IMPURITIES

Presented by M NAGA HANUSHA

INTRODUCTION
IMPURITIES :
 Definition
Classification
Qualification as per ICH guidelines
 DEGRADATION :
 Definition
 Rationale for reporting and control
 Reporting degradation product content of batches
 Listing of degradation products in specifications
 Qualification
 RESIDUAL SOLVENTS:
o Analytical procedure
o Limits of residual solvents
Definition
The impurities in pharmaceuticals are unwanted
chemicals that remain with the
active pharmaceutical ingredients (APIs) or develop
during formulation or upon aging of both API and
formulation. The presence of these unwanted
chemicals even in trace amount may influence the
efficacy and safety of pharmaceutical product
Classification of impurities
According to ICH guidelines, impurities in the drug
substance produced by chemical synthesis can broadly
be classified into following three categories –
1. Organic Impurities (Process and Drug related)
2. Inorganic Impurities
3. Residual Solvents
 Organic impurities
These impurities mainly arise during the synthetic
process or storage of drug substance.
 Classification:
 Starting materials
 By products
 Degradation products
 Reagents and chiral impurities
 1. Starting materials or intermediates
The impurities from the starting material and
intermediates or by products found in every drug
substance if proper care not exercised to remove them in
the end-product during multistep synthesis
Though product washed with solvent frequently , there is a
chance for the presence of unreacted starting material in
the final product
Example: In the synthesis of baclofen from glutamide
 2. Degradation product
-During manufacturing of bulk drug degradation of end
products results in the formation of impurities
Degradation product arises from synthetic process, storage,
formulation of dosage form and aging
Example: Penicillins and Cephalosporins
 3 . By products
In the synthetic organic chemistry, getting a single end-product with 100%
yeild is seldom. There is always a chance of having by-products because they
can be formed through variety of side reactions, such as
Incomplete reaction
Over reaction
Isomerism
Dimerization

example: production of paracetamol from intermediate p-amino phenol

 Inorganic impurities
Inorganic impurities derive from the manufacturing
process and excipient
Generally,excipient contain high levels of heavy metals
such as-
arsenic,bismuth,cadmium,chromium,copper,iron,lead
,mercury,nickel and sodium
Example: Excipient,hydrogenated oils and fats
 Residual solvents
Residual solvents are potentially undesirable
substances
They are either modify the properties of certain
compounds or may be hazardous to human health
As per the ICH guidelines, the solvents used in the
manufacture of drug substance classified into 4 types
class-1
class-2
class-3
class-4
Class-1
Solvents and their permissible concentration limits are
Class -2
Solvents usage should be limited in pharmaceutical
products because of their inherent toxicity
 Class-3
These are less toxic and posses lower risk to human
health than class1 and class2
Solvents: acetic acid, anisole,butanol

