Non Clinical Drug Development

Subject: Regulatory Affair
Non clinical drug development

Global submission of IND, NDA, ANDA.
Investigation of medicinal products dossier, dossier
(IMPD) and investigator brochure (IB)
Presented By:
Dignesh Khunt
Assistant professor
Department of Pharmaceutics
Shree S. K. Patel College of Pharmaceutical
Education & Research, Ganpat University
Shree S. K. Patel College of Pharmaceutical

Education & Research, Ganpat University 1
Content of presentation
1. Introduction
2. Investigational New Drug (IND)
3. New Drug Application (NDA)
4. Abbreviated New Drug Application
(ANDA)
5. Investigation of Medicinal Products
Dossier (IMPD)
6. Investigator’s Brochure (IB)
Shree S. K. Patel College of Pharmaceutical 2

Introduction
The non-clinical (or pre-clinical) development phase
primarily aims to identify which candidate therapy has
the greatest probability of success, assess its safety, and
build solid scientific foundations before transition to
the clinical development phase.
Also, during the non-clinical development phase, the
candidate compound should meet non-medical
objectives, including defining the intellectual property
rights and making enough medicinal product available
for clinical trials.
The non-clinical development of a medicine is complex
and regulatory-driven.
Continue…
Introduction
The studies in non-clinical development are performed:
 In silico: ‘performed on computer or via computer
simulation’, e.g. predicting the toxicology profile of a
product using its chemical structure from data-based
approaches.
 In vitro (Latin for ‘within the glass’): performing a
procedure in a controlled environment outside of a
living organism, e.g. use of hepatocyte (cells from the
liver) cultures for metabolism studies.
 In vivo (Latin for ’within the living’): experimentation
using a whole, living organism as opposed to tissues or
cells, i.e. animals, humans or plants.
Objectives
Once a candidate compound is identified, the nonclinical
development should start answering the following questions,
and answers will come from specific assessments/studies:
Does it work? → efficacy assessment
How will it be delivered and how will the body react? →
profiling
Is it safe? → toxicology/safety
Is the manufacture viable and controllable?
Non-clinical development activities can continue throughout
the life-cycle of the product, although the earlier these
questions are answered, the easier it is to identify the profile of
the patient who will benefit most.

Types of Applications
Investigational New Drug Application (IND) Applications
for approval to begin experiments on human subjects with
a new drug. It is a part of NDA.
New Drug Application (NDA) Section 505(b)1 of FDCA
Applicable when the sponsor of the pioneer drug has
generated all the preclinical data and clinical studies.
505 (b)2 filing (Hybrid NDA) The applicant can not apply
for ANDA because of certain changes and generates a
partial clinical data.
Abbreviated New Drug Application (ANDA) Section 505 (j)
Application to market a generic drug.
Paragraph IV filing for ANDA When there is still a valid
patent on formulation, polymorph etc. after the expiry of
the basic molecule patent.
R & D activities and regulations
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• Academia Entities Devp/ Mfg /
• Small cos. (NCEs) Marketing

Milestones of new drug approval
process
 Preclinical testing
 Preparation and submission of IND
application
 Review of IND
 Phases 1 to 3 of clinical trials
 Preparation and submission of NDA
 Review and approval or disapproval

Investigational New
Drug Application

INVESTIGATIONAL NEW DRUG
(IND)
Investigational New Drug is defined under 21 CFR 312.3(b)
as ‘ a new drug or biological drug that is used in clinical
investigation’.
The term also includes a biological product used in-vitro for

diagnostic purposes.
After pre-clinical investigations when the new molecule has

been screened for pharmacological activity and acute
toxicity potential in animals the sponsor requires permission
from FDA for its clinical trials in humans.

Continue…
The sponsor submits the application for conduct of human
clinical trials called Investigational New Drug (IND)
application to FDA or DCGI .
Once IND application is submitted , the sponsor must wait
for 30 days before initiating any clinical trial.
Clinical trials in humans can begin only after IND is
reviewed by the FDA and a local institutional review board
(IRB).
IRBs approve clinical trial protocol, informed consent of
all
participants and appropriate steps toShreeprevent subjects
S. K. Patel College from
of Pharmaceutical 13
Purpose of IND
 The main purpose of an Investigational New Drug (IND)
application is to provide the data showing that it is
reasonable to begin tests of a new drug on humans.
 Also, current Federal law requires that a drug be the

subject of an approved marketing application before it is
transported or distributed across state lines. To seek
permission to ship the investigational drug to various
states.

