Lab Science News

The United States Environmental Protection Agency (EPA) will soon release its response to a 2006 National Academy of Sciences (NAS) report recommending changes to the EPA’s 2000 draft assessment of the risks posed by 2,3,7,8 Tetrachlorodibenzo-p-Dioxin.

Dioxins are environmental contaminants according to the Food and Drug Administration’s (FDA) website (September 2009). Most human dioxin exposure, however, occurs through the diet, with more than 95% coming through dietary intake of animal fats. Dioxins enter the food chain primarily in an air-to-leaf/soil-to-animal route.

In anticipation of the upcoming release, the EPA has established a special communication committee to address concerns about the safety of the food supply and other public health issues.

The EPA’s Waste Office, in response to this reassessment, is proposing lowering soil screening levels in residential areas from 1000 parts per trillion (ppt) to 72 ppt. However, given reported health risks, there are some that have been urging the EPA to adopt an even stricter 3.7 ppt-level.

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

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.

For years, dietary supplements have been scrutinized by the media for being marketed as “snake-oil” cure-alls, potentially containing components considered harmful to consumers. Under-regulation by the Food and Drug Administration (FDA) lead to concerns that these products did not fall under the same regulatory requirements as pharmaceuticals. Until now.

 

New FDA regulations for the dietary supplement industry aim to eradicate consumer concern and health risks associated with these products. Dietary supplement manufacturers and distributors are now required to follow Good Manufacturing Practices (GMPs) similar to those of the pharmaceutical industry. The FDA 21 Code of Federal Regulations (CFR) Part 111 was established to insure the identity, purity, quality, strength, and composition of dietary supplements and applies to those involved in the manufacture, packaging, labeling or holding of a dietary supplement, with the exception of retail establishments selling directly to consumers.

The federal government is taking a tiered approach to enforcement: companies with more than 500 employees were required to become compliant by June 2008; companies with 21-499 employees must become compliant before June 2009; and companies with fewer than 20 employees will need to be compliant by 2010.

To become compliant with the GMP guidelines, passed in 2007, dietary supplement companies need to perform analytical testing of their products. Analytical laboratory analysis falls under the category of “manufacture” as defined by FDA CFR.  Therefore, if testing is not performed the dietary supplement company will be considered non-compliant regardless of the reason for not testing. Reasons for not testing range from it being cost prohibitive to it’s impossible as an option for raw materials, in-process or final products. Those non-compliant and unable to meet GMP guidelines will run the risk of not being able to sell their products due to regulatory agency action. This may result in some companies going out of business or, at the least, an increased need for analytical testing.

In some ways, GMPs for dietary supplements have been considered to be more strict than those for pharmaceuticals. For example, many pharmaceutical compounds can be considered “pure” if they meet 90-98 percent of the requirement. Purity constraints for dietary supplements can be as much or more than 100 percent as a requirement. The GMPs for dietary supplements are a combination of GMPs for both food and drugs. The abundance of new regulations may be a response to the public scrutiny the dietary supplement industries have received in recent years.

GMP compliant analytical testing for GMP guidelines may include residual solvent and heavy metals analysis, water determination by Karl Fischer, and microbial limit testing. These tests are designed to ensure product quality and consumer safety, but there is a need for identity testing and potency as well. Identity and potency will confirm for manufacturers that the product label accurately reflects the actual ingredients as well as potency of each batch or lot of product.  In other words, “it is what it is” and the manufacturer has the compliant analytical quality control laboratory documentation to prove it.

This new challenge for production will require substantial new testing in order to maintain compliance. Some dietary supplement companies have already found that outsourcing the testing, though thousands of dollars per year, is a more sensible business strategy than investing millions developing and maintaining their own compliant laboratories. When outsourcing analytical testing to laboratories, the FDA requires the outside lab to be cGMP compliant and FDA inspected. The Quality Unit of compliant laboratories will be able to readily supply information including documentation of quality systems and FDA inspection reports.

Manufacturers may want to assess the most cost effective and efficient means to deal with these new FDA regulations.

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References:

FDA Issues Dietary Supplements Final Rule

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01657.html

 

FDA 21 CFR part 111

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=111&showFR=1FDA