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

2. Points Covered 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

3. Purpose of Module 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

4. Definitions Definitions:
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.

5. 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.

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

7. Organic Impurities (API Related Impurities)

8. 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

9. 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.

10. 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.

11. 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).

12. Specification limit for Organic Impurities For Non-Pharmacopoeia APIs:
The limits must be specified as per the below table
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%
Thresholds of Impurities for Veterinary API’s
Maximum daily dosage
Reporting threshold
Identification Threshold
Qualification Threshold -
0.10%
0.20%
0.50%

13. 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

14. 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).

15. Residual Solvents
Residual Solvents

16. 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.

17. 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.

18. Options for Describing Limits of Class 2 Solvents :
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)

19. Options for Describing Limits of Class 2 Solvents :…
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.

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

21. Limits of Residual Solvents
Class 2 solvents :
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
N,N-Dimethylacetamide
1090
Methylcyclohexane
1180
N,N-Dimethylformamide
880
N-Methylpyrrolidone
530
1,4-Dioxane
380
Nitromethane
Tetrahydrofuran
720
Pyridine
200
Tetralin
Sulfolane
1,1,2-Trichloroethene 80
Toluene
890
Xylene
2170 -

22. Limits of Residual Solvents
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.
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

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

24. Inorganic Impurities
Inorganic Impurities

25. Inorganic Impurities 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)

26. 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….

27. Control of Inorganic Impurities
Specification limit for Heavy Metals:
As specified by Pharmacopeia wherever applicable.
Specification limit where the product is not listed in the pharmacopoeia:

28. Control of Inorganic Impurities
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.

29. Control of Inorganic Impurities
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)
Classification
Oral Exposure
Parenteral Exposure
PDE (µg/day)
Conc. (ppm)
Class IA:
Pt, Pd
100 10 1
Class 1B*:
Ir, Rh, Ru, Os
Class 1C:
Mo, Ni, Cr, V
250 25
2.5
Class 2:
Cu, Mn
2500
Class 3:
Fe, Zn
13000
1300
130

30. 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

31. Specification limit for Non-API related impurities not listed in ICH Q3C Guideline
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:

32. Specification limit for Non-API related impurities not listed in ICH Q3C Guideline
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)

33. Specification limit for Non-API related impurities not listed in ICH Q3C Guideline
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

34. Specification limit for Non-API related impurities not listed in ICH Q3C Guideline
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.

35. Specification limit for Non-API related impurities not listed in ICH Q3C Guideline
A typical calculation for Establishing Exposure Limits (Specification Limit) is attached.

36. 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.

37. Questions?

38. Thank You