PREFORMULATION GUIDANCE
PREFORMULATION GUIDANCE FOR
INDUSTRY
This guidance document represents the author’s current thinking on
preformulation in drug discovery and development. It does not create or
confer any rights for or on any person and does not operate to bind FDA or
the public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statute, regulations, or both.

PREFORMULATION GUIDANCE
Discovering and developing safe and effective new medicines is a long, difficult,
and expensive process. Once a new compound has been identified in the
laboratory, it undergoes the drug development process before it can be marketed
for public use.
The entire drug development process can be summarized in a series of steps
or charts.
Drug Development Steps:
 Preclinical Testing
 Investigational New Drug Application (IND).
 Clinical Trials
 New Drug Application (NDA)
 Approval
Drug Development Steps:
1. Preclinical Testing
Preclinical Testing:
The compound is tested for safety and efficacy in laboratory and animal studies.
Preformulation studies covering the physical and chemical characterization of the
new drug substance are also conducted.
Preclinical Testing Involves:
1. Pharmacology
2. Toxicology
3. Preformulation
4. Formulation
5. Analytical

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6. Pharmacokinetics
1. Pharmacology:
2. Toxicology:
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 [ A test used to determine the mutagenic
potential of a substance based on the mutation rate of bacteria that are
exposed to the substance] .
• One-week or Two-week Range Finders:
 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 vis-a-vis Animal Efficacy Studies
Single Dose Acute Toxicity Testing for Pharmaceuticals
(Refer CDER Guidelines)
3. Preformulation :
Preformulation involves the application of biopharmaceutical principles to the
physicochemical parameters of a drug with the goal of designing an optimum drug
delivery system. Characterization of drug molecule is a very important step at the
preformulation phase of product development. Following studies are conducted

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as basic preformulation studies; special studies are conducted depending on the
type of dosage form and the type of drug molecule:
1. Solubility determination
2. pKa determination
3. Partition coefficient
4. Chemical stability profile
5. Crystal Properties and Polymorphism
6. Particle size, shape and surface area
7. Specifications for New Drug Substances and Products
8. Dosage Form Development Chart
1. 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 molecule in various solvents is determined as a first step. This
information is valuable in developing a formulation. Solubility is usually determined
in a variety of commonly used solvents and some oils if the molecule is lipophilic.
The solubility of a material is usually determined by the equilibrium solubility
method, which employs a saturated solution of the material, obtained by stirring an
excess of material in the solvent for a prolonged period until equilibrium is
achieved.

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Common solvents used for solubility determination are:
I. Water
II. Polyethylene Glycols
III. Propylene Glycol
IV. Glycerin
V. Sorbitol
VI. Ethyl Alcohol
VII. Methanol
VIII. Benzyl Alcohol
IX. Isopropyl Alcohol
X. Tweens
XI. Polysorbates
XII. Castor Oil
XIII. Peanut Oil
XIV. Sesame Oil
XV. Buffers at various pHs
2. pKa determination
Determination of the dissociation constant for a drug capable of ionization within a
pH range of 1 to 10 is important since solubility, and consequently absorption, can
be altered by orders of magnitude with changing pH. The Henderson-Hasselbalch
equation provides an estimate of the ionized and un-ionized drug concentration at
a particular pH.
For acidic compounds:
pH = pKa + log ([ionized drug]/[un-ionized drug])
For basic compounds:
pH = pKa + log ([un-ionized drug]/[ionized drug])

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pKa of a compound is thus a measure of drug un-ionized at a certain pH
pKa = -log K a , where Ka is the acidity or ionization constant of a weak acid.
(K w=[H 3 O+]
For a weak base, K a = K w/K b , where K w is the ionic product of water
x [OH-]) and K b is the basicity or ionization constant of the weak
3. Partition coefficient
Partition coefficient (oil/water) is a measure of a drug's lipophilicity and an
indication of its ability to cross cell membranes. It is defined as the ratio of un-
ionized drug distributed between the organic and aqueous phases at equilibrium.
P o/w = (C oil /C water ) equilibrium
For series of compounds, the partition coefficient can provide an empiric handle in
screening for some biologic properties. For drug delivery, the lipophilic/hydrophilic
balance has been shown to be a contributing factor for the rate and extent of drug
absorption. Although partition coefficient data alone does not provide
understanding of in vivo absorption, it does provide a means of characterizing the
lipophilic/hydrophilic nature of the drug.
Since biological membranes are lipoidal in nature, the rate of drug transfer for
passively absorbed drugs is directly related to the lipophilicity of the moleucle. The
partition coefficient is commonly determined using an oil phase of octanol or
chloroform and water.
Drugs having values of P much greater than 1 are classified as lipophilic, whereas
those with partition coefficients much less than 1 are indicative of a hydrophilic
drug.
Although it appears that the partition coefficient may be the best predictor of
absorption rate, the effect of dissolution rate, pKa, and solubility on absorption
must not be neglected.