Reaching up to the IND stage …
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.
The IND is not an application for marketing approval.

Definitions
Clinical investigation means any experiment in which a
drug is administered or dispensed to one or more human
subjects.
Investigator means an individual under whose immediate
direction the drug is administered or dispensed to a subject.
Sponsor means a person who takes responsibility for and
initiates a clinical investigation.
Sponsor-Investigator means an individual who both
initiates and conducts an investigation and under whose
immediate direction the investigational drug is administered
or dispensed. The term does not include any person other
than an individual.

Investigational New Drug
Applications
In 1987 an IND rewrite was published by FDA which
resulted in a logical flow of information
Especially the CMC section was reformatted to have

information on drug substance (properties, proof of structure,
stability, synthesis and controls) and drug product
(Manufacturing process, controls and stability)
IND has 8 to 11 sections falling under 4 general areas – (i)

animal pharmacology, toxicology and pharmaco-kinetics (ii)
manufacturing information on DS and DP (iii) clinical
protocols and (iv) information on investigator qualifications
Types of IND
 An Investigator IND
Submitted by a physician
A physician might submit a research IND to propose
studying an unapproved drug, or an approved product for a
new indication or in a new patient population
 Emergency Use IND

Allows the FDA to authorize use of an experimental drug in
an emergency situation that does not allow time for
submission of an IND. It is also used for patients who do
not meet the criteria of an existing study protocol, or if an
approved study protocol does not exist.
 Treatment IND
Submited for experimental drugs showing promise in
clinical testing for serious or immediately life-threatening
conditions while the final clinical work is conducted and the
FDA review takes place.

A sponsor shall submit an IND to FDA if the
sponsor intends to conduct a clinical
investigation with an investigational new drug.
A sponsor shall not begin a clinical trial until

the investigation is subject to an approved IND
application.

Criteria for IND application
• A new indication
• Change in the approved route of
administration or dosage level.
• Change in the approved patient population
(vulnerable subjects e.g. pediatrics, elderly,
HIV +ve, immunocompromised)
• Significant change in the promotion of an
approved Drug.

What are the FDA requirements for pre-
clinical studies?
A sponsor must first submit data showing that the drug is reasonably
safe for use in initial, small-scale clinical studies.
 Depending on whether the compound has been studied or marketed

previously, the sponsor may have several options for fulfilling this
requirement:
(1) Compiling existing nonclinical data from past in vitro laboratory or
animal studies on the compound;
(2) Compiling data from previous clinical testing or marketing of the drug
in the United States or another country whose population is relevant to
the U.S. population; or
(3) Undertaking new preclinical studies designed to provide the evidence
necessary to support the safety of administering the compound to
humans.
Preclinical studies
During preclinical drug development, a sponsor evaluates
the drug's toxic and pharmacologic effects through in vitro
and in vivo laboratory animal testing.
Genotoxicity screening
Investigations on drug absorption and metabolism, the
toxicity of the drug's metabolites, and the speed with which
the drug and its metabolites are excreted from the body.
At the preclinical stage, the FDA will generally ask, at a

minimum, that sponsors: (1) develop a pharmacological
profile of the drug; (2) determine the acute toxicity of the
drug in at least two species of animals, and (3) conduct short-
term toxicity studies ranging from 2 weeks to 3 months,
depending on the proposed duration of use of the substance in
the proposed clinical studies. Shree S. K. Patel College of Pharmaceutical 22
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).

Information in IND
Animal Pharmacology and Toxicology Studies - Preclinical data to
permit an assessment as to whether the product is reasonably safe for
initial testing in humans. Also included are any previous experience
with the drug in humans (often foreign use)
Manufacturing Information - Information pertaining to the

composition, manufacturer, stability, and controls used for
manufacturing the drug substance and the drug product. This
information is assessed to ensure that the company can adequately
produce and supply consistent batches of the drug
Clinical Protocols and Investigator Information - Detailed protocols for

proposed clinical studies to assess whether the initial-phase trials will
expose subjects to unnecessary risks.

