Category: Analysis

Could oligonucleotide manufacturing advances redefine therapy

Could oligonucleotide manufacturing advances redefine therapy? 

June 20th 2023

Alejandra Sanchez 

Carla Greig 

Oligonucleotides have the potential to address some of the most devastating diseases that remain stubbornly resistant to treatment. These include neurodegenerative, vascular, respiratory, and oncological illnesses. As exciting as this branch of science is, the oligo industry is still in its commercial infancy. Large-scale oligonucleotide manufacturing is not straightforward, and various challenges need addressing.

To understand these, Alejandra and Carla, two Consultant biomedical engineers at Cambridge Design Partnership (CDP), were invited to take part in the Innovation in Oligonucleotide Manufacturing Symposium hosted by CPI at their new facilities in Glasgow. After an intensive day of discussion between key stakeholders from industry, academia, government, and the regulatory sector, we present the main takeaways. For this to make sense, let’s start from the beginning.

How do oligonucleotides work?

Oligonucleotides are short DNA or RNA molecules, typically around 20  nucleotides (basic building blocks of nucleic acids) in length. They can modulate gene expression, the process by which information included in a gene informs the assembly of a protein molecule. They do this by binding to pre-mRNA and mRNA, the carriers of genetic information before the mature mRNA is translated into proteins. Because mRNAs carry code for all cellular proteins, oligonucleotides could be effective for targets and diseases not treatable by current drugs1.

What is their importance as therapeutic agents?

Oligonucleotide therapeutics prevent or modulate the expression of almost any gene as part of highly targeted treatment. They aim to target the genetic basis of the disease rather than the symptoms. Compared to conventional therapies, oligonucleotides have a higher specificity with reduced side effects. They can target specific molecules that are currently difficult to target, such as RNA. Several oligonucleotide therapeutics are already on the market, with Novartis Pharmaceutical’s Vitravene, for treating cytomegalovirus retinitis in immunocompromised patients, being the first to be approved by the FDA in 1998.

The list of diseases that oligonucleotides can target is ever-growing, with the market valued at USD 5.19 billion in 2020 and expected to rise to USD 26.09 billion by 20302.

How are oligonucleotides manufactured?

Oligonucleotides are synthesized chemically, where nucleotides are added stepwise, resulting in a growing chain. Each nucleotide is subjected to a series of chemical reactions to create a stable component allowing the chain to grow.

The two different types of oligonucleotide manufacturing are solid-phase and liquid-phase synthesis. Solid-phase oligonucleotide synthesis is carried out on a solid insoluble object, such as polystyrene beads, placed in columns that enable all reagents and solvents to pass through freely.

In liquid-phase synthesis, the oligonucleotides are grown on soluble polymeric support within a homogeneous media; the polymer-bound product is commonly recovered from the reaction mixture by precipitation, thus allowing the rapid elimination of excess reagent and soluble by-products.

Solid phase allows high throughput synthesis and purification, with liquid phase taking longer to synthesize the oligonucleotides. However, liquid-phase has the advantage of being performed on a larger scale and typically being less expensive than solid-phase synthesis. Once the desired oligonucleotide has been synthesized, the material can be passed to the next processing steps, including purification, concentration and, commonly, lyophilization.

What are the main challenges in the process?

Oligonucleotide manufacturing is a complex process with many limitations, especially in scalability. The major problems researchers face are currently due to high expenses regarding the raw materials for oligonucleotide synthesis, a lack of funding for oligonucleotide therapies, and a shortage of skilled resources in the oligonucleotide synthesis field. These problems create substantial bottlenecks in the research required for therapeutic oligonucleotides and, ultimately, the clinical use of these therapies.

Key takeaways on the manufacturing of oligonucleotides 

  • Moving towards liquid-phase oligonucleotide synthesis. Solid-phase oligonucleotide synthesis is a great tool for rapidly making lots of oligos in the lab. However, it has drawbacks when manufacturing hundreds of kg or even multi-ton quantities per year, which might be the case for emergent nucleotide products targeting more common diseases3.

    The major problems include:

    • As the oligo grows, the space for the fresh nucleotides to diffuse and react gets tight, leading to incomplete couplings. This results in an altered sequence of monomers and incorrect genetic information in the final product, which must be removed by extensive and expensive processes.
    • It is hard to scale up the solid beds (insoluble particles to which the oligonucleotide is bound during synthesis).
    • The synthesis and purification steps generate large amounts of organic and aqueous waste.

