Regulation of Chemical Substances in Europe: What it Means for the Pharmaceutical Industry

REACH is a European Union (EU) regulation that deals with the registration, evaluation, authorization and restriction of chemical substances. It aims to protect health and the environment by identifying the properties of certain chemical substances. A number of the requirements also apply to the pharmaceutical industry.

The regulation has specific implications for manufacturers of substances or articles in non-EU regions, including the Asia Pacific region. Producers and exporters in these regions will be required to register the substances they supply or use for their products, via an 'Only Representative' (OR). Alternatively, they would need to provide European importers with detailed information pertaining to such substances.

Phased Implementation
REACH requires the registration of the existing 30,000 substances produced or imported within the EU. It is a directive that will have a significant impact on transparency and accountability within the global chemical industry.

The regulation requires companies to register any substances imported or manufactured in quantities of more than 1 metric ton per year, with the European Chemical Agency (ECHA). Additional information, including substance toxicological data plus a risk assessment for the various uses of substances, is also required at registration. Establishing which regulations are applicable to the pharmaceutical industry can prove complex, as certain substances used in pharmaceutical processes are exempt from one or more REACH procedures.

In order to facilitate the first-phase of the regulatory implementation, there is a phase-in period for existing substances that will extend their registration timeframe over a 10-year period, to 2018. Substance registration will be prioritized according to the phase-in timeline, based on material volume and hazardous characteristics. To benefit from this phase-in, a pre-registration period ending December 1, 2008 for existing substances was implemented.

Substances introduced to the EU market after 1981 do not benefit from the 10-year phase-in and require registration within 18 months of the date stet the ECHA has been notified of the production, or intended production, of the 1 metric ton per year quantity.

'Late' Pre-Registration
Following the end of the pre-registration period, companies should assess any gaps in their REACH policies and evaluate potential risk through the documentation of products that have not been pre-registered.

To ensure continuity in supply, companies which import into the EU, or export to Asia from the EU, may find the need to partner with alternative raw materials suppliers that have already registered their products, or have the opportunity to 'late pre-register' them. 'Late pre-registration' can be granted to phase-in substances that will exceed 1 ton per year for the first time after November 30, 2008.

Substances of Very High Concern (SVHCs) is another area that is covered by REACH. The use of these highly toxic substances needs to be known and controlled by the EU. Only about 15 toxic substances have been submitted for authorization. Listed in Annex XIV, to be published in mid-2009 by the ECHA, their use will only be permitted after authorization is granted by the relevant authorities, and is only for applications covered by that authorization for a limited period of time.

Several list revisions are anticipated, with the aim of eventually adding all SVHCs to Annex XIV. In the long term, the plan is to phase out any substance which poses a risk to humans or the environment within the EU.

The International Chemical Secretariat (ChemSec), in collaboration with leading Non-Governmental Organizations (NGOs) in both EU and non-EU regions, have developed the REACH "Substitute It Now!" (SIN) list, designed to provide an indication of the risk substances that should be replaced.

With the exception of a few high risk materials, such as cobalt chloride, the impact of the current authorization list on the pharmaceutical industry should be minimal. To promote production efficiency, sustainability and cost efficiency, pharmaceutical companies should eliminate the use of SVHCs as early as possible in their drug development processes.

Restriction can apply to all substances, without volume limits. Such substances and their restriction details are described in the current Directive 76/769/EC, which will be replaced by Annex XVII as of June 1, 2009. The new Annex will reflect the same regulatory requirements as the current directive.

Making Exceptions
Many pharmaceutical companies that have evaluated their REACH readiness have concluded that the safest approach is to assume that all chemicals are subject to the regulation, with the following four exceptions:

1. APIs and Excipients - Subject to the regulation but exempt from registration, evaluation and authorization if previously registered with the European Medicines Agency (EMEA) as an ingredient of a medicinal product for human or veterinary use. Only quantities used as registered APIs or excipients will be exempt. But if the same substance is also produced for another use eg, food additives, it is still subject to the regulation.

2. Pharmaceutical Intermediates - Nonisolated intermediates or intermediates produced and kept within a reactor vessel to be transformed into a final molecule or any another intermediate are not subject to REACH. Isolated intermediates must be registered according to different rules and are not subject to authorization procedures. They are also exempt from the evaluation process provided they remain at the production site of origin. Transported isolated intermediates are subject to registration and evaluation.

