REACH's Impact on the Pharmaceutical Industry

The European Union’s newly instituted Registration, Evaluation, Authorization and restriction of Chemicals (REACH) regulation has a number of requirements that apply to the pharmaceutical industry. Wading through the regulations and what they mean to this industry can be confusing as certain substances used in the pharmaceutical processes are exempt from one or more REACH procedures.

Under the “No Data-No Market” mantra, REACH requirements state that companies are required to register any substances imported or manufactured in quantities of more than 1 metric ton per year with the European Chemicals Agency (ECHA). Substance toxicological data as well as risk assessment of the various uses is required information at registration.

Phase-in period spreads registration costs

The REACH regulation requires registration of the existing 30,000 substances produced or imported within the European Union, which will result in a huge impact in the chemical industry. To make the first-phase of the regulation’s implementation easier, the EU has initiated a phase-in period for existing substances that will extend their registration timeframe over a 10-year time period to 2018. Substance registration will be prioritized according to the phase-in timeline (see Figure 1), based on volume and hazardous characteristics of the materials.

Figure 1. Click to enlarge.

To benefit from this phase-in period, preregistration of existing substances before Dec. 1, 2008 is essential, creating a sense of urgency with many companies.

New substances introduced on the EU market after 1981 do not benefit from this phase-in, so require REACH registration within 18 months.

Authorization and restriction procedures

As of September 2008, only 16 toxic substances were submitted for authorization. Listed in Annex XIV, scheduled to be published in mid-2009 by ECHA, they will only be able to be used after authorization by the relevant authorities and only for usage covered by that authorization for a limited period of time.

Several list revisions are expected to occur, with the aim of eventually adding all Substances of Very High Concern (SVHC) to Annex XIV. (Materials identified as SVHCs have characteristics such as CMR 1 & 2 [Carcinogenic, Mutagenic and substances toxic for Reproduction], PBT [Persistent, Bioaccumulative and Toxic] and vPvB [very Persistent and very Bioaccumulative]). Roughly any substance at risk for humans and the environment will be phased out in the European market.

In order to emphasize the goals of the REACH authorization process, the International Chemical Secretariat (ChemSec), in collaboration with leading nongovernmental organizations (NGOs) in the EU and beyond, developed the REACH SIN (Substitute It Now!) list. Published Sept. 17, 2008, this list is designed to be an indicator as to which risk substances should be replaced.

Although few substitutions will be required in a short term, such as cobalt chloride, the impact of the current authorization list on the pharmaceutical industry should be limited. For production, sustainability and cost effective reasons, pharmaceutical companies should therefore avoid usage of SVHC as early as possible in their drug-development processes.

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

What Procedure for what Material
To stay on top of these new regulations, pharmaceutical companies need to rapidly evaluate their readiness to meet REACH requirements. Many are finding that the safest approach is to assume that all chemicals are subject to REACH, taking into account the following four special cases.

Case 1: APIs and excipients. Active pharmaceutical ingredients (APIs) and excipients are subject to REACH but 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 quantities used as a registered API or excipient will be exempt; however, if the same substance is also produced for another use, such as food additives, it is still subject to REACH regulation.

Case 2: Pharmaceutical intermediates. Nonisolated intermediates, that is, 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 have to be registered according to different rules, although they are not subject to authorization procedures. They are exempt from the evaluation process as well, provided they remain at the production site of origin. However, transported isolated intermediates are subject to REACH registration and evaluation.

Information in the registration dossier of both categories of isolated intermediates (i.e., “on site” or “transported”) may be limited to existing information, provided the manufacturer can prove the intermediates are manufactured and used under “strictly controlled conditions.” Strictly controlled conditions comprise rigorous substance containment, procedural, and control technologies that minimize substance emission and any resulting exposure.These conditions are usually met in pharmaceutical production sites, but they must be fully documented and available to the regulatory authorities.

Case 3: Starting materials and reagents. All starting materials and reagents are subject to REACH and are required to go through the registration process if they are produced or imported in quantities of more than 1 metric ton per year, per company (i.e., per legal entity). Moreover, compliance with authorization and restriction requirements is mandatory, even for volumes lower than 1 metric ton.

Case 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 the 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 to 10 years upon proper application. Even with a PPORD exemption, however, users must document controlled use and apply health and environmental measures.

Because common starting materials and reagents used in larger applications will generally lead to REACH registration by its supplier, PPORD notification may be of less interest.

Table I summarizes requirements for various chemicals used by the pharmaceutical industry.

Table I: REACH requirements for various chemical types.

