Compliance Requirements/Chapter Scope
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.
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.
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.
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.
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.
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.
<467> gives you the option of testing either all of the individual components or the final finished product.
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.
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.
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.
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.
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.
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'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.
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).
The USP method has been tested on some, but not all USP products and active ingredients.
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.
USP did not experiment with salting agents because we found that method as written provides acceptable sensitivity.
● 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.
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.
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.
ICH applies only to new products. <467> applies the same requirements to all existing products covered by USP monographs.
Changes to Methods
When using procedure C, a spiked solution will compensate for the differences in recovery.
This has not been discussed internally yet.
The General Notices allow for the use of an appropriately validated method.
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.
The General Notices also allow for the use of other validated methods.
The manufacturer may use an alternative validated method.