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Impurities in Drug Substance
&
Drug Products
15 July 2015

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What is an Impurity?:
"Any component of the drug substance that
is not the chemical entity defined as the
drug substance and affects the purity of
active ingredient or drug substances”.
Similarly, “an impurity in a drug product is
any component of the drug product that is
not the chemical entity defined as the drug
substance or an excipient in the drug
product.”

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As per USP:
As per United State Pharmacopoeia:
The United States Pharmacopoeia (USP)
classifies impurities in two sections-ordinary
impurities and organic volatile impurities.

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Common terms for Impurities:
1)Intermediate, Penultimate
intermediate and By-products
2) Transformation products
3) Interaction product
4) Related product
5) Degradation product

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1) Intermediate, Penultimate intermediate and By-products :
The compounds produced during synthesis
of the desired material are called
intermediates, especially if they have been
isolated and characterized. The penultimate
intermediates are the last compound in the
synthesis chain prior to the production of
the final desired compound. By-products are
unplanned compounds produced in between
the reaction. It may or may not be possible
to theorize all of them.

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2) Transformation Products :
3) Interaction products :
Transformation Products:
They are very similar to by-products which
relates to theorized and non-theorized
products that may be produced in the
reaction.
Interaction Products:
Interaction products that could occur
between various involved chemicals
intentionally or unintentionally.

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4) Related Products :
5) Degradation Products:
Related Products:
These products have similar chemical
structure and potentially similar biological
activity.
Degradation Products:
These compounds are products due to
decomposition of the active ingredient or
the material of interest.

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Classification of Impurities:
Impurities in drug substance can be
classified into the following categories:
1)Organic Impurities ( Process & drug
related)
2) In-organic Impurities
3) Residual Solvents

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Organic Impurities (Process & drug related) :
This type of impurities in bulk
pharmaceutical chemicals those are
innocuous by virtue of having no significant
undesirable biological activity in the
amounts present. Organic impurities can
arise during the manufacturing process
and/or storage of the drug substance.

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Organic Impurities (Process & drug related) :
They can be identified or unidentified,
volatile or non-volatile, and include:
Starting materials or Intermediates,
Degradation Products & Enantiomeric
Impurities.

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Organic Impurities (Process & drug related) :
Starting Materials or Intermediates:
These are the most common impurities
found in every API unless a proper care is
taken in every step involved throughout the
multi-step synthesis. Although the end
products are always washed with solvents,
there are always chances of having the
residual unreacted starting materials may
remain unless the manufacturers are very
careful about the impurities.

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Organic Impurities (Process & drug related) :
Degradation Products:
Impurities can also be formed by
degradation of the end product during
manufacturing of bulk drugs. However,
degradation products resulting from storage
or formulation to different dosage forms or
aging are common impurities in the
medicines.

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Organic Impurities (Process & drug related) :
Reagents, ligands, and catalysts:
These chemicals are less commonly found in
APIs; however, in some cases they may
pose a problem as impurities.
Enantiomeric impurities:
The single enantiomeric form of a chiral
drug is now considered as an improved
chemical entity that may offer a better
pharmacological profile and an increased
therapeutic index with a more favourable
adverse.

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In-Organic Impurities :
Inorganic impurities may also derive from
the manufacturing processes used for bulk
drugs. They are normally known and
identified and include the following:
Reagents, ligands, and catalysts:
The chances of having these impurities are
rare: however, in some processes, these
could create a problem unless the
manufacturers take proper care during
production.

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In-Organic Impurities :
Heavy Metals :
The main sources of heavy metals are the
water used in the processes and the
reactors (if stainless steel reactors are
used), where acidification or acid hydrolysis
takes place. These impurities of heavy
metals can easily be avoided using
demineralized water and glass-lined
reactors.

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In-Organic Impurities :
Other material(filter aids & charcoal) :
The filters or filtering aids such as
centrifuge bags are routinely used in the
bulk drugs manufacturing plants, and, in
many cases, activated carbon is also used.
The regular monitoring of fibers and black
particles in the bulk drugs is essential to
avoid these contaminations.

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Organic Volatile Impurities :
Organic Volatile Impurities :
Organic Volatile Impurities relates to
residual solvents that may be found in the
drug substance.
Chiral Impurity :
Compounds having similar chemical
structure but different spatial orientation
leading to different optical rotation are of
great importance because of the resulting
optical isomers. The undesired optical
isomer is considered as a chiral isomer.

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Formulation Related Impurities :
Number of impurities in a drug product can
arise out of inert ingredients used to
formulate a drug substance. In the process
of formulation, a drug substance is
subjected to a variety of conditions that can
lead to its degradation or other deleterious
reaction.

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Formulation Related Impurities :
Solutions and suspensions are potentially
prone to degradation due to hydrolysis. The
water used in the formulation cannot only
contribute its own impurities; it can also
provide a ripe situation for hydrolysis and
catalysis. Similar reactions are possible in
other solvents that may be used.

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Impurities forming during formulation :
a) Method related.
b) Environmental related
The primary environmental factors that
can reduce stability include the following
Exposures to adverse temperatures
Light-especially UV light
Humidity

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Impurities forming during formulation :
C) Formation of Impurities by ageing:
I. Mutual interaction amongst
ingredients
II. Functional group- related typical
degradation
Ester hydrolysis
Hydrolysis
Oxidative Degradation
Photolytic Cleavage
De-carboxylation

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Isolation & Characterisation of the Impurity :
Number of methods can be used for
isolation and characterization of
impurities. But the application of any
method depends on the nature of
impurity (i.e.) its structure,
physicochemical properties and
availability.

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Isolation & Characterisation of the Impurity :
The following methods are commonly
used for the isolation, they are
Extraction
Column Chromatography
Preparative Separations

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Requirement of the control of the Impurity :
Impurities often possess unwanted
pharmacological or toxicological effects by
which any benefits from their administration
may be outweighed. Impurities will have
different disastrous efficacy, different
bioavailability, adverse effects and toxic
effects. In case of chiral impurities.

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Requirement of the control of the Impurity :
one isomer may produce the desired
therapeutic activities, while the other may
be inactive or in worst cases, produce
unwanted effects.

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Control of Impurities with the limits :
Control of the organic impurities in new
drug substances is based on the maximum
daily dose and total daily intake (TDI) of the
impurities. Table1.3 provides the ICH
threshold for control of the organic
impurities in new drug substances.

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Control of Impurities with the limits :
Depending on whether the maximum daily
dose is higher or lower than 2g, organic
impurities in a new drug substance at (or
greater than) 0.05% or 0.1% requires
identification.

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Control of Impurities with the limits :
Based on the maximum daily dose, the
identification thresholds for organic
impurities in new drug products are divided
into four groups to give more consideration
to low dose drug products. For most of the
new drug products, the maximum daily
dose is between 10mg–2g/day. Therefore,
any impurities at 0.2% or greater would
have to be identified.

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Control of Impurities with the limits :
Organic impurity threshold in new drug
substances based on ICHQ3A:
Drug Substance Impurity Limits
Each identified specified impurity Not more than 0.5 per cent
Each unidentified impurity Not more than 0.3 per cent
Total impurities Not more than 1.0 per cent
Degradation Product Impurity Limits
Each identified degraded product Not more than 1.0 per cent
Each unidentified degraded product Not more than 0.5 per cent
Total degraded products Not more than 2.0 per cent

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