Master files need expansion
Another piece of legislation high on IPEC– Europe's agenda is the European Master File system, and specifically the fact that
the system is limited to nonbiological active pharmaceutical ingredients (APIs). This limitation serves as a disincentive
to bringing novel excipients to market, and presents intellectual property issues for companies who have invested in developing
them, according to Kate Denton of Novozymes Biopharma (Lund, Sweden), and who serves on IPEC–Europe's regulatory affairs committee.
In contrast to the situation in the US and Japan, a novel excipient cannot be filed in Europe with the regulatory authority
for reference by pharmaceutical manufacturers who want to use it. Instead, the developer has to make that proprietary information
available to its customers, and must file it alongside marketing authorization applications. The nature of excipients often
means that protection via patent is not possible.
For APIs, this route is well-established. The procedure allows generics companies to source actives for their products, referring
to the master file in marketing applications. The API manufacturers' process and production approach remains confidential.
This approach also prevents duplicated efforts because it avoids multiple assessments and duplication of reviews, reducing
administrative workload on excipient suppliers, pharmaceutical manufacturers, and regulators.
IPEC–Europe has put forward a position to lobby the European Commission to place adding an extension to the Master File system
on its agenda. There are encouraging signs that this may occur, as the EC's consultation paper on the Future of Pharmaceuticals
for Human Use in Europe has flagged the need to review the Master File system.
Caution urged on REACH
REACH, the EU's landmark new legislation covering the Registration, Evaluation, Authorization, and Restriction of Chemical
substances, has been a source of considerable controversy and debate over the past few years and instituted a major change
in policy. In effect, the legislation puts the burden of proof on manufacturers—not authorities—to show that a substance used
in a product is safe.
Although REACH covers all chemicals produced or imported in quantities greater than 1 tonne per year, medicinal products are
exempt, provided they are used in accordance with EC Directive 2001/83. But one key factor in the law prevents pharmaceutical
companies from choosing to ignore the new regulation. Any substance that is used in other applications as well as pharmaceuticals
has to be preregistered this year, and fully registered between 2010 and 2018 depending on the tonnage produced or imported
into the EUeach year.
"Preregistration must be done before Dec. 1, 2008 in order allow a substance to stay on the market thereafter," Sylvie Thevenet
of Dow Corning (Lyon,France) told the IPEC–Europe seminar. "Those that are not preregistered by that date will have to undergo
a full registration process in December, or be withdrawn from sale."
A failure to preregister or register could affect the continuity of supply of ingredients. Companies should consider whether
to preregister substances if their supplier does not intend to, make sure nonEuropean suppliers are aware of REACH, and comply
when a supplier asks for usage information.
Harmonization efforts in question
Janeen Skutnik of Pfizer Global Manufacturing (Belgium), chair-elect of IPEC–Americas, addressed the IPEC–Europe group as
well, focusing on the slow progress with harmonization of the US, European, and Japanese pharmacopoeias. She boldly asked,
"Is it time to circumvent the entire process by allowing mutual recognition of monographs between the European, US and Japanese
"If it could be accepted that all three have valid processes, and that monographs from any of the three could be cited and
accepted without additional filings, variations or validation, this would minimize use of resources at companies and regulators,
and reduce non-value-added testing," said Skutnik.
Duplicated testing because of a lack of harmonization provides no benefit to patients, wastes time and resources, and creates
environmental problems: tons of solvents are dumped because duplicate and triplicate tests are required.
Acknowledging that this revolutionary approach to compendial harmonization is a long way from reality, Skutnik noted that
an evolutionary approach—such as prospective programs to develop monographs and new chapters with involvement from the three
pharmacopoeias—could accelerate the process.
The seminar clearly revealed that EU regulation of pharmaceutical excipients is in a state of flux. Also present was a sense
of optimism that, with collaboration between industry, regulators, and other stakeholders, improvements to the operating environment
for excipient suppliers and users are possible.
Phil Taylor is a freelance pharmaceutical writer and editor based in the United Kingdom. He has been covering IPEC issues since 2003,
. IPEC, the International Pharmaceutical Excipients Council, is made up of three independent associations: the Americas, Japan,
and Europe (