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4. Chemical stability profile
Preformulation stability studies are usually the first 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.
Factors affecting chemical stability critical in rational dosage form design include
temperature, pH and dosage form diluent. The method of sterilization of parenteral
products will be largely dependent on the temperature stability of the drug. Drugs
having decreased stability at elevated temperatures cannot be sterilized by
autoclaving but must be sterilized by another means, e.g., filtration. The effect of
pH on drug stability is important in the development of both oral and parenteral
dosage forms; acid labile drugs intended for oral administration must be protected
from the highly acidic environment of the stomach. Buffer selection for parenteral
dosage forms will be largely based on the stability characteristics of the drug.
• Solid-State Stability
• Solution-Phase Stability
• Compatibility Studies: Stability in the Presence of Excipients
• Typical Stability Protocol for a New Chemical Entity

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• 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. Repetitive testing of
the initial bulk lot in parallel with newer bulk lots should be expected, and adequate
material should be set aside for these studies.
In general, solid state reactions are much slower and more difficult to interpret than
solution state reactions, and it is customary to use stress conditions in the
investigation of stability. The data obtained under stress conditions are then
extrapolated to make a prediction of stability under appropriate storage conditions.
Stress conditions utilized by the scientists are:
• Elevated temperature Studies
• Stability under High-Humidity Conditions
• Photolytic Stability
• Oxidative Stability
• Elevated temperature Studies
The elevated temperatures most commonly used are 40°, 50° and 60° C in
conjunction with ambient humidity. Occasionally, higher temperatures are
used. The samples stored at the highest temperature should be examined for
physical and chemical changes at weekly intervals, and any change, when
compared to an appropriate control (usually a sample stored at 5°C), should be
noted. If a substantial change is seen, samples stored at lower temperatures are
examined. If no change is seen after 30 days at 60°C, the stability prognosis is
excellent. Corroborative evidence must be obtained by monitoring the samples
stored at lower temperatures for longer durations. Samples stored at room

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temperature and at 5°C may be followed for as long as 6 months. The data
obtained at elevated temperatures may be extrapolated using the Arrhenius
treatment to determine the degradation rate at a lower temperature.
Arrhenius Equation:
K = A e-Ea/RT
E : activation energy; R: gas constant
a
logK = logA - (E a /2.303RT)
Plotting the rate of reaction (K) against 1/T allows the calculation of rate at any
temperature and therefore a prediction of shelf-life (t 90 , time to 90% potency). This
forms the basis of many accelerated stability tests.
Not all solid-state reactions are amenable to Arrhenius treatment. Their
heterogeneous nature makes elucidation of the kinetic order and prediction
difficult. Long-term lower temperature studies are, therefore, an essential part of a
good stability program.
• Stability under High-Humidity Conditions
In the presence of moisture, many drug substances hydrolyze, react with other
excipeints, or oxidize. These reactions can be accelerated by exposing the solid
drug to different relative-humidity conditions. Controlled humidity environments
can be readily obtained using laboratory desiccators containing saturated solutions
of various salts.
Preformulation data of this nature are useful in determining if the material should
be protected and stored in a controlled low-humidity environment, or if the use of
an aqueous-based granulation system, in the case of a solid dosage form, should

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be avoided. They may also caution against the use of excipients that absorb
moisure significantly.
• Photolytic Stability
Many drug substances fade or darken on exposure to light. Usually the extent of
degradation is small and limited to the exposed surface area. This can be
controlled by using amber glass or an opaque container or by incorporating a dye
in the product to mask the discoloration (if the only issue is aesthetics).
Exposure of the drug substance to 400 and 900 footcandles of illumination for 4-
and 2-week periods, respectively, is adequate to provide some idea of
photosensitivity. Over these periods, the samples should be examined frequently
for change in appearance and for chemical loss, and they should be compared
against samples stored under the same conditions but protected from light.
Source : ICH

