Understanding Regulatory Requirements of Drugs and Pharmaceuticals

REGULATORY 
REQUIREMENTS 
OF
DRUGS 
AND
 
PHARMACEUTICALS
 
DRUGS
 
REGULATION
 
Dru
g
 
r
e
g
u
la
ti
o
n
 
i
s
 
the
 
c
o
n
t
r
o
l
 
of
 
dru
g
 
us
e
 
by
 
i
n
t
ern
a
ti
o
na
l
  
ag
r
e
eme
n
t
 
a
n
d
/
o
r
 
b
y
 
r
egul
a
t
o
r
y
authorities
 
such
 
as
 
A
d
min
i
s
t
r
a
tion
 
(
F
D
A),
 
t
h
e
 
U
S
 
F
o
o
d
 
a
n
d
 
Drug
t
h
e
  
Eu
r
o
pea
n
  
M
e
d
i
c
i
nal
 
Agency
 
(EMA)
 
and
 
the
 
Japanese
 
Pharmaceutical
 
and
 
Agency
 
(PMDA).
 
This
 
inc
l
udes
 
Medical
 
Devices
r
egul
a
tions
  
c
o
nce
r
ned
 
wi
t
h
 
the
 
de
v
elo
p
me
n
t,
 
approval, 
manufacturing 
and 
marketing 
of
 
drugs.
 
FDA
 
Role 
and
 
Organization
 
FDA 
is 
organized 
into 
a 
number of 
offices 
and 
centers 
headed
by 
a 
commissioner 
who is 
appointed by 
the 
President 
with
consent 
of 
the
 
senate
These 
offices 
and 
centers are 
assigned 
with 
different
responsibilities 
to 
accomplish 
the 
objective of
 
FDA
 
1.
Center 
for 
Drug 
Evaluation 
and 
Research
 
(CDER)
2.
Center 
for 
Biologic 
Evaluation 
and 
Research
 
(CBER)
3.
Center 
for 
Devices 
and 
Radiological 
Health
 
(CDRH)
4.
Center 
for 
Food 
Safety 
and 
Applied 
Nutrition 
(CFSAN)
5.
Center 
for 
Veterinary 
medicine
 
(CVM)
 
TYPES 
OF
 
APPLICATIONS
 
Investigational 
New Drug
 
Application
New Drug
 Application
Abbreviated 
New Drug
 
Application
Biologic 
License
 
Application
Over-the-counter 
(OTC) 
drug
 
application
Clinical
 
Hold
IND
 
Filing
IND
 
Approval
Drug
 
Discovery
and
Lead
 
Compound
Selection
 
Biologic
Activity
 
testing
(in
 
vivo)
 
Formulation
development
 
and
stability
 
 
       
 
Chemical
 
Synthesis
 
and 
Scale 
up
 
testing
 
Safety
 
Testing
 
in
Animals
 
IND
 
Application
 
Phase 
I 
Clinical
 
trials
 
Phase 
II 
Clinical 
trials
 
Phase 
III
 
Clinical
trials
NDA 
Filing
FDA
 
Disapproval
FDA
 
Conditional
Approval
FDA
 
Approval
MARKET
Post-Approval
 
Safety
report to
 
FDA
 
PRE-CLINICAL
 
TESTING
 
(4+
 
YEARS)
 
CLINICAL
 
TESTING
(6+
 
YEARS)
 
Fig: the new drug approval
 
process
 
Revision
 
Revision
 
Investigational 
New Drug
 
(IND)
 
It deals with 
a 
new chemical 
entity, 
which will be 
tested 
for
obtaining evidence of 
safety 
and 
effectiveness 
in 
accordance
with the 
regulation. 
It 
is the 
vehicle through 
a 
new 
drug
advances 
into 
next 
stage 
of drug development i.e. 
Clinical
trials
 
Types 
of
 
INDs
 
1.
Investigator 
IND
:- It 
is 
submitted by 
a 
physician 
who 
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
proposed 
studying 
an 
unapproved 
drug, 
or an 
approved
product 
for 
a 
new 
indication or 
in a 
new patient
 
population.
2.
Emergency 
Use 
IND
:-This allow 
the 
FDA to 
authorize an
experimental 
drug 
in 
an 
emergency 
situation 
that 
does not
allow 
for 
submission of 
an IND in 
accordance 
with 
21CFR,
Sec. 
312.23 
0r 
Sec.312.20. 
It 
is also 
used 
for 
patient 
who do
not 
meet 
the criteria of 
an 
existing study 
protocol, 
or 
if an
approved 
study 
protocol 
does not
 
exist.
3. 
Treatment 
IND
:- It 
is 
submitted 
for 
experimental drugs
showing 
promise 
in 
clinical testing 
for 
serious 
or 
immediately
life-threatening conditions 
while the 
final 
work 
is 
conducted
and the 
FDA 
review 
takes
 
place.
 
