New and existing NDAs and ANDAs for drug products are required to meet USP <232> and <233> for elemental impurities
As of January 1, 2018, generic and branded drug products are required to meet FDA industry guidance regarding elemental impurities. The limits and procedures for the screening and quantification of potentially toxic metal impurities are defined in the United States Pharmacopeia (USP) <232> and <233> chapters.
Heavy metal elemental impurities don’t provide any benefit to patients, and they pose serious risks to patient health. Non-compliance to regulations, including USP 232 & 233, can result in the delay of launch dates of biopharmaceutical products if finished drug products don’t comply with regulations. In the second installment of this 2-part blog series, our team has answered your most frequently asked technical questions about elemental impurities testing.
Did you miss the first blog? Check it out.
Can a standard method be run for USP 232/233 metals testing, or does a method need to be developed for elemental impurities?
Method development is needed to account for the variations in matrix from one drug product to another. We are, however, able to carry out “screens” for metals using semi-quantitative methods. Get in touch with our scientists to find out more.
Is method validation required for USP 232 and 233?
Typically, method validation is only performed if metals are found to be close enough to the USP/ICH level causing concern.
Can multiple metals be analyzed in the same run or by the same method?
Yes, with the correct setup and correction factors, Avomeen’s scientists can quantify up to 64 metals in a single run. However, we typically analyze anywhere from 7 to 24 metals based on the specific needs of our clients. Do you want to explore your options for analyzing multiple elemental impurities by a single method? Talk to a scientist.
How are acceptable limits determined for each metal in a finished drug product?
The metal limits are calculated based on the maximum daily dosage (MDD) and the permitted daily exposure (PDE) based on the route of administration. Metals levels have been harmonized across USP and ICH organizations. For novel (or unestablished) administration routes, Avomeen’s regulatory and scientific experts can assist in establishing and justifying limits.
Which metals are typically found above the USP/ICH limits for elemental impurities?
In the past, we have found both Ni (nickel) and Cu (copper) above the USP/ICH limits. Commonly, contaminants present from either the raw materials or the manufacturing process can severely impact the quality of the finished product. Avomeen can assist in determining sources of contamination.
What do I do if one or more metals exceed limits / fails during USP 232/233 testing? How can Avomeen help?
Avomeen has expertise in other areas of pharmaceutical analysis and CMC testing where we can help identify sources of contamination. One of these is extractables and leachables studies under USP <1663>/<1664>. As part of a standard E&L study, we will look for extractable metals coming from the manufacturing line components as well as the final container/closure system.
If you missed the first installment in the series, check it out to find answers to the most frequently asked questions about the testing process and working with Avomeen for elemental impurities testing. Do you have more questions for our elemental analysis team? Let’s talk.
Our featured blogger is Mike Lindenmuth, Avomeen’s Director of Business Development for the Mid-Atlantic and Southeast regions. Mike has been involved in the pharmaceutical industry for nearly 20 years, from working in drug discovery to serving in technical sales and business development roles for organizations supporting pharmaceutical research and development.