Setting spec limit for imps

Setting Specification
Limits for Impurities in
Active Pharmaceutical
Ingredient (API’s)
January, 2015
1

Points Covered
Classification of Impurities
Setting the specification limit for Organic Impurities
Setting the specification limit for Residual Solvents
Setting the specification limit for Inorganic Impurities
Setting the specification limit for the Solvents or Reagents
(Not related to API) not listed in ICH Q3C Guideline
2
Points Covered

Purpose of Module
To create awareness to the employees on setting the
specification limit for Impurities in the final API as
per the ICH Q3A and Q3C Guidelines
3
Purpose of Module

What is an Impurity:
Any component of the API that is not the chemical entity
defined as the API is called as an impurity.
Identified Impurity:
An impurity for which a structural characterisation has been
achieved.
Specified Impurity:
An impurity that is individually listed and limited with a
specific acceptance criterion in the specification. Can be
either identified or unidentified.
4
Definitions:
Definitions

Definitions:…
Unidentified Impurity:
An impurity for which a structural characterisation has not
been achieved and that is defined solely by qualitative
analytical properties (e.g. chromatographic retention time).
Unspecified Impurity:
An impurity that is limited by a general acceptance criterion,
but not individually listed with its own specific acceptance
criterion in the specification.
Qualification:
Process of acquiring and evaluating data that establishes the
biological safety of an individual impurity or a given impurity
profile at the level(s) specified.
5
Definitions

Classification of Impurities
Impurities are classified into the following
categories:
Organic impurities (API-related Impurities)
Inorganic impurities
Residual solvents
6

Organic Impurities
Organic Impurities
(API Related Impurities)
7

Organic Impurities
Organic Impurities:
Organic impurities can 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
8

Specification limit for Organic Impurities:
When the product is listed in Major Pharmacopoeia
like, USP or EP.
The impurity limits must comply the requirements of the
Pharmacopoeia.
If the impurity limits are different in all the pharmacopoeia,
then the stringent limit must be adopted.
The limit for any unspecified impurities must be defined as
not more than 0.10% or 0.05% based on the dosage (For
Veterinary APIs Not more than 0.20%), eventhough the
pharmacopoeia specifies the higher limit.
9
Specification Limit for Organic Impurities

Specification limit for Organic Impurities:…
Where the product is listed in Major Pharmacopoeia
like, USP or EP:...
Wherever Pharmacopeia gives a limit of more than 0.10%
or 0.05% based on the dosage (0.20% for Veterinary APIs)
for impurities in general, such limits are applicable only for
known impurities listed in the monograph.
When the pharmacopoeia contains the test for
Chromatographic purity by TLC (instead of HPLC), a suitable
HPLC, GC … method needs to be adopted specifying the
impurity limits inline with the ICH Guidelines.
10

Specification limit for Organic Impurities:…
Where the product is listed in Major Pharmacopoeia
like, USP or EP:….
Thin-layer chromatography methods should only be used
for control of a specified impurity and where liquid
chromatography, gas chromatography or capillary
electrophoresis methods are inappropriate (usually due to a
lack of a suitable detection system).
11

Specification limit for Organic Impurities For
Non-Pharmacopoeia APIs:
The limits must be specified as per the below table
12
Thresholds of Impurities for Human API’s
Maximum
daily dosage
Reporting
threshold
Identification
Threshold
Qualification
Threshold
< 2 g/day 0.05% 0.10% or 1.0 mg per
day intake (whichever
is lower)
0.15% or 1.0 mg per day
intake (whichever is
lower)
> 2 g/day 0.03% 0.05% 0.05%
Thresholds of Impurities for Veterinary API’s
Maximum
daily dosage
Reporting
threshold
Identification
Threshold
Qualification
Threshold
- 0.10% 0.20% 0.50%