 

  • Liquid-phase synthesis stands as a promising approach to increase the yield of the overall process while allowing the production of large amounts of oligonucleotides in, potentially, a more sustainable manner4.

 

  • New alternatives to current purification methods are under investigation. Promising approaches to simplifying the purification steps show good results in the investigational phase5. Examples are membrane-sieving technology and biocatalytic processes used for phase separation. In the biocatalytic process, oligonucleotides are synthesized in a single operation, with fewer impurities and by-product production, and in aqueous media. All these are promising features that target the current limitations of existing synthesis methods3.

 

  • New approaches come with new challenges: The development of novel and alternative technologies offers opportunities to address some of the limitations of solid-phase synthesis while also creating new challenges. For instance, using nanofiltration membranes to support the synthesis of oligonucleotides in liquid phase can present issues such as membrane stability and fouling. Another concern regarding the enzymatic approach is the availability of raw material with the right purity.
    If we consider the bigger picture, another novel approach in the pharmaceutical industry is the adoption of digital manufacturing technologies. However, this up-and-coming tool may come with its own challenges due to lack of pharmaceutical manufacturing expertise and the high cost of initial funds.

 

  • Raw materials suppliers are already working towards reducing the gap. Strategies to reduce the prices of chemicals and deliver sustainable solutions are already underway. For instance, Honeywell US, a major supplier of the raw material required for oligonucleotide production, recycles solvents and assigns dedicated chemical drums to individual businesses to avoid cross-contamination.

Big wins for early pioneers

At CDP, we see every challenge as an opportunity, and we are pleased to know that governments and large industries have already recognized these problems.  Major efforts to accelerate research in the UK have been launched, not only as funding from governmental innovation agencies but also from pharmaceutical companies. In addition, the 18 oligonucleotide therapies already approved by the US Food and Drug Administration (FDA) for clinical use are leading the way6.

There is a need for rapid adoption of next-generation processes that reduce risk, cut costs and save time while enabling on-demand therapies for every patient. However, regulatory-wise, standards in this industry are yet to be established. The risk around safety and efficacy remains a significant concern: How do we ensure we have the right sequence in each molecule? How do these molecules behave for a specific treatment? And what is the risk for the patient? These are just a few questions that still need to be addressed.

The event at CPI highlighted the importance of bringing experts together to shape the path and accelerate innovation. Understanding the challenges in the oligonucleotide space and planning around them will allow us to drive successful manufacturing at scale. The moment to build the future is now!

References
  1. Kole R, Krainer AR, Altman S. Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40. doi: 10.1038/nrd3625.
  2. Allied Market Research, Oligonucleotide Synthesis Market report, Code A08356, July 2021
  3. Sarah Lovelock, “Biocatalytic approaches to therapeutic oligonucleotide manufacture” in “Enzyme Engineering XXVI”, Andy Bommarius, Georgia Institute of Technology, USA; Vesna Mitchell, Codexis, USA; Doug Fuerst, GSK, USA Eds, ECI Symposium Series, (2022). https://dc.engconfintl.org/enzyme_xxvi/37. Abstract: https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1034&context=enzyme_xxvi&type=additional
  4. J. Org. Chem. 2021, 86, 1, 49–61 Publication Date: November 30, 2020 https://doi.org/10.1021/acs.joc.0c02291
  5. Dousis A, Ravichandran K, Hobert EM, Moore MJ, Rabideau AE. Nat Biotechnol. 2023 Apr;41(4):560-568. doi: 10.1038/s41587-022-01525-6.
  6. Martin Egli, Muthiah Manoharan, Nucleic Acids Research, Volume 51, Issue 6, 11 April 2023, Pages 2529–2573.
environmental sustainability||||||||||

Are we there yet? An honest progress report on our environmental sustainability

April 26th 2023

Matt Morris 

Shweta Shewale 

“We’re all on a mission to achieve sustainability, working together to build a better business for people and planet”. While it may be true, statements like this don’t offer much insight into what we’re actually doing about our environmental impact. Instead, we’d like to provide an honest assessment of where we are now, what actions we’ve taken so far, and where we’re focusing our efforts in the future.

Sustainability communications are often full of cliché. In their excellent research report ‘Words that work’, creative communications consultancy Radley Yeldar analyzed the websites of 50 of the Forbes 100 most valuable brands and found the same words and phrases repeatedly cropping up. One of the most popular was the notion of a ‘sustainability journey’.

