Brazil’s Anvisa to Publish Revised Excipient GMP Guideline

The revisions come as Brazilian pharmaceutical companies are concerned about confusion over the difference between retest and expiration dates for excipient suppliers, David Schoneker, director of global regulatory affairs at Colorcon, told attendees of Excipient Fest in Baltimore on Tuesday.

Some local excipient manufacturers have been disposing of excipients after the prescribed retest date, which they assumed was also the expiration date of the inactive drug products, Schoneker said. The confusion was related to the Portuguese term for “shelf life,​” which was equating the retest and expiration dates for some of the excipients, he added, noting the “concept of expiration date and retest date was not well understood and the GMP guideline needed some work to get it right​.”

The intervals for the retesting of pharmaceutical excipients are typically a fraction of the expiration intervals, which help to explain when an excipient no longer complies with the stability and specifications from when it was produced, Schoneker explained.

“When we talk about retest interval, you’ve determined at what level degradation​” might have begun to occur so testing can take place to ensure the excipient should still be left on the market, he said.

“The use of retest intervals as expiration intervals led to unnecessary drug rejections and the potential for drug shortages​” without any patient safety benefit, Schoneker said. In August 2012 a team from IPEC-Americas did a side-by-side comparison between the Brazilian and IPEC guidelines to discuss necessary changes. Another workshop is planned for this August, potentially prior to when Anvisa releases the new guidelines.

However, the revisions to the GMP guideline, which was first published in early 2012, will not come with an additional draft or be available for public comment, he noted.

Titanium Dioxide in Brazil​

Schoneker also pointed out that late last year a Brazilian bill approved by the country’s Environmental & Sustainable Development Commission would prohibit titanium dioxide in food as a health risk. Although the bill was unrelated to pharmaceutical products, a number of large pharma companies were concerned that it could be extended to their industry, which would pose serious problems considering pigment grade titanium dioxide is used in nearly all drug products, Schoneker said.

But upon further review, it seems the bill confused nano grade titanium dioxide with pigment grade titanium dioxide and the published literature causing the controversy was not scientific, Schoneker said.

“When people start talking about nano grades, everyone gets nervous​,” he said. “There are absolutely no safety issues with pigment grade​” titanium dioxide.

IPEC in Argentina​

Similar to Brazil, Argentina also lacks definitive regulations around its excipients but the development towards such regulations is progressing. Over the past two years, two of IPEC’s GMP guides have been translated into Argentinian Spanish, and the IPEC GDP audit guideline will be translated soon.

An Argentinian regulation governing genotoxic impurities from 2012 also caused some major concerns among the excipient manufacturers in the country. The regulation created hurdles for excipient manufacturers and was previously excluded from ICH guidelines on such toxicities, Schoneker said.

IPEC’s work in Brazil and Argentina may eventually lead to a new group for IPEC. Latin America has “completely different regulations in many of the countries, and it’s probably a little early to start thinking about an IPEC-Latin America​,” Schoneker said, noting that once the international group has begun work with some of the major markets, such a group might be formed “further down the road​.”