Investigational 
New Drug
 
Application
Criteria 
for
 
application
 
A 
clinical 
study 
is 
required 
for 
an IND if it is 
intended 
to
support
 
a:
New Indication.
Change 
in the 
approved route 
of 
administration 
or 
dosage
level.
Change 
in the 
approved 
patient population 
or 
a 
population
at
 
greater 
or increased of 
risk
 
.
Significant 
change 
in the 
promotion 
of 
an 
approved
 
drug
Application
 
Content
 
Animal 
Pharmacology 
and 
Toxicology
 
studies.
Chemistry 
and 
Manufacturing
 
Information.
Clinical 
Protocols 
and 
Investigator
Information.
 
NEW DRUG 
APPLICATION
 
(NDA)
 
 
The 
New 
Drug 
Application 
(NDA) 
is 
the 
vehicle in 
the 
United
States 
through 
which drug 
sponsors formally propose that 
the
FDA 
approve 
a 
new pharmaceutical 
for 
sale 
and 
marketing. NDA 
is
responsible 
for 
are 
providing 
enough 
information 
to 
permit 
FDA
reviewers to 
establish 
the
 
following:
Whether the 
drug 
safe 
and 
effective 
in 
its proposed use(s)
when 
used 
as 
directed, 
and 
do 
the 
benefits of 
the 
drug
outweigh 
the
 
risks.
Whether 
the 
drug’s proposed 
labeling 
(package 
insert)
appropriate, 
and 
what should 
it
 
contain.
Whether the 
methods 
used in 
manufacturing (Good
Manufacturing 
Practice, 
GMP) the drug 
and the 
controls 
used
to 
maintain 
the 
drug’s 
quality 
adequate 
to 
preserve 
the 
drug’s
identity, 
strength, 
quality, 
and
 
purity.
 
Fundamentals 
of 
NDA
 
Submission
 
As 
outlined 
in 
Form 
FDA-356h, 
Application 
to Market 
a 
New
Drug 
for 
Human Use Or 
As An 
Antibiotic Drug 
For 
Human Use,
NDAs can consist 
of 
as 
many 
as 15 
different
 
sections:
Index
Summary
Chemistry, 
Manufacturing, 
and
 
Control;
Samples, Method 
Validation 
Package, 
and
 
Labeling
Nonclinical 
Pharmacology 
and
 Toxicology
Human Pharmacokinetics 
and
 
Bioavailability
Microbiology 
(for 
anti-microbial 
drugs only);
Clinical
 
Data;
Safety 
Update 
Report (typically 
submitted 
120 
days 
after
the 
NDA's
 
submission);
Statistical;
Case Report
 
Tabulations;
Case 
Report
 
Forms;
Patent
 
Information;
Patent 
Certification;
 
and
Other 
Information
Classification 
of drugs in
 
NDA
 
CDER classifies 
new 
drug applications with a 
code
 
that
reflects 
both the 
type 
of drug being 
submitted 
and 
its
intended
 
uses.
New 
Molecular
 
Entity
New Salt 
of 
Previously 
Approved 
Drug (not 
a 
new 
molecular
entity)
New 
Formulation 
of 
Previously 
Approved 
Drug 
(not 
a 
new
 
salt
OR a 
new 
molecular
 
entity)
New 
Combination 
of 
Two 
or 
More
 
Drugs
Al
r
eady
 
Ma
r
k
e
t
ed
 
D
r
u
g
 
P
r
o
du
c
t
 
-
 
Dupli
c
a
tion
 
(
i
.
e.
,
 
n
e
w
manufacturer)
New
 
Indication
 
(claim)
 
for
 
Already
 
Marketed
 
Drug
 
(includes
switching 
marketing status from 
prescription 
to
 
OTC)
Already 
Marketed 
Drug 
Product 
- No 
Previously 
Approved
 
NDA
 
GENERAL 
REQUIREMENTS 
for 
filing 
an
NDA
 
The
 
new
 
(present)
 
