The sourcing of active pharmaceutical ingredients (APIs) and intermediates is an international affair. Much attention has
been focused on using offshore sites for pharmaceutical manufacturing to secure low-cost production. Although this approach
certainly remains an important issue, regulatory concerns are dominating the headlines in global sourcing. For 2008, the implementation
of the REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals) regulation, a new European Union policy
on chemicals and their safe use, looms large.
The terms of REACH
REACH came into force in the EU on June 1, 2007, with the goal of establishing a uniform system for assessing the risk posed
by new and existing chemicals (See sidebar, "Basic elements of REACH").
REACH requires EU-based manufacturers and EU-based importers doing business, directly or indirectly in Europe, to register
chemicals and their uses with the newly created European Chemicals Agency (see sidebar, "REACH and the European Chemicals
Agency"). Companies will eventually be required to provide toxicity data for substances produced or imported into the EU in
quantities above 1 metric ton per year. Companies will also be required to submit a comprehensive risk assessment, called
a chemical safety report, covering the various uses of the materials they register. For approximately 1500–2000 chemical substances,
companies will have to go through an authorization process to get permission to continue to use those substances (1).
Patricia Van Arnum
The aim of REACH is to create a single system for "existing" and "new" substances. Substances are classified as non-phase-in
substances (those not produced or marketed prior to the entry into force of REACH) and phase-in substances [substances listed
in the European Inventory of Existing Chemical Substances (EINECS) or those that have been manufactured in the EU, but not
marketed, in the past 15 years]. Approximately 30,000 phase-in substances (excluding intermediates) are expected to be registered
during REACH's 11-year implementation.
Manufacturers and suppliers are facing the first critical phase in REACH implementation. Preregistration is from June 1,
2008, to Dec.1, 2008. To preregister an existing compound, the name of the compound, the Chemical Abstract Service (CAS)
number, the EINECS number, the name and address of the registrant, and the tonnage must be reported to the European Chemicals
Agency in Helsinki (1).
Compliance with REACHis an important consideration for chemical manufacturers and suppliers, including those that supply the
pharmaceutical industry. "The major concern is that many in the industry do not know what the requirements are. The regulations
are very complex, and the guidance provided by the EU has done little in the way of making the requirements for companies
easier to understand," says Tucker Helmes, senior director of the Visions Department of the Synthetic Organic Chemical Manufacturers Association (SOCMA). SOCMAis the US-based trade association representing custom and batch manufacturers, including contract manufacturers
of APIs and intermediates.
"There is also concern about the quality and number of staffers in Helsinki. The European Chemicals Agency is far from fully
staffed, and there is concern that it won't be ready in time for preregistration," says Helmes.
REACH and the European Chemicals Agency
Another point for consideration is whether pharmaceutical ingredients are exempt from REACH. The REACH regulation exempts
substances used in medicinal products that fall within the scope of Regulation 726/2004 (centralized procedures), Directive
2001/82/EC (veterinary use), and Directive 2001/83/EC (human use). The REACH regulation, however, does not clearly state
whether the exemption applies to ingredients before they are incorporated into finished pharmaceutical products. Therefore,
there is some uncertainty as to what extent pharmaceutical ingredients (such as APIs, excipients, and intermediates) are
subject to REACH. The European Commission plans to review those exemptions in Annexes IVand V of the REACH regulation by June
Nonisolated intermediates are exempt. On-site isolated intermediates and transported isolated intermediates are subject to
lesser registration requirements. Also, substances used for product- and process-oriented research and development may be
exempted from registration for certain time periods (1, 2).
"My understanding is that finished pharmaceutical products are exempt from REACH registration. Makers of APIs or intermediates
that are sold to US drug manufacturers only should not have an obligation. It would be a worry only for APIs or intermediates
sold directly into the EU," says Helmes.
Basic elements of the REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals) regulation
Under REACH, EU-based manufacturers and EU-based importers will need to obtain information on the substances they manufacture
or import to assess the risks and to ensure that the risks are properly managed (1). Registration documents the execution
of this responsibility. Manufacturers and importers must submit a technical dossier for substances in quantities of 1 metric
ton or more and a chemical safety report for substances in quantities of 10 metric tons or more (1). REACH provides transitional
periods for registering phase-in substances, provided the substance is preregistered.