This presentation provides information regarding sources of impurities in API

2. CONTENTS
INTRODUCTION
SOURCES OF IMPURITIES
TYPES OF IMPURITIES
SOURCES OF ORGANIC IMPURITIES
GENOTOXIC IMPURITIES
REFERENCES
2

3. IMPURITIES?
Impurities are chemical substances composed of liquid, gas, or solid,
which differ from the chemical composition of the material or compound.
They are either naturally occurring or added during synthesis of a
chemical / commercial product.
During production, impurities may be purposely, accidentally, added into
the substance.
3

4. Standards have been established for permitted levels of
various impurities in a manufactured product.
A material's level of purity can only be stated as being
more or less pure than some other material.
Inorganic contaminants are not considered as an impurity
unless they are toxic, such as heavy metal or arsenic.
4

5. SOURCES OF IMPURITIES
Majority of the impurities are occurred during the synthetic
route of manufacturing process.
There are several possibilities of synthesizing a drug
It is possible that the same product of different sources may give
rise to different impurities.
5

6. The situation with the organic impurities.
•Toxicity is unknown.
•Not easily predictable.
•For this reason the ICH guidelines set threshold
limit above which the identification of the
impurity is obligatory.
6

7. The number of INORGANIC IMPURITIES and RESIDUAL
SOLVENTS are limited.
• Easily identified.
• Physiological effects and toxicity are well known.
• The limits set by the pharmacopoeias & ICH guidelines
guarantee that the harmful effects of these impurities do not
contribute to the toxicity or the side effects of the drug
substances.
7

8. TYPES OF IMPURITIES
According to
ICH guidelines
8

9. a) ORGANIC IMPURITIES
Arise during the
manufacturing process
and/or storage of the new
drug substance.
They can be identified or
unidentified, volatile or non-
volatile, and include:
Starting materials By-products Intermediates
Degradation
products
Reagents, ligands
and catalysts
9

10. b) INORGANIC IMPURITIES
Results from the
manufacturing
process.
They are
normally known
and identified and
include:
Reagents, ligands and
catalysts
Heavy metals or other
residual metals
Inorganic salts
Other materials (e.g.,
filter aids, charcoal)
10

11. c) RESIDUAL SOLVENTS
Solvents are
inorganic or organic
liquids.
They are used as vehicles
for the preparation of
solutions or suspensions
in the synthesis of a new
drug substance.
Since these are generally
of known toxicity, the
selection of appropriate
controls is easily
accomplished.
11

12. SOURCES OF ORGANIC IMPURITIES
•Arise during the manufacturing process or storage of the
drug substance.
•These impurities are derived from drug substance
synthetic processes and degradation reactions in drug
substances and drug products.
12

13. SYNTHETIC PROCESS
IMPURITY
DEGRADATION PROCESS
IMPURITY
•Starting materials
•Intermediates
•Reagents
•Ligands
•Catalysts used in the chemical
synthesis
•By-products from the side-
reactions of the chemical
synthesis.
ENANTIOMERIC
IMPURITIES
Degradation products of the
drug substances and drug
products occurs due to storage
or stress conditions
13

14. 14

15.  These synthetic impurities are usually referred to as Process impurities.
 The goal is to determine the structures and origins of these impurities.
 This knowledge is critical for improving the synthetic chemical process,
in order to eliminate or minimize process impurities.
15

16. a) STARTING MATERIALS & INTERMEDIATES
“Starting materials and intermediates are used to construct the final
form of a drug substance”
Unreacted starting materials and intermediates, involved in the last steps of the synthesis, can
potentially survive the synthetic and purification process and appear in the final product as
impurities.
SYNTHESIS OF TIPRANAVIR
 Aniline - Intermediate in the last step of the synthesis.
 Due to the similarity between the structures of aniline and the final product, it is
difficult to totally eliminate it in the subsequent purification step.
 Consequently, it appears in the drug substance at around 0.1%.
16

17. b) IMPURITIES IN THE STARTING MATERIALS
“Impurities present in the staring materials follows the same reaction
pathways as the starting material itself, and the reaction products could carry
over to the final product as process impurities”
Example :The presence of a 4-trifluoromethyl positional isomer in
3- trifluoromethyl-alpha-ethylbenzhydrol (flumecinol), due to the presence of
4- trifluoromethylbenzene impurity in the starting material, 3-trifluoromethylbenzene.
17

18. c) REAGENTS, LIGANDS AND CATALYSTS
These are less commonly found in APIs.
However, in some cases they may pose a problem as impurities.
Chemical reagents, ligands, and catalysts used in the synthesis of a drug substance can be
carried over to the final products as trace level impurities.
Example:
SYNTHESIS OF A ß LACTAM DRUG SUBSTANCE:
Carbonic acid chloromethyl tetrahydro-pyran-4-yl ester (CCMTHP) - alkylating agent,
was observed in the final product as an impurity.
18

19. “Many chemical reactions are promoted by metal based catalysts”
Example:
A Ziegler-Natta catalyst contains titanium
Grubb’s catalyst contains ruthenium
Adam’s catalyst contains platinum.
In some cases, reagents or catalysts may react with intermediates or final
products to form by-products.
Example:
Pyridine, a catalyst used in the course of synthesis of mazipridone, reacts
with an intermediate to form a pyridinium impurity.
19

20. d) BY-PRODUCTS OF THE SYNTHESIS
By-products can
be formed
through a variety
of side reactions,
such as:
By-products from
the side reactions
are the common
process
impurities in
drugs.
The side-
reactions are
common during
the synthesis of
drug substances.
Chemical
reactions are not
100% selective;
Incomplete reaction ,Over reaction,Isomerisation ,Dimerisation ,Rearrangement
Unwanted reactions of starting materials ,Intermediates with chemical reagents
Catalysts.
20