NDA
 
regulations
 
require
 
that
 
an
 
application
 
be
submitted 
in 
two 
copies
 
:
(A)
an 
archival copy 
that 
serves as 
a permanent 
record 
of 
the
submission,
 
and
(B)
a 
review
 
copy.
The 
review copy 
is 
made up 
of 
a 
number of 
separate 
technical
volumes, 
each 
tailored 
to 
the 
needs of 
the 
disciplines 
involved 
in 
the
review.
Both the 
archival 
and 
review 
copies 
are submitted 
in 
hard 
copy, 
the
regulations permit 
an 
application 
to 
submit 
the 
archival 
copy 
as
microfiche.
The 
NDA 
application 
form 
(FORM 
FDA 
356h 
) 
consists 
of: 
Twelve 
items
(including 
index) 
deals with 
the 
safety 
and efficacy 
features 
of drug
product, 
two are 
concerned 
with 
patent
 
information
The 
archival copy 
is a 
complete copy 
of 
an 
application
submission and 
must 
be bound 
in a 
blue 
cover
 
jacket.
The 
archival copy 
should 
include a 
blue 
cover letter
 
to:
Confirm 
any 
agreement 
or 
understanding 
between 
the
FDA 
and the
 
agreement;
Identify 
the 
contact 
person 
regarding 
the
 
application
Identify 
the 
reviewing 
division of 
the 
FDA 
and include 
HFD
number;
Convey 
any 
other 
important information 
about the
application.
 
The 
review copy 
is divided 
into 
six technical sections 
(“review 
sections”) and
should 
be 
submitted 
with 
each 
review 
section 
separately 
bound in 
a 
specific
color:
 
Each 
review 
section should 
contain 
the
following:
(i)
a 
copy 
of 
the 
cover letter attached to 
the 
archival
copy;
(ii)
a 
completed 
application 
form FDA
 
356h;
(iii)
a 
copy 
of 
the 
summary 
(defined
 
below);
(iv)
a 
copy 
of 
the 
general index 
of 
the 
entire
 
application;
(v)
an 
index 
specific 
to 
that 
particular 
review
 
section;
(vi)
letters 
of 
reference 
or authorization, 
if
 
appropriate;
(vii)
patent
 
information
 
ABBREVIATED 
NEW 
DRUG
 APPLICATION
 
In addition 
to 
approving 
new 
drug products 
, the 
FDA
is 
charged 
with the 
approval 
of 
generic products 
(21
CFR 
314), which 
is accomplished 
through
 
CDER’s
Office 
of Generic
 
Drugs.
An 
Abbreviated 
New 
Drug 
Application 
(ANDA)
contains 
data 
submitted to FDA's Center 
for 
Drug
Evaluation 
and 
Research, 
Office 
of Generic Drugs, 
for
review
 
and 
ultimate  approval  
of a 
generic drug
product.
The 
reviewing 
process 
for 
generic drug is 
focused 
on
bioequivalence 
testing 
rather 
than 
safety 
and
efficacy.
 
To 
be 
considered bioequivalent, 
both 
rate 
and 
extend
of 
drug absorption must 
be within 
established
parameter 
in comparison 
to 
the 
reference
 
drug.
Use of 
bioequivalence 
as 
the 
base 
for 
approving
generic 
drug 
products 
was 
established by 
the "Drug
Price Competition and 
Patent 
Term 
Restoration 
Act  
of
1984," 
also known as the 
WAXMAN-HATCH
 
ACT.
 
Guidelines 
available 
for
 
ANDA:
 
V
ari
o
u
s
 
g
uideli
n
es
 
h
a
v
e
 
b
ee
n
 
d
e
v
eloped
 
t
o
 
a
s
s
i
s
t
applicants 
in 
preparing 
and 
filing
 
ANDAs
Format 
& 
content 
for 
the 
following
 
sections:
a.
Application
 
summary
b.
Chemistry, 
Manufacturing 
and 
controls
 
section
c.
Non 
clinical 
pharmacology 
and 
toxicology
 
section
d.
Human 
pharmacokinetics 
& 
bioavailability
 
section
e.
Clinical 
and 
statically
 section
f.
Microbiology
 
section
 
ANDA requires 
the 
submission 
of
 
:
Detailed 
descriptions 
of the
 
components
Manufacturing,
 
controls,
 
packaging,
 
and
 
labeling
 
su
ffi
cie
n
t
 
t
o
 
ass
u
r
e
 
the
 
b
i
o
av
ai
l
abi
l
ity
 
(whic
h
 
c
an
 
b
e
 
i
n
 
fi
nal
,
 
pr
i
n
t
ed
 
f
orm)
,
 
d
a
t
a
or
 
bioequivalence 
of the 
drug 
to 
be
 marketed.
 
