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The pharmaceutical industry must understand its responsibilities to improve the safety of chemicals as defined by the REACH initiative.
The Registration, Evaluation, Authorisation (and restriction) of Chemicals (REACH) initiative came into force on 1st June 2007. The aim of the directive is: to improve the safety of chemicals on the European market; to ensure that manufacturers and importers of chemicals are aware and responsible for managing risks associated with their use; to allow the free movement of substances throughout the EU market; to enhance innovation and competitiveness in the EU chemicals industry; and to promote the use of alternative methods of hazard assessment.
(LEWIS MULATERO/GETTY IMAGES)
A major part of REACH was the requirement for manufacturers or importers of substances to preregister them with the central European Chemicals Agency (ECHA) before 1 December 2008 to obtain phase in status. The registration package is supported by a standard set of data on that substance where the amount of data required is proportionate to the amount of substance manufactured or supplied. If a substance was not registered, then the data on it will not be available and as a result, no one will no longer be able to manufacture or supply them legally, i.e., no data, no market!
Three years following on from its introduction and the picture is now much clearer about pharmaceutical companies' obligations under REACH. Challenges remain, however, to ensure that supply chains are not disrupted and brand value damaged through poor REACH plan execution and the inactivity of key participants in the REACH scheme.
Initial signals in the media were confusing back in 2007/8. Pharmaceuticals were stated as being exempt from the main provisions of registration, evaluation, authorisation and downstream use of chemicals where they fell within the scope of Regulation 726/2004 (governing the centralised procedure), the Human Use Directive 2001/83 and the Veterinary Use Directive 2001/82. Closer examination, however, indicated that this did not cover chemicals used in the synthesis of drug actives (e.g. starting materials, reagents, solvents, catalysts, intermediates), ingredients in oral healthcare products and chemicals used in immediate and outer packaging.
Moreover, there was the other, as yet, unquantifiable risk at the time that substances with multiple uses beyond pharmaceutical excipient use in medicinal products may be affected by certain commercial considerations; i.e., the costs involved for a supplier registering a substance for its general use might far outweigh its commercial viability. Manufacturing or importing might therefore cease altogether, leaving the pharmaceutical company with no choice but to source elsewhere or substitute and reformulate its products with all the consequent costs involved.
Any substance that is used in applications in addition to those in the pharmaceuticals industry has had to go through the pre-registration process to achieve phase-in status of being fully registered between 2010 and 2018. As a manufacturer or importer, the pharmaceutical industry will be required to register any substances (> 1 tonne) that they manufacture or import directly into the EU. Furthermore, as a downstream user, the pharmaceutical industry needs to provide information on human and environmental exposure and emissions to the suppliers from whom they obtain the substances.
With this in mind, the pharmaceutical industry with its wealth and depth of experience and expertise in managing proscriptive regulation, set about developing their game plans.
A pharmaceutical company is now responsible for taking a number of actions to reduce their chemical supply risk, including:
A downstream user will eventually have to seek authorisation for any substances of very high concern (SVHC) that they wish to use whilst also ensuring that their supply chains are not disrupted as a result of any post-REACH market restructuring.
Information gathering then started for many pharmaceutical companies about the use of materials and EHS hazard data required to meet the first REACH registration milestone of November 2010 for phase-in substances. This will be a continuing process beyond 2018; companies will need to continuously work with suppliers to ensure that they meet their REACH obligations and, in collaboration with other companies via Substance Information Exchange Fora (SIEFs) (see sidebar), to share any hazard data they have on substances of mutual interest that require REACH registration.
Sidebar: What is a SIEF (Substance Information Exchange Forum)?
The management of supply chain communications is essential in this scenario, not only to allow accurate documentation and sharing of information, but also to manage communication between all parties involved — EU manufacturers and importers. There is therefore an obvious need for efficient processes and IT solutions. It is also vital that these reach beyond a company's immediate supply chain partners and to the supplier's supplier.
While the actions required by the pharmaceutical industry to meet REACH requirements are clearer now that the 1 December 2008 preregistration deadline has passed, using the right data sharing IT system is still crucial to registration success in December 2010 and beyond.
The path to REACH registration is being made even more difficult because of overloaded IT systems that do not facilitate the essential communication between SIEF members. The problem of inadequate IT provision is also exacerbated by the general malaise of the majority of 2010 substance registrants. In fact the ECHA stated in December 2009 that, of the estimated 9000 substances that have to be registered by the December 2010 deadline, approximately 75% had yet to nominate a lead registrant and are behind in their SIEF operations.
To date, lack of communication between prospective SIEF members has proved to be the major stumbling block in the registration process, which will impact pharmaceutical companies involved with these substances, either as a potential registrant or as a downstream user.
While grappling with inadequate software systems, companies have also struggled with the complexity of establishing, running and participating in a SIEF, which could logistically involve communication between hundreds, if not thousands, of members. This problem is partly because REACH software programmes have had to be revamped because of the unanticipated surge in preregistrations. The underestimation of the number of pre-registrations is so enormous that IT systems designed for much smaller numbers were not able to cope when the preparations for drawing up registration dossiers began.
Pharmaceutical companies may well have had an insight into this confusion as some service provider organisations competed for what they perceive as the coveted SIEF Forum Facilitator (SFF) role. They expected that this would give them license to bill other SIEF members for their services, the result being multiple and overlapping communications about the same substance from different sources.
Software systems are, however, still evolving and being enhanced to meet the ever changing demands of REACH and to allow SIEF members to communicate effectively. Innovation and development has struggled to keep pace with these rapidly evolving requirements that REACH is imposing on us all. It is very much about being fleet of foot and flexible in development.
