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Is the current regulatory framework fit for Synthetic Biology? Our perspective on the EU landscape and the need for enhanced risk management.

By Marthe Van de Vliet (MSc); Marta Tomaselli (PhD, MSc) - Deloitte Belgium Risk Advisory

Disclaimer: The aim of this article is to provide a perspective on Synthetic Biology and its application in the Cell and Gene Therapy (CGT) domain. It has solely been written for informative purposes and does not provide any regulatory and/or legal advice for the development of CGT products.

What is Synthetic Biology?

The concept of Synthetic Biology (SynBio) dates back to the 2000s when the combination of advances in biotechnology, engineering and computational sciences allowed to “apply engineering principles to the design and development process of new biological functions or components” (Donati, et al. 2022).

SynBio is a way of thinking, designing and implementing changes in biological systems. It is a transversal discipline, covering different fields from agriculture to medicine and many more (see Figure 1). For the scope of this article, we will review how SynBio is currently regulated in the European Union (EU) and the regulatory challenges that medicinal SynBio products, in particular CGT products, face.

CAR-T therapy for example, is a gene therapy designed to treat blood cancers and was introduced on the European market in 2018 (EMA 2022). This therapy consists of reinjecting the patient’s own immune cells, which have been engineered to produce a higher amount of an antibody that targets the patient’s cancer cells. This product can be classified as SynBio, because the patient cells have been administered genetic material to manipulate the production of such antigen (Voigt 2020).

When compared to traditional pharmaceutical products, CGT products face more challenges during their regulatory journey. Nevertheless, thanks to CGT, patients who are not responding to conventional treatments are offered a last-resort cancer therapy. These personalized therapies have high success rates and can cure a patient for life. Consequently, numerous big pharmaceutical companies have decided to work on similar therapies, using the patient’s own immune system to produce an effective therapy, through the engineering of cells targeting specific diseases (liquid tumors especially) (Voigt 2020).

How does the EU define Synthetic Biology?

In 2014, The European Commission (EC) requested the Scientific Committees on Consumer Safety (SCCS), Emerging and Newly Identified Health Risks (SCENIHR) and Health and Environmental Risks (SCHER) to issue three opinions on SynBio. The first one covers the SynBio definition (SCHER, SCENIHR and SCCS 2014), while the other two focus on risk assessment (SCENIHR, SCHER and SCCS 2015) and biosafety of SynBio products (SCENIHR, SCHER and SCCS 2015).

The first final opinion by these groups of independent experts delivered the following operational definition of SynBio:

SynBio is the application of science, technology and engineering to facilitate and accelerate the design, manufacture and/or modification of genetic materials in living organisms.

The opinion stresses that the new technologies indicated as SynBio have enabled faster and easier design and manufacturing of genetically modified organisms (GMOs) and for this reason they are currently encompassed as genetic modification (GM), defined in the European Directives 2001/18/EC and 2009/41/EC.

Nevertheless, no quantifiable and currently measurable inclusion and exclusion criteria could be identified to define what type of process, tool or products belong to SynBio. The opinion defines SynBio as any organism, system, material, product, or application resulting from introduction, assembly, or alteration of the genetic material in a living organism. This qualitative classification does not help an unambiguous differentiation of SynBio processes from GM products.

The two additional opinions issued by SCCS, SCENIHR and SCHER focus on the risk assessment (SCENIHR, SCHER and SCCS 2015) and biosafety of SynBio products (SCENIHR, SCHER and SCCS 2015). Both documents conclude that, despite the regulatory framework in place for GMOs and the availability of chemical risk assessments for SynBio products, there are new risks to be accounted for. Newly identified risks are not only linked to the novelty of the techniques, but also to the speed and complexity of the performed changes. The analysis of such risks should not be restricted to the immediate output of a SynBio product but should also evaluate the systemic effects of the change within the organism and its environment.

Challenges of the SynBio regulatory landscape in EU

The broad definition of SynBio in EU combined with the GMO implication, and absence of sub categories within SynBio, leads to a lack of clarity on what is to be considered a SynBio product. This shows that the advances in technology, research and science, are outpacing regulatory and legal frameworks, making these unfit for purpose (MacIntyre 2015, Baulcombe, et al. 2014).

Advanced Therapy Medicinal Products (ATMPs), such as the gene therapy mentioned in Section 1, are often obtained through SynBio techniques and are therefore considered GMOs. Figure 2 aims to show how CGT relate to SynBio and GMOs. Due to their difference with traditional pharmaceuticals, additional measures to ensure product quality, safety for the patient, monitoring of their health and environmental sustainability, should be put in place. This can be achieved through clear and specific regulations governing these products.

