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Meeting the Criteria of the Upcoming Revised USP Monograph < >: Residual solvents
Sky Countryman
In 1988, the United States Pharmacopoeia (USP) provided control limits and testing criteria for seven organic volatile impurities (OVIs) under official monograph <467>. The compounds were chosen based on relative toxicity and only applied to drug substances and some excipients.1 In an effort to harmonize with the International Conference for Harmonization (ICH), the USP has proposed the adoption of a slightly modified version of Quality-3C (Q3C) methodology, which has been scheduled for implementation on July 1, 2008.
The ICH Q3C methodology provides a risk-based approach to residual solvent analysis that considers a patient’s exposure to a solvent residue in the drug product.2 Solvents have been classified, based on their potential health risks, into three main classes:
• Class 1: Solvents should not be used because of the unacceptable toxicities or deleterious environmental effects.
• Class 2: Solvents should be limited because of inherent toxicities.
• Class 3: Solvents may be regarded as less toxic and of lower risk to human health.
Testing is only required for those solvents used in the manufacturing or purification process of drug substances, excipients, or products. This allows each company to determine which solvents it uses in production and to develop
testing procedures that address their specific needs.
It is the responsibility of the drug manufacturer to qualify the purity of all the components used in the manufacturing of the drug product. This would pertain to items such as excipients, of which some contain residual levels of Class 1 solvents by nature of the manufacturing process and/or nature of the starting materials (i.e., ethyl cellulose).3 Herein, we discuss the main advantages and disadvantages of using headspace versus direct liquid injection techniques to meet the <467> guidelines.
A strategic approach that meets <467> guidelines
Figure 1: Headspace sample partition coefficient (K)
Click to enlarge. |
Although the total number of solvents that now require testing has increased, a company is only required to test for those solvents that are likely to be present in the drug formulation. Since the solvents used in process development at each company are likely to be different, a company should consider developing a chromatographic testing system that addresses their
specific needs.
In general, the strategy should be to develop a general testing method for residual solvents that:
• resolves all solvents of interest likely to be present in their drug substances, excipients, and/or products
• reduces analysis time for maximum sample throughput
• obtains high accuracy and precision independent of the matrix
• detects compounds at or below their control limits
• provides qualitative and quantitative data that is consistent with USP/PhEur testing requirements.
To determine the solvents that will be relevant to your company, you must interview your scientists involved in process development and any vendors for excipients and/or drug substance that are included in your formulation. Once this list has been compiled, compare it to the USP <467> list of solvents to determine what Class 1, 2, and 3 solvents are likely to be present. Based on your company’s list of solvents, you can now design a strategy to accurately determine the level of residual solvents in your drug formulation.
Injection techniques — headspace versus direct liquid
The main advantage of using headspace as an injection technique is that only the volatile portion of the sample is introduced into the column. Drug products often contain non-volatile components that can damage the GC column and cause problems with the analysis. However, there are certain Class 2 solvents that are not detected via headspace injection.4 Depending on the solvents a company uses for manufacturing of a drug formulation, liquid injections might be necessary.
Class 2 solvents not detected via headspace injection
Formamide
2-Ethoxyethanol
2-Methoxyethanol
Ethylene glycol
N-methylpyrrolidone
Sulfolane
Headspace Injection
| Table 1: Mass ions for co-eluting peaks |
Peak |
Compound |
Mass Ion |
11 |
Ethyl format |
31 |
12 |
Methly acetate |
43 |
14 |
Carbon tetrachloride |
117 |
15 |
1,1,1-Trichloroethane |
97 |
17 |
Isopropyl acetate |
43 |
18 |
MEK |
43 |
30 |
n-Propanol |
31 |
40 |
m-Xylene |
91/106 |
41 |
Butanol |
56 |
42 |
Nitromethane |
30 |
To remain consistent with <467> methodology, headspace injection should be used whenever possible. Warning: improper sample preparation and operating conditions is the most common source of error in <467>. Samples should be prepared in either a water or organic solution. Since many of the regulated solvents and drug components are more soluble in an organic solvent, an organic dilution solvent is usually recommended for the general method.
Method sensitivity is largely affected by the concentration of the analyte in the gas phase. To achieve the detection limits required by <467>, it is important to drive as much analyte out of solution into the headspace as possible. There are several common strategies that can be employed to achieve this result:
1. Increase the vial temperature,
2. Increase the equilibration time, and/or
3. Add matrix modifiers (salts) to increase the ionic strength of the solvent.
When working with headspace injection techniques, the sample matrix can significantly affect the quantitative performance of the GC method. In a given matrix, each analyte will have a unique partition coefficient (K), which is an equilibrium distribution of the analyte between the liquid phase and the gas phase (Figure 1). To eliminate this matrix effect, many companies have explored the use of standard addition methods. These methods also provide flexibility if a last-minute solvent change is made during formulations.
