Impurities in drug substances and drug products

1. ICH Guideline-Impurities in Drug
Substances and Drug Products
Presented By - Shilpa Thakre
M.Pharm- Pharmaceutical Chemistry

2. ICH Guidelines
2
Q3A (R2) Impurities in New Drug Substances
Q3B (R2) Impurities in New Drug Products
Q3C (R6) Maintenance of the Guideline for Residual Solvents
Q3C (R8)
Maintenance
EWG
Maintenance of the Guideline for Residual Solvents
Q3D (R1) Guideline for Elemental Impurities
Q3D (R2)
Maintenance
EWG
Revision of Q3D(R1) for cutaneous and transdermal
products
Q3D Training – Implementation of Guideline for Elemental
Impurities
Q3E Informal
WG
Impurity: Assessment and Control of Extractables and
Leachables for Pharmaceuticals and Biologics

3. Sterile…
3
 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
 Residual Solvents
Impurities in Drug Substances
Key Points to be covered:

4. Classification of Impurities
4
Impurity
Organic
Inorganic
Residual
Solvents

5. Rationale for Reporting and Control of Impurities
and Degradation products
5
 The applicant should summarize the impurities/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.
 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.

6. Analytical procedure
6
 Analytical procedures should be validated
and suitable for detection and
quantification of impurities.
 Quantitation limit should be Not more
than Reporting Threshold.
 Reference Standards should be evaluated
and characterized.

7. Identification, Reporting and Qualification of
Impurities
7
 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.
Maximum Daily Dose 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 %

8. Listing of Impurities in Specification
8
 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
Inorganic Impurities
Residual Solvents

9. Illustration of Reporting Impurity Results for
Identification and Qualification in an Application
9
Example 1: 0.5 g Maximum Daily Dose
 Reporting threshold = 0.05%
 Identification threshold = 0.10%
 Qualification threshold = 0.15%
"Raw" Result (%) Reported Result (%)
Reporting threshold =
0.05%
Calculated Total
Daily Intake
(TDI) (mg) of the
impurity
(rounded result
in mg)
Action
Identification
(Threshold
0.10%
exceeded?)
Qualification
(Threshold
0.15%
exceeded?)
0.044 Not reported 0.2 None None
0.0963 0.10 0.5 None None
0.12 0.12 0.6 Yes Yes
0.1649 0.16 0.8 Yes Yes

10. Illustration of Reporting Impurity Results for
Identification and Qualification in an Application
10
Example 2: 0.8 g Maximum Daily Dose
 Reporting threshold = 0.05%
 Identification threshold = 0.10%
 Qualification threshold = 1.0 mg TDI
"Raw" Result (%) Reported Result (%)
Reporting threshold =
0.05%
Calculated Total
Daily Intake
(TDI) (mg) of the
Degradation
product (rounded
result in mg)
Action
Identification
(Threshold
0.10%
exceeded?)
Qualification
(Threshold
1.0 mg TDI
exceeded?)
0.066 0.07 0.8 None None
0.124 0.12 1.0 Yes None
0.143 0.14 1.1 Yes Yes

11. Decision Tree for Identification and Qualification
11

12. DecisionTreefor
IdentificationandQualification(Contd)
Decision Tree for Identification and Qualification
…
12
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
Any clinical relevant
adverse effects?
Yes No

13. Residual Solvents
13
 Residual solvents are potentially undesirable substances.
 They either modify the properties of certain compounds or may be hazardous to
human health.
 The residual solvents also 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.
Residual solvents are those solvents which are used as vehicles for the
preparation of solution / suspensions in the synthesis of a new drug substance.

14. Residual Solvents
14
Class I
• Solvents to be avoided
Class 2
• Solvents to be limited
Class 3
• Solvents with low toxic
potential
Class
4
• Solvents for which No
Adequate Toxicological Data
was Found

15. Sterile…
15
 Introduction
 Reporting Degradation Products Content of Batches
 Listing of Degradation Products in Specifications
 Qualification of Degradation Products
Impurities in Drug Products
Key Points to be covered:

16. Introduction
16
 The objective of the guideline makes recommendation to applicant on the content and
qualification of impurities in new drug products produced from chemically synthesized 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.

17. Reporting degradation products content of
batches
17
 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%).

18. Listing of Degradation products in Specification
18
 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.
 Total degradation products.

19. Qualification of Degradation products
19

20. Illustration of Reporting Degradation products Results for
Identification and Qualification in an Application
20
Example: 50mg Maximum Daily Dose
 Reporting threshold = 0.1%
 Identification threshold = 0.2%
 Qualification threshold = 200µg
"Raw" Result (%) Reported Result (%)
Reporting threshold =
0.1%
Total Daily
Intake (TDI) of
the degradation
products
(rounded result
in µg)
Action
Identification
(Threshold
0.2%
exceeded?)
Qualification
(Threshold
200 µg TDI
exceeded?)
0.04 Not reported 20 None None
0.2143 0.2 100 None None
0.349 0.3 150 Yes None
0.550 0.6 300 Yes Yes

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