CMC of NDA - Praful

Chemistry, Manufacturing
and Control (CMC)

requirements of an NDA
Prepared by:
Praful P. Dedhiya
M.Pharm( Sem-II)(Q.A)
Roll no-04
Maliba Pharmacy College

Gopal Vidyanagar
CONTENTS
 What is New Drug?
 What is New Drug Application?
 When NDA comes?
 NDA format and content
 CMC section
 Conclusion
 References
2
What is New Drug?
A new drug is defined as any drug with a composition that is not generally
recognized as safe and effective (GRASE) for a use for which it is labeled.
 There is a new intended use for the drug.
 There is a new drug use of a combination of approved drugs.
 The proportion of active ingredients in combination is changed.
 The dosage, method or duration of administration or application is
changed.
3
What is New Drug Application?
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.
4
WHEN NDA COMES?
 New Chemical Entity (NCE)
 Patent
 Preclinical testing
 IND submission
 Clinical testing
 NDA submission
 FDA approval
 In market
5
6
NDA FORMAT AND CONTENT
7
NDA Format
No. 1 Archival copy – selected CRFs and CRF
tabulations, safety (ADR) tabulations
No. 2 Review copy – five to six technical sections with
selected tabulations of data
1. Index – Archival copy
Technical Sections
Supporting Information
2. Summary
a. Proposed text of labeling
b. Pharmacological class and scientific rationale
c. Marketing History
d. Chemistry, manufacturing etc
e. Nonclinical pharmacology
f. Human pharmacokinetics and bioavailability
g. Microbiology
h. Clinical data; Statistics
i. Benefit/risk discussion
88
3. Technical section – Data and information (five to six reports)
-Chemistry, Manufacturing and Controls
-Nonclinical Pharmacology and Toxicology
-Microbiology
-Human Bioavailability and Pharmacokinetics
-Clinical data
-Statistical data
4. Samples and labeling
5. CRFs and tabulations (CRFs for deaths and drop-outs)
6. Other (References to previously submitted material; English

translations)
9
10
11
12
13
CMC SECTION
A section describing the composition, manufacture,
and specification of the drug substance and the drug
product, including the following:
i. The Drug Substance
ii. The Drug Product
iii. Environmental Impact
iv. …
v. …
14
CMC Section for CMC Section for
The Drug Substance The Drug Product
Names Components
Structural Formula and Chemical Name(s) Composition
Physical and Chemical Properties Specifications and Analytical Methods for

Inactive Components
Proof of Structure Manufacturer
Stability Method of Manufacture, Packaging Procedure
and In-Process Control
Manufacturer Specifications and Methods for Drug Product
Method of Manufacture Container/Closure System(s)

Process Controls Stability
Specifications and Analytical Methods
Container/Closure System(s) 15
NAMES
 Include the establishhed (generic) and proprietary
(trade) name(s), synonyms, Chemical Abstract Service
(CAS) registry number, and code number(s).
16
Names Components

Inactive Components

STRUCTURAL FORMULA AND CHEMICAL NAME(S)
The chemical structure(s), molecular formula(s),
molecular weight(s) and chemical name(s) should be
shown.
18
Names Components

Inactive Components

PHYSICAL AND CHEMICAL PROPERTIES
 Organoleptic properties (e.g., appearance, odor, taste)
 Solid state form, i.e., the preferred crystalline

polymorph
 Solubility profile (including aqueous solubility as a
function of pH)
 pH, pKa or pKb
 Melting and/or boiling range
 Specific gravity or bulk density
 Spectroscopical characteristics such as specific

rotation, refrective index, fluorescence 20
 Isomeric composition
Names Components

Inactive Components

PROOF OF STRUCTURE
 The elucidation and confirmation of structure should include
physical and chemical information derived from applicable
analyses such as:
 Elemental analysis
 Functional group analysis
 Derivatization
 Degradation studies
 Complex formation (e.g. chelates)
 Mass spectrometry
 Chromatography
 UV, IR, NMR spectroscopy
 ORD or x-ray diffraction 22
Names Components

Inactive Components

STABILITY
The results of studies conducted on the drug
substance should be described fully.
In addition, based on these results,
recommendations for the storage conditions and
expiration dating period should be discussed.
24
Names Components

Inactive Components

MANUFACTURER
The name and address of the manufacturer
26
Names Components

Inactive Components

METHOD OF MANUFACTURE
Full description of the method used in the isolation
and purification of the drug substance.
Also, list starting materials, reagents, solvents and
auxiliary materials with specifications and
statement of the quality of each.
28
Names Components

Inactive Components

PROCESS CONTROLS
A briefdescription of the control checks performed
at each stage of the manufacturing process and
packaging of the drug substance should be
provided.
30
Names Components