The 
labeling 
should be 
prepared 
in 
accordance
with 
that 
specified in 
DESI 
(Drug 
efficacy study
implementation) 
Notice or other 
Federal
Register
 
COMPARISON
REFERENC
E
S
 
1.
The 
theory and 
practice 
of 
Industrial
Pharmacy ,Leon 
Lachman 
and 
Herbert 
A.
Lieberman Indian 
Edition 
2009,page no. 
856-
871
2.
The Science
 
and
 
Practice
 
of 
Pharmacy,
Remington
 
21
st
 
Edition, 
Volume 
1 . 
Page 
no
965-975.
3.
http://www.fda.gov/AboutFDA/Transparency
/Basics/ucm194879.htm
Thank
 
You
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Drug regulation involves controlling drug use through international agreement authorities like the FDA, EMA, and PMDA. The FDA plays a crucial role in drug evaluation and research, biologic evaluation, devices, and food safety. There are various types of applications for drug approval, along with a detailed process from pre-clinical testing to market approval. Investigational New Drug (IND) applications are submitted for safety and effectiveness testing. Different types of INDs include Investigator IND and Emergency Use IND. The regulatory process ensures the safety and efficacy of drugs before they reach the market.


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  1. REGULATORY REQUIREMENTS OF DRUGS AND PHARMACEUTICALS

  2. DRUGS REGULATION Drug regulation is the control of drug use by international agreement authorities such as Administration (FDA), the Agency (EMA) and the Japanese Pharmaceutical and Agency (PMDA). This includes Medical Devices regulations concerned approval, manufacturing and marketing of drugs. and/or US European by regulatory and Medicinal the Food Drug with the development,

  3. FDA Role and Organization FDA is organized into a number of offices and centers headed by a commissioner who is appointed by the President with consent of the senate These offices and centers are assigned with different responsibilities to accomplish the objective ofFDA 1. Center for Drug Evaluation and Research (CDER) 2. Center for Biologic Evaluation and Research (CBER) 3. Center for Devices and Radiological Health (CDRH) 4. Center for Food Safety and Applied Nutrition (CFSAN) 5. Center for Veterinary medicine (CVM)

  4. TYPES OF APPLICATIONS Investigational New Drug Application New Drug Application Abbreviated New Drug Application Biologic License Application Over-the-counter (OTC) drug application

  5. ClinicalHold PRE-CLINICALTESTING (4+YEARS) Revision ChemicalSynthesis and Scale uptesting DrugDiscovery and LeadCompound Selection Biologic Activitytesting (invivo) Formulation developmentand stability INDApplication IND Filing SafetyTestingin Animals IND Approval CLINICALTESTING (6+YEARS) Phase IIIClinical trials Phase II Clinical trials Phase I Clinicaltrials Revision NDA Filing FDAConditional Approval FDADisapproval FDAApproval MARKET Post-ApprovalSafety report toFDA Fig: the new drug approvalprocess

  6. Investigational New Drug (IND) It deals with a new chemical entity, which will be tested for obtaining evidence of safety and effectiveness in accordance with the regulation. It is the vehicle through a new drug advances into next stage of drug development i.e. Clinical trials

  7. Types of INDs 1. Investigator IND:- It is submitted by a physician who 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 proposed studying an unapproved drug, or an approved product for a new indication or in a new patient population. Emergency Use IND:-This allow the FDA to authorize an experimental drug in an emergency situation that does not allow for submission of an IND in accordance with 21CFR, Sec. 312.23 0r Sec.312.20. It is also used for patient who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist. 2.

  8. 3. Treatment IND:- It is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final work is conducted and the FDA review takesplace.

  9. Investigational New Drug Application

  10. Criteria for application A clinical study is required for an IND if it is intended to support a: New Indication. Change in the approved route of administration or dosage level. Change in the approved patient population or a population at greater or increased of risk . Significant change in the promotion of an approveddrug

  11. Application Content Animal Pharmacology and Toxicology studies. Chemistry and Manufacturing Information. Clinical Protocols and Investigator Information.

  12. NEW DRUG APPLICATION (NDA) The New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. NDA is responsible for are providing enough information to permit FDA reviewersto establish the following: Whether the drug safe and effective in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks. Whether the drug s proposed labeling (package insert) appropriate, and what should it contain. Whether the methods used in manufacturing (Good Manufacturing Practice, GMP) the drug and the controls used to maintain the drug s quality adequate to preserve the drug s identity, strength, quality, and purity.

