The USP (US Pharmacopeia) General Chapters <232> Elemental Impurities—Limits and <233> Elemental Impurities—Procedures were expected to come into force in May 2014, but due to industry concerns about alignment with the ICH (International Conference on Harmonisation), USP decided to delay the dates by which industry will have to come into compliance. IPEC (International Pharmaceutical Excipient Council) previously called for the implementation deadline to be extended because of the ICH’s development of separate limits.
“These deferrals will allow USP to work closely with ICH Q3D to align their activities with the implementation of General Chapters <232> and <233>,” the USP said in a statement. “The deferral also allows USP to work with those affected by the new elemental impurity standards. In this regard, USP plans to form an Advisory Group on the Implementation of General Chapters <232> and <233>.”
USP said it is participating as an observer in the ICH Q3D process and looks forward to the document reaching step 2, which is expected to come in June.
Cause for Delay
Dr. Todd Cecil, vice president of monograph modernization and medicines compendium for USP, told In-Pharmatechnologist.com the delay is due to industry comments on the feasibility of the deadline and concerns related to the ICH guidance. He also said that despite some differences, the ICH and USP requirements are the same in terms of the options for calculating impurities, the permissible daily exposure limits and the routes of administration among others. However, the ICH does include some additional metals not included in the USP general chapters, Dr. Cecil said.
The ICH is still ironing out specific limit levels and metals to include, he added, though he expressed confidence in their toxicologists' decisions, especially as USP holds weekly discussions with them.
USP is also working with the US FDA and individual manufacturers to resolve scientific issues from the elemental impurities requirements. The FDA is expected to issue guidance soon on the issue, he added.
Experts previously told us that a few manufacturers are concerned that some of their products might not meet the required limits. But Dr. Cecil noted that monographs for specific active substances, excipients and finished products can be altered to override a general chapter or notice if those products or ingredients prove to be safe. “We have ways to allow exceptions so long as FDA is in agreement with them,” he added.
This is the second time that USP has agreed to delay the chapters following industry appeals. And according to a Q&A on their release, the USP has not set a new deadline for when the general chapters will be applied.
Burden on Industry
In order to comply with the new limits for elemental impurities, pharmaceutical companies will need to acquire new equipment and devote expertise to conducting the tests.
But Dr. Cecil said the impact on companies’ bottom line should be minimal. “The technology for the testing is not new,” he said, noting that third party testing labs are ready and waiting for pharmaceutical companies. Some are charging $100 per sample, which is “not going to put anyone out of business,” he said.
Other General Chapters
USP General Chapter <231> on Heavy Metals will also be omitted once General Chapters <232> and <233> become applicable, in order for manufacturers to have a reasonable amount of time to meet the new requirements.
USP also plans to omit other elemental metal general chapters such as <251> Lead, <211> Arsenic, and <261> Mercury. “These general chapters are referenced in a number of USP-NF monographs and a careful review of these monographs will be undertaken before removing these references,” the convention said, noting a timeframe will be laid out in the future.