What do “preclinical” and
“nonclinical” mean?
Let us look at the composition of the
words. “Pre” is Latin for “before” or
“previous to,” while “non” is Latin for
“negation” or “absence.” According to the
Merriam-Webster dictionary, preclinical
refers to studies occurring prior to clinical
testing. Meanwhile, nonclinical refers to
studies not related to, involving, or
concerned with the direct observation and
treatment of living patients.
Continue….
Regulatory agencies do not seem to make a
strong distinction in usage of the two terms.
The EMA uses either word in guideline
titles and uses them interchangeably within
the text. Meanwhile, the FDA specifically
chooses to use the word nonclinical with a
disclaimer that these studies are “often
referred to as preclinical studies when
conducted before first-in-human clinical
studies.”
Continue…
 The FDA offers a more substantive definition of
nonclinical laboratory studies in Section 58.3 of
Good Laboratory Practice for Nonclinical Laboratory Stu
dies
:
 Nonclinical laboratory study means in vivo or in vitro
experiments in which test articles are studied
prospectively in test systems under laboratory conditions
to determine their safety. The term does not include
studies utilizing human subjects or clinical studies or field
trials in animals. The term does not include basic
exploratory studies carried out to determine whether a
test article has any potential utility or to determine
physical or chemical characteristics of a test article.
Standard NCE or NME Programs
1. For a non-oncology new chemical entity (NCE) or new molecular entity
(NME) programs, efficacy studies and pharmacokinetics studies
typically take place first.
2. Then come non-GLP and GLP toxicology studies (typically conducted
in two species: rodent and non-rodent) as well as safety pharmacology
(central nervous system and respiratory studies typically conducted in
rodents, as well as cardiovascular studies typically conducted in non-
rodents).
3. A subset of genotoxicity studies must be started before an IND is filed (in
vitro mutagenesis and chromosomal aberration studies), and the remainder
must be completed before Phase II of clinical trials (in vivo micronucleus
studies typically conducted in rodents).
4. Long-term and chronic toxicology studies, carcinogenicity studies
(typically two years long in rodents), and reproductive studies (fertility,
teratology, and pre-post-natal studies) must take place before NDA filing.
5. ADME

IND phase
An IND may be submitted for one or more phases of
an investigation. The clinical investigation of a
previously untested drug is generally divided into
the following three phases:
Phase 1: safety, proof of concept, and exploratory
Phase 2: safety, efficacy, and dose ranging
Phase 3: efficacy confirmatory, dose ranging, and
safety

Exempt Clinical Investigations
 Whether a clinical investigation is exempt often comes
down to the motivation and the risk involved in the study.
If there is an intent to use the study results commercially or
there is a high or heightened risk to study participants, then
an IND will be required.
 Clinical studies that are exempt from IND requirements
include:
1. Certain Research with Marketed (Approved) Drugs.
2. Bioavailability/Bioequivalence Studies
3. Radioactive or Cold Isotope
4. Dietary Supplements and Food.

1. Certain Research with Marketed (Approved) Drugs. To be
exempt [21 CFR 312.2(b)],
1) the drug must be lawfully marketed in the US,
2) the study cannot be intended to support a new indication or
other significant change in product labelling,
3) the study cannot be intended to support a significant
change in advertising for the drug or be used to promote the
drug, and
4) the study cannot significantly increase risks for those
taking the drug. In addition, the investigation must follow
Institutional Review Board (IRB; 21 CFR 56) and informed
consent requirements (21 CFR 50).

2. Bioavailability/Bioequivalence Studies. BA/BE studies
compare unapproved (often generic) versions of drugs to
approved drugs. In order for a BA/BE study to be exempt (21
CFR 320.31),
1) the drug product must not contain new chemical entities*,
2) be radioactively labeled, or be cytotoxic,
3) dosing of both the reference and investigational drugs must
follow the approved drug label for the reference product, and
4) the sponsor must retain test article samples and adhere to
safety reporting requirements.
*21 CFR 314.108(a): New chemical entity means a drug that contains no
active moiety that has been approved by FDA in any other NDA submitted
under section 505(b) of the Federal Food, Drug, and Cosmetic Act.