Registration

Evaluation

Authorization

Restriction

Comments

Registered APIs and excipients with EMEA

Exempt

Exempt

Exempt

Exempt

If not registered with EMEA, the regular procedure applies.

Nonisolated intermediates

Exempt

Exempt

Exempt

Exempt

Onsite isolated intermediates

Subject (under different regime)

Exempt

Exempt

Subject

Under strictly controlled conditions, the registration dossier information can be limited to already available information.

Transported isolated intermediates

Subject (under different regime)

Subject

Exempt

Subject

Under strictly controlled conditions, the registration dossier information can be limited to already available information.

Starting materials and reagents

Subject

Subject

Subject

Subject

Substances used under PPORD

Exempt for 5 years

Exempt but handled safely

Subject

Subject

Supplier and user must apply for the exemption.

REACH is Registration, Evaluation, Authorization and restriction of Chemicals.
EMEA is European Medicines Agency.
API is active pharmaceutical ingredient.
PPORD is product- and process-oriented research and development.

Source: SAFC Supply Solutions.

Sharing confidential data via SIEFs
All companies preregistering substances are required to participate in a Substance Information Exchange Forum (SIEF), an exchange forum that has been established under the objective of providing more transparency on substances, like classification, physicochemical, human health, and environmental properties.

SIEF participation must continue throughout the entire registration process, and allows for expensive procedure costs to be shared among the forum members. However, participation also mandates that companies exchange product data in order to prepare a common registration dossier. The proprietary nature of the pharmaceutical industry makes one ask, “What about confidentiality?”

A preregistrant can request not to participate in the SIEF only if there is a relevant rationale such as costs, confidentiality, disagreement with SIEF leader, etc. Declining SIEF participation means 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.  

REACH and its impact on material supply

The pharmaceutical industry is concerned that potential short-term impacts of REACH regulations could result in an interruption in the supply of some starting materials or reagents that have not been preregistered by EU suppliers, or by suppliers outside the EU who have failed to appoint an “Only Representative.” (Late preregistration can be granted to phase-in substances that will exceed 1 metric ton per year for the first time after Nov. 30, 2008). The registration procedures may also affect the materials provided by many of their outsourced manufacturing partners.

Investigations into orphan substances-those that have not been preregistered by any supplier but have a user with more than 1 metric ton per year requirements-are due to be revealed early in 2009. However, substance withdrawal may also be a consequence due to supplier portfolio rationalization. The industry’s first interruption of supply occurred in June 2008, and further interruptions are expected to be a continuing challenge to the industry. The industry should also expect additional substance withdrawals to occur later this year and in early 2009.

For a pharmaceutical company, understanding your supply chain, developing strategies for ensuring product availability, and communication with suppliers is key for avoiding interruptions in chemical supply as outlined below.

Know your supply chain. Knowing your supply chain is essential considering all the challenges associated with purchased substances. All your supply-chain participants should be prepared to implement REACH. No matter the volume you are purchasing, this applies to all critical starting materials and reagents.

However, obtaining REACH compliance proof from your supplier could be difficult. As an official REACH compliance certificate is not available, a supplier cannot prove REACH readiness until the entire registration process is complete-between 2010 and 2018 for phase-in substances. Thus, companies must collaborate closely with their suppliers to ensure the appropriate efforts are being made.

Ensure product availability. Dec. 1, 2008 signals the end of the preregistration period. The next step after preregistration will be for companies to assess remaining gaps and evaluate risks by documenting which products have not been preregistered. To ensure continuous supply, many companies may find the need to partner with alternative raw materials suppliers that have their products registered, or have the possibility to late preregister them. Late preregistration can be granted to phase-in substances that will exceed 1 metric ton per year for the first time after Nov. 30, 2008.

Communication is key. To minimize the impact of negative supply issues, the pharmaceutical industry and their suppliers must use this preregistration period to work in close alignment on REACH implementation. Good communication against REACH objectives will be a primary key in achieving these objectives and can be accelerated by proactively identifying registration/substitution requirements. If these critical steps are not taken and registration processes are not considered in time, many companies could face serious supply shortages in the materials key to their development and commercialization programs, thus, the consequences of not meeting REACH regulations could be considered extremely unacceptable.

Conclusion
Understanding the requirements of REACH and working closely with suppliers is critical for compliance and to ensure the continuous flow of product through the supply chain.

Carole Garcia is market segment manager of pharmaceutical raw materials for SAFC Supply Solutions, tel.+ 33 474 822853, carole.garcia@sial.com.