General Chapter <467>—Residual Solvents

Compliance Requirements/Chapter Scope

  1. What are USP’s expectations relating to General Chapter <467> between now and July 1, 2008 and after July 1, 2008 for all pharmaceutical companies?

    The USP General Notices require all products to meet the requirements in General Chapter <467> by July 1, 2008. The purpose of the chapter is to limit the amount of solvent that patients receive.

  2. Are dermatological products and topical products required to comply with <467>?

    USP defers to FDA on enforcement questions, but the chapter does include language indicating that in some cases the ICH limit may not be appropriate. This language is not specific to dermatological and topical products.

  3. Protein manufacturers do not use solvents in their manufacturing processes. What are the expectations with regards to <467> in proteins?

    The chapter states that no testing is required if you know that solvents are not present. However, it is always prudent to evaluate your starting materials and finished product.

  4. Is it possible that USP will consider setting standards for residual solvents in packaging components?

    Residual solvents in packaging are not addressed by this chapter. We are aware of extractables and leechables, and we may consider this aspect in the future.

  5. ICH Q3C does not apply to existing commercial drug product. Please confirm that the USP requirement applies to all existing commercial drug products.

    That is correct. USP sees no reason to exclude product from the <467> requirements, as the goal is to limit residual solvents in all products.

  6. Is it accurate to state that <467> applies only to products that are labeled "USP" or "NF", and that if the substance or product is not labeled "USP" or "NF", then <467> is only guidance?

    No. If the product or substance is covered by a USP or NF monograph, the monograph standards and the General Notices apply, whether or not it is labeled "USP" or "NF", The General Notices requirement that the substance or product comply with <467> applies to all substances and products covered by USP and NF monographs.

  7. <467> applies to the drug product. Are manufacturers of finished products required to test the active ingredient and the excipients?

    467> gives you the option of testing either all of the individual components or the final finished product.

  8. If we use Water for Injection for dilution of drug substances to make drug products, do we need to test Water for Injection for residual solvents?

    If you don't use any of the solvents listed in the manufacture of Water for Injection, <467> does not require you to test the water for solvents.

  9. How do the <467> requirements apply to animal health items, if at all? Will the chapter apply to veterinary products in the future? If so, when?

    The <467> requirements apply to items for veterinary use. However, the current limits are based on human use and limits for different species of animals probably would need to be different.

  10. What about material that is not an API or Excipient, but is a material used in the API, or a salt or hydrochloric acid? Q3C does not address the issue of raw materials used in an API.

    The bottom line is to assure the material that is going out to patients does not harm them. If you do option 1, this test takes care of the solvent issues for these materials. It's up to the manufacturer to make sure the product complies with the limits for solvents.

  11. Do we need to confirm that no solvent contamination occurs during packaging or repackaging?

    The chapter covers only those solvents used in the manufacturing process. Accidental contamination during packaging, handling, or shipping should be managed through good handling and shipping practices.

Vendor Materials

  1. Do we need to perform a complete residual solvent analysis to verify the information provided by our vendor?

    It is up to the manufacturer to determine whether or not to test. The decision may depend on the confidence and the relationship between the manufacturer and supplier. The manufacturer may choose to audit the vendor.

  2. If an excipient manufacturer states that class 2 solvents are present in their excipient, but below the option 1 limit, does the drug product manufacturer have to test for these solvents?

    Use good science and prudent behavior in a GMP environment to demonstrate the absence of solvent. If the presence or absence can’t be demonstrated, test the product.

USP Methods

  1. What is the history/source of the USP method? Could the USP make changes to the method in the future?

    USP's primary source for these methods is the European Pharmacopeia (EP) method. The USP is under continuous revision, and we make changes to the methods to improve existing procedures or to allow the user to obtain better results. USP may revise this chapter in response to additional comments received.

  2. Chromatographic question: How does USP propose to deal with peak co—elutions in the current proposed chapter?

    There are two procedures, A&B. These procedures provide orthogonal separation. For quantitative analysis, A is preferred, but B should be used if A does not work (for instance, due to co—eluting peaks).

  3. Has the USP method been tested by USP on drug products and excipients?

    The USP method has been tested on some, but not all USP products and active ingredients.

  4. What happens to peaks in sample that are non—target solvent peaks?

    If you come up with an unexpected peak while looking for a specific solvent, use good science to identify the peak and work with a toxicologist for the acceptable level in that material.

  5. During method development, did USP experiment with "salting" agent for the headspace analysis? If so, what did you find as far as efficacy for increasing responses — or "inefficacy"?

    USP did not experiment with salting agents because we found that method as written provides acceptable sensitivity.

  6. How do you suggest testing a product that only has class 3 solvents present that cumulatively are greater than 0.5%? Example:
    Ethanol 0.3%
    Ethyl Ether 0.2%
    1—propanol 0.3%

    It is not appropriate to use Loss on Drying (LOD) if the amount of class 3 solvent exceeds 0.5%. In those cases, gas chromatography should be used. If you have process validation information indicating that you can reduce the amount of class 3 solvent to 0.5% or lower in the final product, you can discuss with FDA the possibility of using LOD.

  7. If a material has class 3 and Class 1 or 2 solvents in it, what is the USP method, since procedures A, B, and C are only for class 2 solvents and Loss on Drying (LOD) is only for class 3?

    If you have a Class 3 solvent and either a Class 1 or 2 solvent, use LOD to demonstrate acceptance in class 3 as long as LOD result is not more than 0.5%. If it is more than 0.5%, use gas chromatography to demonstrate compliance.

Harmonization

  1. If USP is working to harmonize USP General Chapters, why doesn't USP completely harmonize <467> with the EP before implementing the chapter?

    There are only minor differences between the USP and EP methods. The reference standard mixtures are different in the USP. Also, the calculation is different. In the USP, methods A and B are limit tests, method C is a quantitative test. Other than those minor changes, the chapter is harmonized.

  2. Industry has just finished implementing ICH Q3C to meet European regulatory expectations. Can the USP clarify what is additionally expected to achieve compliance with <467>?

    ICH applies only to new products. <467> applies the same requirements to all existing products covered by USP monographs.

Changes to Methods

  1. The USP method shows less recovery for some of the solvents. Will USP propose recovery correction factor for calculations?

    When using procedure C, a spiked solution will compensate for the differences in recovery.

  2. Would USP consider separating methods in <467> to a separate chapter?

    This has not been discussed internally yet.

Alternative Methods

  1. Can USP adopt the ICH language that allows the use of an appropriately validated method?

    The General Notices allow for the use of an appropriately validated method.

  2. The USP methods still have many drawbacks and may not be able to detect or quantitate certain solvents. How can the industry comply with the requirements if an alternative method has not been developed or validated?

    Under the General Notices, manufacturers may use alternative methods if those methods are validated. Ultimately, the solvents known to be present in the product should be controlled before it goes to market. The manufacturer should ensure that appropriate controls are in place and demonstrate that the solvent residues are safe for patients.

  3. Can USP add a statement to <467> that will provide companies the flexibility to use the USP method or their own validated procedure?

    The General Notices also allow for the use of other validated methods.

  4. For a drug to be classified as USP grade, must the manufacturer follow the methods in <467>, or can they use an alternate, validated method?

    The manufacturer may use an alternative validated method.