RNA technology and processing
mRNA therapeutics: development and manufacturing trends in a rapidly evolving space
What are some trends in the mRNA space surrounding the growing desire for speed-to-market, and what hurdles are impeding the achievement of this goal?
Jing Zhu at ReciBioPharm
Following the success of the first mRNA vaccine to gain FDA approval in 2021 (Pfizer-BioNTech's COVID-19 vaccine), this revolutionary drug modality – which offers the potential to treat a multitude of diseases – has been in the spotlight.1 Realising the potential of mRNA as a tool for enabling precise and specific protein expression, researchers and drug developers have quickly expanded the mRNA pipeline with therapies targeting a variety of indications. As of April 2023, over 300 mRNA therapeutics are in development, with 69% and 31% at preclinical and clinical stages respectively.2 These innovative therapies use mRNA in novel and creative ways to achieve an impactful outcome.
mRNA Vaccines and saRNA
By introducing mRNA encoding to a ‘foreign’ protein, such as the COVID-19 spike protein, mRNA vaccines prime the immune system to specifically recognise and manifest a response to viruses upon infection. Following the success of the global COVID-19 mRNA vaccine rollout, developers are applying this technology to target other infectious diseases, rare diseases, cancers and indications associated with bacterial infection.3 Self-amplifying mRNAs (saRNAs) have recently entered the spotlight as a promising technology platform for vaccine development. The mRNA is expanded intracellularly, mimicking a viral infection and resulting in sustained levels of the target protein. As a result, self-amplifying mRNA can enable potent and long-lasting immune responses.4
Gene editing
In terms of safety, the short-lived expression of the encoded proteins makes mRNA an ideal vehicle for delivering gene editing machinery, such as CRISPR-Cas 9. Although these therapeutics are early in their development, there has been preclinical success, with one study demonstrating the highly effective delivery of mRNA encoding CRISPR-Cas9 components to the lungs of mice.5
Personalised medicines
There is an increasing need for personalised medicines, particularly in the oncology space, where patients’ tumours present specific molecular features in the form of neoantigens (abnormal antigens). These neoantigens are promising targets for vaccine-induced immune responses and could hold the key to personalised mRNA cancer therapeutics with encouraging results already seen in clinical studies.6,7 With a wide array of potential therapeutic uses, it is not surprising that the global mRNA therapeutic market has been predicted to grow at a compound annual growth rate of 16.8% between 2021 and 2026, reaching a value of $101.3bn by the end of the period.8
Exploring the advantages of mRNA technologies
As well as the many therapeutic applications of mRNA, there are several other key benefits for patients, drug developers and manufacturers driving its adoption.
Safety
Unlike in many gene therapies delivering genetic material, mRNA is not integrated into the patient’s cell genome and is quickly degraded by cellular processes. The presence of mRNA in patient cells is therefore transient and carries a low risk of infection or insertional mutagenesis. As mRNA is also produced in a cell-independent process, it has minimal safety concerns surrounding contamination with toxic agents.
Efficacy
Technological advancements in the last three years have improved mRNA stability and supported its packaging into lipid nanoparticles (LNPs), enhancing cell delivery.9 These improvements have also heightened mRNA efficacy by increasing the translation efficiency of the protein encoded.10
Rapid, scalable production
One of the most significant advantages of mRNA therapeutics is its relatively fast, scalable and inexpensive production that enables mRNA to be chemically synthesised in just a few days. Forgoing the need for the bacterial or mammalian cell cultivation typically required for most antiviral vaccines, mRNA manufacturing relies on a one- or two-step in vitro reaction. This is followed by a purification platform that can include DNase digestion, precipitation, chromatography or tangential flow filtration and encapsulation into LNPs.
Meeting the trending demand for speed
For all therapeutics, an accelerated pathway to commercialisation is becoming increasingly sought after, with a key focus on shortening timelines to investigational new drug (IND) applications. The trend for speed in project progression is primarily driven by the desire to reach patients requiring critical medicines sooner and the need to demonstrate the potential for return on investment (ROI).
Although still restrained by the oftentimes slow clinical trial setup and approval processes, mRNA therapeutics offer the rapid and scalable manufacturing needed to meet demands for accelerated timelines. This was a key reason for the success of mRNA vaccines in tackling the COVID-19 pandemic, where combined phases, pre-approval and rapid large-scale manufacturing enabled delivery to market in a very short time period.11
Understanding challenging trends facing mRNA therapeutics
Despite the benefits offered by mRNA technologies, there are still several difficulties drug developers and manufacturers are facing as they aim to progress their products to market at speed.
