The Chemistry, manufacturing and controls (CMC) section is a very important part of a pharmaceutical
clinical trial or marketing application. There have been cases of pharmaceuticals being denied approval
because the quality of the product and the manufacturing process was not shown to be of a sufficiently
high standard. Regulators need to be assured that there is consistency between the product tested
during the clinical trials and commercialization batches produced years later.

The ICH and FDA has provided several guidance documents designed to help pharmaceutical companies
with the CMC expectations of their product. These include:

FDA’s Guidance for Industry, “INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing,
and Controls Information”
ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology
ICH Q3C(R6) Impurities: Residual Solvents
ICH Q6A Specification: Test Procedures and Acceptance Criteria for New Drug Substances and
New Drug Products: Chemical Substances

The FDA promotes the graded nature of CMC requirements. The further along in clinical trials, the more
information that is needed. In this section you will find a series of CMC requirements to support an IND
(investigational new drug application) or NDA (new drug application). The amount of CMC information
needed varies according to other clinical trial factors such as size, duration, dosage form and prior
usage.

ICH Q6A breaks down the required CMC tests into two categories: Universal tests which are applicable
to all new drug substances or drug products and specific tests which are tests that can be considered on
a case by case basis. To be clear on the definitions, drug substance is the unformulated active substance
while the drug product is the final product once formulated with excipients.

CMC Universal Tests – New Drug Substance

Description

A statement about the physical state of the drug substance (solid, liquid, ect.) and color.

Identification

Tests that are specific for identification of new drug substance. If the product is
optically active there may be a need for chiral assay. A stability indicating procedure should be
included.

Impurities

The drug substance must be tested for impurities, including organic and inorganic
impurities and residual solvents.

CMC Universal Tests – New Drug Product

Description

A description of the dosage form (size, shape and color).

Identification

Identity tests should establish the identity of the drug product. These tests
should be able to discriminate between compounds of closely related structure which are likely
to be present. Stability indicating assays to determine strength should be included.

Impurities

The drug product must be tested for impurities, including organic and inorganic
degradation products and residual solvents.

CMC Specific Tests – New Drug Substance

Physicochemical Properties

Common tests for physicochemical properties include pH, melting
point, solubility, pKa, hygroscopicity, X-ray diffraction, viscosity, osmolality, partition coefficient
and refractive index.

Particle Size

Drug substances intended for use in solid or suspension products should have
testing for particle size distribution carried out. Particle size can have an effect on dissolution
rates, bioavailability and stability.

Polymorphic Forms

Some drug substances exist in different crystalline forms which will have
different physical properties. Differences in these forms could affect the performance of the
drug. If different forms exist and affect the drug, then the appropriate solid state should be
specified.

Chiral Assays

For chiral drug substances which are developed as a single enantiomer, control of
the other enantiomer should be considered in the same manner as for other impurities. Identity
tests should be capable of distinguishing both enantiomers.

Water Content

When the drug substance is known to be hygroscopic or degraded by moisture it is important to perform water content testing. The Karl Fischer method is preferred over loss on drying procedures.

Inorganic Impurities

Based on the manufacturing process there may be a need to test for inorganic impurities.

Microbial testing

Sterile drugs will need to be tested for sterility and the level of endotoxins
may be need to be tested if the product is injectable. Microbial limits testing, which is a
measure of the bioburden on the product and also tests for the absence of objectionable
organisms, may be used to test nonsterile products.

CMC Specific Tests – New Drug Products

These tests are dependent of the dosage form of the new drug product. The following dosage forms will
be addressed in the table below: solid oral tablets and hard capsules, liquid oral including powders that
are intended for reconstitution as oral liquids, and parenterals.