  13. Fundamentals of NDA Submission As outlined in Form FDA-356h, Application to Market a New Drug for Human Use Or As An Antibiotic Drug For Human Use, NDAs can consist of as many as 15 different sections: Index Summary Chemistry, Manufacturing, and Control; Samples, Method Validation Package, and Labeling Nonclinical Pharmacology and Toxicology Human Pharmacokinetics andBioavailability Microbiology (for anti-microbial drugs only);

  14. ClinicalData; Safety Update Report (typically submitted 120 days after the NDA's submission); Statistical; Case ReportTabulations; Case ReportForms; PatentInformation; Patent Certification;and Other Information

  15. Classification of drugs in NDA CDER classifies new drug applications with a code that reflects both the type of drug being submitted and its intended uses. New Molecular Entity New Salt of Previously Approved Drug (not a new molecular entity) New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) New Combination of Two or More Drugs Already Marketed Drug Product - Duplication (i.e., new manufacturer) New Indication (claim) for Already Marketed Drug (includes switching marketing status from prescription to OTC) Already Marketed Drug Product - No Previously Approved NDA

  16. GENERAL REQUIREMENTS for filing an NDA The new (present) NDA regulations require that an application be submitted in two copies : (A)an archival copy that serves as a permanent record of the submission, and (B) a review copy. The review copy is made up of a number of separate technical volumes, each tailored to the needs of the disciplines involved in the review. Both the archival and review copies are submitted in hard copy, the regulations permit an application to submit the archival copy as microfiche. The NDA application form (FORM FDA 356h ) consists of: Twelve items (including index) deals with the safety and efficacy features of drug product, two are concerned with patent information

  17. The archival copy is a complete copy of an application submission and must be bound in a blue coverjacket. The archival copy should include a blue cover letterto: Confirm any agreement or understanding between the FDA and the agreement; Identify the contact person regarding the application Identify the reviewing division of the FDA and include HFD number; Convey any other important information about the application.

  18. The review copy is divided into six technical sections (review sections) and should be submitted with each review section separately bound in a specific color: REVIEW SECTION COLOUR CODE (i) Chemistry, Manufacturing and Controls(CMC) RED (ii) Nonclinical Pharmacology andToxicology YELLOW (iii) Human Pharmacokinetics and Bioavailability ORANGE (iv) Microbiology (if required) WHITE (v) ClinicalData LIGHT BROWN (vi) Statistical GREEN

  19. Each review section should contain the following: (i)a copy of the cover letter attached to the archival copy; (ii) a completed application form FDA356h; (iii) a copy of the summary (defined below); (iv) a copy of the general index of the entire application; (v) an index specific to that particular review section; (vi) letters of reference or authorization, if appropriate; (vii) patent information

  20. ABBREVIATED NEW DRUG APPLICATION In addition to approving new drug products , the FDA is charged with the approval of generic products (21 CFR 314), which is accomplished through CDER s Office of Generic Drugs. An Abbreviated New Drug Application (ANDA) contains data submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, for review and ultimate approval product. The reviewing process for generic drug is focused on bioequivalence testing efficacy. of a generic drug rather than safety and

  21. To be considered bioequivalent, both rate and extend of drug absorption must be within established parameter in comparison to the reference drug. Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the WAXMAN-HATCH ACT.

  22. Guidelines available forANDA: Various guidelines have been developed to assist applicants in preparing and filingANDAs Format & content for the following sections: a. Applicationsummary b. Chemistry, Manufacturing and controls section c. Non clinical pharmacology and toxicology section d. Human pharmacokinetics & bioavailability section e. Clinical and statically section f.Microbiology section

  23. ANDA requires the submission of : Detailed descriptions of the components Manufacturing, controls, packaging, and labeling (which can be in final, printed form), data or sufficient bioequivalence of the drug to be marketed. The labeling should be prepared in accordance with that specified in DESI (Drug efficacy study implementation) Notice Register to assure the bioavailability or other Federal

  24. COMPARISON NDA ANDA Applicable for new drug Take longer time ( 12-15 years) Applicable for genericdrug Compare to NDA less time taken(1-2years) Comparatively less Cost of drugs are less Nonclinical studies and clinical investigations are nonessential except bioavailability and bioequivalence More expenditure of money Cost of drugs are more Nonclinical studies and clinical investigations are essential

  25. REFERENCES 1. The theory and practice of Industrial Pharmacy ,Leon Lachman and Herbert A. Lieberman Indian Edition 2009,page no. 856- 871 2. The Science and Practice of Pharmacy, Remington 21stEdition, Volume 1 . Page no 965-975. 3. http://www.fda.gov/AboutFDA/Transparency /Basics/ucm194879.htm

  26. Thank You

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