Information in the registration dossier of both categories (ie, 'on-site' or 'transported') may be limited to existing information, provided the manufacturer can prove that the intermediates are manufactured and used under 'strictly controlled conditions,' comprising rigorous substance containment, procedural and control technologies that minimize substance emission and any resulting exposure. These conditions must be fully documented and available to the regulatory authorities.

3. Starting Materials and Reagents - All starting materials and reagents are subject to the regulation and must go through the registration process if they are produced or imported in quantities of more than 1 ton per year, per company (ie, per legal entity). Compliance with authorization and restriction requirements is mandatory, even for volumes lower than 1 ton.

4. PPORD Exemption in Drug Development and Clinical Trials - For APIs, excipients, intermediates, starting materials and reagents used during drug development and clinical trials, an exemption can be obtained via a Product-and-Process- Oriented Research and Development (PPORD) notification.

ECHA issues the exemption following the notification, discharging both supplier and user from registering substances produced or imported in more than 1 metric ton per year. This exemption is valid for five years and can be extended for an additional 5-10 years upon proper application. However, even with a PPORD exemption, users must document controlled use and apply health and environmental measures.

In Discussion
All companies pre-registering substances must participate in a Substance Information Exchange Forum (SIEF), established to encourage greater transparency on substances, in terms of classification, physicochemical, human health and environmental properties. For Asia Pacific pharmaceutical companies, participation in a forum would be handled by their appointed OR.

Participation continues throughout the entire registration process, allowing for expensive procedure costs to be shared between forum members. Participation stipulates that members exchange product data to prepare a common registration dossier, raising concerns over confidentiality. Pre-registrants may only request not to participate in the forum if there are legitimate reasons such as cost, confidentiality issues or disagreement with a SIEF leader. Declining participation necessitates the submission of a separate registration dossier for substances and the elimination of the longer phase-in period. A full registration dossier must be submitted to REACH within 18 months.

There are concerns within the pharmaceutical industry that the potential short-term impacts of REACH could result in interruption to the supply of some starting materials or reagents that have not been pre-registered by EU suppliers, or by non- EU suppliers that have failed to appoint an OR. The registration procedures may also affect the materials provided by outsourced manufacturing partners.

Your REACH Guide

Investigations into 'orphan substances,' which have not been pre-registered by a supplier but have a user with requirements of more than 1 ton per year, are due to be revealed early in 2009. Substance withdrawal may also be a consequence, as suppliers look to rationalize their product portfolios.

Implications for Asia
REACH presents Asian pharmaceutical companies with challenges. For example, there should be minimal impact on Asian companies which export APIs into Europe, as APIs are exempt from the main legislation. However, if a manufacturer is sending an intermediate to be finished in Europe in quantities of more than 1 ton per year, the product must be registered. Also, as a new substance, the intermediate cannot benefit from pre-registration and needs to be submitted for registration with ECHA within an 18-month timeframe, once 1 ton of product has been manufactured.

Asian companies with suppliers in Europe will also need to ensure that their suppliers and products are now REACH registered. Previously, products being exported from the EU to Asian markets did not have to fulfill the same criteria as products supplied to the EU. However, since the introduction of the regulation, this is no longer the case.

REACH offers Asian businesses a means of simplifying the registration process, as a REACH Implementation Timeline. (Source: SAFC Supply Solutions) Policy & Projections non-EU manufacturer may appoint an EUbased OR to handle its pre-registration and registration. It is essential that the relationship between the Asian manufacturer and importer is based on trust and confidentiality. Not only will the agent have access to the client's intellectual property (IP) but is also likely to be dealing with the IP of the clients' competitors.

In China, the government carries out an assessment of representatives and advises manufacturers/exporters to use one of its recommended agents.

Asian pharmaceutical companies in the EU supply chain should be prepared to implement REACH, regardless of the volume of critical starting materials and reagents being purchased. Obtaining proof of compliance from EU suppliers may prove difficult, as an official REACH compliance certificate will not be available until the entire registration process has been completed - between 2010 and 2018 for phase-in substances. This underlines the importance for companies to collaborate closely with their suppliers to ensure that appropriate efforts are being made.