Residual Solvent Limit in Raw Material (API) – SOP

Residual solvent in pharmaceuticals is defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

LIMIT OF RESIDUAL SOLVENTS IN DRUG PRODUCT

1.0   Purpose:

    • The purpose of this Standard Operating Procedure (SOP) is to describe the limit of residual solvent. 

2.0   Scope:

    • This SOP is applicable to the limit of residual solvent in case of raw materials at the Quality Control Department.

3.0   References and Annexures – Limit of Residual Solvent:

    • References:

    • IP: Indian pharmacopoeia
    • BP: British pharmacopoeia
    • USP: United States pharmacopoeia
    • ICH Q3C(R5) :Impurities: Guideline for Residual Solvents
    • IH: In house
    • Annexures:Residual Solvent Limit

    • IP – Limit of Residual Solvent (Annexure-1)
    • USP – Limit of Residual Solvent (Annexure-2)
    • BP – Limit of Residual Solvent (Annexure-3)
    • ICH – Limit of Residual Solvent (Annexure-4)

4.0   Responsibilities – Limit of Residual Solvent:

    • Analyst :

    • To check the manufacturer COA with SOP Annexures.
    • Inform about the abnormalities to section head or designee.
    • To make entry of residual solvent result in the Analytical template.
    • Quality Control Head or Designee :

    • Ensure practice is being followed as per SOP.
    • Quality Assurance :

    • Check the SOP.
    • To ensure the implementation of the system as per SOP.
    • Quality head, Regulatory Affairs, and Plant Head or designee :

    • To review and approve the SOP.

5.0   Abbreviations and Definition and of terms used in Limit of Residual Solvent:

    • Abbreviations:

    • STP: Standard Testing Procedure.
    • B.No.:Batch Number.
    • PDE: Permitted Daily Exposure
    • COA: Certificate Of Analysis
    • GIM: Goods Inward Memo
    • Definition and of terms :

    • Residual solvents:-Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

6.0   Procedure – Limit of Residual Solvent:

    • After receiving of raw material GIM along with COA, QC Officer shall check the grade of material(IP, BP, USP, or Inhouse) as per manufacturer’s COA.
    • QC Officer shall review the residual solvent limit and result for the pharmacopeia limit with respective Annexures and from manufacturers COA.
    • For in house material ICH residual solvent limit shall be considered for reference.
    • If the residual solvents result of the manufacturer is higher side than the respective Annexures limit then reject the material.
    • If results are within the respective Annexures limit then release the batch.
    • Classification of Residual Solvents by Risk Assessment:

    • Residual solvents are evaluated for their possible risk to human health and classified three classes as follows as per ICH Guideline:
    • Class 1 solvents:
    • Solvents to be avoided known human carcinogens, strongly suspected human carcinogens, and environmental hazards.
    • Class 2 solvents:
    • Solvents to be limited for Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.
    • Solvents suspected of other significant but reversible toxicities.
    • Class 3 solvents:
    • 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.

Annexure 1 – Limit of Residual Solvent as per IP

  • Class -1: Residual Solvents –

S.No.

Name of residual solvent Limit of residual solvents

Concern

1 Benzene

2

Carcinogens
2 Carbon tetrachloride

4

Toxic and environmental hazard
3 1,2-Dichloroethane

5

Toxic
4 1,1-Dichloroethene

8

Toxic
5 1,1,1-Trichloroethane

1500

Environmental hazard
  • Class -2: Residual Solvents –

S.No.

Name of residual solvent Limit of residual solvents (In ppm)

PDE (mg/day)

1 Acetonitrile

410

4.1

2 Chlorobenzene

360

3.6

3 Chloroform

60

0.6

4 Cyclohexane

3880

38.8

5 1,2-Dichloroethene

1870

18.7

6 Dichloromethane

600

6.0

7 1,2-Dimethoxyethane

100

1

8 N, N-Dimethylacetamide

1090

10.9

9 N, N-Dimethylformamide

880

8.8

10 1,4-Dioxane

380

3.8

11 2-Ethoxyethanol**

160

1.6

12 Ethylene glycol**

6.2

620

13 Formamide**

2.2

220

14 Hexane

2.9

290

15 Methanol

30.0

3000

16 2-Methoxyethanol**

0.5

50

17 Methyl butyl ketone

0.5

50

18 Methylcyclohexane

11.8

1180

19 N-Methylpyrrolidone**

5.3

530

20 Nitromethane

0.5

50

21 Pyridine

2

200

22 Sulpholane**

1.6

160

23 Tetrahydrofuran

7.2

720

24 Tetralin

1.0

100

25 Toluene

8.9

890

26 1,1,2-Trichloroethene

0.8

80

27 Xylene*

21.4

2170

*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethylbenzene

** Not readily detected by head-space injection gas chromatography. Other appropriate procedures should be used for control.
  • Class -3: Residual Solvents –

