PHA619 – LEC
PHARMACEUTICAL DOSAGE FORMS, DRUG DELIVERY
SYSTEMS, AND MEDICAL DEVICES
Chapter 2:
NEW DRUG DEVELOPMENT AND APPROVAL PROCESS
ACRONYMS
Clinical Drug Materials (CTM)
- Dosage formulations used for clinical evaluation
of a new drug
Investigational New Drug (IND)
- Protects the right and safety of the subjects
- Ensures investigational plan is sound and
designed to achieve the stated objectives
New Drug Application (NDA)
- Gains permission to market the drug product
Supplemental New Drug Application (SNDA)
- Application by the sponsor of approved NDA to
make changes
Abbreviated New Drug Application (ANDA)
- Nonclinical laboratory studies and clinical
investigations may be omitted, except those
pertaining to the drug’s bioavailability
Biologics License Application (BLA)
- Manufacture of biologicals (blood products,
vaccines, and toxins)
International Conference on Harmonization (ICH)
- Brings together regulatory requirements
- Establishes (long range goal) a uniform set of
standard for drug registration within geographic
area
FACTORS TRIGGERED RAPID DRUG DEVELOPMENT
AND PRODUCTION IN THE US
- Pharmaceutical industry’s discovery of new
drugs and development into commercial
products
- Scientific and biomedical information generated
worldwide (research institutes, academic center
and industry)
- Combined efforts in drug discovery and
development (chemists, biologists, molecular
biologists, pharmacologists, toxicologists,
statisticians, physicians, pharmacists and
pharmaceutical scientist, engineers, and etc.)
- Rapid growth of pharmaceutical industry during
WWII
- Development of other antibiotics
- Post-war drug discovery with development of
many new agents
Federal Food, Drug and Cosmetic Act
- New drug be approved by the Food and Drug
Administration (FDA) before legally introduced
in interstate commerce.
- Preformulation studies (physical and chemical
properties of the agent).
- Formulation studies follows
o Develop initial feature of proposed
pharmaceutical product/dosage form
Drug Substance
- Active ingredient/component that produces
pharmacologic activity
- Produced by:
o Chemical synthesis
o Enzymatic reaction
o Recovery from a natural product
o Recombinant DNA technology
o Fermentation
o Combination of these processes
- Purification needed before use in a drug
product
New Chemical Entity (NCE)
- Drug substance with unknown clinical,
toxicologic, physical and chemical properties
Drug Product
- Finished dosage form (containing the drug
substances + other excipients/inert substances)
SOURCE OF NEW DRUG
A. Variety of natural sources
- Serendipity / result of tireless pursuit
- Plant materials have served as a reservoir of
potential new drug
- Conversion of botanic folklore remedies into
modern wonder drugs
B. Synthesis in the laboratory
VARIETY OF NATURAL SOURCES
Reserpine
- tranquilizer and hyposensitive agent
- Medicinal chemical isolated by design from the
folklore remedy Rauwolfia serpentine
Perwinkle or Vinca rosea
- For diabetes mellitus
Paclitaxel (taxol)
- for ovarian cancer
- from an extract of the pacific yew tree
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Other plant constituent
- inactive or unimportant therapeutically rDNA
- chemically modified to yield important drug
with profound pharmacologic activity
- examples, species of Dioscorea (Mexican yams)
o rich in chemical steroids structure:
cortisone and estrogens
o semi synthetically produces
Animals have served human in their search for drugs:
Cattle, sheep, and swine from the endocrine gland
- hormonal substances: thyroid extract, insulin,
and pituitary hormone (replacement therapy in
the human body) MoAB
Pregnant Mares (from urine)
- rich source of estrogen
Production of various biologic product
- serums, antitoxins, and vaccines (life saving)
- small pox vaccine – pioneering work of Edward
Jenner in England in 1796.
- Cultures of renal monkey – poliomyelitis
vaccines
- Fluids of chicks embryo – mumps and influenza
vaccines
- Duck embryo – rubella (German measles)
vaccines
- Skin of bovine calves inoculated with vaccinia
virus – small pox vaccines
SYNTHESIS IN THE LABOTATORY / MOLECULAR
MANIPULATION
- Change natural chemical to different chemical