We can see how this happens – in fact, in the first draft of this article, we followed this same path. We want to talk about the progress we’ve made, which we’re proud of, but we know we’ve got a long way to go. We’ve got plans that we want to share – how do we communicate this process while it’s happening? There’s an obvious metaphor!

Part of the reason brands lapse into cliché, says Radley Yeldar, is fear of criticism if they’re brutally honest. So, we’ll try to take their advice, and be brave. Here goes.

An honest assessment

CDP is an Employee-Owned company. A little over a year ago, a group of employee-owners, supported by the management team, started an initiative to measure our performance against the B Impact Assessment, a widely used framework for all-round sustainability impact. Overall, we were very happy with how we measured up – many of the policies, actions and outcomes the assessment checks for were already established.

However, one of the reasons to go through this process was to identify any gaps in our performance. There was one area we decided to focus on, because frankly it was a little behind many other parts of the assessment – our work to improve our environmental sustainability.

What makes us want to improve?

Beyond a desire to have the most positive impact we can, there were three compelling reasons for us to take action:

  1. We’re delighted that more and more of the global brands we work with are committing to ambitious environmental sustainability targets – we want to help them achieve these goals and give them the confidence that we are just as committed to having a positive environmental impact.
  2. We work hard to reflect the needs and priorities of our employee-owners – our only shareholder and biggest asset. Surveys and engagement events have made clear that environmental sustainability is important to them.
  3. We have recently transitioned to a ‘large’ company under UK law, which entails new reporting requirements – the perfect time, therefore, to embed new measurement and reporting systems across the company.

Making a change through our client work

There are two ways that we can have an impact on the environment – through our business operations, and through the innovation, design, and development work we do on behalf of our clients.

Whilst we feel it’s important to minimize the environmental impact of our own operations, helping our clients to ‘improve lives through innovation’ (our purpose) allows us to contribute to environmental and social benefits at a scale well beyond that which we can achieve alone. As an example, a quick calculation showed that the annual production of a particular dry powder inhaler – a typical project we might deliver for a client – was responsible for more than 50 times our annual carbon footprint. Or, put another way, if we helped a client to reduce the carbon impact of that product by just 2%, we would save the equivalent of CDP’s annual carbon footprint.

Recognizing this, we’ve invested in growing our capability in sustainability and cleantech, helping our clients reduce their environmental impact and develop new technologies, including:

  • Developing packaging design and sustainability guidelines for one of the world’s largest consumer packaged goods companies
  • Helping multiple blue chip clients transition from fossil-fuel-derived plastic packaging to alternatives such as paper. Highlights include a patented, first-of-its-kind, single-mold paper bottle for Pulpex
  • Performing a life cycle assessment to benchmark the environmental impacts of a connected autoinjector, and using this to drive design changes that minimize these impacts
  • Designing and developing a pop-up solar car park and electric vehicle charging hub for 3ti Energy Hubs, which won Best New Product at The Electric Vehicle Innovation & Excellence Awards (EVIEs)
  • Winning a hackathon run by Cambridge Institute for Sustainability Leadership (CISL) and British Antarctic Survey (BAS) to help BAS achieve net zero at their Rothera research station in Antarctica

Changes in our own operations

In the last year, we’ve also made significant progress on how our business operations impact the environment; much of this was enabled through moving to a new purpose-built facility, which involved over three years of rigorous planning and attention to detail:

Net zero HQ

Our new UK headquarters at Bourn Quarter is built to be net zero over its lifetime. It doesn’t rely on fossil fuels for heating and is designed to high standards of energy efficiency. On-site power generation includes 1,500m2 of rooftop solar panels across our Innovation Centre and Pilot Production Centre buildings – that’s an area larger than five tennis courts!

Supply network with shared values

Recognizing that much of our impact occurs through our suppliers, we’re starting to factor environmental impact into our supplier selection. In the last year, we’ve brought in Wilson Vale as our catering partner – their central operations are certified carbon neutral, and at Bourn Quarter they serve seasonal food and take steps to minimize food waste. They calculate how many people are typically on-site on certain days and incorporate any leftovers into the following day’s meals – for example, as an option in the salad bar.

Measuring what matters

Our science and engineering teams know that accurate data is crucial to optimizing any process. So, we’ve set up systems to monitor our energy use, carbon emissions, and waste – the areas of greatest impact from our operations. Electricity consumption data from our first few months in Bourn Quarter will allow us to optimize our heating and lighting usage. We’re also collecting data on our recycling, food and general waste streams, to generate insights that will support future improvements.