21. e) PRODUCTS OF OVER-REACTION
“In many cases the previous steps of the syntheses are not selective enough
and the reagents attack the intermediate at the desired site”
Synthesis of Nanodralone decanoate:
-Last step - Decanoylation of the 17-OH group.
-Overreaction:The reagents also attack the 4-ene- 3 oxo group leading to an enol
ester- type impurity (3, 17β- dihydroxyestra-3, 5- diene disdecanoate).
21

22. f) PRODUCTS OF SIDE REACTIONS
Side reactions are unavoidable in drug synthesis.
Side reactions leads to trace level impurities to be detected and
elucidated during impurity profiling.
The formation of diketopiperazine derivative is a typical side reaction
in peptide synthesis.
22

23. DIKETOPIPERAZINE DERIVATIVE
23

24. 24

25. IMPURITIES ORIGINATING FROM
DEGRADATION OF THE DRUG SUBSTANCE
Impurities can also be formed by degradation of the end product during
manufacturing of bulk drugs.
Degradation products resulting from storage or formulation to different dosage
forms or aging are common impurities in the medicines.
The definition of degradation product in the ICH guidelines is a molecule
resulting from a chemical change in the substance brought about by overtime
or due to the action of light, temperature, pH / water or by reaction with
excipient and/or the intermediate container closure system.
25

26. Example:
In the case of aspartame, in the presence of moisture, hydrolysis occurs
to form the degradation products L- aspartyl- LPhenyalanine and 3-
benzyl-6-carboxymethyl 2, 5-diketopierazine.
A third degradation product β-L- aspartyl-L-phenylalanine methyl
ester is also known to form.
Aspartame degradation also occurs during prolonged heat treatment.
26

27.  The majority of therapeutic chiral drugs used as pure enantiomers are
natural products
 High level of Enantio selectivity of their biosynthesis excludes the
presence of enantiomeric impurities
 In Synthetic chiral drugs, the racemates which are usually marketed, if
the pure enantiomer is administered, the antipode is considered to be
an impurity.
 The reason for its presence can be either the incomplete enantio
selectivity of the syntheses or incomplete resolution of the enantiomers
of the racemate.
ENANTIOMERIC IMPURITY
27

28. ICH guidelines exclude enantiomeric impurities, pharmacopoeias consider
them as ordinary impurities.
A single enantiomeric form of 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 reaction profile.
However, the pharmacokinetic profile of Levofloxacin (S-Isomeric form)
and Ofloxacin (R- isomeric form) are comparable, suggesting the lack of
advantages of single isomer in this regard.
The prominent single isomer drugs, which are being marketed, include
levofloxacin (S-ofloxacin), levalbuterol (R-albuterol) and esomeprazole
(Someprazole).
28

29. Examples of drugs containing enantiomeric impurities are:
Dexchlorophenarmine maleate (R enantiomer impurity allowed <0.5%)
Timolol maleate (R enantiomer impurity allowed < 1%)
Clopidogrel sulphate (R enantiomer impurity allowed < 1%)
*In general, an individual API may contain all of the above mentioned
types of organic impurities varying from negligible to significant level.
29

30. 30

31. GENOTOXIC IMPURITIES
The property of chemical agents that damages the genetic information
within a cell causing mutations, which may lead to cancer.
“All mutagens are genotoxic, whereas not all genotoxic substances are
mutagenic”
Genotoxic impurities have also been defined as an “impurity that has been
demonstrated to be genotoxic in an appropriate genotoxicity test model,
e.g., bacterial gene mutation (Ames) test”.
31

32. A FIVE-CLASS SYSTEM FOR CATEGORIZING
GENOTOXIC IMPURITIES
CLASS1: “Impurities known to be genotoxic (mutagenic) and carcinogenic”
It includes known animal carcinogens with reliable data for a
genotoxic mechanism, and human carcinogens.
The genotoxic nature of the impurity is demonstrated using published
data on the chemical structure.
32

33. CLASS2: “Impurities knownto be genotoxic(mutagenic), but with unknown carcinogenic
potential”
It includes impurities with demonstrated mutagenicity based
on testing of the impurity in conventional genotoxicity tests.
CLASS3: “Impurities that havean alerting structure unrelated to thestructureof the API,and of
unknowngenotoxic(mutagenic) potential”
It includes impurities with functional moieties that can be linked to
genotoxicity based on structure
These moieties have not been tested as isolated compounds and are
identified based on chemistry and using SAR.
33

34. CLASS4:
”Impurities with an alerting structure related to the API and impurities that containan alerting
functional moiety that is shared withthe structure of the API”
CLASS5:
No alerting structure or indicationof genotoxic potential.
34

35. REFERENCES:
https://www.agilent.com/cs/library/primers/Public/5991-1876EN.pdf
https://www.quora.com/What-are-the-sources-of-impurities-in-pharmaceutical-chemicals
https://www.google.com/search?rlz=1C1CHBD_enIN728IN733&sxsrf=ACYBGNQnHQ
HhVobDMABD1qyiU8R_3I0AA:1569165696641&q=What+are+genotoxic+impurities%3F&sa=X
&ved=2ahUKEwi8jsTf3eTkAhVMWH0KHZqpCXcQzmd6BAgMEAw&biw=1242&bih=553
https://www.slideshare.net/KamalAmbalia/impurities-in-drug-substance-in-drug-product
http://www.nihs.go.jp/dgm/files/dgmheadoffice_reguratory5.pdf
35

36. 36