Specification limit for Organic Impurities:….
For Non Pharmacopoeia APIs:….
For the API’s having both human and veterinary applications,
the limits must be specified considering it as Human API.
If the maximum daily dosage is more than 2.0g/day, limit for
Identified and Unidentified impurities is 0.05%.
The limit for Unidentified impurity is 0.10% if the daily
dosage is ≤ 1g/day. The limit for Identified impurity is 0.15% if
the daily dosage is ≤ 0.66g/day.
If the maximum daily dosage is more than the dosages
mentioned above and less than 2g/day, the limits for Identified
and Unidentified impurities are calculated as :
% limit = (1.0 X 100)/ max daily dosage in mg
13

Specification limit for Organic Impurities:….
For Non Pharmacopoeia APIs:….
For Veterinary API’s the limit for Identified and
Unidentified impurities are 0.50% and 0.20%
respectively.
Higher limits can be specified only if the Biological
safety of the impurity is established (i.e., if the impurity
is qualified).
14

Residual Solvents
Residual Solvents
15

Residual Solvents
Introduction:
Residual solvents are the organic volatile chemicals that
are used or produced in the manufacture of drug
substances or excipients, or in the preparation of drug
products. The solvents are not completely removed by
practical manufacturing techniques.
Since there is no therapeutic benefit from residual
solvents, all residual solvents should be removed to the
extent possible to meet product specifications.
16

Residual Solvents
Classification of Residual Solvents by Risk
Assessment:
Class 1 solvents: Solvents to be avoided
Known human carcinogens, strongly suspected human
carcinogens, and environmental hazards.
Class 2 solvents: Solvents to be limited
Non-genotoxic animal carcinogens or possible causative
agents of other irreversible toxicity such as neurotoxicity or
teratogenicity.
Class 3 solvents: Solvents with low toxic potential
Solvents with low toxic potential to man; no health-based
exposure limit is needed. Class 3 solvents have PDEs of 50
mg or more per day.
17

Residual Solvents
Options for Describing Limits of Class 2
Solvents :
Two options are available when setting limits for Class 2
solvents.
Option 1: The concentration limits in ppm stated in ICH
Q3C Guideline can be used. They were calculated using
the formula given below, by assuming a product mass of
10 g administered daily.
1000 X PDE (mg/day)
Concentration (ppm) = ----------------------------
dose (g/day)
18

Residual Solvents
Options for Describing Limits of Class 2
Solvents :…
Option 2: The limits are calculated using the above
formula based on the PDE reported in the ICH Q3C
Guideline and the maximum daily dosage of the Drug
substance.
The limits calculated are acceptable provided that it
has been demonstrated that the residual solvent has
been reduced to the practical minimum. The limits
should be realistic in relation to analytical precision,
manufacturing capability.
19

Limits of Residual Solvents
Class 1 solvents :
20
Solvent Concentration limit
(ppm)
Benzene 2
Carbon tetrachloride 4
1,2-Dichloroethane 5
1,1-Dichloroethene 8
1,1,1-Trichloroethane 1500

Class 2 solvents :
21
Solvent Limit (ppm) Solvent Limit (ppm)
Acetonitrile 410 2-Ethoxyethanol 160
Chlorobenzene 360 Ethyleneglycol 620
Chloroform 60 Formamide 220
Cyclohexane 3880 Hexane 290
1,2-Dichloroethene 1870 Methanol 3000
Dichloromethane 600 2-Methoxyethanol 50
1,2-Dimethoxyethane 100 Methylbutyl ketone 50
N,N-Dimethylacetamide 1090 Methylcyclohexane 1180
N,N-Dimethylformamide 880 N-Methylpyrrolidone 530
1,4-Dioxane 380 Nitromethane 50
Tetrahydrofuran 720 Pyridine 200
Tetralin 100 Sulfolane 160
1,1,2-Trichloroethene 80 Toluene 890
Xylene 2170 - -

Class 3 solvents :
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) is acceptable.
22
Solvent Solvent Solvent
Acetic acid Ethanol 3-Methyl-1-butanol
Acetone Ethyl acetate Methylethyl ketone
Anisole Ethyl ether Methylisobutyl ketone
1-Butanol Ethyl formate 2-Methyl-1-propanol
2-Butanol Formic acid Pentane
Butyl acetate Heptane 1-Pentanol
tert-Butylmethyl ether Isobutyl acetate 1-Propanol
Cumene Isopropyl acetate 2-Propanol
Dimethyl sulfoxide Methyl acetate Propyl acetate

