This presentation explains ICH guideline - Q3AR2 in an understandable way by giving examples. How to impart in the dossier, format for writing impurities in drug substance is given in the book: 1. https://www.scribd.com/book/429190300/Impurities-In-Drug-Substances-ICH-Explained 2. https://www.smashwords.com/books/view/961598 a small book explaining ICH guidelines - impurities in new drug substances with examples also available in https://books2search.com/impurities-in-drug-substances-ich-explained-9780463960592 https://www.chapters.indigo.ca/en-ca/books/contributor/author/kiran-nivedh/

1. IMPURITIES IN NEW DRUG SUBSTANCES
By
Kiran Nivedh
Freelance writer
knowaboutregulatory@gmail.com

2. NEWS PAPER CUTTINGS

3. WHERE ARE WE GOING TO WALK?
What is
an
impurity?
Why to
control it?
Overview
of how an
impurity
arises?
Perspectives
of impurities
Classifica
tion of
impurities
Origin of
organic,
inorganic
and solvent
impurities
Rationale
for the
reporting
and
control of
impurities
Analytical
Procedures
Listing of
impurities in
specifications
Threshold
of
impurities
Decision tree
for
identification
and
qualification

4. WHAT IS AN IMPURITY?
Any component in the API which is not the API
They are not introduced accidently or maliciously
They may or may not be potentially harmful.

5. WHY CONTROL IMPURITIES
Impurities may lower the shelf life of the substances- impurities in the excipients.
Impurities may cause difficulties during formulations and use of the substances- Presence of KIO3 in KI solution
Sometimes Impurities changes the physical and chemical properties of the substances- ‘W’- sodium pyrosulfite and oxygen-
discolorization and precipitation ; Thiomersal – Bromide, chloride, iodine- Form different soluble halides of cationic mercury compounds
Therapeutic effect can be decreased- sunlight having about 8000 foot-candles (86111.283 Lux) can destruct nearly 34% of vitamin–B
in 24 h
Harmful when present above certain limits – Arsenic, Benzene and Toluene etc.
It may change odour, colour, taste of the substance – Impurities due to colouring and flavoring substance- phenolic compounds in sodium
salicylate
And many………

6. WHERE COMES THE IMPURITIES IN DRUG SUBSTANCES?
Probability
Probability for impurity occurring
Steps
Drug
Substances
API Synthesis API Purification Packing and
Storage

7. SOURCES OF IMPURITIES IN DRUG SUBSTANCES
Starting Materials or intermediates
• In the synthesis of baclofen the last step carried out with beta-(p-chlorophenyl) gutarimide, which on reaction with NaOH/
NaOCl at room temperature yields a potential impurity p-chloro phenyl glutaric acid
• Degradation product during manufacturing of bulk drugs degradation of end products results in the formation of impurities.
Hydrochlorothiazide has a known degradation pathway through which it degrades to the starting material as disulfonamide in
its synthesis
By – products
• Formed through variety of side reactions, such as incomplete reaction, over reaction, isomerization, dimerization, rearrangement
or unwanted reactions between starting materials or intermediate with chemical reagents or catalysts- Paracetamol bulk
production, diacetylated paracetamol may forms as a by- product.
Residual solvents
. Potentially undesirable substances. They either modify the properties of certain compounds or may be hazardous to human
health. affect physicochemical properties of the bulk drug substances such as crystallinity of bulk drug, which in turn may affect
the dissolution properties, odor and color changes in finished products.

8. SOURCES OF IMPURITIES IN DRUG SUBSTANCES
Method related impurity
A known impurity, 1-(2, 6-dichlorophenyl) indolin-2-one is formed in the diclofenac sodium ampoules. Formation of this
impurity depends on initial pH of the preparation and the condition of sterilization i.e., autoclave method (123±2
deg C) that enforce the intramolecular cyclic reaction of diclofenac sodium forming indolinone derivative and sodium
hydroxide .
Environmental related impurity
Temperature, Light - UV light, Humidity
Impurities on Aging
Mutual interaction amongst ingredients - Most often, vitamins are highly prone to instability on aging in different
dosage forms. i.e., degradation of vitamins such as folic acid, thiamine and cyanocobalamines does not yield toxic
impurities but lose their potency well below compendial specifications

