Impurities in Drug

Substance & Drug

Product

VINOD JAISWAR
 Introduction
• This presentation is made with reference to the preparation of the
API.

• This is because the API is the source of the majority of impurities.

• When considering FPPs, the focus is largely on degradants, although

excipient-API and leaching from containers must not be
overlooked.
 What kinds of impurities are there?
• Things we add during preparation:
Solvents, metal catalysts, starting materials, reagents

• Things we unintentionally add during preparation:

Starting materials impurities; impurities within solvents, pesticides...

• Unwanted things that are made during preparation:

Reaction intermediates, related-substances

• Things that are formed after preparation:

Degradation products
 What are the potential impurities?
SM Potential Impurities
impuritie API SM
s Reagents
Solvents Residue of the SM
By- Catalysts
products Residue of the intermediate
Reaction Impurities in the SM
intermediate Reagents
Reagents
By- Solvents Solvents
products Catalysts Catalysts
Degradatio Final API Reaction by-products
n
Degradation products
Excipient-API Solvents? Excipient-API interactions
interactions
Container closure interactions
Container-
API FPP
interactions
When to specify impurities

The ICH divides impurities into

• Organic impurities (process- and drug-related)

• Residual solvents

• Inorganic impurities
 Impurities Limit
(Identification Threshold -
Unknown impurity)
Regardless of the related
Maximum daily dose Identification Threshold - The lower of:
substance requirements
of an applicable
% of API TDI
pharmacopoeia
API <2g 0.10% 1.0 mg
monograph, a test for
>2g 0.05% - any unspecified impurity
FPP < 1 mg 1.0% 5 ug and total impurities
1 mg – 10 mg 0.5% 20 ug should be included.
> 10 mg – 2 g 0.2% 2 mg
>2g 0.10% -
 Impurities Limit
(Qualification Threshold-
Known impurity)
Maximum daily dose Qualification Threshold - The lower of: Impurity above the
% of API TDI
applicable ICH
API < 2g 0.15% 1.0 mg
> 2g 0.05% -
qualification
FPP < 10 mg 1.0% 50 ug threshold needs to
10 mg - 100 mg 0.5% 200 ug be qualified.
> 100 mg - 2 g 0.2% 3 mg
>2g 0.15% -
 Impurities Limit
(Reporting Threshold-LOQ)
Impurity above the applicable ICH qualification
threshold needs to be qualified.

Maximum daily dose Qualification Threshold - The lower of:

% of API
API < 2g 0.05%

> 2g 0.03%
FPP <1g 0.10%

>1g 0.05%

LOQ need to be at least half of this limit. Lower the LOQ more method is sensitive. LOQ need to define
by visual, S/N ( 10-30) & Regression by slope method.
 Residual solvents
ICH limits apply – Q3C(R4)

• Class I solvents – See table 1, Q3C(R4)

• Class II solvents – 2 methods for calculating limits
Option 1 – Table of Q3C(R4) - predefined limits.
Good for APIs and FPPs
Option 2 – A limit based upon the calculated total exposure to the solvent in the FPP.

• Class III solvents – 5000 ppm is acceptable without further justification; might be controlled by
LOD (0.5%)
Class III solvent limits above 5000 ppm are permissible, but it would tend to indicate poor
manufacturing control.
Metal-ELEMENTAL
IMPURITIES

Harmonized pharmaceutical elemental impurity

regulations for USP 232 & ICH Q3D
To meet these low regulated levels, new analytical protocols for measuring elemental impurities using spectroscopic technique s are employed
using either:
•Inductively coupled plasma optical emission spectroscopy (ICP-OES)
•Inductively coupled plasma mass spectrometry (ICP-MS)
•Graphite furnace atomic absorption (AA)
Permitted daily exposures (PDE) for elemental impurities

Cd Pb As Hg Co V Ni Tl Au Pd Ir Os Rh Ru Se Ag Pt Li Sb Ba Mo Cu Sn Cr
Element
Class 1 1 1 1 2A 2A 2A 2B 2B 2B 2B 2B 2B 2B 2B 2B 2B 3 3 3 3 3 3 3

5 5 15 30 50 100 200 8 100 100 100 100 100 100 150 150 100 550 1200 1400 3000 3000 6000 11000
Oral PDE
(µg/day)

2 5 15 3 5 10 20 8 100 10 10 10 10 10 80 10 10 250 90 700 1500 300 600 1100

Parenteral
PDE
(µg/day)

2 5 2 1 3 1 5 8 1 1 1 1 1 1 130 7 1 25 20 300 10 30 60 3
Inhalation
PDE
(µg/day)
 Further information
• They must undertake a rigorous testing investigation, including use of appropriate
test methods.
• Monographs & DMF are an excellent source of information on possible related
substances and degradation impurities but are not complete.

• When applying thresholds consider TDI and RRF of the impurity

Thank you