Awareness and engagement

We’ve worked hard to bring our entire organization with us, so that everyone feels ready and empowered to help identify and solve problems. This type of unified effort reflects the culture of our company, rather than a passion project for a small group of champions working in isolation.

We’re achieving this through regular all-company ‘town hall’, updates, interactive ‘lunch and learns’, and immersive Climate Fresk sessions – three- to four-hour workshops which explore the fundamental science behind climate change.

Are we there yet?

Whilst we’re proud of what we’ve achieved so far, it’s just the start of an ongoing process to manage and improve our environmental impact, and we’ve got a lot more work to do! As Peter Drucker famously put it, “you can’t improve what you don’t measure” – quantifying our carbon, waste and water impact is the foundation for both transparent reporting and further progress. We’re looking forward to using the measurement and analysis systems we’ve established to benchmark our performance and assess the effect of improvements we make. We plan to publish our first impact report later this year – and we’ll be aiming for openness, honesty, and a minimum of sustainability cliché!

If you have similar ambitions and would like to discuss this in more detail – particularly if you’re close to Cambridge (UK) or Raleigh, North Carolina (USA) – please get in contact.

respiratory drug delivery|

Key trends in respiratory drug delivery

January 25th 2023

Mark Allen 

Senior Consultant Biomedical Engineer

It was great to be back in person for the Drug Delivery to the Lungs conference in Edinburgh recently. Here, we share insights on three major themes from the event and a trend we think will reshape the future of respiratory drug delivery in the next 10-20 years.

Sustainable pMDIs

The shift in pMDIs from using HFC propellants towards less polluting gases has gained momentum with California imposing a ban on the sale and distribution of R227ea from the end of 2030 and R134a from the end of 2032, including medical use. This provides an end-of-the-line for the sale of all current pMDI products in California.

The transition needs formulators, device designers, scientists, and other disciplines to collaborate to solve the challenges presented by the different physical properties of the new gases. The assessment of all types of inhalers from a sustainability perspective has advanced, too, with life cycle analysis (LCA) and carbon credits schemes being discussed – our sustainability team provides reviews and recommendations for a range of medical devices to help our clients improve their devices and provide evidence to back up their green credentials.

Usability for adherence

Time and again, studies show that it’s challenging to measure asthma and COPD patients’ adherence to their medication. Medication adherence appears much lower than for other diseases – estimates range from 22-78% adherence, compared to 70% for diabetes.

Low adherence needs to be addressed by making devices easier to use and tailoring them to the patient’s needs. Reducing user steps is key to make using the device easier, but patient feedback and tailoring to specific needs are necessary, too – something connected inhalers could help solve through digital reminders appropriate to the patient’s needs. Independently verifying that increased adherence is due to connected or smart inhalers is difficult to prove – something the industry is investigating.

Modelling of drug delivery

Several talks at this year’s event covered modelling, with in-silico methods advancing in capability and popularity over the last 10 years. Topics covered included constructing a full airway model to assess drug deposition under different breathing profiles and using maths with physiological signals to detect disease and drug-induced changes. Posters demonstrated an even wider range of possible models, including our own.

Our modelling and simulation teams produce models for clients that highlight potential robustness issues with mechanical components and digital sensing techniques at early stages to determine suitable technologies for medical devices.

Learning from the past, looking to the future

Federico Lavorini, Professor and Consultant in Respiratory Medicine at the Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy, gave an excellent summary of drug delivery over the last 100 years, including innovations where design has reduced user error.

Further talks considered what pharma could learn from other markets, especially as we move from ‘sick care’ to ‘health care’ – where technology identifies and treats conditions before they become symptomatic. Our Drug Delivery and Insight & Strategy teams work closely together to understand upcoming trends and draw on insights into consumer expectations from the consumer and digital markets for our clients.

Biologic treatments are coming to respiratory drug delivery and are likely to use Soft Mist Inhalers (SMIs) and Dry Powder Inhalers (DPIs) for delivery, with current trends looking to lean heavily on DPIs. This is likely to lead to the development of new, higher-performance DPIs to provide the best efficiency delivering these high-cost treatments to the patient. We have dramatically increased the performance of DPI engines for our clients through our science-based approach to increase fine particle fraction for their devices.