    • These solvents are less toxic and of lower risk to human health.
    • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements,
    • The concentration limits of 5000ppm would be acceptable for the solvents in the below table.

S.NO.

Name of residual solvent

1 Acetic acid
2 Acetone
3 Anisole
4 1-Butanol
5 2-Butanol
6 Butyl acetate
7 tetra-Butylmethyl ether
8 Dimethyl sulfoxide
9 Ethanol
10 Ethyl acetate
11 Ethyl ether
12 Ethyl formate
13 Formic acid
14 Heptane
15 Isobutyl acetate
16 Isopropyl acetate
17 Methyl acetate
18 3-Methyl-1-butanol
19 Methyl ethyl ketone
20 Methyl isobutyl ketone
21 2-Methyl-1-propanol
22 Pentane
23 1-Pentanol
24 1-Propanol
25 2-Propanol
26 Propyl acetate
27 Cumene
28 Tetrahydrofuran

Annexure 2 – Limit of Residual Solvent as per USP

  • Class -1: Residual Solvents –

S.No.

Name of residual solvent Limit of residual solvents

Concern

1 Benzene

2

Carcinogens
2 Carbon tetrachloride

4

Toxic and environmental hazard
3 1,2-Dichloroethane

5

Toxic
4 1,1-Dichloroethene

8

Toxic
5 1,1,1-Trichloroethane

1500

Environmental hazard
  • Class -2: Residual Solvents –

S.No.

Name of residual solvent Limit of residual solvents (In ppm)

PDE (mg/day)

1 Acetonitrile

410

4.1

2 Chlorobenzene

360

3.6

3 Chloroform

60

0.6

4 Cumene

70

0.7

5 Cyclohexane

3880

38.8

6 1,2-Dichloroethene

1870

18.7

7 Methylene chloride

600

6.0

8 1,2-Dimethoxyethane

100

1.0

9 N, N-Dimethylacetamide

1090

10.9

10 N, N-Dimethylformamide

880

8.8

11 1,4-Dioxane

380

3.8

12 2-Ethoxyethanol

160

1.6

13 Ethylene glycol**

6.2

620

14 Formamide**

2.2

220

15 Hexane

2.9

290

16 Methanol

30.0

3000

17 2-Methoxyethanol**

0.5

50

18 Methyl butyl ketone

0.5

50

19 Methylcyclohexane

11.8

1180

20 N-Methylpyrrolidone**

5.3

530

21 Nitromethane

0.5

50

22 Pyridine

2

200

23 Sulpholane**

1.6

160

24 Tetrahydrofuran[3]

7.2

720

25 Tetralin

1.0

100

26 Toluene

8.9

890

27 1,1,2-Trichloroethene

0.8

80

28 Xylene*

21.4

2170

*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethylbenzene
** Not readily detected by head-space injection gas chromatography. Other appropriate procedures should be used for control.
  • Class -3: Residual Solvents –

    • These residual solvents are less toxic and of lower risk to human health.
    • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements,
    • The concentration limits of 5000ppm would be acceptable for the solvents in below table-3
 S.No. Name of residual solvent S.No. Name of residual solvent
1 Acetic acid 15 Isobutyl acetate
2 Acetone 16 Isopropyl acetate
3 Anisole 17 Methyl acetate
4 1-Butanol 18 3-Methyl-1-butanol
5 2-Butanol 19 Methyl ethyl ketone
6 Butyl acetate 20 Methyl isobutyl ketone
7 tetra-Butylmethyl ether 21 2-Methyl-1-propanol
8 Dimethyl sulfoxide 22 Pentane
9 Ethanol 23 1-Pentanol
10 Ethyl acetate 24 1-Propanol
11 Ethyl ether 25 2-Propanol
12 Ethyl formate 26 Propyl acetate
13 Formic acid 27 Cumene
14 Heptane 28 Tetrahydrofuran
    • The residual solvent listed below table may also be of interest to manufacturers of drug substances, Excipients, or drug products.
    • However, no adequate toxicological data on which to base a PDE was found and mention as follows.

