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USP 467 for Residual Solvents: Manufacturers Face Challenges with Pharmaceutical Impurities

October 14th, 2009

Residual SolventsPharmaceutical manufacturers may face various challenges when attempting to meet the United States Pharmacopeia (USP) requirements for residual solvents (volatile organic chemicals).

Residual solvents in pharmaceuticals are trace level impurities of volatile organic compounds in final products or excipients. In general, residual solvents originate from manufacturing processes related to the preparation of drug products. They can also form during product packaging and storage.

In 2008, the USP implemented new testing requirements for the control of residual solvents. The requirements, known as General Chapter <467>, replaced the previous USP General Chapter designated under Organic Volatile Impurities. Today it applies to all compendial drug substances, not just final products. The requirements are designed to ensure that the potential presence of residual solvents is reduced to relatively low concentrations.

The initial challenge for manufacturers is identifying solvents that could potentially be present in their products (i.e. raw materials, excipients, or final products), which must be verified by analytical testing. Manufacturers must also manage the source of solvents on an ongoing basis. Any changes that occur related to the manufacturing process of the associated raw materials, excipients, or final products can potentially result in changes in residual solvents levels.

Residual solvents are separated into three classes based on risk assessment studies, which are related to their potential toxicity level. The following comments briefly discuss the three classes of solvents.

Class 1 solvents are generally avoided in pharmaceutical manufacturing, because they are known human carcinogens or they are strongly suspected carcinogens. In addition, Class 1 solvents create problems related to environmental considerations. Table 1 lists the compounds and the maximum allowable concentrations (in the product/excipient/raw material tested).

Class 2 solvents are limited use solvents that are not genotoxic carcinogens, but are possible causative agents of other irreversible toxicity, such as neurotoxicity or teratogenicity. This class is considered less toxic than the first class, so usage is permitted. Table 2 lists the compounds and the maximum allowable concentrations. In addition to the maximum allowable concentrations in the material tested, they also have established limits referenced as Permitted Day Exposure (PDE), which vary depending on the individual compound. The expression of PDE was established to specifically apply to pharmaceutical products. A more in-depth discussion of this can be found in the FDA publication at

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128317.pdf

Class 3 solvents, listed in Table 3, exhibit low to minimal potential human health-related toxicity. The maximum allowable concentration for these compounds is generally 5000 ppm. They have PDEs of 50 mg or more per day, depending on the individual compound.

Additionally, there are ten more compounds that are warranted for testing by the USP, but have not been classified due to insufficient toxicity data. These are listed in Table 4.

Table 1. USP Class 1 Residual Solvents

Solvent

PDE

(mg/day)

Concentration limit (ppm)

Benzene

None

2

Carbon tetrachloride

None

4

1,2-Dichloroethane

None

5

1,1-Dichloroethene

None

8

1,1,1-Trichloroethane

None

1500

Table 2. USP Class 2 Residual Solvents

Solvent

PDE

(mg/day)

Concentration limit (ppm)

Acetonitrile

4.1

410

Chlorobenzene

3.6

360

Chloroform

0.6

60

Cyclohexane

38.8

3880

1,2-Dichloroethene

18.7

1870

1,2-Dimethoxyethane

1.0

100

N,N-Dimethylacetamide

10.9

1090

N,N-Dimethylformamide

8.8

880

1,4-Dioxane

3.8

380

2-Ethoxyethanol

1.6

160

Ethylene glycol

6.2

620

Formamide

2.2

220

Hexane

2.9

290

Methanol

30.0

3000

2-Methoxyethanol

0.5

50

Methylbutylketone

0.5

50

Methylcyclohexane

11.8

1180

Methylene chloride

6.0

600

N-Methylpyrrolidone1

5.3

530

Nitromethane

0.5

50

Pyridine

2.0

200

Sulfolane

1.6

160

Tetrahydrofuran

7.2

720

Tetralin

1.0

100

Toluene

8.9

890

Trichloroethylene

0.8

80

Xylene*

21.7

2170

*Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene

Table 3. USP Class 3 Residual Solvents

Solvent

PDE

(mg/day)

Concentration limit (ppm)

