2. IMPURITIES IN DRUG SUBSTANCES
TOPICS TO BE COvERED:
Introduction
Classification of Impurities
Rationale for the Reporting and Control of Impurities
Analytical Procedure
Identification, Reporting and Qualification of
Impurities
Listing of Impurities in Specification
Illustration of Reporting Impurity Results for
Identification and Qualification in an Application
Decision Tree for Identification and Qualification
More on Residual Solvents
2
3. INTRODUCTION
Objective:
The
objective
of
the
guideline
makes
recommendation to applicant on reporting,
identifying and qualifying information on impurities
in new drug substance.
What is impurity?
Any component of the new drug substance that is not
the chemical entity defined as the new drug
substance.
or
Any component that is not the drug substance or an
excipient.
3
4. ClASSIfICATION Of IMPURITIES
Impurities can be classified into the following categories:
1. Organic impurities (process- and drug-related)
2. Inorganic impurities
3. Residual solvents
4
5. 1. 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
Reagents, ligand and catalysts
5
6. 2. INORGANIC IMPURITIES:
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)
6
7. 3. RESIDUAl SOlvENTS:
Solvents are inorganic or organic liquids used as vehicles
for the preparation of solutions or suspensions in the
synthesis of a new drug substance.
Residual solvents in pharmaceuticals are defined as
organic volatile chemicals that are used or produced in the
manufacture of drug substances.
7
8. RATIONAlE fOR THE REPORTING
AND CONTROl Of IMPURITIES
Organic Impurity:
The actual and potential impurities most likely to arise during the
synthesis, purification, and storage of the new drug substance
should be summarised.
Inorganic Impurity:
Inorganic impurities are normally detected and quantified using
pharmacopoeial or other appropriate procedures. Carry-over of
catalysts to the new drug substance should be evaluated during
development
Residual Solvent:
The control of residues of the solvents used in the manufacturing
process for the new drug substance should be discussed and
presented according to the ICH Q3C Guideline for Residual
Solvents.
8
9. ANAlyTICAl PROCEDURE
Analytical Procedures should be validated and
demonstrate that it is suitable for the detection and
quantification of the impurities.
Reference standards used in the analytical procedures
for control of impurities should be evaluated and
characterised according to their intended uses.
9
10. IDENTIfICATION, REPORTING AND
QUAlIfICATION Of IMPURITIES
Quantitative results should be presented numerically,
and not in general terms such as “complies”, “meets
limit” etc.
Below 1.0%, the results should be reported to two
decimal places (e.g., 0.06%, 0.13%); at and above
1.0%, the results should be reported to one decimal
place (e.g., 1.3%).
Results should be rounded using conventional rules.
10
11. IDENTIfICATION, REPORTING AND
QUAlIfICATION Of IMPURITIES (CONTD.)
Thresholds:
Maximum
Daily Dose
≤ 2g/day
Reporting
Threshold
0.05%
> 2g/day
0.03%
Identification
Threshold
0.10% or 1.0 mg
per day intake
(whichever is lower)
0.05%
Qualification
Threshold
0.15% or 1.0 mg per day
intake
(whichever is lower)
0.05%
Any impurity at a level greater than (>) the identification threshold should
be identified.
Any impurity at a level greater than (>) the reporting threshold (and total
impurities observed in these batches of the new drug substance should be
reported.
All impurities at a level greater than (>) the reporting threshold should be
summed and reported as total impurities.
All impurities at a level greater than (>) the qualification threshold should
be qualified.
11
12. LISTING OF IMPURITIES IN SPECIFICATION
The specification for a new drug substance should include a list of
impurities.
The selection of impurities in the new drug substance specification
should be based on the impurities found in batches manufactured by the
proposed commercial process.
Specified impurities can be identified or unidentified.
In summary, the new drug substance specification should include, where
applicable, the following list of impurities:
Organic Impurities
Each specified identified impurity
Each specified unidentified impurity
Any unspecified impurity with an acceptance criterion of not
more than (≤) the identification threshold
Total impurities
Residual Solvents
Inorganic Impurities
12
13. DEFINITION
Impurity Profile:
A description of the identified and unidentified impurities present in a
new drug substance.
Potential Impurity:
An impurity that theoretically can arise during manufacture or storage. It
may or may not actually appear in the new drug substance.
Identified Impurity:
An impurity for which a structural characterisation has been achieved.
