The Swedish Medical Products Agency (MPA) issued a report in July 2011 about how environmental standards in pharmaceutical production can be sharpened within the European Union. MPA issued the report to the Swedish government to address concerns over pharmaceutical production in low-cost countries, such as India and China, and the related environmental impact. The report was discussed at the Informal Meeting of Ministers for Health on July 6th in Warsaw, according to MPA.
“The proposal is unique and forces all manufacturers to follow the GMP rules on pharmaceuticals sold on the EU markets,” said MPA in a July 4, 2011, statement. “Today a considerable share of pharmaceutical manufacturing and production of raw materials and semi-products takes place in low-cost countries, and many large companies plan to locate even more of their production there. In the first decade of the 21st century, Swedish research findings have revealed emissions from the manufacturing of pharmaceuticals in India on a scale that can seriously impact the health of humans and animals, as well as the environment.”
MPA took up the task of how to consider the environmental impact of pharmaceutical production as part of consideration of green pharmaceutical production overall as well as in improving manufacturing conditions in low-cost countries. One factor coming into play was release of Swedish research findings that showed that emissions from drug manufacturing in India, particularly with respect to multiresistant bacteria strains, could pose risk to health and the environment. The Swedish government commissioned MPA in 2009 and 2011 to draw up a platform to enable Swedish initiatives in considering the environmental impact of global pharmaceutical production. That work also involves participation from the research foundation, MistraPharma, a group funded by the Swedish Foundation for Strategic Environmental Research (Mistra), which examines the environmental impact of pharmaceuticals. Part of MistraPharma’s work is to identify what pharmaceutical substances in use today constitute a substantial risk to water environments and to draw up recommendations and technologies for enhanced treatment of medicinal products in wastewater. MistrPharma’s work includes consideration of the spread of antibiotic-resistant bacteria as a result of production emissions, according to the MPA report (1). Other EU efforts include the European Commission’s role in compiling reports from EU member countries about the problem of pollution and soils and waters with pharmaceutical residues and to determine whether EU legislation needs to be changed. The EU’s Baltic Strategy is a further initiative that is considering the relationship between the environment and medicinal products. That work is slated to begin in the autumn of 2011, which will include input from Sweden’s MPA, according to the report (1).
Working toward a proposal
In 2009, MPA, in consultation with the Swedish Environmental Protection Agency and the Swedish Chemicals Agency, was commissioned by the Swedish government to chart the possibility of tightening environmental requirements in the manufacturing of medicinal products and active substances for medicinal products in Sweden and abroad. The scope of these proposals included possible legislation, voluntary industry initiatives, and global initiatives at the United Nations level. In December 2009, MPA submitted eight proposed measures to the government. The main proposal was to require environmental certification of production facilities within the framework of GMP requirements. In 2011, MPA, in consultation with the Swedish Chemicals Agency and the Swedish Protection Agency, was commissioned by the Swedish government to create a platform to enable the initiation of a revision of EU legislation on GMP, if deemed suitable, to include environmental considerations. As part of that effort, MPA was to develop concrete proposals for changes in GMP legislation by June 30, 2011.
Rationale for proposal
MPA issued its report in June 2011. The report includes proposals for regulations for environmental control and medicinal products within the framework of GMP. “What is unique about existing regulations regarding production and GMP is that they also impact third-[world] countries, as manufacturers wishing to export medicinal products to the EU are obligated to comply with regulations for production that apply in the EU. By also placing rules for environmental control among manufacturing regulations, they also have an impact on third-[world] countries,” said the MPA report. A further advantage of placing environmental requirements within the framework of GMP, according to the MPA report, is that there is a well-developed and well-functioning inspection system for monitoring manufacturing and GMP. “By placing environmental requirements within the framework of GMP, inspection protocols will also apply to the monitoring of compliance with environmental regulations. Thus no new system needs to be set up; all that is needed is the additional of internal or external environmental expertise,” according to the MPA report (1).
In its report, MPA made four proposals: changes in the EU medicinal products directive, introduction of a new EU regulation, suggestions for proposed substances for priority attention, and a broad framework to identify further substances (1).
Changes in medicinal products directive. In its proposal, MPA recommended that a measure be inserted in EU medicinal products directives, which would require manufacturers to comply with the requirements of a special new legal document, new EU legislation, in which emission levels for certain substances are stated. The requirement would be part of GMP compliance. MPA also recommended that a special legal document stating emission levels be adopted as there are not other legal documents in EU environmental legislation that would be suitable for that purpose.
Introduction of a new EU regulation. MPA recommends that a new EU regulation be created to stipulate the medicinal substances that need to be controlled in terms of emissions from production as well as the emission levels that are not permissible. MPA says a new regulation is preferable because it would come directly into force in all EU member countries and would not have to be implemented in national legislation.