 

S.No.

Name of residual solvent S.No.

Name of residual solvent

1

1,1-Diethoxypropane

6

Methyl isopropyl ketone

2

1,1-Dimethoxymethane

7

Methyltetrahydrofuran

3

2,2-Dimethoxypropane

8

Solvent hexane

4

Isooctane

9

Trichloroacetic acid

5

Isopropyl Ether

10

Trifluoroacetic acid

 

Annexure 3 – Limit of Residual Solvent as per BP

  • Class -1: Residual Solvents –

 S.No.

Name of residual solvent Limit of residual solvents

Concern

1 Benzene

2

Carcinogens
2 Carbon tetrachloride

4

Toxic and environmental hazard
3 1,2-Dichloroethane

5

Toxic
4 1,1-Dichloroethene

8

Toxic
5 1,1,1-Trichloroethane

1500

Environmental hazard
  • Class -2: Residual Solvents –

S.No.

Name of residual solvent Limit of residual solvents (In ppm)

PDE (mg/day)

1 Acetonitrile

410

4.1

2 Chlorobenzene

360

3.6

3 Chloroform

60

0.6

4 Cumene

70

0.7

5 Cyclohexane

3880

38.8

6 1,2-Dichloroethene

1870

18.7

7 Methylene chloride

600

6.0

8 1,2-Dimethoxyethane

1.0

100

9 N, N-Dimethylacetamide

10.9

1090

10 N, N-Dimethylformamide

8.8

880

11 1,4-Dioxane

3.8

380

12 2-Ethoxyethanol

1.6

160

13 Ethylene glycol**

6.2

620

14 Formamide**

2.2

220

15 Hexane

2.9

290

16 Methanol

30.0

3000

17 2-Methoxyethanol**

0.5

50

18 Methyl butyl ketone

0.5

50

19 Methylcyclohexane

11.8

1180

20 N-Methylpyrrolidone**

5.3

530

21 Nitromethane

0.5

50

22 Pyridine

2

200

23 Sulpholane**

1.6

160

24 Tetrahydrofuran[3]

7.2

720

25 Tetralin

1.0

100

26 Toluene

8.9

890

27 1,1,2-Trichloroethene

0.8

80

28 Xylene*

21.4

2170

*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethylbenzene
** Not readily detected by head-space injection gas chromatography. Other appropriate procedures should be used for control.
  • Class -3: Residual Solvents –

    • These solvents are less toxic and of lower risk to human health.
    • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements,
    • The concentration limits of 5000ppm would be acceptable for the solvents in the below table.
S.No. Name of residual solvent S.No. Name of residual solvent
1 Acetic acid 15 Isobutyl acetate
2 Acetone 16 Isopropyl acetate
3 Anisole 17 Methyl acetate
4 1-Butanol 18 3-Methyl-1-butanol
5 2-Butanol 19 Methyl ethyl ketone
6 Butyl acetate 20 Methyl isobutyl ketone
7 tetra-Butylmethyl ether 21 2-Methyl-1-propanol
8 Dimethyl sulfoxide 22 Pentane
9 Ethanol 23 1-Pentanol
10 Ethyl acetate 24 1-Propanol
11 Ethyl ether 25 2-Propanol
12 Ethyl formate 26 Propyl acetate
13 Formic acid 27 Cumene
14 Heptane 28 Tetrahydrofuran
    • The residual solvent listed in the below table may also be of interest to manufacturers of drug substances, Excipients, or drug products.
    • However, no adequate toxicological data on which to base a PDE was found.
S.No. Name of residual solvent S.No. Name of residual solvent
1 1,1-Diethoxypropane 6 Methyl isopropyl ketone
2 1,1-Dimethoxymethane 7 Methyltetrahydrofuran
3 2,2-Dimethoxypropane 8 Solvent hexane
4 Isooctane 9 Trichloroacetic acid
5 Isopropyl Ether 10 Trifluoroacetic acid

Annexure 4 – Limit of Residual Solvent as per ICH

  • Class -1: Residual Solvents –

S.No. Name of residual solvent Limit of residual solvents Concern
1 Benzene 2 Carcinogens
2 Carbon tetrachloride 4 Toxic and environmental hazard
3 1,2-Dichloroethane 5 Toxic
4 1,1-Dichloroethene 8 Toxic
5 1,1,1-Trichloroethane 1500 Environmental hazard
  • Class -2: Residual Solvents –

   S.No.