Funding challenges
The market downturn and global economic volatility of the past two years have made investors more cautious about investing in mid- or later-stage privately held biotechs.12 Many biotechs are therefore currently struggling to raise the capital needed to progress their projects. With long timelines unappealing to investors who typically want a return in three to five years, it is becoming increasingly important for biotechs to adjust their approaches amid a competitive funding environment.13 Although the mRNA production process is rapid, developers must utilise innovative tactics to further shorten timelines and demonstrate the potential for faster ROI.
Regulatory challenges
As mRNA technologies are relatively new, their regulation at the Food and Drug Administration (FDA) and international levels are complex and often unclear or contradictory. Although the World Health Organization (WHO) has published guidelines for the assessment of quality, safety and efficacy of mRNA vaccines to address the fact that no specific regulations existed before 2020, it is widely acknowledged that some regulatory flexibility is needed.14
The complexity and disparities between regulations surrounding mRNA drug production are likely to become more pronounced with the continuing advancement of mRNA technologies. Owning the responsibility to ensure the safety of patients is paramount – drug developers and manufacturers must employ their understanding of the technology and their judgement to ensure adequate controls and measures are in place.
Analytical and quality control bottlenecks
Although regulatory guidelines for the evaluation of quality, safety and efficacy of mRNA products are still under consideration, developers must still define specifications for critical process steps and acceptance criteria, intermediates, drug substances and drug products. As with many other biotechnologies, analytical development and ensuring quality control (QC) are key areas that can delay mRNA projects’ progression. With analytical development going hand-in-hand with process development, bottlenecks are common. The demand for speed has resulted in developers increasingly employing innovative analytical technologies that allow for rigorous product quantification, characterisation, product identity, purity and quality.
Overcoming the hurdles of mRNA production
As we move into an era that values the potential of increasingly advanced mRNA therapeutics, overcoming the challenges presented by current trends is critical to bringing these revolutionary therapeutics to patients. To fully understand the difficulties involved, partnering with contract development and manufacturing organisations (CDMOs) that have adapted to meet the needs of mRNA projects and deliver at speed will be crucial.
End-to-end offerings
One way in which specialist mRNA CDMOs can facilitate the speed required in mRNA production and help overcome funding challenges and bottlenecks is by providing end-to-end support. This is particularly beneficial if these end-to-end services can be delivered from the same facility. This helps prevent project delays from occurring due to tech transfer issues and material changes while enabling seamless integration. Additionally, by working with a single team, a collaborative culture can be built, strengthening communication and enabling faster resolutions to potential problems.
“Our increasing understanding of genetics and molecular biology continues to expand the capabilities of mRNA”
In-house capabilities
As well as offering in-house QC capabilities to enable faster batch and product release, having plasmid production under the same roof can further accelerate timelines. As a starting material for mRNA production, offering plasmid manufacturing in-house allows for greater control and agility over mRNA development and manufacturing timelines.
Efficient quality management systems
Safeguarding quality in terms of facilities and equipment, materials, production, packaging and labelling and laboratory requires a robust quality management system built on a quality-by-design approach and created to ensure regulatory compliance. Incorporating an effective quality system is essential when aiming for accelerated therapeutic production, particularly when considering the time it can take to onboard new raw materials and guarantee their safety. Use of best-practice software, such as automated monitoring systems for critical equipment and the phase-appropriate application of cGMP, can further improve speed.
Regulatory support
Despite unclear regulatory guidance surrounding mRNA therapeutics, successfully progressing to clinical phases and onto commercial stages necessitates applications to the relevant regulatory bodies. This includes IND filing and biologics license application to the FDA. With expertise in mRNA production, experienced CDMOs can provide regulatory support with an understanding of the necessary measures needed to demonstrate compliance.
Looking ahead
Our increasing understanding of genetics and molecular biology continues to expand the capabilities of mRNA technologies with growing numbers of products in the pipeline targeting a variety of diverse indications. Now that the industry has begun to realise the potential of mRNA technologies, mRNA developers and manufacturers must weather the challenges and trends on the horizon. The demand for speed-to-market can be expected to continue influencing decision-making in mRNA production and innovative solutions must be employed to meet these needs. By seeking support from a CDMO offering experience and expertise in mRNA production, developers can ensure their mRNA therapeutics progress at speed to reach the patients who need them.
References:
Jing Zhu is the vice president of Nucleic Acid & Viral Vector Technology at ReciBioPharm, and is responsible for overseeing process development activities and technology platform establishment. Before joining ReciBioPharm, Jing was the director of Process and Analytical Development at a number of biotech start-ups, leading the development of new technology platforms for gene therapy applications, and steering CMC activities for several IND enabling projects. He also led the phase 1 clinical trial of an mRNA COVID-19 vaccine. Prior to this, Jing was the R&D manager of Pharma Purification Analytics at Thermo Fisher, with a special focus on gene therapy applications.
Innovations in Pharmaceutical Technology (IPT)
IPT provides a platform for cutting-edge ideas, concepts, and developments shaping the future of pharmaceutical R&D.