3. Radioactive or Cold Isotopes. Use of drugs with radioactive
or cold isotopes can be IND-exempt if they are used in basic
research (e.g., metabolism, physiology, or biochemistry
studies). For radioactive isotopes, use must be approved by a
Radioactive Drug Research Committee (RDRC), must involve
doses not known to cause pharmacological effects in humans,
and must include total radiation in the smallest amount
practical. For cold isotopes, studies are exempted when
1) the isotope-containing product is used for basic research, 2)
the dose is not known to cause pharmacological effects in
humans,
3) the product adheres to regulatory standards for quality, and
4) the study follows IRB and informed consent requirements.

4. Dietary Supplements and Food. Dietary
supplements and food are not considered drugs.
Unlike drug trials, clinical investigations involving
dietary supplements or food do not require an IND to
investigate effects on body function or structure but
only to investigate an effect on disease.
For example, studying the effect of fiber on bowel
regularity would not require an IND but investigating
the ability of fiber to treat chronic diarrhea would.

Continue…

Common quiz
https://www.accessdata.fda.gov/cder/cmc/
topic10/topic10/da_01_10_0005.htm
http://regardd.org/drugs/is-my-study-exe
mpt

Format and content of IND
1. Cover sheet ( Form FDA 1571).
2. A table of contents.
3. Introductory statement and General Investigational
Plan.
4. Investigator’s Brochure.
5. Protocols.
6. Chemistry, Manufacturing and Control information.
7. Pharmacology and Toxicology Information.
8. Previous human experience with IP.
9. Additional Information.
13
CLARIFICATIONS OF PRESENT IND REGULATIONS
An IND submission for Phase 1 studies is required by regulation to
contain the sections enumerated below.
A. Cover Sheet
B. Table of Contents
C. Introductory Statement and General Investigational Plan
Regulations repeatedly describe this section as brief. Ordinarily, two to

three pages should suffice. The information requested here is intended
to place the developmental plan for the drug into perspective and to
help FDA anticipate sponsor needs.

D. Investigator's Brochure
E. Protocols
The regulation requires submission of a copy of the protocol for the

conduct of each proposed clinical trial. It is recognized that the phase I
protocols are part of an early learning process and should be adaptable
as information is obtained, and that the principal concern at this stage
of development is that the study be conducted safely.
The regulations state that Phase 1 protocols should be directed

primarily at providing an outline of the investigation: an estimate of
the number of subjects to be included; a description of safety
exclusions; and a description of the dosing plan, including duration,
dose, or method to be used in determining dose.

F. Chemistry, Manufacturing, and Control Information

Each phase of investigation should include sufficient CMC
information to ensure the proper quality, identity, purity,
and strength of drug substance and drug product. The type
and extent of information submitted will depend on
 The phase of the investigation

 The extent of human study
 The duration of investigation
 Nature and source of the drug substance, and
 The dosage form of the product

Although in each phase of the investigation sufficient information
should be submitted to assure the proper identification, quality,
purity, and strength of the investigational drug, the amount of
information needed to make that assurance will vary with the phase
of the investigation, the proposed duration of the investigation, the
dosage form, and the amount of information otherwise available.
For example, although stability data are required in all phases of the
IND to demonstrate that the new drug substance and drug product
are within acceptable chemical and physical limits for the planned
duration of the proposed clinical investigation, if very short-term
tests are proposed, the supporting stability data can be
correspondingly very limited.

F. Chemistry, Manufacturing, and Control Information
1. Chemistry and Manufacturing Introduction
2. Drug Substance
Information on the drug substance should be submitted in a summary

report containing the following items.
a. A description of the drug substance, including its physical, chemical, or

biological characteristics:
A brief description of the drug substance and some evidence to support

its proposed chemical structure should be submitted. It is understood
that the amount of structure information will be limited in the early stage
of drug development.
b. The name and address of its manufacturer

2. Drug Substance
c. The general method of preparation of the drug substance
A brief description of the manufacturing process, including a list of the

reagents, solvents, and catalysts used, should be submitted. A detailed
flow diagram is suggested as the usual, most effective, presentation of
this information. More information may be needed to assess the safety
of biotechnology-derived drugs or drugs extracted from human or
animal sources.

