Frequently Asked Questions: Reagents and Impurities
- Where is more information about reagents specified in USP monographs located?
- What are chemical names/structures of impurities?
- The monograph does not list the test for residual solvents. Must this requirement still be complied with?
- Must a complete residual solvent analysis be performed to verify the information provided by our vendor?
- Can alternative procedures to those described in USP be used?
- Are dermatological products and topical products required to comply with <467>?
- Is it accurate to state that General Chapter <467> Residual Soavents 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?
- <467> applies to the drug product. Are manufacturers of finished products required to test the active ingredient and the excipients?
- 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?
- 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?
- 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 1 and Class 2 Solvents and Loss on Drying (LOD) is only for Class 3?
- Do we need to confirm that no solvent contamination occurs during packaging or repackaging?
- 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?
- 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.
- 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?
Reagent specifications and suggestions are available in the Reagents section.
The chemical names/structures/mass of the impurities are either not available or may be confidential information. Therefore, such requests will be handled through the USP Document Disclosure Policy by the Executive Secretariat/Legal Division. This policy is articulated in the USP Code of Ethics: Standards-Setting Processes. USP has set guidelines according to this policy to handle such inquiries including the related fees ($200/hr for professional time spent) to investigate the request for such information. This is to ensure that appropriate expenses are covered.
The test for residual solvents will not be listed in monographs. However you still need to comply with the standard as per General Notices section 5.60.20.
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.
The General Notices allow for the use of alternative procedures, provided they are validated.
USP defers to FDA on enforcement questions, but the chapter applies to all dosage forms and routes of administration.
Is it accurate to state that General Chapter <467> Residual Solvents 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.
<467> gives you the option of testing either all of the individual components or the final finished product.
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.
The manufacturer may use an alternative validated method.
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 requirement is not more than 0.5%. If it is more than 0.5 use any appropriate validated procedure to demonstrate compliance.
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.
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 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 <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.