IMPURITY AND

STABILITY STUDIES
Presented by
PREETHI P R
1ST Year M.Pharm
Pharmaceutical Analysis
CONTENTS
• Definition

• Classification of Impurities in Drug Substance

• Qualification of Impurities as per ICH Guidelines

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DEFENITION

• 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.

OR

• 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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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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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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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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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

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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They can be identified or unidentified, volatile or non-volatile, and include-

Starting materials or Intermediates,

Degradation Products,

Enantiomeric Impurities.

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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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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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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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Inorganic 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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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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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 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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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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Residual Solvents
• Residual solvents are defined as the organic volatile chemicals that are used or
produced in the manufacture of drug or excipients or in the preparation of drug
products.

• ICH Q3C recommends acceptable amounts for residual solvents in

pharmaceuticals for the safety of patients.

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Impurities forming during formulation

a) Method related.

b) Environmental related

The primary environmental factors thatcan reduce stability include the following-

• Exposures to adverse temperatures

• Light-especially UV light

• Humidity

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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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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. 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.

• Table provides the ICH threshold for control of the organic impurities in new drug
substances

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 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.

 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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Qualification of Impurities as per ICH
Guidelines
Organic impurity threshold in new drug substances based on ICHQ3A

Drug Substance Impurity Limits

Each identified specified Not more than 0.5 per cent

impurity
Not more than 0.3 per cent
Each unidentified impurity
Not more than 1.0 per cent
Total impurities

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RATIONALE FOR THE REPORTING
AND CONTROL OF IMPURITIES
• Organic Impurity
The actual and potential impurities most likely to arise during the synthesis and storage of the new
drug substance should be summarised.
• Inorganic impurity
Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate
procedures.
• Residual Solvents
The control of residues of the solvents used in the manufacturing process for the new drug substance
should be discussed and prevented according to te ICH Q3C guideline for residual solvents.

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ANALYTICAL PROCEDURE
• Analytical procedures should be validated and demonstrate that it is suitable for
the detection and quantification of the impurities.

• Reference standards used in the analytical procedures for the control of impurities
should be evaluated and characterized according to their intended uses.

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The ICH Q3A(R2) guidance on new drug substances provides the following
thresholds

THRESHOLDS REPORTING IDENTIFICATIO QUALIFICATIO

MAXIMUM THRESHOLD N THRESHOLD N THRESHOLD
DAILY DOSE
≤ 2g/day 0.05% 0.10% or 1.0 mg 0.15% or 1.0 mg
per day intake per day intake
(whichever is (whichever is
lower) lower)
>2g/day 0.03% 0.05% 0.05%
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• Any impurity at a level greater than the identification threshold should be
identified.

• Any impurity at a level greater than the reporting threshold of the new drug
substance should be reported.

• All impurities at a level greater than the qualification threshold should be

qualified.

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LISTING OF IMPURITIES IN
SPECIFICATION
• The specification for a new drug substance should include a list of impurities.

• The selection of impurities in the new drug substance specification should be

based on the impurities found in batches manufactured by the proposed
commercial process.

• Specified impurities can be identified or unidentified.

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The new drug substance specification should include where applicable, the
following list of impurities
Organic impurities
Each specified identified impurity
Each specified unidentified impurity
Any unspecified impurity with an acceptable criteria of not more than the
identification threshold.
Total impurities
Residual solvents
Inorganic impurities

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ILLUSTRATION OF REPORTING IMPURITY RESULTS FOR
IDENTIFICATION AND QUALIFICATION

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DECISION TREE FOR IDENTIFICATION
AND QUALIFICATION OF IMPURITY

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THANK YOU

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