The association offered recent cosmetics legislation in the EU as a model for how that regulation may be developed and presented. For example, a regulation recently adopted by the European Parliament, EC Directive 2009/1223/EU, contains annexes in which substances are listed that are prohibited for use in cosmetic products or for which limitations to their use are specified (1, 2). The power to adopt changes in the annexes was delegated to the European Commission. “An equivalent setup in itself would entail multiple advantages: emission limits apply to the entire EU, they have the same structure in all Member States, and changes are less complicated to effect in that the Commission can make them,” said the MPA report (1).
Proposed substances for priority attention. The MPA report specifies that priority substances should be specified in the new EU regulation. These substances would include substances for which there is scientific evidence that these substances negatively affect the external environment, and therefore public health. Substances, such as antibiotics, certain medicinal products with hormone-disrupting properties, and substances that may constitute a risk to the environment because they are used and produced in large volumes are examples of priority substances. In consideration of this prioritization, MPA further points to the EU Framework Directive for Water, which contains four medicinal products on a list of proposed priority substances that constitute a significant risk to the water environment (1, 3). These products include two hormones, 17 beta oestradiol and 17 alpha ethinyloestradiol, and two anti-inflammatory products, diklofenak and ibuprofren.
Identification of further candidates. MPA recommends that the new EU regulation establish a procedure on how to further identify substances and determine concentration limits, a task to be addressed by a EU body with the relevant environmental expertise. MPA does not offer a detailed proposal for how this procedure should be established or what EU body should be specifically charged with this responsibility. It suggests the responsibility would lie between the European Medicines Agency and cooperation between EMA and a EU chemicals authority, such as the European Chemicals Agency (ECHA), as well as engagement from other stakeholders.
MPA recommends that consideration should be given to introducing requirements for monitoring and documenting concentrations in wastewater of all active substances produced at a facility. This requirement also would entail establishing a validated method for measuring active substances. MPA suggests that the process for the prioritization of new substances could begin with a general limit for the emission of active substances in manufacturing that correspond to what applies to applications for authorization of a medicinal product. “This would eliminate any necessity to gather environmental data for individual substances,” said the MPA report (1). “In a later phase, when environmental data might be required or become available in some other manner, substance-specific limits can be established for priority substances,” according to the report (1).
MPA also suggests collecting environmental information about pharmaceutical substances through a database, which could be maintained by the EU medicinal products authority and EMA in a manner in which ECHA maintains the database relating to the requirements of REACH (Registration, Evaluation, Authorization and Restriction of Chemicals), a regulation on the registration and testing of chemicals in the EU. The MPA report also says that other practices of REACH can serve as a model, such as in setting up a candidate list and in providing direction on how to engage both EU authorities and individual EU member states in setting up certain substances in the legislation.
Although most sections of REACH exempt human medicinal products and veterinary medicinal products, one section that can be applied deals with limits on the production, release for sale, and use of certain harmful substances and preparations. The MPA report points out that it is thus possible to introduce a limit for a certain substance used in medicinal products, but in practice it is not probable that this would be done as REACH is general legislation and not adapted to such a specially regulated field as medicinal products. Nor would REARCH entail the registration of data about the use of medicinal products as human and veterinary medicinal products are exempted from the registration requirement.
But the MPA report points out that REACH can be used as a model for creating new EU legislation from the process for identifying substances for new limits and substances that may not be used without authorization. For example, REACH has a candidate list available on the ECHA website, which includes prioritized substances for authorization assessment and for which REACH specifies a specially delineated process for how new substances are placed on the candidate list. “Such a public list can function as a kind of Nota Bene list of substances that are being singled out for special monitoring, which sends a signal to the industry regarding what substances are in the pipeline and have been deemed to warrant special attention,” said MPA in its report (1). Initiatives for new limits under REACH can be taken both by ECHA and a member state, which composes a so-called limits file whose contents are specified by REACH. “This, too, is a process that can serve as a model when new legislation is drafted. It can be important that individual Member Countries are allowed to take the initiative for placing a certain substance in the legislation,” according to the MPA report (1).
1. Swedish Medical Products Agency, “Platform to Enable the Initiation of a Revision of EU Legislation on Good Manufacturing Practives, GMP, In Order for Legislation Also to Comprehend Environmental Considerations (Uppsala, Sweden, Jun 16, 2011).
2. EC Regulation 1223/2009, Cosmetic Products (Brussels, Nov. 2009).
3. EC Directive 2000/60/EC, EU Water Framework Directive (Brussels, Oct. 2000).