Elemental impurities. The ICH Q3D guideline and the USP general chapters on elemental impurities currently under development will head toward implementation
in the next few years. These guidelines and chapters will have a significant impact on the pharmaceutical and excipient industry
going forward. Many excipients contain small amounts of elemental impurities and these amounts may cause some drug products
to exceed the limits proposed. As a result, some drug products may need to be reformulated. It is the opinion of IPEC that
the official implementation timeline of these guidelines and chapters be delayed until appropriate characterization studies
can be carried out by excipient manufacturers to fully understand what levels of these elemental impurities may exist in their
In the past, excipient users had to perform a heavy-metals limit test. This test did not provide much useful information about
the actual impurity levels were in the excipients. IPEC plans to work with the industry to encourage appropriate analytical
studies once the ICH Q3D limits are known so that this information can be shared with pharmaceutical users. Pharma-excipient
users can then establish the appropriate calculations to determine what levels of elemental impurities may exist in the finished
dosage form and whether their drug products comply with the established limits.
Other areas of focus. IPEC has identified and is working on several other excipient-control areas that need further guidance. These include:
- QbD: excipient variability in chemical and physical properties and the effect of this variability on drug product manufacturability
- Coprocessed excipients: supporting analytical data to build safety bridging arguments to component safety data
- Atypical actives: excipients being used as APIs that are not manufactured using ICH Q7 (4).
There are still many gaps in IPEC-Americas' TEC system. However, the organization is dedicated to continue to develop appropriate
guidelines and whitepapers to fill these gaps and find ways of combining all of IPEC's tools into a workable system of controls
that begin with excipient design and ends with patient consumption. If IPEC can do this, patient safety will surely be improved.
David R. Schoneker is vice-chair for Scientific and Regulatory Policy at the International Pharmaceutical Excipients Council of the Americas
(IPEC–Americas). He is a member of Pharmaceutical Technology's editorial advisory board.
1. M. Steinberg et al., Regul. Toxicol. and Pharmacol.
24, 149–154 (1006).
2. FDA, Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (Rockville, MD, May 2005).
3. C. DeMerlis et al., Pharm. Technol.
33 (11) 72–82 (2009).
4. ICH, Q7 Good Manufacturing Guide for Active Pharmaceutical Ingredients (Geneva. November 2000) Nov. 10, 2000.