9. SOURCES OF IMPURITIES IN DRUG SUBSTANCES
Hydrolysis
A reaction in which water is the reactant causing precipitation. Well-known examples of such reactions in pharmaceutical
compounds are esters and amides - Aspirin
Oxidation, Photolysis and Decarboxylation
• Drugs which prone to oxidation are hydrocortisone, methotrexate, adinazolam, catecholamine, conjugated-dienes
(Vitamin–A), heterocyclic aromatic rings, nitroso and nitrite
Metals – catalyze oxidation of drugs and their degradation pathway.
• Photolytic cleavage on aging includes examples of pharmaceutical drugs or products that are prone to degradation on
exposure to UV-light
• Some of the carboxylic acids such as p-amino salicylic acid shown loss of carbon dioxide from carboxyl group when
heated
Packaging material
Impurities result also from packaging materials i.e., containers and closures
Extractable or leachables – Emerge from glass, rubber stoppers and plastic materials, in which oxides like NO2,SiO2, CaO,
MgO from glass, styrene from polystyrene, diethylhexylpthalate (DEHP) plasticizer in PVC,, zinc stearate stabilizer in PVC and
polypropylene.

10. PERSPECTIVES OF IMPURITIES
Chemistry Aspects:
 Classification
 Identification of impurities
 Report generation
 Listing of impurities
 Brief discussion on impurities
Safety Aspects:
 Qualification of impurities

11. CLASSIFICATION OF IMPURITIES (ICH)
Inorganic
Organic
Impurities
Residual
Solvents

12. ORIGIN OF ORGANIC IMPURITIES
Organic
Impurities
Starting
Materials
By-Products
Intermediate
Degradation
Product
Reagents
Ligands and
Catalysts
2-methyl analogue
(from 2-methylpropiophenone)
- Tolperisone
Aniline in Tripranavir
Pyridine ( catalyst) in mazipridone
Pyrazole ( Ligands) in nanojars
Diacetylated paracetamol in
paracetamol
carbonic acid chloromethyl tetrahydro-pyran-4-yl ester
(CCMTHP), in the synthesis of a ß lactam
Hydrolysis of mannitol
containing methyl
prednisolone sodium

13. ORIGIN OF INORGANIC IMPURITIES
Inorganic
Impurities
Heavy
Metals
Inorganic
Salts
Filter Aids,
Charcoal, etc.
Catalysts
Reagents
Ligands
mineral powders,
diatomite Barium in potassium bromide
synthesis
Chloride salts platinum EDTA
arsenic, bismuth

14. ORIGIN OF SOLVENT IMPURITIESORIGIN OF
Residual
Solvent
Impurities
Vehicles During
synthesis - Residues
Dissolution during
Purification-
Residues
Dissolution during
crystallization -
Residues
Used during
formulation-
Residues
Toluene in CPM Acetone
PEG
Water

15. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Organic Impurities
Can be actual and Potential impurities
Can be identified or unidentified
Can be volatile or non- volatile

16. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Organic Impurities

17. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Organic Impurities
Origin

18. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Organic Impurities
Categorized

19. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Organic Impurities
Two decimal
Places (< 1%)
One decimal
Place (>1 %)

20. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Summary of the laboratory studies conducted to detect impurities
– Should include development process batches and proposed commercial batches
Example as follows

21. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES - ORGANIC
Studies to characterize the structure of actual impurities
Example:-

22. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES- INORGANIC
Inorganic Impurities:
Detected and identified using pharmacopoeial or other appropriate procedures
Information on carry over of catalysts
Justification of inclusion or exclusion in the specification
Acceptance criteria based on pharmacopoeial standards or known safety data

23. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES- INORGANIC
Example - - - - - - -
Two decimal
Places (< 1%)
One decimal
Place (>1 %)

24. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES- INORGANIC
Example - - - - - - -

25. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES- SOLVENTS
Discussed and presented as per ICH Q3C
Include:
 List of residual solvents at different stages
identified,
 Limits established
 Data of the residual solvents

26. ANALYTICAL PROCEDURES
Procedures shall be validated/ verified
Lower precision techniques also accepted when justified eg. Thin layer
chromatography
Quantitation limit should not be more than reporting threshold
Organic impurities measured – comparing analytical response to an reference
standard (Known Impurities)
– comparing the new drug substance
(Unknown impurities)

