M.Pharm Pharmaceutics 1 sem

1. CMC ,Post approval regulatory affairs
Prepared by :-Arjun S.Dhawale
M.Pharm Pharmaceutics 1yr
Kamla Nehru College of Pharmacy,
Butibori , Nagpur .

2. Content:-
1 - Introduction .
2 - What is CMC Regulations affairs .
3 - Pharmaceutical quality .
4 - Chemistry .
5 - Manufacturing .
6 - Controls .
7 - Post regulatory affairs .
8 - Conclusion .

3. Introduction:-
The chemistry, manufacturing, and controls (CMC) section of a regulatory filing
investigational new drug (IND), IND amendments, IND annual reports, new drug
application (NDA) or biologics license application (BLA), postapproval CMC
supplements, NDA annual reports] contains detailed information pertaining to
the characteristics, manufacturing, and quality aspects of the drug substance
and drug product.
Under the International Conference on Harmonization (ICH) common technical
document (CTD) format, the CMC section is referred to as the quality section
and the structure is outlined in the ICH CTD guidance.

4. What is CMC regulations affairs ?
Pharmaceutical companies are legally required to obtain and maintain
regulatory approvals.
Regulatory Affairs is a discipline and strategic function within the overall
organizational structure of a pharmaceutical company that directly interacts with
government regulatory agencies concerning regulatory approvals.
The Food and Drug Administration (FDA), European Medicines Agency (EMA),
Japanese Pharmaceuticals and Medical Devices Agency (PMDA), for example,
are government regulatory agencies typically involved in the approval process.

5. Chemistry, Manufacturing, and Controls (CMC ) Regulatory Affairs (RA) is a
specific area within RA that has the ultimate responsibility for providing CMC
regulatory leadership and strategy required to achieve regulatory approvals.
As a strategic function, CMC RA collaborates closely with multiple scientific,
technical, quality, and commercial areas within a company or with external
contract manufacturing organizations (CMOs). “To help companies effectively
and efficiently achieve regulatory approvals,”

6. Pharmaceutical Quality :-
The consistency of their quality will be assured from batch to batch. The contents of
these quality sections will evolve with time and experience in both quantity and detail of
information. The quality section of a marketing application (CTD/NDA) describes the
CMC processes for commercial product, and therefore these sections of a marketing
application are very detailed.
However, for an IND application, while the same basic information is required, it may
be supplied in much less detail because of the preliminary stage of development. The
CMC information filed in an IND or NDA/CTD is reviewed by the agency to ensure that
the drug substance and drug product meet the “quality standards” and do not pose any
significant safety risk or compromise efficacy during the intended use in the targeted
patient population.

7. Chemistry :-
Nomenclature :-
All appropriate names or designations for the drug substance
should be provided along with any codes, abbreviations, or nicknames used in the
application to identify the drug substance.
1-Chemical Name .
2-IUPAC Name .
3-International Nonproprietary Names [INNs] .

8. Structure :-
This first section contains only summary information relating to
structure and other characteristics. More detailed information concerning proof
of structure is to be provided in the characterization section. Information that is
expected to be provided here includes
1. One or more drawings to show the overall chemical structure of the drug
substance, including stereochemistry,
2. Molecular formula, and
3. Molecular weight.
For a naturally derived protein drug substance, the information should include
1. The number of amino acid residues,
2. The amino acid sequence indicating glycosylation sites or any other posttranslational
modifications, and
3. A general description of the molecule (e.g., shape, disulfide bonds, subunit
composition)

9. General properties:-
A list of the general physicochemical properties of the drug
substance should be provided. Relevant properties are those physical, chemical,
biological, and microbiological attributes relating to the identity, strength, quality,
purity, and/or potency of the drug substance and, as appropriate, drug product. The
information should include, as appropriate, the following:
1. A general description of the drug substance (e.g., appearance, color,
physical state)
2. Melting or boiling points
3. Optical rotation
4. Solubility profile (aqueous and nonaqueous, as applicable)
5. Solution pH
6. Partition coefficients
7. Dissociation constants
8. Identification of the physical form
9. Biological activities

10. Manufacturng :-
Manufacturer detail. The name, address, and manufacturing responsibility should be provided
for each firm (including contract manufacturers and testing laboratories) and each site (i.e.,
facility) that will be involved in the manufacturing or testing of the drug substance.
Method of manufacture. This section should include a schematic flow diagram that gives the
steps of the manufacturing process and shows where each material enters the process. The
entire manufacturing process from the starting materials to the final drug substance released for
testing should be depicted. This schematic flow diagram should be accompanied by a narrative
description of the manufacturing process that represents the sequence of manufacturing steps
undertaken and should include the scale of production. The narrative provided should include
more details than that provided in the flow diagram. The description should identify all process
controls along with any associated numeric ranges, limits, or acceptance criteria.

11. Controls :-
Control of Drug Substance .
The proposed specifications for the drug substance used to produce the drug product should be
provided. A specification is defined as a list of tests, references to analytical procedures, and
appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests
described.
Guidance on setting specifications is outlined in guidance ICH Q6A; for biotechnology products,
the guidance is outlined in ICH Q6B. The specification establishes criteria to which each batch
of drug substance should conform to be considered acceptable for its intended use.
Conformation to specification means that the drug substance, when tested according to the
listed analytical procedures, will meet the listed acceptance criteria. The specification sheet
should list all tests to which each batch of a drug substance will conform and the associated
acceptance criteria and should also include a reference to the analytical procedures that will be
used to perform each test.

12. Batch analysis, which is a collation of analytical data for all the tests included in the
specifications, should be provided for all drug substance batches used for :-
(i) Nonclinical studies .
(ii) Drug product clinical efficacy and safety,bioavailability, and bioequivalence .
(iii) Primary stability studies.
The information submitted on each of the batches should include a description of the batch. The
description should include the following :-
1. Batch identity (i.e., batch number) and size
2. Date of manufacture
3. Site of manufacture
4. Manufacturing process, where applicable
5. Use of batch (e.g., clinical, stability)

13. CMC REGULATORY COMPLIANCE :-
After review and approval/acceptance of the CMC information by the agency,the CMC
processes and procedures described in the IND/CTD/NDA become a binding commitment.
Thus, all future batches of that particular drug substance and drug product will be manufactured
by the processes and procedures described in the regulatory filing(s) so that they meet the
quality criteria described in the application.
Continuing to maintain this commitment is referred to as CMC Regulatory Compliance.

14. Post approval regulatory affairs :-
The FDA may require a post-approval study at the time of approval of a Premarket Approval
(PMA) , Humanitarian Device Exemption (HDE) , or product development protocol (PDP)
application to help assure continued safety and effectiveness (or continued probable benefit ,i
the case of an HDE) of the approved drug product of medical device .
A sponsor’s failure to comply with any post-approval requirement may be grouns for
withdrawing approval i.e. whether the post approval study will be terminated or revised/replaced
.

17. Conclusion :-
CMC Information for the drug substance and drug product of an investigationaland commercial
drug is provided in the quality module of a dossier submitted in CTD format. It is inevitable that
the information will continue to change because of various improvements and necessities
throughout development and postapproval.
It is the sponsor’s responsibility to perform adequate assessment of the changes to
demonstrate that the changes have adverse affect on the identity,strength, quality, purity, or
potency of the drug as they may relate to the safety or effectiveness of the drug.
Communicating the changes and the change assessments to the FDA by appropriate regulatory
process is critical for maintaining CMC regulatory conformance and complying with the Food,
Drug, and Cosmetic Act.

18. Thank You