How we can help

Our team are experienced in all stages of the development of drug delivery devices for a wide range of scenarios and applications in the medical industry, with a dedicated team working in these areas. Here at CDP, we have these specialists all under one roof to partner with you to bring your device to market and can also draw on the learnings of our colleagues in consumer markets to guide on relevant future consumer expectations.

Five ways to take cultured meat mainstream

Five ways to take cultured meat mainstream

November 18th 2022

Richard Owen 

Bio-Scientist

Better for the environment and better for animals, cultured meat is an ascendant industry and could grow even faster with these five improvements.

COP27 climate negotiations look set to conclude with steady – if not stellar – progress on reaching a consensus as to how the world can avoid catastrophic climate change. However, one area almost absent in the outcomes so far is how we can reduce the environmental impact of animal agriculture, which is estimated to make up 20% of global greenhouse gas emissions – that’s more than the entire global transport sector.

That doesn’t mean nothing is happening. In recent years, we’ve seen massive investment in one potential solution to this problem: Cultured meat, grown in a lab from a few animal cells, has the potential to counter some of the biggest issues facing humanity, including global warming, land degradation, and water usage.

On November 16, the sector marked a significant milestone as the US Food and Drug Administration (FDA) raised no questions to UPSIDE Foods pre-market consultation for its cultured chicken products for human consumption. It needs final approval and isn’t on sale yet, but this is a significant hurdle crossed.

How can the cultured meat sector build on this moment and realize the enormous potential to contribute to a sustainable future? We’ve identified five steps producers need to take:

1) Think differently to scale up efficiently

We know we can make cultured meat, but the costs and scale mean it isn’t yet an everyday item. Pharma-style processes and equipment just aren’t designed for food-based products and so won’t get the sector where it needs to be.

We need a mix of new thinking, processes, and products. Rather than focus on pharma, technology should be brought in from other sectors, such as the brewing, textiles, and food ingredients industries, as their process throughput and manufacturing costs are closer to what’s needed for this market.

Ingredients and structural components must be fully defined and standardized before cell bio-fermentation can become a high throughput, low intervention process, like brewing or baking.

2) Don’t obsess about patents

While patents are critical to many industries and bio-based start-ups, they aren’t so important in the cultured meat sector. Most companies have specific cell lines, cell sources, ingredients, and fermentation protocols.

Due to the way cells develop according to their genotype and environment, they’re highly likely to develop in a unique way. Patenting engineered cell lines, cell collection procedures, formulation recipes, differentiation techniques or fermentation protocols is unnecessary, as they would be very difficult to replicate.

It’s much better to keep the know-how in-house, in a similar way to the ‘secret recipes’ of malt whisky manufacturers – they all start with water, yeast and malted barley, but make very different products.

3) Think beyond the butchers

Many cultured meats closely replicate products you’d find on a butcher’s block. While the industry is young, this gently introduces consumers to a new type of product.

However, there’s huge potential to make new products that aren’t replicas of butcher-shop cuts. How about mixing and matching cell textures, fat content, and fiber lengths to create a cross between pate and streaky bacon?

Amazing new products could be created, potentially formulated to be cooked to a certain style, e.g. slow-cooked or medium rare. This could excite consumers and show that this new technique could create a whole new and exciting range of meat products.

4) Get the branding right

Cultured meat companies have a lot of heavy lifting to do to educate the consumer. Meat in its raw state is often considered a generic product; only after cooking does it normally appear as a brand.

Linkage to other existing brands is one option, such as endorsement by well-known chefs or restaurants. Other options include trying to emulate exotic breeds such as Wagyu beef, ostrich, or kudu (antelope). First-movers will have an advantage; later entrants may have to specialize to grab and retain a niche.

5) Embrace the difference between pharma and food products

The pharma industry has advanced the science used by cultured meat producers.

However, the goal of cultured meat producers is to produce a tasty, safe piece of food, rather than a viable drug therapeutic that must engraft in a patient and perform a complex variety of immunological functions.

This means costs and testing procedures should be very different. Much of the cost of pharma production of cell and gene therapies lies in sample collection and testing during manufacture and quality control. There’s a huge list of different attributes that need to be tested, from intracellular mycoplasma to cell viability, potency, and cellular identity.

Conversely, once the manufacturing process for cultured meat has been appropriately established and validated, automated in-process monitoring can remove the need for almost all final batch-based tests.

In addition, more automated diagnostic-style testing regimes can be used instead of the labor-intensive R&D-style analytical methods.