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).
13
14. DEFINITION (CONTD.)
Specified Impurity:
An impurity that is individually listed and limited with a specific
acceptance criterion in the new drug substance specification. A specified
impurity can be either identified or unidentified.
Unspecified impurity:
An impurity that is limited by a general acceptance criterion, but not
individually listed with its own specific acceptance criterion, in the new
drug substance specification.
Enantiomeric Impurity:
A compound with the same molecular formula as the drug substance that
differs in the spatial arrangement of atoms within the molecule and is a
non-superimposable mirror image.
14
15. ILLUSTRATION OF REPORTING IMPURITy
RESULTS FOR IDENTIFICATION AND
QUALIFICATION
Example 1: 0.5 g Maximum Daily Dose
Reporting threshold
= 0.05%
Identification threshold
= 0.10%
Qualification threshold
= 0.15%
"Raw" Result
(%)
0.044
0.0963
0.12
0.1649
Reported Calculated Total
Result
Daily Intake
(%)
(TDI) (mg) of
Reporting
the impurity
threshold (rounded result
=0.05%
in mg)
Not
reported
0.10
0.12
0.16
Action
Identification
Qualification
(Threshold
(Threshold
0.10%
0.15%
exceeded?)
exceeded?)
0.2
None
None
0.5
0.6
0.8
None
Yes
Yes
None
None
Yes
15
16. ILLUSTRATION OF REPORTING IMPURITy
RESULTS FOR IDENTIFICATION AND
QUALIFICATION (CONTD.)
Example 2: 0.8 g Maximum Daily Dose
Reporting threshold
= 0.05%
Identification threshold
= 0.10%
Qualification threshold
= 1.0 mg TDI
“Raw” Result
(%)
0.066
0.124
0.143
Reported Calculated Total
Result
Daily Intake
(%)
(TDI) (mg)
Reporting of the impurity
threshold (rounded result
=0.05%
in mg)
0.07
0.12
0.14
0.6
1.0
1.1
Action
Identification
Qualification
(Threshold
(Threshold 1.0
0.10%
mg TDI
exceeded?)
exceeded?)
None
yes
yes
None
None
Yes
16
17. DECISION TREE FOR
IDENTIFICATION AND QUALIFICATION OF
IMPURITy
Is impurity greater than
identification threshold?
Yes
No
Yes
Structure
identified
Any known human
relevant risks?
No
No
Reduce to NMT(≤)
Identification threshold
Yes
No further
action
Yes
No
Consider……
Yes
No
Reduce to NMT(≤)
Qualification
threshold
Yes
Greater than
Qualification
threshold
No
Reduce to
safe level
18. DECISION TREE FOR IDENTIFICATION AND
QUALIFICATION OF IMPURITy (CONTD.)
Consider patient population and duration of use and consider conducting:
Genotoxicity studies (point mutation, chromosomal aberration)
General toxicity studies (one species, usually 14 to 90 days)
Other specific toxicity endpoints, as appropriate
Yes
Any clinically relevant
adverse effects?
No
19. MORE ON RESIDUAL SOLvENTS
ICH Q3C, recommends acceptable amounts for residual solvents
in pharmaceuticals for the safety of patients.
It recommends use of less toxic solvents and describes levels
considered to be toxicologically acceptable for some residual
solvents.
Appropriate selection of the solvent for the synthesis of drug
substance may enhance the yield, or determine characteristics
such as crystal form, purity, and solubility.
Since there is no therapeutic benefit from residual solvents, all
residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or
other quality-based requirements.
20. MORE ON RESIDUAL SOLvENTS
(CONTD.)
CLASSIFICATION
SOLvENTS:
Solvent
OF
RESIDUAL
Concentration limit
(ppm)
Concern
Benzene
Carbon tetrachloride
2
4
1,2-Dichloroethane
1,1-Dichloroethene
1,1,1-Trichloroethane
5
8
1500
Carcinogen
Toxic and environmental
hazard
Toxic
Toxic
Environmental hazard
23. MORE ON REsidual sOlvENts
(cONtd.)
ICH Q3C defines options for the definition of
acceptance criteria for class 2 solvents
OptiON 1:
⇒
tabulated limits, calculated on the basis of a TDI
(Tolerable Daily Intake) of 10 g of the product
OptiON 2:
⇒
Products that are administered in doses greater
than 10 g per day should be considered under
Option 2
24. MORE ON REsidual sOlvENts
(cONtd.)
