Implications of REACH for the Pharma Industry
How will the new regulations affect your EU imports?
By Carole Garcia
Actions needed by the pharmaceutical industry to meet the requirements of the European Union’s new Registration, Evaluation and Authorization of Chemicals (REACH) regulation are gradually becoming clearer now that the December 1, 2008 pre-registration deadline has passed. There has been considerable and ongoing confusion about the requirements of REACH amongst pharmaceutical firms: in some cases, substances used in drug manufacture are exempt from REACH, but this applies only in certain specific situations (See Know Your Exemptions below).
It is essential that pharmaceutical companies rapidly review their compliance with REACH requirements. Under the “No Data – No Market” message from REACH, companies have to register substances imported or manufactured in quantities of more than one tonne per year, providing toxicological data on the substance and risk assessment on their uses to the European Chemical Agency (ECHA). Users of substances have to make sure that their use is included in the registration and that they comply with authorization and restriction requirements under REACH.
In order to enable the smooth implementation of REACH a phase-in period allows a longer timeframe for the registration of pre-registered substances of as long as 10 years, instead of the 18 months for a new substance registration. Firms that have not pre-registered had to stop production or importation as of June 1, 2008. Tens of thousands of substances have already been pre-registered, including many key pharmaceutical raw materials, but unfortunately, that does not mean that supply of those materials will be guaranteed.
It is essential that companies assess any gaps in their REACH policies and evaluate potential risk through the documentation of products that have not been pre-registered. To ensure supply continuity, companies may need to partner with alternative raw materials suppliers that have their products registered, or have the opportunity to ‘late pre-register’ them. ‘Late pre-registration’ can be granted to phase-in substances that will exceed one tonne per year for the first time after November 30, 2008.
Pharmaceutical companies must also be aware of the potential for restriction of Substances of Very High Concern (SVHCs). So far, only 15 such substances have been submitted for REACH authorization. Listed in Annex XIV, to be published in mid-2009 by the ECHA, their use will only be permitted after authorization by the relevant authorities and then, only for applications covered by that authorization for a limited period. Several list revisions are anticipated, with the aim of eventually adding all SVHCs to Annex XIV.
The International Chemical Secretariat (ChemSec), in collaboration with leading NGOs, are developing the REACH SIN List (Substitute It Now!). This first SIN list was published on September 17, 2008, and provides first guidance for the industry on which substances need to be substituted. Generally, any substance considered an SVHC is likely to be placed on the Authorization list in the long term, and pharmaceutical companies should avoid their usage when possible during drug development steps. This will save time and money required later for authorization notification, and R&D for substitution.
Given that all substances used in pharmaceutical industry are subject to some requirements under REACH, there is clearly going to be significant impact. The main initial short-term effect is a possible interruption of supply of some starting materials or reagents that have not been pre-registered by EU suppliers, or from suppliers outside the EU who have not appointed an ‘Only Representative’ — an independent third party that takes on the REACH obligations.
The number of ‘orphan’ substances — those that have not been pre-registered by any supplier, but have a user with more than 1 tonne/year—will be known by early 2009. However, substance withdrawal may also happen separately as a consequence of supplier portfolio rationalization. Either way, the first interruption of supply already occurred in June 2008 and additional substance withdrawals may occur in early 2009. As mentioned, pre-registration does not guarantee that supply will be maintained.
Pharmaceutical companies must quickly assess what substances they produce or import that are subject to REACH, and what steps must be taken to be in compliance. The most difficult part is to assess the supply chain of purchased substances. It is important to list the substances bought within the EU and make sure that all the participants in the supply chain are ready to implement REACH. This should be done for all critical starting materials and reagents, whatever the volume purchased.
However, it can be difficult to obtain proof of REACH compliance from a supplier. A supplier cannot prove REACH readiness until the full registration is done (between 2010 and 2018 for phase-in substances), and there is no certificate of compliance. Companies must work closely with their suppliers to ensure that the appropriate efforts are being made.
It is important for suppliers and users to work very closely on REACH implementation to avoid any potential problems. Communication will be a key component of achieving that objective to identify proactively the registration/substitution need. If that is not done, companies can face serious problems if supply of key raw materials dries up and there is no alternative plan in place.
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Know Your Exemptions
For pharmaceutical companies, exceptions fall into four categories:
1. APIs and Excipients
Active pharmaceutical ingredients (APIs) and excipients are subject to REACH, but they are exempt from registration, evaluation and authorization if they are already registered with the European Medicines Agency (EMEA) as an ingredient of a medicinal product for human or veterinary use. Only the quantities used as a registered API or excipient will be exempt, however — if the same substance is also produced for another use, then, that remaining volume is subject to all the requirements of REACH.
2. Pharmaceutical Intermediates
Pharmaceutical Intermediates are subject to REACH, except if they are non-isolated, meaning that they are produced and kept within a reactor vessel and transformed into a final molecule or another intermediate. Isolated intermediates have to be registered under a different regime, and are not subject to authorization. Moreover, they are exempt from evaluation by the ECHA, provided they remain at a particular site. Transported isolated intermediates are subject to evaluation. The registration dossier of both categories may be limited to information that is already available if the manufacturer can prove that the intermediate is manufactured and used under strictly controlled conditions.
3. Starting Materials and Reagents
Starting materials and reagents are fully subject to REACH and are required to go through the registration process if they are produced or imported in quantities of more than 1 tonne per year per company (more specifically, per legal entity). Moreover, the compliance regarding the authorization and restriction requirements is mandatory, even for volumes lower than 1 tonne.
4. PPORD Exemption
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. This is submitted to the ECHA, and exempts the supplier and the user from registration of substances produced or imported in more than 1 tonne/year for five years, and is extendable by a further 5-10 years. However, when an exemption is obtained using a PPORD, users must document and apply measures that the substance is used in controlled conditions that preserve health of workers and the environment. A PPORD exemption may be granted even for common starting materials and reagents, but the global production volumes of those chemicals will usually lead to a separate registration by the manufacturer or importer.