27. ANALYTICAL PROCEDURES
- signifies that this characteristic is not normally evaluated
+ signifies that this characteristic is normally evaluated
(1) in cases where reproducibility (see glossary) has been performed, intermediate precision is not needed
(2) lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s)
(3) may be needed in some cases
Type of analytical procedure TESTING FOR IMPURITIES
characteristics quantitat. Limit
Accuracy + -
Precision
Repeatability
Interm.Precision
+ -
+ (1) -
Specificity (2) + +
Detection Limit - (3) +
Quantitation Limit + -
Linearity + -
Range + -

28. LISTING OF IMPURITIES IN SPECIFICATIONS
Should include:-
Organic impurities
 Specified Identified
 Specified Unidentified
 Any unspecified impurity with an acceptance criteria NMT the identification threshold
 Total Impurities
Residual Solvents
Inorganic Impurities

29. LISTING OF IMPURITIES IN SPECIFICATIONS-
ORGANIC IMPURITIES
Selection of impurities based on impurities present in the batches manufactured by the proposed
commercial process
Impurity routinely observed in batch data or long-term stability trials should be controlled by the
impurity specifications
Impurities above the ICH identification threshold need to be identified and individually specified in
the specifications.
Impurities observed below the ICH identification threshold need not be individually specified in the
specifications. They can be controlled under the limit for any unspecified impurity.
Regardless of the related substance requirements of an applicable pharmacopoeial
monograph, a test for any unspecified impurity and total impurities should be included
Remove or Omit in Specification:
The absence of specific test should be demonstrated on at least 3 production batches or 6 pilot
scale batches, if wanted to remove or omit

30. LISTING OF IMPURITIES IN SPECIFICATIONS-
RESIDUAL SOLVENTS
Remove or Omit in Specification:
The absence of specific test should be demonstrated on at least 3 production batches or 6 pilot scale batches,
if wanted to remove or omit

31. LISTING OF IMPURITIES IN SPECIFICATIONS –
METAL RESIDUES
Metal residues: EMEA/CHMP/SWP/4446/2000

32. LISTING OF IMPURITIES IN SPECIFICATIONS -
GENOTOXIN
If a genotoxin is formed or is likely to be formed during manufacture or storage then a limit
for this impurity should be included in specifications.
If batch data (6 pilot or 3 production) demonstrate that levels of the impurity are at or below
30% of the allowable limit then non-routine testing may be adopted. It should still be
specified.
 For instance, if ‘A’ and ‘B’ were used in the last step, but ‘A’ was not detected then it may be
appropriate to test once annually.
 if ‘A’ and ‘B’ were used in the first of three steps, but ‘A’ was not detected then it may be
appropriate to specify the test is to be applied when there is a change in manufacture.

33. THRESHOLD OF IMPURITIES
[1] The amount of drug substance administered per day
[2] Higher reporting thresholds should be scientifically justified
[3] Lower thresholds can be appropriate if the impurity is unusually toxic

34. Decision Tree for Identification and Qualification
Yes
No
Consider patient population and duration of use and
consider conducting:
 Genotoxicity studies (point mutation,
chromosomal aberration)a
 General toxicity studies (one species, usually
14 to 90 days)b
 Other specific toxicity endpoints, as
appropriate
Is impurity greater
than identification
thresholdc
?
Yes
Yes
No
Structure
identified?
Any
clinically
relevant adverse
effects?
Qualified
Yes No No action
No
Greater than
qualification
thresholdc
?
Yes
Any
known human
relevant risksd?
No
Reduce to
safe level
Reduce
to not more than
() identification
thresholdc?
Reduce
to not more than
() qualification
thresholdc?
No further
action
No action
Reduce to
safe level
Yes
No
Yes
No

35. If Not , Thank You !

36. REFERENCES
Q3A(R2)- Impurities in New Drug Substances
Pharmaceutical Impurities: An Overview N. Rama Rao, S. S. Mani Kiran* and Prasanthi N.L. , ijper,
Indian J.Pharm. Educ. Res. 44(3), Jul-Sep, 2010
https://www.slideshare.net/lingeswararaopunati/impurities-71511950
WHO PQ model Dossier
Establishing Impurity specifications by Dr. Antony Fake PhD – WHO prequalification medicines
programme
The Role Of Relative Response Factor In Related Substances Method Development By High
Performance Liquid Chromatography (Hplc) V V.Kalyana Chakravarthy*, G. Kishore Babu, R.
Lakshmana Dasu, P. Prathyusha And G. Aparna Kiran, Vol.4, No.4 (2011), 919-943, Rasayan J.
Chem