Acetic acid

>50

5000

Acetone

>50

5000

Anisole

>50

5000

1-Butanol

>50

5000

2-Butanol

>50

5000

Butyl acetate

>50

5000

tert-Butylmethyl ether

>50

5000

Cumene

>50

5000

Dimethyl sulfoxide

>50

5000

Ethanol

>50

5000

Ethyl acetate

>50

5000

Ethyl ether

>50

5000

Ethyl formate

>50

5000

Formic acid

>50

5000

Heptane

>50

5000

Isobutyl acetate

>50

5000

Isopropyl acetate

>50

5000

Methyl acetate

>50

5000

3-Methyl-1-butanol

>50

5000

Methylethyl ketone

>50

5000

Methylisobutyl ketone

>50

5000

2-Methyl-1-propanol

>50

5000

Pentane

>50

5000

1-Pentanol

>50

5000

1-Propanol

>50

5000

2-Propanol

>50

5000

Propyl acetate

>50

5000

Table 4. Other Residual Solvents

Solvent

PDE

(mg/day)1

Concentration limit (ppm)1

1,1-Diethoxypropane

Not Set

Not Set

1,1-Dimethoxymethane

Not Set

Not Set

2,2-Dimethoxypropane

Not Set

Not Set

Isooctane

Not Set

Not Set

Isopropyl ether

Not Set

Not Set

Methylisopropyl ketone

Not Set

Not Set

Methyltetrahydrofuran

Not Set

Not Set

Petroleum ether

Not Set

Not Set

Trichloroacetic acid

Not Set

Not Set

Trifluoroacetic acid

Not Set

Not Set

1Limits not established due to lack of toxicity data.

Again, for discussion and definitions related to the determination of the toxicity factors and associated limits, refer to the following FDA document:

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128317.pdf

The analytical testing prescribed for the determination of residual solvents is not particularly complex in theory. However, it does require the use of specialized equipment, as well as the expertise of analysts well versed in the determination of volatile organic compounds. Since the procedure was written as a general method to be used for a variety of materials, recognizing and addressing problems associated with various matrices requires considerable expertise in the analytical chemistry laboratory.

The majority of the solvents on the list can be analyzed using the revised USP <467> method of static headspace extraction followed by gas chromatography with flame ionization detection. However, there are six Class 2 residual solvents that are not volatile enough for headspace testing, so they require analysis by direct injection. In addition, formic acid (a Class 3 solvent) requires analysis by an alternative HPLC method with post-column derivatization. Both the direct injection and HPLC methods must be developed and validated by the analytical laboratory, which requires adequate planning to accommodate the additional time to complete the studies.

The chemists at Columbia Analytical routinely analyze samples for these solvents. They can provide information on the analytical protocols and challenges that are involved in residual solvent testing.

Learn more about Lab Testing for Pharmaceuticals
Learn about USP 467 Testing for Residual Solvents

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30 Responses to “USP 467 for Residual Solvents: Manufacturers Face Challenges with Pharmaceutical Impurities”

  1. Dr Kuldeep Jain Says:

    what is residual solvent of petroleum ether(100-120°C) limit in API

  2. Jeff Grindstaff Says:

    Dr. Jain,
    There is currently no limit set for petroleum ether. Since petroleum ether is comprised primarily of C6 hydrocarbons, it can be tested for by USP using the published limit of hexane. Hexane is a Class 2 solvent with a limit of 290ppm.

  3. Sathish Says:

    is it right to keep the limit of petroleum ether is also 290 ppm on the basis of C6 hydrocarbons.

  4. admin Says:

    Hello Sathish,

    Could you please clarify your request? I’m not sure I understand your question.

    Thanks,

    Columbia Analytical Services, Inc.

  5. kiaie Says:

    what is residual solvent of petroleum ether(40-60°C) limit in API

  6. admin Says:

    Hello Kiaie,

    Petroleum ether is not listed in USP<467> so there is no set limit. You would probably need to work with the FDA to determine a limit.

    Thanks,

    Columbia Analytical Services, Inc.

  7. Dr. B.S.Kalakoti Says:

    Dear Sir(s)
    Currently every one is asking class 3 solvents less than 50ppm, is this rule of US-FDS and Japan and EC?
    Kindly enlighten me

  8. Dr. B.S.Kalakoti Says:

    Kindly update me on residual solvents limit presently. Its <50 ppm or 5000 in US FDA

  9. Rajesh Pawar Says:

    What is residual solvent of Tert-butanol limit in API

  10. admin Says:

    Hello Rajesh,

    Tert-butanol is not listed in the USP <467> method, so we cannot provide a limit.