ExaMplE fOR OptiON 2:
Concentration (ppm) =
Component
Amount in formulation
1000 x PDE
dose
Acetonitrile content
Daily exposure
Drug substance
0.3 g
800 ppm
0.24 mg
Excipient 1
0.9 g
400 ppm
0.36 mg
Excipient 2
3.8 g
800 ppm
3.04 mg
Drug Product
5.0 g
728 ppm
3.64 mg
PDE (Permitted Daily Exposure) limit : 4.1 mg/day, limit: 410 ppm
25. iMpuRitiEs iN dRuG pROducts
tOpics tO bE cOvEREd:
Introduction
Rationale for the Reporting and Control of
Degradation Products
Analytical Procedure
Reporting Degradation Products Content of Batches
Listing of Degradation Products in Specifications
Qualification of Degradation Products
Decision Tree for Identification and Qualification of a
Degradation Products
25
26. iNtROductiON
Objective:
The objective of the guideline makes recommendation
to applicant on the content and qualification of
impurities in new drug products produced from
chemically synthesised new drug substance.
What is Degradation Product?
An impurity resulting from a chemical change in the
drug substance brought about during manufacture
and/or storage of the new drug product by the effect of,
for example, light, temperature, pH, water, or by
reaction with an excipient and/or the immediate
container closure system.
26
27. RatiONalE fOR tHE REpORtiNG aNd
cONtROl Of dEGRadatiON pROducts
The applicant should summarize the degradation
products observed during manufacture and/or stability
studies of the 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 excipients
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 excipients). The impurity
profiles of the batches representative of the proposed
commercial process should be compared with the
profiles of batches used in development and any
differences discussed.
27
28. RatiONalE fOR tHE REpORtiNG aNd
cONtROl Of dEGRadatiON pROducts
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 thresholds.
When identification of a degradation product is not
feasible, a summary of the laboratory studies
demonstrating the unsuccessful efforts to identify it
should be included in the registration application.
28
29. aNalytical pROcEduRE
Analytical Procedures should be validated and
demonstrate that it is suitable for the detection and
quantification of the 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 quantitation limit for the analytical procedure
should be not more than (≤) the reporting threshold.
29
30. REpORtiNG dEGRadatiON
pROducts 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.
Quantitative results should be presented numerically, and
not in general terms such as “complies”, “meets limit” etc.
Any degradation product at a level greater than (>) the
reporting threshold, 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%, the results should be reported to the number of
decimal places (e.g., 0.06%) in the applicable reporting
threshold; at and above 1.0%, the results should be reported
to one decimal place (e.g., 1.3%).
30
31. listiNG Of dEGRadatiON pROducts
iN spEcificatiON
The specification for a new drug product should include a list
of degradation products.
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 product 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
31
Total degradation products.
32. dEfiNitiON
Degradation Profile:
A description of the degradation products observed in the drug
substance or drug product.
Development Studies:
Studies conducted to scale-up, optimise, and validate the manufacturing
process for a drug product.
Identification Threshold:
A limit above (>) which a degradation product should be identified.
Identified Degradation Product:
A degradation product for which a structural characterisation has been
achieved.
New Drug Substance:
The designated therapeutic moiety that has not been previously
registered in a region or member state (also referred to as a new
molecular entity or new chemical entity). It can be a complex, simple
ester, or salt of a previously approved substance.
32
33. dEfiNitiON (cONtd.)
Qualification:
The process of acquiring and evaluating data that establishes the biological
safety of an individual degradation product or a given degradation profile at
the level(s) specified.
Qualification Threshold:
A limit above (>) which a degradation product should be qualified.
Reporting Threshold:
A limit above (>) which a degradation product should be reported.
Specified Degradation Product:
A degradation product that is individually listed and limited with a specific
acceptance criterion in the new drug product specification. A specified
degradation product can be either identified or unidentified.
Unidentified Degradation Product:
A degradation product for which a structural characterisation has not been
achieved and that is defined solely by qualitative analytical properties (e.g.,
chromatographic retention time).
Unspecified Degradation Product:
A degradation product that is limited by a general acceptance criterion, but
not individually listed with its own specific acceptance criterion, in the new
33
drug product specification.
