PRODUCT DEVELOPMENT AND TECHNOLOGY TRANSFER (MQA – 104 T)

UNIT I
IND, NDA, ANDA, SNDA

Presented By Submitted to

V. Manikandan, Dr. R. Murali, M. Pharm., Ph. D,

Roll No. 2061050003, Assistant Professor,
M. Pharm (Pharmaceutical Quality Assurance) – I Year, Department of Pharmacy,
Batch : 2020-2022, Annamalai University.
Department of Pharmacy,
Annamalai University.
Investigational New Drug (IND) Application
• 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.
• 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.
• FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or
potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential
in animals, wants to test its diagnostic or therapeutic potential in humans.
• At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes
a new drug subject to specific requirements of the drug regulatory system.

There are three IND types

• An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under
whose immediate direction the investigational drug is administered or dispensed. 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 in accordance with 21CFR , Sec. 312.23 or Sec. 312.20. 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 is submitted 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.
There are two IND categories
• Commercial
• Research (non-commercial)
The IND application must contain 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. 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. 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.
• Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an
institutional review board (IRB), and to adhere to the investigational new drug regulations.
Pre-IND Consultation Program
• CDER's Pre-Investigational New Drug Application (IND) Consultation Program fosters early communications
between sponsors and new drug review divisions to provide guidance on the data necessary to warrant IND
submission. The review divisions are organized generally along therapeutic class.
Guidance Documents for INDs
• Guidance documents represent the Agency's current thinking on a particular subject. These documents provide
FDA review staff and applicants/sponsors with guidelines to the processing, content, and evaluation/approval of
applications and also to the design, production, manufacturing, and testing of regulated products. They also
establish policies intended to achieve consistency in the Agency's regulatory approach and establish inspection
and enforcement procedures.
• Because guidance's are not regulations or laws, they are not enforceable, either through administrative actions or
through the courts. An alternative approach may be used if it satisfies the requirements of the applicable statute,
regulations, or both. For information on a specific guidance document, please contact the originating office.
Laws, Regulations, Policies and Procedures
• The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency
to protect the consumer's health, safety, and pocketbook.

• The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S. The law is intended to
assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary conditions; that
drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made from
appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.

Code of Federal Regulations (CFR)

• The final regulations published in the Federal Register (daily published record of proposed rules, final rules,
meeting notices, etc.) are collected in the Code Of Federal Regulations (CFR).
• The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. The FDA's portion of
the CFR interprets the Federal Food, Drug, and Cosmetic Act and related statutes. Section 21 of the
CFR contains most regulations pertaining to food and drugs. The regulations document all actions of all drug
sponsors that are required under Federal law.
Manual of Policies and Procedures (MaPPs)
• CDER's Manual of Policies and Procedures (MaPPs) are approved instructions for internal practices and
procedures followed by CDER staff to help standardize the new drug review process and other activities. All
MAPPs are available for the public to review for a better understanding of office policies, definitions, staff
responsibilities and procedures.
Emergency Use of an Investigational Drug or Biologic
• Emergency Use of an Investigational Drug or Biologic - Information Sheet
• The Guidance for Institutional Review Boards and Clinical Investigators contains information on: Obtaining an
Emergency IND, Emergency Exemption from Prospective IRB, Approval Exception from Informed Consent,
and Requirement Planned Emergency Research, Informed Consent Exception.
• Physician Request for a Single Patient IND for Compassionate or Emergency Use
• Instructions for Sponsors of Emergency Investigational New Drug (EIND) Applications for Antimicrobial
Products. From the Office of Antimicrobial Products, Division of Antiviral Products
New Drug Application (NDA)
• For decades, the regulation and control of new drugs in the United States has been based on the New Drug
Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S.
commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the
FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal
studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.
• The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key
decisions:
i. Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug
outweigh the risks.
ii. Whether the drug's proposed labeling (package •insert) is appropriate, and what it should contain.
iii. Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality
are adequate to preserve the drug's identity, strength, quality, and purity.
 iv. The documentation required in an NDA is supposed to tell the drug's whole story, including what
happened during the clinical tests, what the ingredients of the drug are, the results of the animal studies,
how the drug behaves in the body, and how it is manufactured, processed and packaged. The following
resources provide summaries on NDA content, format, and classification, plus the NDA review process:

Guidance Documents for NDAs

• Guidance documents represent the Agency's current thinking on a particular subject. These documents are
prepared for FDA review staff and applicants/sponsors to provide guidelines to the processing, content, and
evaluation/approval of applications and also to the design, production, manufacturing, and testing of regulated
products.
• They also establish policies intended to achieve consistency in the Agency's regulatory approach and establish
inspection and enforcement procedures. Because guidances are not regulations or laws, they are not
enforceable, either through administrative actions or through the courts.
• An alternative approach may be used if such approach satisfies the requirements of the applicable statute,
regulations, or both. For information on a specific guidance document, please contact the originating office.
Laws, Regulations, Policies and Procedures
• The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency
to protect the consumer's health, safety, and pocketbook.
• The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S. With numerous
amendments, it is the most extensive law of its kind in the world.
• The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under
sanitary conditions; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe
and made from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not
deceptive.
Code Of Federal Regulations (CFR)
• The final regulations published in the Federal Register (daily published record of proposed rules, final rules,
meeting notices, etc.) are collected in the CFR.
• The CFR is divided into 50 titles which represent broad areas subject to Federal regulations. The FDA's portion
of the CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes.
• Section 21 of the CFR contains all regulations pertaining to food and drugs. The regulations document all
actions of all drug sponsors that are required under Federal law.
CDER's Manual of Policies and Procedures (MaPPs)
• These documents are approved instructions for internal practices and procedures followed by CDER staff to help
standardize the new drug review process and other activities.
• MaPPs define external activities as well. All MaPPs are available for the public to review to get a better
understanding of office policies, definitions, staff responsibilities and procedures.
Abbreviated New Drug Application (ANDA)
• An abbreviated new drug application (ANDA) contains data which is submitted to FDA for the review and
potential approval of a generic drug product.
• Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective,
lower cost alternative to the brand-name drug it references.
• A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of
administration, quality, performance characteristics, and intended use. All approved products, both innovator and
generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).
• Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical
(animal) and clinical (human) data to establish safety and effectiveness.
• Instead, generic applicants must scientifically demonstrate that their product is performs in the same manner as
the innovator drug. One way applicants demonstrate that a generic product performs in the same way as the
innovator drug is to measure the time it takes the generic drug to reach the bloodstream in healthy volunteers.
• This demonstration of “bioequivalence” gives the rate of absorption, or bioavailability, of the generic drug,
which can then be compared to that of the innovator drug.
• To be approved by FDA, the generic version must deliver the same amount of active ingredients into a patient's
bloodstream in the same amount of time as the innovator drug.
• The "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the Hatch-Waxman
Amendments, established bioequivalence as the basis for approving generic copies of drug products.
• These Amendments permit FDA to approve applications to market generic versions of brand-name drugs
without repeating costly and duplicative clinical trials to establish safety and efficacy.
• Under the Hatch-Waxman Amendments, brand-name companies gained patent term extension to account for the
time the patented product is under review by FDA and also gained certain periods of marketing exclusivity.
• In addition to the ANDA approval pathway, generic drug companies gained the ability to challenge patents in
court prior to marketing as well as 180-day generic drug exclusivity.
Guidance Documents for ANDAs
• Guidance documents represent the Agency's current thinking on a particular topic. These documents provide
guidelines for the content, evaluation, and ultimate approval of applications and also to the design, production,
manufacturing, and testing of regulated products for FDA review staff, applicants, and ANDA holders.
i. Generic Drugs Guidances (Search "Generics" under topics)
ii. Biopharmaceutics Guidances (Search "Biopharmaceutics" under topics)
iii. Product-Specific Guidances for Generic Drug Development
Laws, Regulations, Policies, and Procedures
• The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the United States. The law is
intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary
conditions; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made
from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.
Code of Federal Regulations
• The final regulations published in the Federal Register (a daily published record of proposed rules, final rules,
meeting notices, etc.) are collected in the Code of Federal Regulations (CFR). Section 21 of the CFR contains
most of the regulations pertaining to food and drugs. The regulations document most actions of all drug
applicants that are required under Federal law. The following regulations directly apply to the ANDA process:
i. 21CFR Part 314: Applications for FDA Approval to Market a New Drug
ii. 21CFR Part 320: Bioavailability and Bioequivalence Requirements
Manual of Policies and Procedures
• CDER's Manual of Policies and Procedures (MAPPs) document internal practices and procedures followed by
CDER staff to help standardize the drug review process and other activities, both internal and external. Chapter
5200 covers generic drugs processes and activities.
Supplement New Drug Application (SNDA)
Supplement
• A supplement is an application to allow a company to make changes in a product that already has an approved
new drug application (NDA). CDER must approve all important NDA changes (in packaging or ingredients, for
instance) to ensure the conditions originally set for the product are still met.

Supplement Number
• A supplement number is associated with an existing FDA New Drug Application (NDA) number. Companies are
allowed to make changes to drugs or their labels after they have been approved. To change a label, market a new
dosage or strength of a drug, or change the way it manufactures a drug, a company must submit a supplemental
new drug application (sNDA). Each sNDA is assigned a number which is usually, but not always, sequential,
starting with 001.
Supplement Type
• Companies are allowed to make changes to drugs or their labels after they have been approved. To change a
label, market a new dosage or strength of a drug, or change the way it manufactures a drug, a company must
submit a supplemental new drug application (sNDA). The supplement type refers to the kind of change that was
approved by FDA. This includes changes in manufacturing, patient population, and formulation.

Why change is required

• May wish to alter / improve the product or to introduce additional safeguard
• To meet the market requirements scale up, add manufacturing site.
• Post approval changes include:
i. Components and composition,
ii. Manufacturing sites,
iii. Manufacturing process,
iv. Specifications,
v. Container closure system,
 vi. Labeling,
vii. Miscellaneous changes
viii. Multiplerelated changes.
• An applicant should consider all relevant CDER guidance documents &submit all necessary information to
support a given change.
Condition
• Changes may have potential impact on the quality, safety or efficacy of products.
• Any change to prequalified products are subject to approval by FDA &CDER.
Guidance on variation as per us FDA
• Three categories of variations according to their potential impact on pharmaceutical quality
• Major changes: Substantial potential to have an adverse effect on the identity, strength, quality, purity, or
potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.
• These are labelled as Prior Approval Supplement
• Moderate changes: Moderate potential to have an adverse effect 2 types.
• 1 requires the submission of a supplement to FDA at least 30 days before the distribution of drug product
labelled as Supplement - Changes Being Effected in 30 Days.
• 2 for which distribution can occur when FDA receives the supplement labelled as Supplement - Changes Being
Effected.
• If FDA disapproves may cease distribution.
• FDA say prior approval supplement is required.
• Information is missing: Distribution is delayed until amendment is made.
• Minor changes: Has minimal potential to have an adverse effect. The applicant must describe minor changes in
its next Annual Report
References
 https://www.fda.gov
 The Pharmaceutical Sciences ; The Pharma Path Way ‘Pure and Applied Pharmacy’ By D. A Sawant, Pragathi
Books Pvt .Ltd.
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