    Thank you,

    Columbia Analytical Services, Inc.
    Now part of the ALS group

  11. Pervaiz Qureshi Says:

    Dear Dr. Kalakoti,
    Here is the answer to your question.
    The ppm limits for all Class 3 solvents as per USP is 5000, and the PDE (Permitted Daily Exposure) is >50 mg/day. Is it clear?

  12. Julie Says:

    Dear Sir/Madam,
    Could you advise what is the concentration limit allowed in API (active pharmaceutical ingredient) for o-xylene? Is there any guideline for it?

    Thank you very much.

    Regards,
    Juliani

  13. dinesh Says:

    I am using Acetone in my product the results come to 14000 as a residual solvent please suggest me suitable method to minimize it i am using it for my oral suspension.

  14. William Allen Says:

    For solvents found in Table 4 (Diisopropyl ether) what would best fit for determination of concentration in API?

  15. Chris Rundell Says:

    All,

    Regarding the limits for solvents not listed in USP , appendix 3 of the monograph provides guidance for solvents not listed.

    – Chris

  16. here Says:

    Well said!

  17. Jiangao Says:

    Does FDA request external standard or internal standard, or both are OK, for the GC analysis?

    What are the six Class 2 residual solvents that are not volatile enough for headspace testing?

    Jiangao

  18. admin Says:

    Hello Jiangao,

    Thank you for your query.

    The USP Method is an external method and does not specify an option for the use of an internal standard. When changes or improvements are made to a USP method, a revalidation is required. The solvents that are not amenable to headspace are formamide, 2-ethoxyethanol, 2-methoxyethanol, ethylene glycol, N-methylpyrrolidine and sulfolane.

    Thank you,

    Jeff Grindstaff
    Laboratory Director
    ALS Environmental

    Formerly Columbia Analytical Services, Inc.

  19. M. Suresh Says:

    Dear All,
    Please provide me sequence of injections as per USP.

    Kind regards,
    Suresh.M
    Manager-Validations.

  20. namrata Says:

    while calculating limit in PDE concentraion= 1000 X MOLECULAR WEIGHT OF SOLVENT / 24.45 IT IS STATED in USP what is 24.45 IT INDICATES WHAT ?

  21. Jaydeep Raj Says:

    what is residual solvent of petroleum ether(100-120°C) limit in API ?

  22. Pervaiz Qureshi Says:

    Hi All,

    Does anyone knows a source of maximum daily dose for Dexedrine Capsule (Dextroamphetamine Sulfate Extended Release Capsule?

  23. vinod Says:

    is there any usp( or any pharmacopoeia) method available for determination of class 3 residual solvents (acetone 2-propanol….),using head space-GC. or any validated method is available for determining class 3 residual solvents using head space-GC.

  24. admin Says:

    Hello,

    USP<467> is available for the determination of class 3 residual solvents.

    Thank you,

    Jeff Grindstaff
    ALS | Environmental

  25. mary Says:

    Hello,
    Does anyone know the limit for petroleum ether? in suppository dosage form.

  26. admin Says:

    Hello Mary,

    Thank you for contacting us! We suggest that you contact the FDA with your question for the latest information.

    Thank you,

    ALS Environmental
    Formerly Columbia Analytical Services, Inc.

    http://www.alsglobal.com

  27. Pervaiz Qureshi Says:

    The Daily max. dosage of an injection is over 700 mg/day that exceed the daily allowable limit of 10 g. Mass. According to our product it is almost over 150 g, it is not even close to option 1. Can I use Option 2 for 150 gram total mass, even it 15 times higher than the allowable limit for option 1?
    Can anyone help me?

  28. Rahul Says:

    My product is having 30000 ppm of class -3 solvent. daily dose of drug is 250 mg. (Injection) . By calculation 30000 ppm means 3% ( 3g/100g) . Means for 250 mg it is around 7.5 mg. (by calculation) and PDE is 50 mg /day.
    My drug is ok or not ?

  29. Chandra Says:

    Dear Sir,
    We would like to conduct test for USD 467 – residual solvent for mineral oil.
    Please advise, which nearest ALS lab can do the test ?
    Our factory located in Indonesia.
    Thanks and regards,

  30. Peter Kaltenboeck Says:

    Hello,
    is there a recommendation for the number of repeated injections of the different solutions (class 1 standard, class 1 SST solutíon, class 2 standards, test solution, spiked test solution, standard solution)?
    Kind regards,
    Peter

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