2. Drug Substance
d. The acceptable limits and analytical methods used to assure the

identity, strength, quality, and purity of the drug substance:
A brief description of the test methods used should be submitted.

Proposed acceptable limits supported by simple analytical data, (e.g.,
IR spectrum to prove the identity, and HPLC chromatograms to
support the purity level and impurities profile) of the clinical trials
material should be provided. Submission of a copy of the certificate of
analysis is also suggested.
e. Information to support the stability of the drug substance during the

toxicologic studies and the proposed clinical study(ies)

3. Drug Product
Information on the drug product should be submitted in a summary

report containing the following items:
a. A list of all components, which may include reasonable alternatives

for inactive compounds, used in the manufacture of the investigational
drug product, including both those components intended to appear in
the drug product and those which may not appear, but which are used
in the manufacturing process:
The quality (e.g., NF, ACS) of the inactive ingredients should be cited.

3. Drug Product
b. Where applicable, the quantitative composition of the investigational

new drug product, including any reasonable variations that may be
expected during the investigational stage:
c. The name and address of the drug product manufacturer: The full
street address(es) of the manufacturer(s) of the clinical trial drug
product should be submitted.

3. Drug Product
d. A brief, general description of the method of manufacturing and

packaging procedures as appropriate for the product:
e. The acceptable limits and analytical methods used to assure the

identity, strength, quality, and purity of the drug product:
f. Information to support the stability of the drug product

during the toxicologic studies and the proposed clinical study(ies):

4. A brief general description of the composition, manufacture, and

control of any placebo to be used in the proposed clinical trial(s)
5. A copy of all labels and labeling to be provided to each investigator
6. A claim for categorical exclusion from or submission of an

environmental assessment

G. Pharmacology and Toxicology Information
1. Pharmacology and Drug Distribution

This section should contain, if known: 1) a description of the pharmacologic effects
and mechanism(s) of actions of the drug in animals, and 2) information on the
absorption, distribution, metabolism, and excretions of the drug.
2. Toxicology: Integrated Summary

3. Toxicology - Full Data Tabulation
4. Toxicology - GLP Certification
5. Monitoring of Effects of these Clarifications:
H. Previous Human Experience with the Investigational Drug
Present regulations require this information only if there has been previous human
experience with the investigational drug. If there has been no previous human
experience, the submission should so state.

Summary:
An article that is not approved in the nation (US) as drug
• Approved drug that is not used according to approved label
( or used in a new combination of approved drugs)
• IND application is a request to FDA for authorization to
administer to ID to humans
An IND required anytime when we want to conduct a clinical
trial of an unapproved drug
• An act further define a new drug as “any drug the
composition of which is such that such drug is not
generally recognized as safe and effective for use under
conditions prescribed, recommended, suggested in
labeling.

NEW DRUG APPLICATION (NDA)

NEW DRUG APPLICATION (NDA)
The New Drug Application is the vehicle through which
the drug sponsors formally propose FDA or DCGI to
approve a new investigational drug for sale and
marketing after Phase IIIA Pivot trials.
The official definition of New Drug is in Sec 201(p) of
Federal Drug, Food and Cosmetics Act as;
Any new drug , the composition of which is such that it is not recognized
among experts qualified by scientific training as safe and effective for
use under prescribed, recommended or suggested conditions.
Or
Any drug the composition of which is such that it as a result of
investigations to determine safety and efficacy for use has become
recognized, but which has not, otherwise in such investigations been
used to a material extent.
Goals of NDA
 To prove safety and efficacy of the drug for the

proposed use(s)
 Benefits v/s risks
 Appropriate labeling (package insert)
 The methods used in manufacturing the drug and the
controls

DRUG PRODUCT (NDA's and ANDA's)
I. INTRODUCTION
A. Components
B. Composition
1. Statement of Composition
2. Batch Formula
C. Specifications and Analytical Methods for Inactive