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• Oxidative Stability
The sensitivity of each new drug entity to atmospheric oxygen must be evaluated
to establish if the final product should be packaged under inert atmospheric
conditions and if it should contain an antioxidant. Sensitivity to oxidation of a solid
drug can be ascertained by investigating its stability in an atmosphere of high
oxygen tension. Usually a 40% oxygen atmosphere allows for a rapid
evaluation. Results should be compared against those obtained under inert or
ambient atmospheres.
• 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.
Solution stability investigations usually commence with probing experiments to
confirm decay at the extremes of pH and temperature (e.g., 0.1N HCl, water, and
0.1N NaOH all at 90°C). These intentionally degraded samples may be used to
confirm assay specificity as well as to provide estimates for maximum rates of
degradation. This initial experiment should be followed by the generation of a
complete pH-rate profile to identify the pH of maximum stability. Aqueous buffers
are used to produce solutions over a wide range of pH values with constant levels
of drug, cosolvent and ionic strength.
Reactions in solutions proceed considerably more rapidly than the corresponding
solid-state reactions. Degradation in solution thus offers a rapid method for the
generation of degradation products. The latter are often needed for the purpose of
identification (to study their toxicity) and the development of analytical methods.
Even for a drug substance intended to be formulated into a solid dosage form such
as a tablet, a limited solution-phase stability study must be undertaken. Among
others, these studies are necessary to assure that the drug substance does not

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degrade intolerably when exposed to gastrointestinal fluids. Thus, the stability of
drug in buffers ranging from pH 1 to 8 should be investigated. If the drug is
observed to degrade rapidly in acidic solutions, a less soluble or less susceptible
chemical form may show increased relative bioavailability. Alternately, an enteric
dosage form may be recommended for such a compound.
The availability of pH-rate profile data is sometimes useful in predicting the solid-
state stability of salt forms or the stability of a drug in the presence of acidic and
basic excipients.
If a drug substance is adjudged to be physically or chemically unstable when
exposed to moisture, a direct compression or nonaqueous-solvent granulation
procedure is to be recommended for the preparation of tablets. Before using a
nonaqueous solvent for this purpose, stability of the drug in the solvent must be
ascertained.
Light Stability:
Some solution samples should be subjected to a light stability test, which includes
protective packaging in amber glass containers. Control samples for this light test
may be stored in cardboard packages or wrapped in aluminum foil.
Oxidation:
Some of the solution samples should also be subjected to further testing with:
• Excessive headspace of oxygen
• Headspace of an inert gas such as helium or nitrogen
• Inorganic antioxidant such as sodium metabisulfite
• Organic antioxidant such as butylated hyrdroxytoluene-BHT
Analysis of these samples will give an idea of oxidation potential of the drug.

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pH-Rate Profile:
To generate a pH-rate profile, stability data generated at each pH and temperature
condition are analyzed kinetically to yield the apparent decay rate constants. All of
the rate constants at a single temperature are then plotted as a function of
pH. The minimum in this curve is the pH of maximum stability.
An Arrhenius plot is constructed by plotting the logarithm of the apparent decay
rate constant versus the reciprocal of the absolute temperature at which each
particular buffer solution was stored during the stability test. If this relationship is
linear, one may assume a constant decay mechanism over this temperature range
and calculate an activation energy (E a ) from the slope (-E a/R) of the line described
by:
ln k = - (E a /R)(1/T) + C
Where C is a constant of integration and R is the gas constant.
A broken or nonlinear Arrhenius plot suggests a change in the rate-limiting step of
the reaction or a change in decay mechanism, thus making extrapolation unreliable.

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• Compatibility Studies: Stability in the Presence of Excipients
Compatibility Studies:
In the tablet dosage form the drug is in intimate contact with one or more
excipients; the latter could affect the stability of the drug. Knowledge of drug-
excipient interactions is therefore very useful to the formulator in selecting
appropriate excipients.
Example:
A typical tablet contains binders, disintegrants, lubricants, and fillers. Compatibility
screening for a new drug must consider two or more excipients from each
class. The ratio of drug to excipient used in these tests is very much at the
discretion of the preformulation scientist.
The three techniques commonly employed in drug-excipient compatibility
screening are:
• Thin-layer chromatography
• Differential thermal analysis
• Diffuse reflectance sprectroscop
Thin-Layer Chromatography:
This involves storage of drug-excipients mixture both \"as is\" and granulated with
water at elevated temperatures. The granulation may be carried out so that the
mixture contains fixed amounts (e.g., 5%) of moisture. The mixtures are sealed in
ampoules to prevent any escape of moisture at elevated temperatures. The
samples are examined periodically for appearance and analyzed for any
decomposition using thin-layer chromatography. Unstressed samples are used as
controls. Any change in the chromatograph such as the appearance of a new spot

