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FDA releases draft guidance for residual solvent analysis (USP <467>)
By Dr. Ludwig Huber
Chief Advisor for Global FDA Compliance, LabCompliance
The new United States Pharmacopeia-National Formulary (USP-NF) General Chapter <467> Residual Solvents took effect on July 1, 2008 [1]. The adoption of the International Conference on Harmonization (ICH) Q3C standards [2,3] in the general chapter of the USP places new testing requirements on pharmaceutical firms, while eliminating the tests for Organic Volatile Impurities (OVIs) from the individual monographs. In August 2008, the U.S. Food and Drug Administration (FDA) released a new draft guidance that has recommendations for compliance with the new USP Chapter <467> [4].
This article:
- Summarizes the main content of the new FDA guidance.
- Gives recommendations for implementation.
- Outlines how technologies developed by Agilent can help to implement the new USP chapter with better performance.
Essential contents of the new FDA guidance
- Beginning July 1, 2008, the U.S. FDA requires that drugs with an official USP monograph that are marketed in the U.S. meet the requirements of the new USP Chapter <467>.
- For compendial drug products, either approved or non-approved under a new drug application (NDA) or abbreviated new drug application (ANDA), the FDA will accept the use of analytical procedures other than those included in the revised chapter. But you must properly document and validate the alternative procedures, and you must verify their suitability under actual conditions.
- For approved drugs, you should report changes to USP procedures in annual product reviews, with a summary of technical studies and tests. You should keep full test details at the manufacturing site for review.
- NDA and ANDA applicants for non-compendial drug products should limit residual solvents as described in the FDA guidance Q3C [4].
Recommendations for implementation
The guidance is very much in line with FDA’s general recommendations that alternative methods can be used as long as they provide the same performance as methods defined by USP. Despite this flexibility, we recommend that you follow the documented methods as defined by USP. There are several advantages:
- Such methods require only verification, which is less time-consuming than full validation.
- FDA laboratories most likely will follow USP procedures if they re-analyze samples submitted as part of the new drug approval process. When you use the same USP methods, the likelihood of getting the same results is high and can shorten the approval cycle.
- In general, FDA investigators are more familiar with USP procedures than with alternative methods. Use of USP procedures will facilitate inspections by eliminating extended discussions.
Better ways to comply with the new regulations
The method of choice for residual solvent analysis is headspace (HS) GC with a flame-ionization detector (FID), or with a mass-selective detector when you need identification and confirmation. In the past, users of headspace systems faced a number of problems related to poor peak area precision, poor sensitivity, and long sample turn-around time. But Agilent has developed technology based on headspace GC and GC/MSD that conforms to the new USP <467> guidelines and that overcomes previous limitations.
The Agilent total solution gives you:
- Backflush and faster oven cool-downs for shorter GC cycle time.
- Capillary Flow Technology that solves difficult chromatographic problems.
- Easy-to-use Agilent Lab Advisor software for higher uptime and automatic documentation of maintenance.
- Faster GC/MSD electronics that enable synchronous SIM/scan, which gives increased information.
- Trace Ion Detection technology that provides more capabilities at trace levels in GC/MSD.
- High-quality Agilent J&W capillary GC columns and supplies.
Agilent has also developed Application Notes with recommendations for optimization [5,6], and offers a free poster with flow charts and tables so you can learn more about the new USP chapter [7].
A recent Application Note describes how to gain productivity with simultaneous analysis of residual solvents using matched Agilent J&W DB-WAX and DB-624 columns in a single GC run. The DB-WAX column is equivalent to USP Phase G16, while the DB-624 column is equivalent to USP Phase G43. The method meets the requirements of the latest USP revision and uses the Agilent G1888 headspace sampler and the Agilent 7890A GC with dual flame-ionization detection. The analysis requires no modifications to the GC; you simply use an Agilent two-holed ferrule and an Agilent two-holed column nut to make the single connection at the injection port. The dual analysis provides high precision and sensitivity, with a GC cycle time of less than one hour per sample.
This dual-column GC approach allows the combination of three procedures from the USP monograph. The monograph suggests an initial analysis using a G43 (DB-624) phase. If a compound is measured above the specified concentration limit, then Procedure B with a G16 (DB-WAX) phase is used to confirm its identity. Neither procedure is quantitative, so to determine the concentration, the monograph specifies Procedure C, which uses whichever phase gives the fewest co-elutions. All three procedures are combined by use of simultaneous dual-capillary-column GC.
To read details about this time-saving setup, download Agilent Application Note 5989-8085EN. For more information about residual solvent analysis, visit our industry page for drug manufacturing QA/QC.
References
- “USP General Chapter <467> Residual Solvents,” 2008.
- United States Food and Drug Administration, “Guidance for Industry: Q3C – Tables and List,” 2003.
- United States Food and Drug Administration, “Guidance for Industry: Q3C Impurities: Residual Solvents,” 1997.
- United Stated Food and Drug Administration, “Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States,” 2008, Draft
- R.L. Firor and A.E. Gudat, “The determination of residual solvents in pharmaceuticals using the Agilent G1888 headspace/6890N GC/5975 inert MSD system,” Agilent publication number 5989-3196EN, 2005.
- A.E. Gudat, R.L. Firor and U. Bober, “Better precision, sensitivity, and higher sample throughput for the analysis of residual solvents in pharmaceuticals,” Agilent publication number 5989-6023EN, 2007.
- Free residual solvents information kit including a new poster: “All the facts about residual solvent analysis.”
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