structure Goal Drug
1. Development of pharmaceutical drug products
(result of genetic engineering)
- Submicroscopic manipulation of the double
helix, the spiral DNA chain of life
Two basic technologies that drive the genetic field of
drug development:
- Recombinant DNA (rDNA)
- Monoclonal Anti-body products (moAB) Lead Compound
production
SIMILARITIES of rDNA and MoAB
- Manipulate and produce proteins (building
blocks of living matter)
- Production techniques influence cells in their
ability to produce proteins
DIFFERENCES
- More fundamental
- Produce any protein
- GENE SPLICING – genetic material transplanted
from higher species (human) which induce the
lower organism (bacterium) to make proteins
o Human insulin
o Human growth hormone
o Hepatitis B vaccine
o Epoetin α
o Interferon
- Conducted within cells of higher animals
(including patient)
- Exploits cell to produce an antibody to combat
the specific agent
- Used in home pregnancy testing products
- In medicine: to stage and localize malignant
cells of cancer
- Future: combat disease (lupus erythematosus,
juvenile onset diabetes and myasthenia gravis)
2. Human gene therapy (promising new
technology)
- Prevent, treat, cure, diagnose, or mitigate
human disease caused by genetic disorder
- 1st human gene therapy
o Treat Adenosine deaminase (ADA)
deficiency (condition resulting in
abnormal functioning of the immune
system)
- Produce:
o Desire effect
o Administered by the most desired route
(orally) at minimal dosage and dosing
frequently
o Exhibit no side effects
o Eliminates from the body efficiently,
completely and without residual effect
- Prototype chemical compound
- Fundamental desired biologic or pharmacologic
activity
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Prodrug
- Metabolic biotransformation of compound after
administration to produce desired
pharmacologically active compound
- Inactive prodrug to active compound
(enzymatic biochemical cleavage)
- Ex. Enalapril (enalapril maleate, Vasotec)
o Bioactivated to enalaprilat (ACE
Inhibitor, for hypertension)
- Used for the following reasons:
o Solubility
o Biostability
o Absorption
o Prolonged release
New Drug
- (according to FDA) Not recognized among
experts as safe and effective
- Change in previously approved drug product’s
formulation/method of manufacture
- New combination of 2 or more old
drugs/change in proportions of drugs
- Proposed new use, new dosage regimen, new
route of administration or new dosage form
Orphan Drug
- Treatment IND are sought for to target small
number of patient with rare conditions /
diseases (orphan diseases) where there are no
satisfactory alternative treatments
Orphan Disease
- Rare disease / condition affecting fewer than
200,000 people:
o Chronic lymphocytes
o Leukemia
o Gaucher’s disease
o Cystic fibrosis
o AIDS
Pharmacologic Profile
- In vitro cultures of cells & enzyme systems and
in vivo animal models are used
- Objective: to obtain basic information on the
drug’s effects that may be used to predict safe
and effective use in humans
Molecular Graphics
- Use of computer graphics to present and
manipulate the structure of the drug model to
fit the stimulated molecular structure of the
receptor site
- Complementary tool in drug molecule design
METHODS OF DRUG DISCOVERY
- Some drugs may be result of:
o Fortuitous discovery
o Carefully designed research programs
of:
 Screening
 Molecular modification
 Mechanism-based drug design
Random / non-targeted screening
- Testing of large numbers of systematic organic
compound or substance of natural origin for
biologic activity.
- Detects unknown activity of test compounds /
identifies compromising compounds to be
studied to determine specific activity
- Ex. Bioassays
o Detects and evaluates biological activity
o Differentiates the effects and potency
of test agent compared with controls of
known action and effect
Molecular modification
- Chemical alteration of an organic compound
(frequently a lead compound) to:
o Enhance its usefulness as a drug
o Enhancing specificity for a body’s target
site
o Increasing potency
o Improving rate and extent of absorption
o Modifying time course in the body
o Reducing toxicity