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or a change in the RF values [The distance (d s ) traveled by a sample, relative to
the solvent front (d e ) which is compound specific in each chromatographic system.
The ratio is termed the R f value or resolution factor. This is sometimes known as
relative to front.] of the components is indicative of an interaction. The technique
may be quantities if deemed necessary. If significant interaction is noticed at
elevated temperatures, corroborative evidence must be obtained by examining
mixtures stored at lower temperatures for longer durations. If no interaction is
observed at 60 or 70°C, especially in the presence of moisture, none can be
expected at lower temperatures. Among the advantages of thin-layer
chromatographies in this application are:
• Evidence of degradation is unequivocal.
• The spots corresponding to degradation products can be eluted for possible
identification.
The technique can be quantitated to obtain kinetic data.
•
Differential Thermal Analysis:
Thermal Analysis is useful in the investigation of solid-state interactions. It is also
useful in the detection of eutectics. Thermograms are generated for pure
components and their physical mixtures with other components. In the absence of
any interaction, the thermograms of mixtures show patterns corresponding to those
of the individual components. In the event that interaction occurs, this is indicated
in the thermogram of a mixture by the appearance of one or more new peaks or
the disappearance of one or more peaks corresponding to those of the
components.

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Diffuse Reflectance Spectroscopy:
Diffuse reflectance spectroscopy is gaining increasing popularity among
preformulation scientists as a tool to detect and monitor drug-excipient
interactions. In this technique solid drug, excipients, and their physical mixtures
are exposed to incident radiation. A portion of the incident radiation is partly
absorbed and partly reflected in a diffuse manner. The diffuse reflectance
depends on the packing density of the solid, its particle size, and its crystal form,
among other factors. When these factors are adequately controlled, diffuse
reflectance spectroscopy can be used to investigate physical and chemical
changes occurring on solid surfaces. A shift in the diffuse reflectance spectrum of
the drug due to the presence of the excipient indicates physical adsorption,
whereas the appearance of a new peak indicates chemisorption or formation of a
degradation product.

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Typical Stability Protocol for a New Chemical Entity

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5. Crystal Properties and Polymorphism
Many drug substances can exist in more than one crystalline form with different
space lattice arrangements. This property is known as
polymorphism. Polymorphs generally have different melting points, x-ray
diffraction patterns, and solubilities, even though they are chemically identical.
Differences in the dissolution rates and solubilities of different polymorphic forms of
a given drug are very commonly observed. When the absorption of a drug is
dissolution rate limited, a more soluble and faster-dissolving form may be utilized
to improve the rate and extent of bioavailability.
For drugs prone to degradation in the solid state, the physical form of the drug
influences degradation. Selection of a polymorph that is chemically more stable is
a solution in many cases.
Different polymorphs also lead to different morphology, tensile strength and density
of powder bed which all contribute to compression characteristics of
materials. Some investigation of polymorphism and crystal habit of a drug
substance as it relates to pharmaceutical processing is desirable during its
preformulation evaluation, especially when the active ingredient is expected to
constitute the bulk of the tablet mass.
Although a drug substance may exist in two or more polymorphic forms, only one
form is thermodynamically stable at a given temperature and pressure. The other
forms would convert to the stable form with time. In general, the stable polymorph
exhibits the highest melting point, the lowest solubility, and the maximum chemical
stability.
Various techniques are available for the investigation of the solid state. These
include microscopy (including hot-stage microscopy), infrared spectrophotometry,
single-crystal X-ray and X-ray powder diffraction, thermal analysis, and dilatometry.