Components
D. Manufacturer
E. Methods of Manufacturing and Packaging
1. Production Operations
2. Reprocessing Operations
F. Specifications and Analytical Methods for the

Product
1. Introduction
2. Sampling Methods
3. In-Process Controls
4. Regulatory Specifications and Methods for Drug

Products
G. IND Formulation and placebos

The following information should be included in the application:
A. Components
Provide a list of components, including all substances and in-process materials

used in producing a defined finished drug or placebo product. List all
substances used in the manufacture of a drug product whether or not they
appear in the finished product, and state the quality designation or grade for
each material. Identify each component by its established name, if any, or by
complete chemical name, using structural formulas when necessary for
specific identification.
If any proprietary preparations or other mixtures are used as components,

their identity should include a complete statement of composition and other
information that will properly describe and identify these materials. Justify
proposed alternatives for any listed substances by demonstrating that the use
of these alternatives does not significantly alter the stability and bioavailability
of the drug product and the suitability of manufacturing controls.

B. Composition
B.1. Statement of Composition
A statement of the quantitative composition should specify, by unit

dose, a definite weight or measure for each active drug substance
and a definite weight, measure, or appropriate range for all other
ingredients contained in the drug product.
B.2. Batch Formula
Provide a complete list of the ingredients and their amounts to be

used for the manufacture of a representative batch of the drug
product. Submit a separate batch formula for each formulation of
the drug product. All ingredients should be included in the batch
formula whether or not they remain in the finished product.

C. Specifications and Analytical Methods for Inactive
Components
Provide acceptance specifications and the corresponding

analytical methods for all inactive components of the
formulation, regardless of whether they remain in the
finished product. Limits and methods (applicable to the
finished dosage form) for components that are removed in
the manufacturing process should be included. Limits and
methods must be included for potentially toxic components.

D. Manufacturer
State the name, location and, where appropriate,

building number of each facility having a part in the
manufacture or controls of the drug product. This
includes the following, as appropriate:
1. Manufacturer(s) of the bulk drug substance(s).

2. Manufacturer(s) of the drug product.
3. Contract packager(s) and/or labeler(s).
4. Contract laboratories performing quality control
tests on raw materials, drug substance, or the finished
drug product.
5. Suppliers of components used in the manufacture
of the drug product.
E.1. Production Operations
To facilitate the evaluation of the production and control of the drug

product, submit a copy of the proposed or actual master/batch
production and control records or a comparably detailed description of
the production process for a representative batch. Describe the
manufacturing and packaging process for a representative batch,
including a description of each production step, actual operating
conditions, equipment to be utilized and points of sampling for in-
process controls.
A schematic diagram of the production process is often helpful. Such a

diagram should include a superimposed materials flow plan, indicating
the equipment used and the points of sampling.

E.2. Reprocessing Operations
Before reprocessing a drug product, the applicant should consider the

effects of reprocessing on stability and bioavailability. To permit
approval of the reprocessing of batches of bulk, in-process, and
finished drug products that do not conform to established
specifications, the original submission of an NDA may include
proposals for reprocessing procedures that cover possible foreseeable
deviations from specifications (e.g., weight variation, content
uniformity, unacceptable tablet coating, etc.).
Such reprocessing may require additional amounts of one or more of

the components; however, the amounts added should not result in a
component being present beyond the reasonable variations provided
for in the formulation.
F. Specifications and Analytical Methods for the Drug
Product
F.1. Introduction
The goal of drug product manufacture is reproducibility within all

specified limits. The significant chemical and physical parameters
important to clinical response of the drug product should be defined
at an early stage in the investigational studies, so that the transition to
routine production lot manufacture may be conducted rationally. A
well-organized drug application should demonstrate that the
manufacturing, sampling, and control processes have been designed to
provide a consistent product that, within any lot and on a lot-to-lot
basis, does not vary beyond the established specifications.

Product
F.2. Sampling Methods
Describe the sampling plan that will be used to assure that the sample
of the drug product obtained is representative of the batch. The plan
should include both the sampling of production batches and the
selection of sub-samples for analytical testing. This plan will, of
course, be applicable only to batches of that particular size, so
procedures for scale-up or scale-down of this sampling plan to other
batch sizes must also be provided. If samples are pooled, a
justification must be given for pooling them.

