Materials in the Spotlight

The regulatory environment for combination products has become increasingly challenging over time. Among the growing number of hurdles in the regulatory pathway is an increased emphasis on supply chain security and traceability. And as part of this mounting focus on the supply chain, raw materials in particular have been the subject of increased regulatory scrutiny due to their role in several recent high-profile incidents.

In 2008, for example, FDA found that more than 20 Chinese suppliers had provided contaminated raw materials for use in the common blood thinner heparin, which was linked to 80 deaths in the United States and numerous cases of allergic reactions. Materials also were at the center of the metal-on-metal hip implant controversy when mounting evidence indicated that metallic wear particles were being generated at far higher rates than anticipated, causing inflammation and damage to the bone and other tissue surrounding the implant.

In 2013, a well-known medical device manufacturer initiated a global recall of its drug-eluting stent based on reports of malfunction (tip separation) of the catheter used to deliver the combination product to the proper position within the blocked artery. FDA classified this as a Class 1 recall, the most serious type.⁴ This indicated “a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death.”⁵

With such events endangering patients and attracting public outcry, heightened scrutiny on raw materials has emerged as an issue in both the United States and abroad. The FDA increasingly is citing raw materials in warning letters while the International Conference on Harmonization (ICH) recently has issued a draft guideline for elemental impurities in drug products, and the European Medicines Agency has implemented new rules for elemental impurity standards for new products.⁶
The agency also is in the process of applying these standards to existing products, although this process has been delayed.⁷ Elemental impurity standards also are being released in other countries.