When analyzing the regulatory landscape of CGT, a broader regulatory framework applies: in addition to the often applied Directives 2001/18/EC and 2009/41/EC covering GMOs, CGT are subject to Regulation EC 1394/2007 on Advanced Therapy Medicinal Products (ATMPs) (EMA 2018). Furthermore, depending on the drug product and target audience, additional regulations might apply to CGT products, such as for orphan drugs (EMA 2018) or medicines for paediatric use (EMA 2018). Next to these regulations, sponsors developing ATMPs should also consider, amongst others, GDPR, data privacy, the regulation on falsified medicines and good manufacturing practices guideline for ATMPs (refer to figure 3). This framework ensures that scientific advances in CGT are regulated and patients are protected. As a result, new therapies to treat diseases which could not be cured through the use of traditional medicines, will be able to safely enter the market (Voigt 2020).

Despite this framework, there are still challenges in the EU legislation that need to be addressed. In gene editing, the biggest debate is linked to the different levels of ethical acceptance among the broad population, due to the difficulty to define a boundary between preventive and therapeutic editing, and editing for perfection. This ethical perspective could be a future project for EMA or an opportunity to define a methodology to categorize SynBio products and refine their definition.

In addition to gene editing, the information security associated with SynBio products is also subject to a new risk landscape. Often information on genetic modification is stored in cloud labs to allow the use of automated devices to perform gene modification, increasing high throughput and reduce human oversight. This bio-data is at risk for tampering, which could lead to the production of harmful organisms, sabotaged drug development, and open new kinds of information security threats (Wintle, et al. 2017). Current legislations and standards are available to define data privacy and cyber/ information security measures, nevertheless they may require additional risk analysis to grasp the new risks and challenges brought by SynBio products.

Risk assessment to tackle the new risks brought by SynBio products

SynBio is a transversal field bringing a diversity of new challenges and risks. The way the product is designed, the engineering approach or the final intended use, can compromise biosafety and/or cause biosecurity accidents. Unauthorized access, dissemination, misuse or the use of SynBio products as bioweapons, can be hazardous to the environment, public health and human kind (MacIntyre 2015, Zeng, et al. 2022).

Multiple articles suggest to tackle these risks by performing risk assessments and implementing customized (risk) management systems (Zeng, et al. 2022, MacIntyre, Engells, et al. 2018). In Figure 4, the Deloitte methodology consisting of a six-phased approach to conduct risk assessments encompassing preparation, risk identification, analysis, and evaluation of the results, followed by risk mitigation and acceptance, is visualized. Implementing measures for timely surveillance of risks (MacIntyre, Engells, et al. 2018) during the SynBio products’ lifecycle enables early identification of issues or incidents. This combined with the use of effective risk registration methods (MacIntyre, Engells, et al. 2018) ensures risks are promptly identified, analyzed (manually or by specific algorithms) and evaluated.

According to our methodology and experience, the scope and focus areas of the risk assessment should be carefully defined at the start of the assessment. One can decide to take into scope the entire end to end process of the SynBio product life cycle and, on top focus on quality procedures and protocols in place. Based on our expertise, we strongly recommend to also evaluate the level of alignment between roles and responsibilities amongst the various stakeholders as the development process of SynBio medicinal products is often complex and cross-functional (e.g. IT, Supply Chain, Quality, Regulatory Affairs, Medical Affairs, Pharmacovigilance, Legal, etc.).

After having defined scope and focus areas, risks can be identified by performing individual stakeholder interviews and cross functional workshops, to obtain insights across the product journey. As per our expertise, this information defines the base for the analysis/evaluation phase. After identifying the risks, a key success factor to the risk assessment is to quantify the risks based on their likelihood and impact, and map this outcome on a heatmap. This data can be obtained through a voting session in a multi-disciplinary workshop and will help to establish priorities. Risks perceived as having a moderate to high impact and vulnerability, can be prioritized accordingly, a pre-requisite to start defining risk mitigation measures.

Following risk mitigation, we observed the different stakeholders should also define acceptance criteria or a scoring system to define when risks can be accepted. Next to risk mitigation, the outcome of the risk evaluation can also be used to define preventive measures. The likelihood and impact of some risks could be drastically reduced, act on the source of potential issues, and eliminate the risk itself. Specifically for SynBio risks, preventive measures could be the setup of new conventions, the design of protocols for the use of SynBio products and development of training programs to strengthen awareness and biosecurity education around this new type of products.


SynBio represents the future of research and industry and is already revolutionizing the way we eat and cure ourselves. SynBio brings scientific innovation and revolutionary personalised therapies to the market, but it also brings a new risk landscape. There is an imperative need for a tailored SynBio regulatory landscape in EU, broader than the GMO regulation (and ATMP regulation specific for CGT), and addressing the ethical dilemma, to streamline and facilitate further development of SynBio in a safe manner. SynBio should be able to deliver the promised benefits to people without causing any harm or threats to biosafety and security. In absence of a tailored regulatory landscape, risk assessments offer the opportunity to map SynBio product specific risks and preserve biosafety/security. Deloitte’s six-phased approach presented here offers a framework to perform this exercise. The outcome of the assessment can then be applied at different time periods of the SynBio products’ lifecycle, to contain potential damage or harm by SynBio, to nature and human kind.

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