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Chart for Setting Acceptance Criteria For Polymorphism in Drug Substances
and Drug Product
Source: ICH

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6. 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. In general, each new drug candidate
should be tested during preformulation with the smallest particle size as is practical
to facilitate preparation of homogeneous samples and maximize the drug's surface
area for interactions.
Various chemical and physical properties of drug substances are affected by their
particle size distribution and shapes. The effect is not only on the physical
properties of solid drugs but also, in some instances, on their biopharmaceutical
behavior. It is generally recognized that poorly soluble drugs showing a
dissolution-rate limiting step in the absorption process will be more readily
bioavailable when administered in a finely subdivided state rather than as a coarse
material.
In case of tablets, size and shape influence the flow and the mixing efficiency of
powders and granules. Size can also be a factor in stability; fine materials are
relatively more open to attack from atmospheric oxygen, the humidity, and
interacting excipients than are coarse materials.
1. Determination of particle size
Classical methods for measuring particle size
Microscopy
Optical microscopy is generally used as the first tool to see and measure sizes of
particles ranging in size from 0.2 microns to 100 microns.

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Advantages
• Easy and convenient
• A size-frequency distribution curve can be plotted by counting the number of
particles in a size range
• Can detect the presence of agglomerates and particles of more than one
component
Disadvantages
• Diameter is obtained from only two dimensions - length and breadth
• No estimation of the depth (thickness) of particle is available
• The number of particles that must be counted to get a good estimate of the
distribution makes the method slow and tedious
Sieving or screening
This method utilizes a series of standard sieves calibrated by the National Bureau
of Standards.
Sieves are generally used for grading coarser particles.
Sieves produced by photoetching and electroforming techniques are now available
with apertures from 90 microns down to as low as 5 microns.
Method:
According to the method of the U.S. Pharmacopoeia for testing powder fineness, a
definite mass of sample is placed on the proper sieve in a mechanical shaker. The
powder is shaken for a definite period of time, and the material that passes through
one sieve and is retained on the next finer sieve is collected and weighed.

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Sedimentation
A number of classical techniques based on sedimentation methods, utilizing
devices such as the Andreasen pipette or recording balances that continuously
collect a settling suspension are known. However, these methods are now in
general disfavor because of their tedious nature.
o Commonly used instruments:
 Royco (based on light scattering)
 Hiac (based on light blockage)
 Coulter Counter (based on blockage of an electrical conductivity path)

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Source: ICH

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Determination of surface area
The determination of the surface areas of powders has been getting increasing
attention in recent years. The techniques employed are relatively simple and
convenient to use, and the data obtained reflect the particle size. The relationship
between the two parameters is an inverse one, in that a grinding operation that
reduces the particle size leads to an increase in the surface area.
Two commonly available methods for determining surface area are:
Adsorption Method
Air Permeability Method
2.1 Adsorption Method
This method is based on the Brunauer, Emmett, Teller (BET) theory of
adsorption. Briefly, the theory states that most substances will adsorb a
monomolecular layer of a gas under certain conditions of partial pressure (of the
gas) and temperature. Knowing the monolayer capacity of an adsorbent (i.e., the
quantity of adsorbate which can be accommodated as a monolayer on the surface
of a solid, the adsorbent) and the area of the adsorbate molecule, the surface area
can, in principle, be calculated.
2.2 Air Permeability Method
The principle resistance to the flow of a fluid, such as air, through a plug of
compacted powder is the surface area of the powder. The greater the surface
area per gram of powder, the greater the resistance to flow. Hence permeability,
for a given pressure drop across the plug, is inversely proportional to specific
surface; measurement of the former provides a means of estimating this parameter.
Because of the simple instrumentation and the speed with which determinations
can be made, permeability methods are widely used pharmaceutically for specific
surface determinations, especially when the aim is to control batch-to-batch
variations. When using this technique for more fundamental studies, it would seem
prudent to calibrate the instrument.

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7. Specifications for New Drug Substances and Products
7.1 Setting Acceptance Criterion for Impurity & Degradation in a New Drug
Product

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7.2 Establishing Identity, Assay And Enantiomeric Impurity Procedures for
Chiral New Drug Substances and New Drug Products containing Chiral Drug
Substances
Source: ICH

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7.3 Microbiological Quality Attributes of Drug Substance and Excipients
Source: ICH

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7.4 Setting Acceptance Criteria for Drug Product Dissolution
 Appropriate type of drug release acceptance criteria
Source: ICH

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 Appropriate test conditions and acceptance criteria
Source: ICH

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 Appropriate acceptance ranges (extended release)
Source: ICH

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 Microbiological Attributes of Non-Sterile Drug Products
Source: ICH