There are two significant barriers to adoption of software that will allow SIEF members to collaborate through online systems, including cost and the "sign up" process (required for some software systems), which can be quite protracted. SIEF members must discuss their requirements with specialist software vendors and select a firm that is able to overcome these barriers.
However, IT solutions aren't the be all and end all of substance registration; no matter how good the IT platform, it will not support poorly designed business processes or make up for the lack of REACH knowledge and understanding — a major challenge at present as there are too few experts around to help facilitate this process. Companies are also, naturally, very anxious at the scale of the task before them, which is to ensure fair data sharing between thousands of substance manufacturers or importers fairly, transparently and in a non-discriminatory way.
REACH places responsibilities on all European manufacturers and those who import into the EU to identify and manage the risks that their substances may pose to human health. The formation of the SIEF is central to the REACH process, allowing SIEF members to share their toxicological data and prevent further animal testing. Effective IT solutions are needed to manage this today so that significant administration problems and rising costs are reduced for the future.
Industry must therefore take responsibility for the task at hand and discuss their needs with software vendors. Like all software tools, however, one must learn to use it and it has to be fed with data, so it needs time to administer — time that not everyone has. As such, it may be that cost and administrative duties are shared across all active participants, i.e., manufacturer, supplier, importer. It may also be useful to consider hiring a consultancy firm to provide manpower for managing the SIEF(s), communications, work planning, cost sharing and administration. The consultancy firm may be contracted by the lead registrant, but the costs will later be shared between all active participants. This works much better than trying to get all SIEF members to contribute up-front, but it does need someone to bite the bullet and provide leadership. The result, however, is that they can see a plan towards registration and a means of getting there.
At the moment there are only around 9000 substances on track for 2010 registration, but for the 2013 deadline, that figure could be 50 000 or higher and perhaps with less data available to assist the registration process. People will look at those substances that make it through to 2010 and, hopefully, reflect on the organisation, the service providers and the software platform used when evaluating the success factors. These will, in turn, guide them with their 2013 choice of partners and IT platforms.
There is no doubt that REACH has had an impact far beyond the EU and is now influencing the thinking and approach to chemical safety in many other emerging international regulations. The Obama Administration is signalling its review of chemical safety legislation in the US. Furthermore, the California Green Chemistry initiative is another example — though quite how this may relate to FDA regulations in the US and the apparent "parallel" regulatory approach of REACH in the EU remains to be seen.
Then there is China where there is a growing awareness of REACH. This means that one day, a similar regulation may come into force there too.
Jean-Paul Rila and Marie-Elene Boivin, NOTOX BV
In accordance with REACH, for all substances that are manufactured or imported in volumes of 10 tonnes or more per year, a Chemical Safety Assessment (CSA) has to be conducted and recorded in a registration dossier as a standalone document — a so-called Chemical Safety Report (CSR). If a substance meets any criterion for classification as dangerous or is considered a PBT (Persistent, Bioaccumulative and Toxic) or vPvB (very Persistent, very Bioaccumulative) chemical, the CSR also has to contain an exposure assessment followed by a risk characterisation.
The exposure assessment basically comprises two elements: development of exposure scenarios and an estimation of exposure. The exposure scenario constitutes the basis for the exposure estimation and is also the major risk communication tool used in the supply chain, together with the safety data sheet. It is therefore essential that the information in the exposure scenario is presented in a standardised and comprehensive way so that it clearly describes the operational conditions and risk management measures in place that guarantee safe use of the substance. In this context, the use descriptor system can help to structure the communication on uses and operational conditions of use between customers and suppliers.
The use descriptor system is based on four elements: sector of use (SU), chemical product category (PC), process category (PROC) and article category (AC). For each descriptor, a selection list is provided so that the right category can be chosen. The combination of the four descriptors allows, in most cases, the accurate description of a substance's identified uses. It can also be used as a summary for the exposure scenario.
The development of exposure scenarios should begin by characterising the uses of a substance using the use descriptor system. However, in most cases, a company will be required to provide more information regarding the conditions of use because this is needed for carrying out an exposure estimate and deriving the final exposure scenario, leading to safe use.
In the last quarter of 2009 we began sending enquiries to our clients to obtain an overview of the substance's use for those registrations that were to be submitted before the REACH deadline of 30 November 2010. Although the enquiries were standardised, the responses we received were quite divergent. In some cases, all applicable use descriptors were taken from the selection lists without relating them to the relevant life cycle stage, whilst in other cases the essential lifecycle steps were mentioned and coupled to the applicable use descriptors. Because of this variation in the information provided, it was quiet a challenge to come to the development of an exposure scenario. It became evident that registrants required a lot of communication and guidance on what was needed to ensure that supplied information complied with the standardised format necessary to create an exposure scenario.
To build exposure scenarios, it is essential that registrants give a complete overview of all of the intended uses in the lifecycle of the substance. Quite some effort is needed in this regard; it requires that the registrant is knowledgeable and understands the processes needed to complete an accurate exposure assessment. Through experience, it became obvious that most companies respond better to the information needs on different lifecycle steps, the use of descriptor systems and minimum information needed for an exposure assessment, during a face-to-face meeting with experts in the field.
Although the use of the descriptor system is supposed to ease the first step of building the exposure assessment (use mapping), from what we have witnessed, it can actually be quite confusing for most people. Companies must, however, be fully aware of standard reporting protocols required for developing an accurate and acceptable exposure assessment as well as their obligations. If this knowledge is not available in-house, companies should look to third parties that specialise in REACH and risk assessments to ensure that they fully comply with the requirements needed for REACH registration.
Dr Jean-Paul Rila is Regulatory Affairs Manager at NOTOX BV (The Netherlands).
Dr Marie-Elene Y. Boivin is Section Head Regulatory Affairs at NOTOX BV (The Netherlands).