Product
F.3. In-Process Controls
The analytical controls used during the various stages of

manufacturing and processing of the dosage form should be fully
described. Where feasible, the in-process specifications should be
supported by appropriate data that may include, but should not be
limited to, representative master/batch production and control
records. In particular, when these records are submitted in support
of a supplemental application that proposes the deletion or
broadening of specifications, the records should cover a consecutive
series of batches. Information on in-process controls in
manufacturing is essential to a through review of the
manufacturing and processing of the drug.

Product
F.4. Regulatory Specifications and Methods for Drug Products
Regulatory specifications are the defined limits (e.g., physical, chemical,

biological, microbiological) within which test results for a drug substance or
drug product should fall when determined by the regulatory methodology.
The regulatory methodology is the procedure or set of procedures used by the
FDA to ascertain whether or not the drug substance or drug product is in
conformance with the approved regulatory specifications in the NDA.
Regulatory specifications may differ from in-house product release

specifications. All drug products require assay and identity tests and
specifications. Assay and identity specifications using a well-characterized
reference standard and description of physical characteristics (e.g.,
appearance, odor, etc., where applicable) are required. A description of other
attributes should also be considered for inclusion, depending on the type of
dosage form.

Product
The following list is advisory, and is not exhaustive.
F.4.a. Tablets, capsules, and other solid dosage forms
(1) Uniformity of dosage units.
(2) Rate of release of the active ingredient from the dosage form by
methodology (e.g., dissolution rate), as appropriate for the dosage
form.
(3) Moisture content, where applicable. Special consideration should

be given to dosage forms in which a major component is known to
be hygroscopic.
(4) Softening or melting points for suppositories.

F.4. Placebos
For matching placebos used in clinical studies, a full

description should be provided of the precautions that will
be taken to ensure the absence of the new drug substance
from the placebo preparation. The placebo and active
dosage form should be as similar as possible in physical
characteristics and identical in packaging.

Comparison of CMC section of IND
with NDA
The CMC section for the NDA is similar to that

of the IND. The main difference is regarding
more details to be submitted, appropriate
justifications should be provided, appropriate
statistical analysis should be provided
wherever necessary.

reference
https://www.accessdata.fda.gov/scripts/cd
rh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart
=314
https://www.nuventra.com/resources/blog
/ind-requirements-exemptions/

Non Clinical Drug Development

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Non Clinical Drug Development

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Subject: Regulatory Affair

Non clinical drug development

Shree S. K. Patel College of Pharmaceutical

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Mfg. Base Generics

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The term also includes a biological product used in-vitro for

After pre-clinical investigations when the new molecule has

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 Also, current Federal law requires that a drug be the

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The IND is not an application for marketing approval.

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Especially the CMC section was reformatted to have

IND has 8 to 11 sections falling under 4 general areas – (i)

 Emergency Use IND

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A sponsor shall not begin a clinical trial until

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 Depending on whether the compound has been studied or marketed

At the preclinical stage, the FDA will generally ask, at a

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Manufacturing Information - Information pertaining to the

Clinical Protocols and Investigator Information - Detailed protocols for

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C. Introductory Statement and General Investigational Plan

Regulations repeatedly describe this section as brief. Ordinarily, two to

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The regulation requires submission of a copy of the protocol for the

The regulations state that Phase 1 protocols should be directed

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F. Chemistry, Manufacturing, and Control Information

 The phase of the investigation

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1. Chemistry and Manufacturing Introduction

Information on the drug substance should be submitted in a summary

a. A description of the drug substance, including its physical, chemical, or

A brief description of the drug substance and some evidence to support

b. The name and address of its manufacturer

c. The general method of preparation of the drug substance

A brief description of the manufacturing process, including a list of the

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d. The acceptable limits and analytical methods used to assure the

A brief description of the test methods used should be submitted.

e. Information to support the stability of the drug substance during the

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Information on the drug product should be submitted in a summary

a. A list of all components, which may include reasonable alternatives