In the end, 24 elements will need to be evaluated by manufacturers of finished products, which differs from EU guidelines that stipulate limits for 14 elemental impurities, Ulrich Reichert told attendees at the ChemOutsourcing conference on Wednesday.
The parenteral limits, specifically, “are strict, and ICP-MS, [which is one of the techniques used to measure the impurities] will be mandatory,” Reichert told In-Pharmatechnologist.com.
ICH
Under the new ICH guideline, companies will have to create impurity profiles for finished products, which will require testing of reagents and catalysts that are either known to be present or could possibly be present. The limits are based on the maximum daily dose of 10 mg of drug product and will need to be adjusted based on the dosage, Reichert said.
Among the new elements that will need to be evaluated, Reichert pointed out the addition of the so-called ‘Big Four,’ which includes elements classified by the ICH as having the highest potential to be significantly toxic, and includes mercury, lead, cadmium and arsenic.
Manufacturers will likely use one of two methods to detect the impurities: ICP-AES (inductively coupled plasma atomic emission spectroscopy) or ICP-MS (inductively coupled plasma mass spectrometry), the latter of which Reichert said is the “method of choice as it’s very sensitive, but it’s also very expensive.”
Manufacturers may also have to evaluate the stainless steel equipment and container closure systems used to produce and store their drug products to ensure impurities aren’t later added.
“Most of the considerations will be related to excipients,” Reichert said, noting that manufacturers may need analytical and regulatory support to achieve compliance for pharmaceutical substances as well.
IPEC (International Pharmaceutical Excipients Council) Americas asked pharma companies in April to provide more insight on how they plan to deal with ICH Q3D in preparation for the guideline coming out. IPEC noted in a letter to industry that it’s “important to stress that many excipient suppliers may not have information on the presence of many of the elements listed in ICH Q3D.”
European Regs
Unlike what’s expected to come out of the ICH later this month, the EMA (European Medicines Association) established its own set of elemental impurity regulations in 2008 after eight years of development.
The European regulations are meant to control 14 elements that are intentionally added from catalysts and reagents. And unlike the USP general chapters <232> and <233>, which apply to the finished drug product and are expected to be applicable in December 2015, the EU regulations apply only to excipients and drug substances and not to the final drug products.
Reichert noted that the European Pharmacopoeia will implement ICH’s Q3D when it’s finalized.