o Change of physical / chemical
properties to provide desired
pharmaceutical features
Mechanism-based drug design
- Drug design that interferes with the known or
suspected biochemical pathway of mechanism
of a disease process
- Intention: interaction of the drug with:
o Specific cell receptors
o Enzyme systems
o Metabolic processes of the pathogens /
tumor cells
- Resulting in:
o Blocking
o Disruption
o Reversal of the disease process
Non proprietary names
- For single agents
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Proprietary / Trademark names
- Associated with a single chemical entity or with
a mixture of chemicals constituting a specific
proprietary product
Pharmacology
- Enhances:
o Physical and chemical properties
o Biochemical and physiological effects
o Mechanisms of action, absorption,
distribution, biotransformation &
excretion, therapeutic & other uses of
drugs
- Concerned with drugs, their sources,
appearance, chemistry, action, and uses
- Comes from the Latin word pharmaco (drug)
and logos (study of)
SUB AREA OF PHARMACOLOGY
1. Pharmacodynamics
- Study of the biochemical and physiological
effect of drugs and their mechanism of actions
2. Pharmacokinetics
- Deals with the absorption, distribution,
metabolism or biotransformation, and excretion
(ADME) of the drug
TODAY’S EMPHASIS IN DEVELOPMENT OF NEW DRUGS
- Identifying the cause and process of a disease
- Designing drug molecules capable of interfering
with that process
- Precise cause of each disease – not yet known
- Known is most diseases arising from:
o Biochemical imbalance
o Abnormal proliferation of cells
o Endogenous (internal cause) deficiency
o Exogenous (external factor) chemical
toxin or Invasive pathogen (harmful
bacterium)
QUANTITY OF DRUG WILL INFLUENCE ITS EFFECTIVITY
- There is relationship of drugs for:
o Interaction and the capacity of the
specific receptor site
- Following a dose of drug and its transit to the
site of action
o Cell receptors may or may not become
fully saturated with interacting drug
o Receptors fully saturated – effects of
the specific interaction is maximized
o Additional drug present and not
participating in the interaction – serve
as a reservoir to replace drug molecules
that become releases from the complex
Two drugs in a biologic system
- Compete for the same binding sites
- Drug with stronger bonding attraction for the
site prevails
- Bound molecules of the more weakly bound
drug
- May be replaced from the binding site
- Left free in the circulation as unbound drug
METABOLIC CHARACTERIZATION
Drug metabolism (chemical process within living
organism to maintain life)
- Series of animal studies of a proposed drugs
ADME are undertaken to determine:
a. Extent and rate of drug absorption from various
routes of administration, including human use
b. Rate of distribution of drug through the body
and the site or sites and duration of the drug
residence
c. Rate, primary and secondary sites, and the
mechanism of the drugs metabolism in the
body and the chemistry and pharmacology of
any metabolism
d. The proportion of administered dose
eliminated from the body and its rate and route
of elimination
BIOLOGIC CHARACTERIZATION
Specific and non-specific enzymes
- Participate in drug metabolism (livers, kidneys,
lungs, and gut)
Drug following oral administration that enters the
hepatic circulation after absorption from gut
- Exposed to rapid metabolism
1st pass effect
- Transit through the liver and exposure to the
hepatic enzyme system
- To be avoided, other routes of administration
(buccal, rectal) may be used to absorb drug into
the systemic circulation through blood vessels
other that hepatic
ADME studies
- Performed through the collection and analysis
of urine, blood and feces samples, and careful
exam of animal tissue and organs upon autopsy
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DIFFERENT STUDIES IN TOXICOLOGICAL PROFILE
a. Acute or short-term toxicity
- Toxic effect of a test compound when
administered in single dose and/or multiple
doses over short period, usually a single day
- Test compound administered at various levels,
with toxic signs observes
- Doses are ranged to fin dose not to produce
