
Product performance and stability
Clinical studies results
Introduction to
Inhalation Technology
Inhalation Therapy
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Inhaled drug products are products used for therapeutic
treatment via the lungs or nasal mucosa.
Inhalation therapy has been in use for a number of years
to treat asthma and chronic obstructive pulmonary
disease (COPD).
Advantages compared to the traditional drug products:
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Rapid action
Self-administration
Directly targets the lung
Minimizes dose required
Avoids hepatic metabolism (drug metabolism in liver)
Reduces side effects
Inhalation Therapy
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Research has been devoted to
deliver new drugs due to the
large surface area and easy
air-blood interface provided
by the respiratory system.
The lung is a very attractive
target for drug delivery as it
provides direct access to
disease in the treatment of
respiratory diseases, while
providing an enormous
surface area for the
absorption of medications.
Inhalation Therapy
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There are some 300
million alveoli in 2 adult
lungs.
These provide a surface
area of approximately
160 square meters
(70 square meters is the
size of a tennis court).
Types of Diseases Treated
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Asthma
Chronic Obstruction Pulmonary Disease (COPD)
Migraine
Diabetes
Cystic Fibrosis
New Research:
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Erectile Dysfunction
Osteoporosis
Asthma
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Asthma is a chronic disease that affects your
breathing. The airways become inflamed and irritated in
reaction to some kind of substance, which is called a
“trigger”. The airways are the tubes that carry air and
oxygen into and out of the body.
Airways tend to be red and swollen and are easily
irritated in response to “triggers”, such as pollen and
cigarette smoke.
Airways’ inside walls become even more swollen and
the muscles tight; the passages get narrower and less air
flows to the lung tissue.
Asthma
Asthma in the U.S.A.
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In the United States alone, about 20 million citizens (9
million of them are children) have asthma.
Asthma is found in 3% to 5% of adults and 7% to 10%
of children.
Asthma is the most prevalent chronic condition in
children.
Asthma can affect citizens at any age, but half of the
people with asthma develop it during childhood, usually
before age 10.
However, you can develop asthma even as a senior
citizen.
Asthma in the U.S.A.
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Asthma also affects people of all races and ethnic
backgrounds.
The top 6 asthma risk factors include:
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Family history of asthma and/or allergies.
Living in urban areas.
Exposure to second-hand smoke.
Low birth weight in infants.
Health problems such as obesity and chronic sinusitis.
Exposure to job-related irritants.
Asthma in the U.S.A.
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According to the Asthma and Allergy Foundation of
America (AAFA) on Jan. 2010, the 10 worst asthma
cities are:
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Richmond, VA
St. Louis, MO
Chattanooga, TN
Knoxville, TN
Milwaukee, WI
Memphis, TN
Tulsa, OK
Philadelphia, PA
Augusta, GA
Atlanta, GA
Asthma in the U.S.A.
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According to the Asthma and Allergy Foundation of
America (AAFA) on Jan. 2009, the 10 worst asthma
cities are:
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St. Louis, MO
Milwaukee, WI
Birmingham, AL
Chattanooga, TN
Charlotte, NC
Memphis, TN
Knoxville, TN
McAllen, TX
Atlanta, GA
Little Rock, AR
Asthma in the U.S.A.
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Least 10 Challenging Asthma Capitals
The following cities are among the 100 cities in the U.S. with the
highest population. However, among those 100 cities, these are the
10 that ranked the lowest overall in the prevalence, risk, and
medical factors:
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Cape Coral, Florida
Seattle, Washington
Minneapolis, Minnesota
Colorado Springs, Colorado
Portland, Oregon
Palm Bay, Florida
Daytona Beach, Florida
San Francisco, California
Portland, Maine
Boise, Idaho
Inhalation Delivery Systems
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Nebulizers
Nasal Sprays
Metered-Dose Inhalers
Dry-Powder Inhalers
Nebulizers
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Nebulizers use a powered source to
create a fine mist from a solution.
Dosage occurs over minutes as the
patient repeatedly breathes in the mist.
Drug is dissolved in purified water and
inhaled over 10-30 minutes.
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Drug must be water soluble.
Not appropriate for use as portable
treatment for acute asthma attacks.
Equipment is normally bulky and needs a
power source.
Inconvenient due to time of dosage.
Nasal Sprays
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Nasal inhalers are designed to
deposit drugs in the nasal
cavities.
Nasal sprays can use either a
pump or propellant to power the
spray.
Metered-Dose Inhalers
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Metered-dose inhalers utilize a
pressurized liquid (propellant) as the
power to disperse the drug particles.
Metered-Dose Inhalers
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The system consists of
a formulation
containing:
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API
Propellant
Excipients
Device that uses a
container, metering
valve, and spray
generating actuator
Containers can be metal
or glass.
Dry-Powder Inhalers
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The formulation comes in the form of a
dry powder.
Generally, the formulation for these
products consists of the drug substance
and a carrier (lactose and/or glucose).
The carrier prevents aggregation and
helps with the flow of the drug
substance.
Analytical Test Methods
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Appearance
Identification
Microbial
Assay
Purity
Water Content
Dose Content
Uniformity
Fill Weight
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ACI
Ethanol Content
Particle Size
Microscopy
Spray Pattern
Leak Rate
Shot Weight
Temperature Cycling
Particle Size Distribution
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ACI: Andersen Cascade
Impactor
Apparatus with multiple
levels. Each level contains
different cut-off diameter
ranges.
The drug collected is
distributed within the impactor
based on the drug’s
aerodynamic diameter.
Impactors simulate the lung to
determine particle distribution
within the lung.
Particle Size Distribution
Next Generation Impactor (NGI)
Preseparator
Lid
Induction Port
Handle
Bottom Frame
Next Generation Impactor (NGI)
Next Generation Impactor (NGI)
Nozzle Assemblies
Seal Body
Cup Tray
Collection Cups
Next Generation Impactor (NGI)
NGI Collection Cups with Typical Deposition Pattern
Inhalation Therapy: General Considerations
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All Inhalation drug products are complex
combinations of drugs and devices.
Performance of the drug products vary by design.
Patient use and compliance can be affected by the
product design.
New areas of inhalation therapy are being
investigated all the time and new products will
evolve from these developments.