Manufacturers Face Challenges

Manufacturers Face Challenges with Pharmaceutical Impurities

Pharmaceutical 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 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:

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.