Focusing on risks, not hazards, can pave the way for smaller enzyme producers

The Horizon EU funded project OXIPRO is a success story. Several new industrially relevant oxidoreductases, a type of enzymes that can replace fossil-based chemicals in environmentally friendly consumer products, have been identified. Using the power of enzymes, researchers and industry partners in the project have succeeded in developing a bleaching method for fabrics, antimicrobial solution for detergents, making biobased sunblockers to maintain sun protection without harming ecosystems, and reduce the fishy smell in fish protein powder. Along with two inventions currently patent pending and – as we speak – 13 open access publications, these achievements make some of the project’s legacy.

– When it comes to integrating small and medium-sized businesses in a research project, you have done a very good job, advisory board member of the OXIPRO project Prof. Jennifer Littlechild said in a panel discussion on the project’s legacy.

However, in the end scientists and industry partners want to develop products that can be introduced to the market. The story of the 4-year OXIPRO project is indeed a story of knowledge, tools, and partnerships developed, but it is also a story about barriers in forms of policy, regulations and bureaucracy along the way.

Categorized as sensitizers

Let’s have a look at one of the cases from the OXIPRO project. Textiles. You use an enzyme to replace chemicals like hydrogen peroxide and chlorine, which can pollute water systems, but if you want to introduce the product to the market, you need to travel through the tough jungle of regulations.

Enzymes are biological substances, specifically proteins. In the EU, they are still considered chemical substances. If they are produced in industrial volumes (over 1 ton a year), they must be regulated according to the EU’s chemical regulation (REACH), and classified, labelled, and packaged as required (CLP regulation).

Since enzymes are proteins, they may pose allergenic risks to some individuals if they are exposed over a long time and sensitized, just like any other proteins we are exposed to like certain proteins from peanuts, fish, birch pollen, house dust mites or dogs. This means the immune system mistakenly identifies a normally harmless protein as a threat, which may lead to allergic symptoms, like a runny nose or rashes.

– Enzymes are categorized as sensitizers. Therefore, when using enzymes, you must go through many regulatory steps before it can be used in a product, says Anne Lyngbye, Regulatory Affairs Manager in one of the world’s largest producers of enzymes, Novonesis (formerly known as Novozymes). If any, they know the regulatory framework for enzymes within the European Union.

Because of this risk, the enzyme industry and users have strict measures for worker safety.

– And we know that there are very low levels of sensitization when you use enzymes, Lyngbye adds.

The chemical regulation in EU is shifting

The EU is now taking a proactive approach to prevent harmful chemicals from entering the market rather than controlling them when they have been launched.

This means strengthening current chemical regulations and introducing new regulations. Ever heard of ‘SSbD’? It stands for ‘Safe and Sustainable by Design’. SSbD is a framework to guide innovation towards the green industrial transition. It encourages to exclude hazardous chemicals, and secondly to evaluate safety for users and workers and environmental impacts. The framework is now in a test phase.

Should examine if enzymes cause harm

Lyngbye has been working with the regulatory framework for the past 15 years and has a background in several pharmaceutical and biotechnology companies. As far back as she remembers, the risk versus hazard debate has been ongoing as long as she has been working with regulatory framework.

A hazard means that there is a potential for the substance, activity or process to cause harm or adverse effect, while the definition of risk is a combination of the likelihood and the severity to cause harm.

– This has led to regulators banning substances that have an intrinsic ability to cause harm. We think regulators should examine whether there is a real probability that enzymes will actually cause harm, says coordinator of OXIPRO, Gro Bjerga.

A barrier for OXIPRO

Along with the OXIPRO consortium, Bjerga tried to influence regulatory frameworks under the SSbD and REACH to better reflect the specific properties of enzymes.

– We tested the SSbD framework on our cases in OXIPRO, and we ran into the challenges, says Bjerga, and continues:

– The regulators miss out on substances that could contribute significantly to European sustainability goals. Afterall, enzymes are biodegradable, typically used in small amounts, they are generally non-toxic and have a history of safe use. But most importantly, they can bring a positive impact on lowering energy needs, reducing water consumption and pollutions, and facilitating better use of unused resources – circular economy in practice.

Prioritization of hazard assessment may exclude enzymes despite their proven safety and environmental benefits. It creates a major challenge for enzymes.

Those challenges are not unfamiliar to Anne Lyngbye and Novonesis.

– To use an enzyme in a product, you first need to get the enzyme approved. Then you need to show that the product is safe; what is the potential that the enzyme and the end-product can cause harm? Here, you need to map all the steps and activity in the processing of the product.

In this process, both the ones producing the enzyme and the ones making the end product have obligations.

– This is very bureaucratic. At Novonesis, we have toxicologists and other specialists looking at the regulatory framework. As a big company, we have the resources and capacity to do that, but for smaller businesses, this is a challenge, Lyngbye thinks and gives an example:

– REACH placed a responsibility on the producers to ensure safety. Each year registrants must evaluate if the registration dossier is covering the registration volume or whether an update is required. Also new use can trigger a dossier update with the new exposure scenarios. This can be a big burden.

Should take inspiration from the Nordics

Despite the skepticism towards the regulatory framework, both Bjerga and Lyngbye see opportunities for change.

– The probability of enzymes not being classified as respiratory sensitizers are not good. That’s just how it is. But what we can do something about, is getting the regulatory system to focus on risk instead of hazards. Today, it is very hazard-based, explains Lyngbye and adds:

– The EU could take inspiration from the Nordic Swan Ecolabel for cleaning products where the benefits outweigh the hazards and there is no risk with working with the product. Ecolabeling considers the environmental benefits enzymes have, for example that when you wash at lower temperatures, you use less energy, rather than just focusing on the hazards.

Another opportunity is the European Green Deal, a set of initiatives by the European Commission to make the EU climate neutral in 2050. A wide range of new legislations on circular economy, building renovation, biodiversity, farming and innovation have been introduced with it.

The OXIPRO project played a leading role in a Policy Working Group to ensure that enzymes are recognized as essential tools in Europe’s green transition.

Obviously, there is difference on being a big, well-established enzyme producer with a large R&D department as Novonesis and a minor EU-project with a relatively small budget. But Lyngbye and Bjerga agree on one thing:

– We need to stay in contact with regulators and align enzyme production and use with regulatory frameworks and policies like the EU’s Green Deal and the Chemical Strategy for sustainability.