toxic effect, severe toxic effect and
intermediate toxic effect
b. Sub-acute or sub-chronic studies
- Considered: The relationship to project human
clinical studies for safety
- Animal toxicity studies (minimum of two weeks
of daily drug administration at 3 or more dosage
levels to two animal species) are required to
support the initial administration of a single
dose in human clinical testing
c. Chronic toxicity studies
- Drugs intended to be given to humans for a
week or more, animal studies of 90 to 180 days
in length must demonstrate safely
- For chronic human illness, long-term animal
studies of 1 year or longer year
d. Carcinogenicity studies
- For limited number of rat and mouse strains
o There is reasonable information on
spontaneous tumor incidence
- Long-term studies (18-24 months) with
surviving animals killed and studied at defined
weeks during the test period
- Component of chronic testing, undertaken
when the compound has shown sufficient
promise as a drug to enter human clinical trials
e. Reproduction studies
- reveals any effect of an active ingredient on
mammalian reproduction
- evaluated for anatomical abnormalities, growth
and development: maternal parent, fetus,
neonates and weaning offspring
- Fertility and mating behaviour, mutagenecity,
teratology
f. Genetoxicity or Mutagenecity studies
- Determines whether test compound affects
gene mutation or cause chromosome or DNA
damage
- Used in assays to detect mutations: Strains of
Salmonella typhimurium
DIFFERENT PROPERTIES OF DRUG SUBTANCES
INCLUDED IN PRE-FORMULATION STUDIES
1. Drug Solubility
- Drug substance must possess some aqueous
solubility for system absorption and therapeutic
response
- Poorly soluble compounds – incomplete erratic
and/or slow absorption producing minimum
response at desired dosage
2. Partition Coefficient
- Drug molecules must first cross a biologic
membrane of protein and lipid to produce a
pharmacologic response, which acts as a
lipophilic barrier to many drugs
- Measure of its distribution in a lipophilic/
hydrophilic phase system, and is indicative of its
ability to penetrate biologic multiphase system
3. Dissolution Rate
- Speed, rate, at which a drug substance dissolves
in a medium
- Provide indication of drug’s absorption
potential:
o Drug solubility
o Partition coefficient
4. Physical Form and Particle Size
- Affect the drug’s:
o Dissolution rate
o Rate and extent of absorption
5. Stability
- Tests: various temperatures, conditions or
relative humidity and environment of light, air,
and packaging
- Critical in preparing a successful pharmaceutical
product, alone and when combined with
formulation components
- Drugs susceptible to:
o Oxidative decomposition – add
antioxidant stabilizing agent
o Hydrolysis – processing and packaging
required
INITIAL PRODUCT FORMULATION AND CLINICAL TRIAL
MATERIALS (CTM)
- Products formulated (preformulaton studies as
basis) for the clinical studies and for the new
drug with consideration of:
o Dose
o Dosage form
o Route of administration
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 - Clinical supplies / clinical trial materials (CTM)
o Includes:
 Proposed new drug
 Placebos (non-medicated forms
for controlled studies)
 Drug products compared to
new drugs (comparator drugs
or drug product)
Blinded Studies
- Controlled studies where 1 of the parties is not
knowledgeable of which product is being
administered
- Single blind studies
o Patient unaware of the:
 Agent administered
(investigational drug)
 Placebo (comparator drug)
- Double blind studies:
o Neither the patient nor the clinician is
aware of the agent administered
- Includes:
o Advice on the adequacy of data to
support an investigational plan
o Design of a clinical trial / investigational
procedures
o Data to meet requirement of the next
step
o Filing NDA to gain approval for
marketing
FDA REVIEW OF AN IND APPLICATION
- The FDA’s objectives in reviewing IND
- Protect the safety and right of human subjects
- Ensure evaluation of the drug’s safety and
effectiveness
- Objections are best met by the accuracy and
completeness of the IND submission
- Design and conduct of the:
o Investigational plan
o Expertise
o Diligence of the investigators