Inactive Components

SPECIFICATIONS AND ANALYTICAL METHODS
Specifications and analytical methods used to
assure the identity, potency, quality and purity of
the drug substance should be submitted.
32
Names Components

Inactive Components

CONTAINER AND CLOSURE
SYSTEM(S)
Provide information regarding the characteristics of
and quality control test methods for the container,
closure and any other component parts to assure
suitability for their intended use.
34
Names Components

Inactive Components

COMPONENTS
Provide a list of all substances used in producing
the finished dosage form intended for commercial
distribution.
36
Names Components

Inactive Components

COMPOSITION
The actual weights or measures for each active or
inactive ingredient per unit of dose should be
provided.
38
Names Components

Inactive Components

FOR INACTIVE COMPONENTS
Inactive components are usually of compendial
grade or are listed as acceptable food or color
additives under Title 21 CFR.
It is usually acceptable to cross-reference the
appropriate monographs or sections and indicate
which test will be performed routinely by the
sponsor on each lot received.
40
Names Components

Inactive Components

MANUFACTURER
The names and addresses of all manufacturers,
contract packagers and contract analytical
laboratories used for testing raw materials and drug
product should be given.
42
Names Components

Inactive Components
Stability Method of Manufacture, Packaging
Procedure and In-Process Control

METHOD OF MANUFACTURE, PACKAGING
PROCEDURE AND IN-PROCESS CONTROL
This section include a general write-up of the
manufacturing procedure, which incorporates all
processing alternatives that have been previously
validated as producing acceptable product.
44
Names Components

Inactive Components
Manufacturer Specifications and Analytical Methods for
Drug Product
FOR DRUG PRODUCT
The specifications and analytical methods are
intended to assure reproducibility within all
specified limits of product manufacture and thus,
clinical response.
46
Names Components

Inactive Components

CONTAINER/CLOSURE SYSTEM(S)
Provide a detailed description of the physical,
chemical and biological characteristics of the
container , closure and other parts of the drug
product package to assure suitability for its
intended use.
48
Names Components

Inactive Components

STABILITY
The results of studies conducted on the drug
product should be described fully.
In addition, based on these results,
recommendations for the storage conditions and
expiration dating period should be discussed.
50
CMC SECTION
A section describing the composition, manufacture,
and specification of the drug substance and the drug
product, including the following:
i. The Drug Substance
ii. The Drug Product
iii. Environmental Impact
iv. …
v. …
51
(III) ENVIRONMENTAL IMPACT
 The application is required to contain either a claim
for categorical exclusion under 25.30 or 25.31 of this
chapter or an environmental assessment under 25.40
of this chapter.
50
(IV)
 The applicant may, at its option, submit a complete
chemistry, manufacturing, and controls section 90 to
120 days before the anticipated submission of the
remainder of the application. FDA will review such
early submissions as resources permit.
50
(V)
 The applicant shall include a statement certifying that
the field copy of the application has been provided to
the applicant's home FDA district office.
50
CONCLUSION
 The CMC section of an NDA require special attention.
 If industry/innovator become more familiar with these
guidelines, the quality of manufacturing and controls
documentation will be improved and it is hoped, the
frequency and extent of deficiencies will diminish.
 One of the most positive contributions is also
expected to be the economical, reproducible
manufacture of new drugs in well-designed dosage
forms that can be prescribed by physicians with
confidence.
54
CONCLUSION CONTD…
 The careful preparation of the manufacturing and
controls section in an NDA can facilitate FDA
processing, review and approval procedures.
 The result is expected to be potentially faster
commercialization of new products benefiting both
pharmaceutical manufacturers and the patients they
ultimately serve.
55
REFERENCES
 http://www.fda.gov
 RichardA. Guarino and Marcel Dekkar, New

Drug Approval Process, 2nd edition,1987,243-
356.
 Remington,”The Science and Practice of
Pharmacy”, 21st edition, Volume-1,965.
57
Y OU
A N K
T H
58

CMC of NDA - Praful

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CMC of NDA - Praful

Uploaded by

Copyright:

Available Formats

Chemistry, Manufacturing

and Control (CMC)

Maliba Pharmacy College

 When NDA comes?

 NDA format and content

4. Samples and labeling

5. CRFs and tabulations (CRFs for deaths and drop-outs)

6. Other (References to previously submitted material; English

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

 Solid state form, i.e., the preferred crystalline

 Melting and/or boiling range

 Specific gravity or bulk density

 Spectroscopical characteristics such as specific

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)

Specifications and Analytical Methods

Physical and Chemical Properties Specifications and Analytical Methods for

Method of Manufacture Container/Closure System(s)