Optimizing the GC method
Following the conditions specified by the monograph, the total analysis time for all three samples would be more than 3 hours. It isn’t feasible for most companies to spend 3 hours per sample to get identification and quantitation of all target analytes. In a QC department, sample throughput and instrument stability are the primary concerns, therefore most labs have validated their own testing methodologies based on <> requirements.
When choosing the appropriate column dimensions for a specific set of target analytes, there are four main variables that need to be considered: 1. Length (L); 2. Internal diameter (ID); 3. Film thickness (df); and 4. Stationary phase composition. Of the four variables, stationary phase will have the biggest impact on column selectivity. In order to remain consistent with the <467> monograph, a lab should try to work with those phases listed in section <621> of the USP guidelines. The G43 and G16 phases are well suited for solvent analysis and by choosing more efficient column dimensions, a lab should be able to resolve all target analytes in less than 20 minutes.
Figure 2: A fast screening method for 18 commonly used solvents Click to enlarge. |
Figure 2 shows the separation of 18 solvents from Class 1, 2, and 3 using a G16 equivalent phase (Zebron ZB-WAXPLUS). Column length and internal diameter were chosen to achieve maximum resolving power with minimal analysis time. Choosing these conditions allowed the method to be completed in less than 8 minutes with a total cycle time of less than 10 minutes.
Using this method, the results would still need to be confirmed using a G43 phase and then quantitated. Though total analysis time is much less using this method, it still requires three separate tests to confirm and quantitate all compounds. This three-test approach will always be required when using the method specified FID because it does not give any information about the peaks identity. To eliminate the three-test approach would require using both G43 and G16 phases in parallel or simply using a mass spectrometer (MS) detector.
Dual column analysis
Dual column analysis where two phases are connected in parallel using a 5- to 10-meter guard column and a “Y” union are commonplace in environmental testing. By making one injection and splitting the sample into two columns, both Procedures A and B can be accomplished simultaneously. If a calibration curve is run before each batch of samples, and a suitable calibration check is run after each batch of samples to verify the stability of the calibration, then Procedure C could also be run at the same time. The main obstacle of using this type of system is to use one oven program to separate the target analytes on two column phases.
GC-MS analysis
While dual column approaches are widely used and accepted, the decreasing cost of benchtop GC-MS systems make this a much more viable long-term solution. The main advantage of GC-MS is the spectral confirmation it provides of each peak. MS data is widely used and accepted throughout the world and eliminates any possible misidentifications.
Figure 3: Comprehensive testing method for all Class I, II, and III residual solvents by GC-MS
Click to enlarge. |
The chromatographic advantage of GC-MS is that it is able to distinguish co-eluting peaks based on the mass fragmentation pattern. This allows many more compounds to be separated in a shorter time. By choosing the appropriate column phase and dimension, it is possible to develop a fast, sensitive, accurate, and definitive testing method for all Class 1, 2, and 3 solvents simultaneously (Figure 3). Table 1 shows the co-eluting compounds and their mass ions. Only peaks 17 and 18 have the same mass, however both are Class 3 solvents and would only need to be confirmed if the level was about 5,000 ppm.
Conclusion
The new USP regulations are aimed at improving patient safety and will need to be implemented for all products, existing or new. Although the USP has provided a testing method that can be used to identify and quantitate Class 1 and 2 solvents, the method can be improved based on each company’s needs.
Only those solvents used in the manufacturing process must be tested in the final dosage form. For the best solution, each company must consider the number of samples, analysis time, method validation, accuracy, precision, and cost of equipment. Once method performance has been achieved, it is also important to consider if that method can be transferred to other manufacturing facilities. Do they have the knowledge and instrumentation to implement the method?
The changes to the USP <> monograph will not be official until July 2008, but it is important to start formulating a strategy now to become compliant. During the process there is no doubt that other questions and concerns will arise. To ensure the USP addresses as many of these concerns as possible in the new method, an open dialog between industry and the USP is critical.
References
1. Cecil, T. Residual Solvents USP History. Presented at the 2007 USP/PDA Joint Conference: Residual Solvents, North Bethesda, Maryland, 2007.
2. Osterberg, R.E. Impurities: Residual Solvents ICH: Q3C. Presented at the 2007 USP/PDA Joint Conference: Residual Solvents, North Bethesda, Maryland, 2007.
3. Schoneker, D.R. Excipients Manufacturer Perspective. Presented at the 2007 USP/PDA Joint Conference: Residual Solvents, North Bethesda, Maryland, 2007.
4. <> Organic Volatile Impurities. General Notices and Requirements: Applying to Standards, Tests, Assays, and Other Specifications of the United States Pharmacopeia. Material Provided at the 2007 USP/PDA Joint Conference: Residual Solvents, North Bethesda, Maryland, 2007.
Sky Countryman is the GC
Product Manager at Phenomenex. He may be contacted at Chromatography
Techniques@advantagemedia.com.
Phenomenex Inc.
411 Madrid Avenue
Torrance, CA, 90501
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