class-4
Solvents, adequate toxicological data is not available
Qualification of impurities
Qualification of impurities
Qualification of impurities
Degradation products
Definition :
 An impurity resulting from a chemical change in the drug
substance brought about during manufacture and storage of new drug
product by the effect of : light, temperature,pH,H2O or by reaction
with an excipient and the immediate container closure system
Rationale for reporting and control
The applicant should summarize the degradation products
observed during manufacture and/or stability studies of a
new drug product
This summary should be based on sound scientific appraisal
of potential degradation pathways in the new drug product
and impurities arising from the interaction with an excipient
and/or the immediate container closure system
A rationale should be provided for exclusion of those
impurities that are not degradation products (e.g., process
impurities from the drug substance and impurities arising
from excipient)
Any degradation product observed in stability studies
conducted at the recommended storage condition should
be identified when present at a level greater than (>) the
identification threshold
When identification of a degradation product is infeasible,
a summary of the laboratory studies demonstrating the
unsuccessful efforts to identify it should be included in the
registration application
Analytical procedure
The registration application should include documented
evidence that the analytical procedures have been validated
and are suitable for the detection and quantification of
degradation products
In particular, analytical procedures should be validated to
demonstrate specificity for the specified and unspecified
degradation products. As appropriate, this validation should
include samples stored under relevant stress conditions:
light, heat, humidity, acid/base hydrolysis, and oxidation
The quantification limit for the analytical procedure should
be not more than (≤) the reporting threshold
Reporting degradation product content of
batches
Analytical results should be provided in the registration application
for all relevant batches of the new drug product used for clinical,
safety, and stability testing, as well as batches that are representative
of the proposed commercial process
Any degradation product at a level greater than (>) the reporting
threshold (see Attachment 1), and total degradation products
observed in the relevant batches of the new drug product, should be
reported with the analytical procedures indicated
Below 1.0 percent, the results should be reported to the number of
decimal places (e.g., 0.06 percent) in the applicable reporting
threshold
at and above 1.0 percent, the results should be reported to one
decimal place (e.g., 1.3 %)
For each batch of the new drug product described in the
registration application, the documentation should include:
• Batch identity, strength, and size
• Date of manufacture
• Site of manufacture
• Manufacturing process
• Immediate container closure
• Degradation product content, individual and total
• Use of batch (e.g., clinical studies, stability studies)
• Reference to analytical procedure used
• Batch number of the drug substance used in the new drug
product
• Storage conditions for stability studies
Listing of degradation products in
specification
The specification for a new drug product should include a list of
degradation product
The selection of degradation products in the new drug product
specification should be based on the degradation products found in
batches manufactured by the proposed commercial process
Specified degradation products can be identified or unidentified
In summary, the new drug product specification should include, where
applicable, the following list of degradation products:
• Each specified identified degradation product
• Each specified unidentified degradation product
• Any unspecified degradation product with an acceptance criterion
of not more than (≤) the identification threshold
• Total degradation products
Qualification of degradation products
Qualification is the process of acquiring and evaluating data that
establishes the biological safety of an individual degradation product or a
given degradation profile at the levels specified
Degradation products could be considered qualified at levels higher than
those administered in safety studies based on a comparison between
actual doses given in the safety studies and the intended dose of the new
drug product
 Justification of such higher levels should include consideration of
factors such as:
(1) the amount of degradation product administered in previous
safety and/or clinical studies and found to be safe;
(2) the increase in the amount of the degradation product and
(3) other safety factors, as appropriate. If the qualification thresholds
Residual solvents analytical procedure
Analytical procedures shall be validated and suitable
for the detection and qualification of impurities
Reference standards used in analytical procedures for
the control of impurities should be evaluated and
characterized for intended use
The drug substance can be used as a standard to
estimate the levels of impurities
The quantification limit for the analytical procedure
should not be more than(<)the reporting threshold
Limits of residual solvents
Solvents to be avoided
Solvents in Class 1 should not be employed in the manufacture of
drug substances, excipients, and drug products because of their
unacceptable toxicity or their deleterious environmental effect
example
 Solvents to be limited
Solvents should be limited in pharmaceutical products
because of their inherent toxicity. PDEs are given to the nearest 0.1
mg/day, and concentrations are given to the nearest 10 ppm
Solvents with low toxic potential
Solvents in Class 3 may be regard as less toxic and of lower risk to human health.
Class 3 includes no solvent known as a human health hazard at levels normally
o in pharmaceuticals
accepted
It is considered that amounts of these residual solvents of 50 mg per day or less
(corresponding to 5000 ppm or 0.5% under Option 1) would be acceptable without
justification
Higher amounts may also be acceptable provided they are realistic in relation to
manufacturing capability and good manufacturing practice
Class 3 solvents which should be limited by GMP or other quality-based
requirements.
Acetic acid
Acetone
Isobutyl acetate
Anisole
Isopropyl acetate 1
Solvents for which no adequate toxicological data
was found
The following solvents Solvents for which no adequate
toxicological data was found.
 1,1-Diethoxypropane
 Methyl isopropylketone
 1,1-Dimethoxymethane
 Methyl tetra hydro furan
 2,2-Dimethoxypropane
 Petroleum ether Isooctane
Trichloro acetic acid
Isopropyl ether
Trifluoro acetic acid
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