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8. Dosage Form Development Chart
Source: Modified from \"Pharmaceutical Preformulation: The
Physicochemical Properties of Drug Substances\"

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4. Formulation :
Formulation Developments starts immediately after or concurrently with
preformulation studies.
Depending on the dosage form selected, various studies are conducted to
accomplish the goal. Formulations developed are tested for both physical and
chemical stability at accelerated temperatures. To determine the chemical stability
of the formulations, an analytical method needs to be in place (usually an HPLC
method) to identify and quantify the active compound. Care should be taken to
see that the method is selective and specific for the active molecule.
• Solid Dosage Form
• Tablets
• Capsules
• Suppositories
• Liquid Dosage Form
• Parenteral
• Emulsions & Suspensions
• Solutions

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• Semisolid Dosage Form
• Creams
• Gels
• Ointments
• Special Drug Delivery Technologies
• Ophthalmic Delivery
• Nasal Delivery
• Transdermal Delivery
• Microencapsulation

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5. Analytical:
5.1 Validation of Chromatographic Methods
5.2 Stability Testing of Drug Substances and Drug Products (FDA)
5.3 Stability Testing of New Drugs and Products (ICH)
5.4 Validation of Analytical Procedures
5.5 Bioanalytical Methods Validation for Human Studies
5.6 Specifications for New Drug Substances and Products

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6. Pharmacokinetic:
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
Studies in Preclinical Stage:
Drug metabolism in animals in the preclinical stage includes characterization of
ADME (Absorption, Distribution, Metabolism and Excretion) for a single
compound. Studies conducted include:
 Mass balance studies (Radiolabeled drug) in toxicology species
1. Tissue distribution and accumulation
 Dose proportionality kinetics to support toxicology doses selected
1. Plasma concentration increases linearly with dose of drug
2. Lower limit threshold, upper limit plasma concentration
3. Plasma protein binding - % bound vs. Plasma concentration
 Multiple dose kinetics in toxicology species (Toxicokinetics)
1. Plasma and/or tissue accumulation with multiple doses
2. Induction / Inhibition of metabolizing enzymes (Cytochrome P450)
A. Lower plasma conc. with time
B. Toxicity from increased/decreased endogenous molecules
 Metabolite profile, gender differences, interspecies scaling
 Support formulation development

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2. 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. The IND enables a
sponsor to ship an unapproved drug in interstate commerce. Clinical trials may
proceed 30 days after filing unless the FDA places a hold on the proposal.
In many ways, the investigational new drug (IND) application is the result of a
successful preclinical development program. The IND is also the vehicle through
which a sponsor advances to the next stage of drug development known as clinical
trials (human trials).
During a new drug's early preclinical development, the sponsor's primary goal is to
determine if the product is reasonably safe for initial use in humans and if the
compound exhibits pharmacological activity that justifies commercial development.
When a product is identified as a viable candidate for further development, the
sponsor then focuses on collecting the data and information necessary to establish
that the product will not expose humans to unreasonable risks when used in limited,
early-stage clinical studies.
Generally, this includes data and information in three broad areas:
• Animal Pharmacology and Toxicology Studies
Preclinical data to permit an assessment as to whether the product is reasonably
safe for initial testing in humans.
• Manufacturing Information
Information pertaining to the composition, manufacture, stability, and controls
used for manufacturing the drug substance and the drug product. This
information is assessed as to ensure the company can adequately produce and
supply consistent batches of the drug.

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• Clinical Protocols and Investigator Information
Detailed protocols for proposed clinical studies to assess whether the initial-
phase trials will expose subjects to unnecessary risks. Also, information on the
qualifications of clinical investigators--professionals (generally physicians) who
oversee the administration of the experimental compound--to assess whether
they are qualified to fulfill their clinical trial duties.
The IND is not an application for marketing approval. Rather, it is a
request for an exemption from the Federal statute that prohibits an unapproved
drug from being shipped in interstate commerce. Current Federal law requires
that a drug be the subject of an approved marketing application before it is
transported or distributed across state lines. Because a sponsor will probably
want to ship the investigational drug to clinical investigators in many states, it
must seek an exemption from that legal requirement. The IND is the means
through which the sponsor technically obtains this exemption from the FDA;
however, its main purpose is to detail the data that provide documentation that it
is indeed reasonable to proceed with certain human trials with the drug.
Types of INDs
\"Commercial INDs\" are applications that are submitted primarily by
companies whose ultimate goal is to obtain marketing approval for a new product.
However, there is another class of filings broadly known as \"noncommercial\"
INDs. The vast majority of INDs are, in fact, filed for noncommercial research.
These types of INDs include \"Investigator INDs,\" \"Emergency Use INDs,\" and
\"Treatment INDs.\"
For Application Process refer CDER web site

