PERSPECTIVE ON PHARMA

Smart Financing and CROs: investing in digitalisation for drug development

The pursuit of innovation fuels the progress of competitive markets. For the pharmaceutical industry, this has driven a trend to outsource R&D activities to Contract Research Organisations (CROs). CROs boast therapeutic and geographic expertise, are cost-eff ective and, perhaps most importantly, help to speed up the research and delivery process of new medicines.

However, with pharmaceutical, biotechnology and biomed companies of all sizes pursuing outsourcing relationships, CROs are often faced with fi nancing and cash fl ow problems as they oversee the various phases and multi-faceted challenges of the drug delivery process. On the one hand, large pharmaceutical corporations need a CRO to manage the whole drug development process independently, while on the other hand, in order to promote sustainable growth, small and developing biotech frequently require the assistance of smart fi nancing tools and infrastructure.

AUTHOR - SallyAnne Whybrow,

healthcare business development manager, Siemens Financial Services, UK

CROS IN THE UK AND IMPACTS OF THE PANDEMIC

While the CRO market is international by nature and contributes to global healthcare research, the UK has established an impressive footprint. According to the Contract Research Map, there are almost 1700 labs operating in the UK. In England alone, clinical research is worth £2.7 billion a year, and the UK pharmaceutical industry invests £4.3 billion a year into R&D.

Clinical trials – a key aspect of R&D – are predominantly

It is estimated that 50% of clinical trials will be either hybrid or decentralised by 2024.”

undertaken in Europe with the UK leading the pack in early clinical research. Prior to the pandemic, research from the Association of the British Pharmaceutical Industry (ABPI) recognised the UK as a worldleading expert in the areas of heart disease, immunology and conditions aff ecting the nervous system.

As part of the global response to the pandemic, research on chronic illnesses and diseases was suspended as scientists focused their knowledge and attention on the urgent need for a COVID-19 defence. Yet the industry faced a challenge on two fronts: social distancing measures severely restricted its ability to perform clinical trials, all the while being under pressure to conduct more trials to aid in the development of a COVID vaccine. Thus, the impact of the pandemic can be felt equally in the design and delivery of clinical trials as well as the quantity carried out.

CROs have subsequently been compelled to reconsider and change strategies, the result being an increase in hybrid models where traditional clinics operate in parallel with decentralised trials and environments. These decentralised trials off er increased patient convenience and engagement, as well as reducing the time required to carry out the trial by an estimated 15%. Continuous studies amid the successive lockdowns and changing restrictions were made possible via hybrid clinical trials and remote patient monitoring, which also resulted in cost reductions of 15-20%. Furthermore, it is estimated that 50% of clinical trials will be either hybrid or decentralised by 2024, simply put, growth prospects for the CRO market will not be hampered by the lifting of restrictions. This means those organisations that leverage digital technologies in their approach will be best placed to take advantage.

SCALING THE DRUG DEVELOPMENT PATHWAY

While the pandemic infl icted severe disruption to the day-to-day CRO market, the eff ectiveness of the industry’s COVID-19 response has helped propel the market to a swift recovery. There is now an elevated standard for solution delivery that CROs of all sizes will be expected to meet. These CROs must therefore rapidly scale their off ering in order to deliver these standards and tackle the existing backlog of R&D work delayed by the pandemic.

With this in mind, the pace of future research is now expected to be higher with tighter deadlines where CROs are required to react with total fl exibility. This can only be achieved with access to digital ready and high-end clinical chemistry equipment such as high-resolution mass spectrometers that can simultaneously quantify thousands of samples enhancing precision, depth, and throughput. Additionally, smart automation software is breaking down paper barriers, facilitating seamless scheduling, data collation and sharing as well as improved safety and security measures.

The digitalisation of processes is driving modernisation in the industry and accelerating trial speeds, and it is clear that a signifi cant investment in equipment, software and infrastructure, is needed, for research organisations to remain competitive and meet the heightened expectations for seamless drug delivery.