34. THRESHOLDS FOR DEGRADATION
PRODUCTS IN NEW DRUG PRODUCTS
Reporting Thresholds:
Maximum Daily Dose1
Threshold2,3
≤ 1g
0.1%
>1g
0.05%
Identification Thresholds:
Maximum Daily Dose1
Threshold2,3
< 1 mg
1.0% or 5 µg TDI, whichever is lower
1 mg - 10 mg
0.5% or 20 µg TDI, whichever is lower
>10 mg - 2 g
0.2% or 2 mg TDI, whichever is lower
> 2g
0.10%
34
35. THRESHOLDS FOR DEGRADATION PRODUCTS
IN NEW DRUG PRODUCTS (CONTD.)
Qualification Thresholds:
Maximum Daily Dose1
< 10 mg
1.0% or 50 µg TDI, whichever is lower
10 mg - 100 mg
0.5% or 200 µg TDI, whichever is lower
>100 mg - 2 g
0.2% or 3 mg TDI, whichever is lower
>2g
Threshold2,3
0.15%
Notes:
1. The amount of drug substance administered per day
2. Thresholds for degradation products are expressed either as a percentage
of the drug substance or as total daily intake (TDI) of the degradation
product. Lower thresholds can be appropriate if the degradation product
is unusually toxic.
3. Higher thresholds should be scientifically justified.
35
36. ILLUSTRATION OF REPORTING
DEGRADATION PRODUCTS RESULTS FOR
IDENTIFICATION
AND Maximum Daily Dose
Example 1:
50 mg QUALIFICATION
Reporting threshold: 0.1%
Identification threshold: 0.2%
Qualification threshold: 200 μg
'Raw' Result
(%)
0.04
0.2143
0.349
0.550
Reported
Result
Total Daily
Intake (TDI) of
the Degradation
(%)
Product
(Reporting (rounded result
Threshold
in μg)
= 0.1%)
Not
reported
0.2
0.31
0.61
Action
Identification
Qualification
Threshold
Threshold
0.2%
200 μg TDI
exceeded?
exceeded?
20
None
None
100
150
300
None
Yes
Yes
None
None1
Yes1
36
37. ILLUSTRATION OF REPORTING
DEGRADATION PRODUCTS RESULTS FOR
IDENTIFICATION
AND QUALIFICATION
Example 2:
1.9 gram Maximum Daily Dose
Reporting threshold: 0.05%
Identification threshold: 2 mg
Qualification threshold: 3 mg
'Raw' Result
(%)
0.049
0.079
0.183
0.192
Reported
Total Daily
Result
Intake (TDI) of
the Degradation
(%)
Product
(Reporting
Threshold (rounded result
in mg)
= 0.05%)
Not
reported
0.08
0.181
0.191
Action
Identification
Qualification
Threshold
Threshold
2 mg TDI
3 mg TDI
exceeded?
exceeded?
1
None
None
2
3
4
None
Yes
Yes
None
None1, 2
Yes1
37
38. DECISION TREE FOR IDENTIFICATION
AND QUALIFICATION OF A
DEGRADATION PRODUCT
Is degradation product greater
than identification threshold?
Yes
No
Yes
Structure
identified
Any known human
relevant risks?
Reduce to
safe level
No
No
Reduce to NMT(≤)
Identification threshold
Yes
No further
action
Yes
No
Consider……
Yes
No
Reduce to NMT(≤)
Qualification
threshold
Yes
Greater than
Qualification
threshold
No
38
39. DECISION TREE FOR IDENTIFICATION
AND QUALIFICATION OF A
DEGRADATION PRODUCT (CONTD.)
Consider patient population and duration of use and consider conducting:
Genotoxicity studies (point mutation, chromosomal aberration)
General toxicity studies (one species, usually 14 to 90 days)
Other specific toxicity endpoints, as appropriate
Yes
Any clinically relevant
adverse effects?
No
39
40. REFERENCE
ICH Guidelines- Q3A(R2): Impurities in New Drug Substances
ICH Guidelines- Q3B(R2): Impurities in New Drug Products
ICH Guidelines- Q3C(R5): Impurities: Guidelines for Residual Solvents
CPMP/ICH/2737/99 : Impurities in New Drug Substances
CPMP/ICH/283/95 : Impurities: Guidelines for Residual Solvents
ANDAs: Impurities in New Drug Substances, June 2009, Revision 1
40