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3. Clinical Trials
Clinical Trials involve the following phases:
Testing in Humans
Number of Percent of Drugs
Length Purpose
Patients Successfully Tested
Several
Phase I 20 - 100 Mainly safety 70 percent
months
Upto Several Some short-term
Phase II several months to safety, but mainly 33 percent
hundred 2 years effectiveness
Several
Safety,
hundred to
Phase III 1 - 4 years effectiveness, 25 - 30 percent
several
dosage
thousand
Phase IV Post-marketing surveillance
For example, of 100 drugs for which Investigational New Drug applications are
submitted to FDA, about 70 percent will successfully complete Phase I and go on
to Phase II; about 33 percent of the original 100 will complete Phase II and go to
Phase III; and 25 to 30 of the original 100 will clear Phase III (and, on average,
about 20 of the original 100 will ultimately be approved for marketing).

PREFORMULATION GUIDANCE
Phase I Clinical Trials are to determine safety of the new drug entity,
including the safe dosage range.
Phase I includes the initial introduction of an investigational new drug into humans.
These studies are closely monitored and may be conducted in patients, but are
usually conducted in healthy volunteer subjects, and typically last 3-6 months.
These studies are designed to determine the metabolic and pharmacologic actions
of the drug in humans, the side effects associated with increasing doses, and, if
possible, to gain early evidence on effectiveness. During Phase I, sufficient
information about the drug's pharmacokinetics and pharmacological effects should
be obtained to permit the design of well-controlled, scientifically valid, Phase II
studies.
Phase I studies also evaluate drug metabolism, structure-activity relationships, and
the mechanism of action in humans. These studies also determine which
investigational drugs are used as research tools to explore biological phenomena
or disease processes. The total number of subjects included in Phase I studies
varies with the drug, but is generally in the range of twenty to eighty.
In Phase I studies, CDER can impose a clinical hold (i.e., prohibit the study from
proceeding or stop a trial that has started) for reasons of safety, or because of a
sponsor's failure to accurately disclose the risk of study to investigators. Although
CDER routinely provides advice in such cases, investigators may choose to ignore
any advice regarding the design of Phase I studies in areas other than patient
safety.
Phase II Clinical Trials assess the drug's effectiveness.
Phase II includes the early controlled clinical studies conducted to obtain some
preliminary data on the effectiveness of the drug for a particular indication or
indications in patients with the disease or condition. This phase of testing also
helps determine the common short-term side effects and risks associated with the
drug. Phase II studies are typically well-controlled, closely monitored, and

PREFORMULATION GUIDANCE
conducted in a relatively small number of patients, usually involving several
hundred people.
Phase II Trials may last from 6 months to 2 years. Trials may be conducted in a
blind or non-blind manner.
Phase III Clinical Trials determine efficacy and identify adverse reactions in
large populations.
Phase III studies are expanded controlled and uncontrolled trials. They are
performed after preliminary evidence suggesting effectiveness of the drug has
been obtained in Phase II, and are intended to gather the additional information
about effectiveness and safety that is needed to evaluate the overall benefit-risk
relationship of the drug. Phase III studies also provide an adequate basis for
extrapolating the results to the general population and transmitting that information
in the physician labeling. Phase III studies usually include several hundred to
several thousand people.
In both Phase II and III, CDER can impose a clinical hold if a study is unsafe (as in
Phase I), or if the protocol is clearly deficient in design in meeting its stated
objectives. Great care is taken to ensure that this determination is not made in
isolation, but reflects current scientific knowledge, agency experience with the
design of clinical trials, and experience with the class of drugs under investigation.
Phase IV (Post-marketing surveillance)
The objectives of post-marketing surveillance are to identify rare adverse reactions
not detected during pre-licensure studies, monitor increases in known reactions,
identify risk factors or pre-existing conditions that may promote reactions, and
identify particular lots with unusually high rates or types of events.

PREFORMULATION GUIDANCE
4. 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 was 16.2 months.
5. 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