FINANCE AS A KEY ENABLER

Many CROs are turning to smart fi nance to enable sustainable pathways to investment. Smart fi nancing – off ered by specialist fi nanciers – enables the acquisition of technology and equipment for competitive advantage, in a way that is fi nancially sustainable and tailored to the organisation’s specifi c business and cash-fl ow needs. Smart fi nancing off ers three major advantages over generalist fi nance: technology expertise which understands real business outcomes; a breadth of fi nancing solutions which can meet every organisation’s exact needs; and smooth, sophisticated processes which makes the use of smart fi nance seamless and easy. Healthcare fi nanciers who have an in-depth understanding of the drug research and development technology and its applications can provide these tailored fi nancing packages.

CONCLUSION

While COVID-19 has quickened the pace of research, it has also slowed down crucial studies and clinical trials for other illnesses and diseases. To meet these and future challenges, CROs require highend digitalised equipment and technology that can enable processes to get back on track and satisfy the increased demand for their services.

Preserving cash fl ow is a key concern for any business. This is why more and more CROs are turning to smart fi nance options from specialist fi nanciers to enable investment. Specialist fi nanciers collaborate with CROs to adapt fi nance periods and conditions in order to fi t with strategic goals and outcomes, drawing on their in-depth expertise of the drug research and development industry.

FUTUREPROOFING PHARMACEUTICAL FORMULATIONS AGAINST NITROSAMINES: 5 BENEFITS OF USING ANTIOXIDANTS

Nitrosamine contamination of drug products has emerged as a major regulatory issue for the global pharmaceutical industry in recent years – with upcoming legal deadlines requiring drug developers to take timesensitive action.

Ever since the fi rst discovery of N-nitrosamines in valsartan four years ago, nitrosamine mitigation has become a key focus for pharmaceutical manufacturers across the world. To protect patient health, drug developers now have a legal obligation to perform a thorough risk assessment for both new and existing products and, where necessary, implement an appropriate control strategy, which might include reformulation. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have set stringent deadlines by which drug manufacturers are to present their risk mitigation plans for chemical medicines and biological medicines.

WHAT IS NEXT FOR DRUG FORMULATION?

With deadlines from the FDA and EMA fast approaching, drug developers are searching for solutions that will help overcome their formulation challenges in mitigating nitrosamine formation. Manufacturers can review and look to optimise the formulation process of drug products to limit nitrosamine formation and this, in turn, will support learnings for future drug development. However, optimisation of formulation processes may not prevent nitrosamine contamination entirely.

For these reasons, manufacturers may look to block nitrosamine formation in drug products. This is considered the best way to mitigate the risk and ensure that impurity levels are below allowable limits – which is an acceptable daily intake of 18 ng for newly emerging nitrosamine impurities according to current EU regulatory guidance and 26.5 ng/day in the US.

One possible strategy is that the formation of nitrosamines typically occurs under acidic conditions and the risk of contamination is much lower in neutral or basic environments. Formulations that incorporate excipients like sodium carbonate – which modify the microenvironment to a neutral or basic pH – should therefore, in principle, inhibit the development of nitrosamines. However, this strategy is not always suitable because some drug substances are not stable at higher pH levels. Another approach is blocking nitrosamines by including antioxidants, namely ascorbic acid (vitamin

Author:

Anne-Cecile Bayne, global science & innovation lead Pharma & Medical Nutrition, DSM

C) and α-tocopherol (vitamin E), in drug formulations. Discover fi ve benefi ts of choosing this proven, safe and eff ective mitigation strategy below.

5 KEY BENEFITS OF USING ANTIOXIDANTS IN DRUG FORMULATION 1. Block nitrosamine formation

Nitrosamine impurities, like N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), are formed when a nitrosating agent – like nitrous anhydride (N2O3) or nitrosonium ion (NO+) – reacts with a secondary or tertiary amine. Depending on the pH, these nitrosating agents will then react with secondary or tertiary amines to form a nitrosamine.

Any active substance or ingredient whose structure comprises secondary, tertiary amines or tertiary ammonium salts is therefore at risk of nitrosamine formation, as are drugs where the active is stabilised by buff ers containing tertiary or quaternary amines. Drug formulations that include any excipient containing secondary or tertiary amines, or quaternary ammonium salts, are also likely to form nitrosamines.