Open Label FDA DRUG CLASSIFICATION SYSTEM

- All parties are aware of the products - Upon receipt and examination of IND / NDA
administered application
Parallel designs - FDA classifies the drug by:
- Applicable to most clinical trials o Chemical type
Crossover designs o Therapeutic potential
- For comparing different treatments within
individuals since following one treatment, a PHASES OF PRODUCT DEVELOPMENT OF DRUG
patient is “crossed over” to a different PRODUCTS CONTAINING NCEs (page 57)
treatment Preclinical Stage
- Animal pharmacology and toxicology are
THE CLINICAL PROTOCOL obtained
- Part of the IND application - Determines the safety and efficacy of the drug
- Submitted to ensure the appropriate design and - Submission of investigational new drug (IND)
conduct of investigation application for human testing to the FDA
- Includes (page 54):
o Purpose and objectives Phase I
o Investigational plan - Initial introduction (Clinical Testing)
o Number of patients - Subjects: Healthy volunteers (20-100)
o Dosing plan - Determines drug tolerance and toxicity
o Subject selection (assessing safety)
o Clinical procedures, laboratory tests
o Patients’ observations, measurements Phase II
and tests etc. - Controlled clinical studies to several hundred
patients with the disease/conditions are treated
PRE-IND MEETINGS - Safety measures – determines the therapeutic
- FDA advices a sponsor relating to the index (ratio of toxic dose to effective dose)
preparation and submission of IND on: - Final drug formulation developed bioequivalent
o Scientific (same rate and extent of drug absorption to the
o Technical brand drug product) to the dosage form
o Formatting concerns

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Phase III
- Several hundred to several thousand of patients
with the disease/condition treated for which
the drug was developed (controlled and
uncontrolled trials)
- Large scale, multicenter studies performed – to
determine safety and efficacy
- Side effects are monitored
Phase IIIa
- Completed studies sufficient for the NDA
Phase IIIb
- Additional studies are used to gather:
o Supplemental information to support
certain labelling requests
o Information on patients’ quality of life
issues
o Product advantages over already
marketed competing drugs
o Evidence in support of possible
additional drug indications
o Other clues for prospective post
marketing studies
Submission of a New Drug Application (NDA)
- An NDA is submitted to the FDA for review and
approval when clinical trials are completed
Phase IV
- Continual clinical investigation
- Manufacturing scale-up activities
- Drug formulation modified slightly
- To gather supplemental information (labelling,
product advantages, additional indications,
prospective postmarketing studies)
- Product development continues after the FDA’s
market approval of drug product
- Drug product may be improved due to
equipment, regulatory, supply or market
demands
Post marketing reporting of adverse drug experiences
- A drug sponsor is required to report to the FDA
each adverse drug experience that is both
serious (life threatening or fatal) and
unexpected (not contained in the approved
drug product labelling) regardless of the source
of the information within 15 working days of
receipt information
FACTORS IN DETERMINING DRUG’S DOSE
- Age
- Body weight
- Sex
- Body surface area
- Tolerance
- General health status
- Pathologic condition(s)
- Concomitant drug therapy
- Dosage form, time & route of administration
DRUG DOSAGE AND TERMINOLOGY
Usual adult dose and starting dose for the patient
- Amount of drug that produces the desired
effect in the majority of adult patient
Dosage regimen / schedule of dosage
- Determined from:
o Clinical investigation
o Inherent duration of action
o Pharmacokinetics
o Characteristics of the dosage form
Unity of Activity
- Derived from biological assay methods
- Reflects drug’s potency
- Necessary when drug’s (antibiotics and
endocrine products) suitable chemical assay
methods are unavailable
Minimum effective concentration (MEC)
- Drug’s average blood serum concentration
- Determines minimum concentration expected
to produce the drug’s desired effects in a
patient
Minimum toxic concentration (MTC)
- Second level of serum concentration of drug
- Above the average blood serum concentration
level producing toxic effects
- Negates desirable effects of the drug
compromising safety of the patient
ED50 / Median Effective Dose
- Produces the desired intensity of effect in 50%
of the individuals tested
Median Toxic Dose
- Produces a defined toxic effect in 50% of the
individuals testes
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Therapeutic Index
- Relationship between drug’s desired and
undesired effects
- Ratio of drug’s median toxic dose and median
effective dose, TD50/EF50
Maintenance Dosage
- Regularly schedule subsequent administration
to keep the most desirable concentration of
drug in the blood
Initial Priming / Loading Dose
- Required to attain desired concentration of the
drug in the blood of tissues
Prophylactic Dose
- Protects the patient from contracting the illness
Therapeutic Dose
- Administered to the patient after exposure or
contraction of the illness
Rectal, Gastrointestinal tract, Sublingual, Dermal
(skin), and other sites
- Varying rates and degrees of absorption
ROUTES OF ADMINISTRATION
- Fundamental considerations in dosage form
design:
1. Local effects
- Direct application of the drug to the desired site
of action (eye, nose, or skin)
2. Systemic effects
- Entrance of drug into circulatory system and
transport to cellular site of its action
- Direct placement into the bloodstream via IV
injection or absorbed into the venous
circulation following oral/ other routes of
administration