Solvents for which No Adequate Toxicological Data was
Found:
No adequate toxicological data is found for the following
solvents.
23
Solvent Solvent
1,1-Diethoxypropane Methylisopropyl ketone
1,1-Dimethoxymethane Methyltetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid

Inorganic Impurities
24

Introduction:
Inorganic impurities can result 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)
25

Control of Inorganic Impurities
Control of the Impurities:
Detected and quantified using pharmacopoeial or other
appropriate procedures.
Carry over of the catalysts to the API must be evaluated
during the development stage.
Inclusion/exclusion from the specification must be
justified.
Acceptance criteria must be based on pharmacopoeial
or known safety standard.
Controlled by the tests Heavy Metals, Sulfated Ash, test
for specific metal….
26

Specification limit for Heavy Metals:
As specified by Pharmacopeia wherever applicable.
Specification limit where the product is not listed in
the pharmacopoeia:
27

Specification limit for Sulfated Ash:
As specified by Pharmacopeia wherever applicable.
When it is not listed in pharmacopoeia, must be
specified as 0.1%, unless otherwise justified.
Specification limit for Metal Catalysts:
Must be specified inline with the EMEA guideline on
metal Catalysts.
If the metal is not listed, must specify based on the
available toxicology data or any other guidance.
28

Specification limit for some of the metal Impurities:
*The total amount of listed metals should not exceed the indicated limit
(Reference: EMEA Guideline for specification limits for metal resides)
29
Classificatio
n
Oral Exposure Parenteral Exposure
PDE (µg/day) Conc. (ppm) PDE (µg/day) Conc. (ppm)
Class IA:
Pt, Pd
100 10 10 1
Class 1B*:
Ir, Rh, Ru, Os
100 10 10 1
Class 1C:
Mo, Ni, Cr, V
250 25 25 2.5
Class 2:
Cu, Mn
2500 250 250 25
Class 3:
Fe, Zn
13000 1300 1300 130

Specification limit for Non-API related impurities not
listed in ICH Q3C Guideline
Setting the specification limit for the Solvents or
Reagents (Not related to API) not listed in ICH
Q3C Guideline
30

Introduction:
The specification limit for the solvents or reagents which
are not listed in ICH Q3C must be determined based on
the Toxicological data.
Formula for the calculation of the impurity is given in the
next slide:
31

Methods for Establishing Exposure Limits:
Acceptable exposure levels is calculated from the PDE
values inline with the procedure given in ICH Q3C
Guideline as below:
1000 X PDE (mg/day)
Concentration (ppm) = ----------------------------
dose (g/day)
32

Calculation of the PDE Value:
Where PDE value is not available, PDE is derived from
the no-observed-effect level (NOEL), or the lowest-
observed effect level (LOEL) in the most relevant animal
study as follows:
NOEL x Weight Adjustment
PDE = -------------------------------------
F1 x F2 x F3 x F4 x F5
33

Calculation of the PDE Value:…
F1 = A factor to account for extrapolation between species.
F2 = A factor of 10 to account for variability between
individuals.
F3 = A variable factor to account for toxicity studies of short-
term exposure.
F4 = A factor that may be applied in cases of severe toxicity,
e.g. non-genotoxic carcinogenicity, neurotoxicity or
teratogenicity.
F5 = A variable factor that may be applied if the no-effect
level was not established.
34

A typical calculation for Establishing Exposure Limits
(Specification Limit) is attached.
35

References
References:
IMPURITIES IN NEW DRUG SUBSTANCES Q3A.
IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS
Q3C.
GUIDELINE ON THE SPECIFICATION LIMITS FOR
RESIDUES OF METAL CATALYSTS OR METAL REAGENTS.
36

Setting spec limit for imps

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