Known as a nitrosation inhibitor, ascorbic acid is a powerful reducing agent that can react with many nitrosating agents (like NO+ and N2O3), converting them into nitric oxide (NO) and eff ectively blocking nitrosamine formation. By reacting with nitrosating agents at a more rapid rate than nitrite does with secondary amines, the vitamin disarms nitrosating agents and ultimately prevents a reaction between nitrites and vulnerable amines. It has been demonstrated that ascorbic acid inhibits nitrosamine formation more eff ectively at pH 3-4 than other nitritereducing agents. Adequate quantities of α-tocopherol are also proven to be eff ective at reducing the precursor of nitrosating agents, NO2ˉ to NO.

By blocking the formation of nitrosamine impurities, both antioxidants can help to keep nitrosamine levels below the acceptable intake limits, making drug products safe for human use. Emerging research has found that ascorbic acid and α-tocopherol demonstrated greater than 80% inhibition when spiked at 1% levels in solid oral dosage forms.

2. Successfully used across the food industry

For the past 30 years, antioxidants have been used successfully by mitigating nitrosamine formation in foods. Nitrosamines fi rst became a health concern in the 1980s when nitrites were typically added to processed meats to prevent the growth of bacteria. Amines are common chemicals in food products, therefore preserving foods with nitrites induced a reaction and nitrosamines became unintentional byproducts of food preparation and processing. High concentrations of nitrosamine impurities were reported in bacon, sausages and hams at the time – leading to the development of the fi rst mitigation strategies.

Take bacon as an example – when preserved with 150 ppm nitrite, high levels of N-nitrosopyrolidine (NPYR) are formed when the bacon is fried. Reducing the amount of nitrite to 120 ppm and adding 500 ppm ascorbic acid, lowered NPYR levels to 10 ppb. Today, manufacturers using nitrites to preserve food are required to add ascorbic acid to their products to inhibit nitrosamine formation.

3. FDA-recommended strategy

Adding ascorbic acid and α-tocopherol as antioxidants is one of the options recommended by the FDA as a mitigation strategy for pharmaceutical drug products. The inhibitory eff ect of ascorbic acid on nitrosamine formation was fi rst noted in 1976 when investigators proposed that fi nished dosage forms of ‘easily and rapidly nitrosatable drugs’ should include the excipient. The most recent nitrosamine update from the FDA examined the eff ectiveness of antioxidants in oral dosage forms and concluded that ascorbic acid and α-tocopherol are suitable nitrosamine inhibitors in drug products.

4. Off er additional advantages

Next to their effi ciency in blocking nitrosamine formation, in one study both ascorbic acid and α-tocopherol have been demonstrated to impact the carcinogenicity of preformed nitrosamines and other carcinogens directly – reducing tumour yields by up to 60%. When combined, they may also off er potent antioxidant activity, protecting against oxidative stress-induced damage. One study found that α-tocopherol (plus ferulic acid) increased the eff ectiveness of ascorbic acid eight-fold. Additionally, ascorbic acid regenerates α-tocopherol after it scavenges free radicals, further reducing oxidative stress in cells. Both excipients act as stabilisers in fi nished drug product formulations too – helping to protect the active ingredient from degrading and maintaining the effi cacy of the drug.

5. Favourable safety profi le

Ascorbic acid and α-tocopherol are already well-known excipients used across the pharmaceutical and dietary supplement industries. They can be used at high levels without any safety concerns. However, care should be taken to add only the necessary amounts to avoid Maillard reaction with reactive substances, which can cause undesirable colour changes or odours.

REFORMULATING WITH CONFIDENCE

For drug developers to overcome critical drug formulation issues – like nitrosamine contamination – and develop safer therapies, they must adhere to the latest regulations and guidance. Ascorbic acid and α-tocopherol as antioxidants off er developers reliable opportunities to redesign their pharmaceuticals, or innovate new drugs, with reduced risk of nitrosamine formation. Drug developers can look to specialist industry partners, such as DSM, that can off er scientifi c and formulation support as well as regulatory expertise to overcome the nitrosamine challenge in the pharmaceutical space.

Antioxidants can help to keep nitrosamine levels below the acceptable intake limits, making drug products safe for human use.