Drug-Drug Interaction
- Effects of drugs are modifies by prior/
concurrent administration of another drug
- Chemical or physical interaction between the
drug /alteration of the absorption, distribution,
metabolism /excretion patterns of one of the
drugs
- Include “social agents” (tobacco and alcohol)
affecting pharmacokinetics of a number of
drugs and alter drug’s usual dose

TIME AND CONDITIONS OF ADMINISTRATION

Time drug is administered
- Influence dosage

Absorption more rapid

- Stomach and upper portions of intestinal tract
are empty of food

DOSAGE FORM AND ROUTE OF ADMINISTRATION

Intravenous / Parenteral (Injectable)
- Drugs enter blood stream directly and
completely
- Required to achieve the same blood levels /
clinical effects

Oral
- Rarely or if fully absorbed into bloodstream due
to various reasons:
o Physical, chemical, and biologic barriers
to their absorption

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 ROUTES OF DRUG ADMINISTRATION ROUTE OF ADMINISTRATION AND DELIVERY SYSTEM
TERM SITE OF PRIMARY DOSAGE FORMS
Oral Mouth Oral Tablets
Peroral (per osα) Gastrointestinal tract via Capsules
mouth Solutions
Sublingual Under the tongue Syrups
Parenteral Other than the Elixirs
gastrointestinal tract (by Suspensions
injection) Magmas
Intravenous Vein Gels
Intra-arterial Artery Powders
Intracardiac Heart Sublingual Tablets
Intraspinal or Spine Troches, lozenges
Intrathecal Drops (solutions)
Intraosseous Bone Parenteral Solutions
Intra-articular Joint Suspensions
Intrasynovial Joint fluid area Epicutaneous, Ointments, gels
Intracutaneous, Skin Transdermal Cream
Intradermal Infusion pumps
Subcutaneous Beneath the skin Pastes
Intramuscular Muscle Plasters
Epicutaneous Skin surface Powders
(topical) Aerosols
Transdermal Skin surface Lotions
Conjunctival Conjunctiva Transdermal patches,
Intraocular Eye disks, solutions
Intranasal Nose Intraocular, Intraaural Solutions
Aural Ear Suspensions
Intrarespiratory Lung Intranasal Solutions
Rectal Rectum Sprays
Vaginal Vagina Inhalants
Ointments
Intrarespiratory Aerosols
Rectal Solutions
Ointments
Suppositories
Gels
Vaginal Solutions
Ointments
Emulsion foams
Gels
Tablets
Inserts, suppositories,
sponge
Urethral Solutions
Suppositories

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