Name of residual solvent Limit of residual solvents (In ppm)

PDE (mg/day)

1 Acetonitrile

410

4.1

2 Chlorobenzene

360

3.6

3 Chloroform

60

0.6

4 Cumene1

70

0.7

5 Cyclohexane

3880

38.8

6 1,2-Dichloroethene

1870

18.7

7 Dichloromethane

600

6.0

8 1,2-Dimethoxyethane

1.0

100

9 N, N-Dimethylacetamide

10.9

1090

10 N, N-Dimethylformamide

8.8

880

11 1,4-Dioxane

3.8

380

12 2-Ethoxyethanol

1.6

160

13 Ethylene glycol

6.2

620

14 Formamide

2.2

220

15 Hexane

2.9

290

16 Methanol

30.0

3000

17 2-Methoxyethanol

0.5

50

18 Methyl butyl ketone

0.5

50

19 Methylcyclohexane

11.8

1180

20 N-Methylpyrrolidone2

5.3

530

21 Nitromethane

0.5

50

22 Pyridine

2

200

23 Sulfolane

1.6

160

24 Tetrahydrofuran3

7.2

720

25 Tetralin

1.0

100

26 Toluene

8.9

890

27 1,1,2-Trichloroethene

0.8

80

28 Xylene*

21.4

2170

*usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethylbenzene

[1].The information included for Cumene reflects that included in the Revision of PDE Information for Cumene which reached Step 4 in February 2011 and was subsequently incorporated into the core Guideline. See Part IV (pages 22-25).

[2]The information included for N-Methylpyrrolidone reflects that included in the Revision of PDE Information for NMP which reached Step 4 in September 2002 (two mistyping corrections made in October 2002), and was incorporated into the core guideline in November 2005. See Part III (pages 20-21).

[3]The information included for Tetrahydrofuran reflects that included in the Revision of PDE Information for THF which reached Step 4 in September 2002, and was incorporated into the core guideline in November 2005. See Part II (pages 18-19).

  • Class -3: Residual Solvents –

    • These solvents are less toxic and of lower risk to human health.
    • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements.
    • The concentration limits of 5000ppm would be acceptable for the solvents in the below table.

S.No.

Name of residual solvent S.No.

Name of residual solvent

1

Acetic acid

14

Heptane

2

Acetone

15

Isobutyl acetate

3

Anisole

16

Isopropyl acetate

4

1-Butanol

17

Methyl acetate

5

2-Butanol

18

3-Methyl-1-butanol

6

Butyl acetate

19

Methyl ethyl ketone

7

tetra-Butylmethyl ether

20

Methyl isobutyl ketone

8

Dimethyl sulfoxide

21

2-Methyl-1-propanol

9

Ethanol

22

Pentane

10

Ethyl acetate

23

1-Pentanol

11

Ethyl ether

24

1-Propanol

12

Ethyl formate

25

2-Propanol

13

Formic acid

26

Propyl acetate
    • The residual solvent listed in table-4 may also be of interest to manufacturers of drug substances, Excipients, or drug products.
    • However, no adequate toxicological data on which to base a PDE was found.

 S.No.

Name of residual solvent S.No.

Name of residual solvent

1

1,1-Diethoxypropane

6

Methyl isopropyl ketone

2

1,1-Dimethoxymethane

7

Methyltetrahydrofuran

3

2,2-Dimethoxypropane

8

Petroleum Ether

4

Isooctane

9

Trichloroacetic acid

5

Isopropyl Ether

10

Trifluoroacetic acid

*********************************************END******************************************

pharmabeginers

Janki Singh is experienced in Pharmaceuticals, author and founder of Pharma Beginners, an ultimate pharmaceutical blogging platform. Email: [email protected]

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