Meat the pioneers

GOOD Meat cultivated meat brand is part of the California-based sustainable food company Eat Just. Its products have already launched in Singapore. In Autumn 2021, it raised $97 million in funding, adding to another $170 million raised in Spring.

California-based UPSIDE Foods has the claim to fame that it cultivated the world’s first beef meatball. In Spring 2022, it raised $400 million in Series C funding to drive product innovation and infrastructure to make cultured meat at scale.

References

Valdmanis R, Cocks T. Meat on the menu, not the agenda, at cop27 climate conference [Internet]. Reuters. Thomson Reuters; 2022 [cited 2022Nov17]. Available from: https://www.reuters.com/business/cop/meat-menu-not-agenda-cop27-climate-conference-2022-11-15/

Pre-market consultation for human food made using animal cell culture [Internet]. U.S. Food and Drug Administration. FDA; 2022 [cited 2022Nov17]. Available from: https://www.fda.gov/food/cfsan-constituent-updates/fda-completes-first-pre-market-consultation-human-food-made-using-animal-cell-culture-technology

Gelski J. Good meat raises $97 million in latest funding round [Internet]. Meat Poultry. Sosland Publishing; 2021 [cited 2022Nov16]. Available from: https://www.meatpoultry.com/articles/25539-good-meat-raises-97-million-in-latest-funding-round

Hood LL. Huge facility to produce 15,000 tons of lab grown meat per year in the US [Internet]. Futurism. Camden Media Inc; 2022 [cited 2022Nov16]. Available from: https://futurism.com/the-byte/biggest-cultivated-grown-meat-lab

Series C funding brings the upside of meat one (giant) step closer [Internet]. UPSIDE Foods. UPSIDE Foods; 2022 [cited 2022Nov16]. Available from: https://upsidefoods.com/upside-series-c-fundraising-round/

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Clinical Manufacturing

We manufacture Class II and III medical devices – mechanical and electronic, durable and consumable – for our global clients. So, we understand the barriers they face getting their product from design to manufacture for clinical trials.

We’ve invested in the advanced clinical manufacturing facilities, domain expertise, and compliance to overcome our clients’ challenges, from fulfilling the volumes to managing the complexity of the set-ups they need. We’re capable of producing up to 100,000 devices under ISO 13485:2016 certified QMS by Intertek Medical Notified Body, harnessing leading-edge facilities such as ISO Class 7 cleanrooms and our purpose-built 26,000 sq ft UK manufacturing center.

  • Class II and III medical devices
  • Capacity for up to 100,000 devices
  • 26,000 sq ft UK manufacturing center
  • QMS ISO 13485:2016 by Intertek Medical Notified Body

Our expertise extends across aseptic filling and sterilization, which we deliver through collaboration with our proven partners, as well as performing device assembly, labeling, and logistics in-house.

We regularly conduct design verification testing, including developing bespoke test methods, which we subsequently validate, managing the entire validation process for our clients. We create the documentation for design history and technical files, and support with the regulatory submission.

Our clients trust us to advance their Class II and III medical devices, from design to clinical manufacture. These devices create a fast track to user studies and clinical trials, then onwards to the clinic and regulatory submission. Our clinical manufacturing capability, shaped by years of practical experience and harnessed for the world’s leading healthcare companies, is proof of the purpose that unites us: to improve lives through innovation.

  • Assembly
  • Aseptic filling & sterilization
  • Labeling
  • Logistics
  • Design verification testing
  • Packaging
  • Technical and design history file assembly
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Digital PCR||||||

Digital PCR – a technology set to transform clinical testing?

November 10th 2022

Richard Owen 

Bio-Scientist

Pregnancy screening, cancer treatment, organ transplant – digital PCR testing has the power to enhance clinical decision-making. But what is needed to take it mainstream?

Polymerase Chain Reaction (PCR) testing has reached unlikely levels of fame due to the COVID-19 pandemic. However, its latest evolution, digital PCR, could be a real game-changer for commercial diagnostics.

The power of digital PCR

When people talk about PCR testing, they often refer to quantitative PCR. This technology is fantastic at delivering binary answers, for example, whether a disease is present or not. It can also determine to some extent how much of a disease is present in a sample (though the process is inaccurate). Quantitative PCR’s quantification can be improved by calibrators, but this is complex, expensive, and time-consuming for a lab to perform.

Digital PCR advances this technology to deliver precise quantification and improves detection of low-frequency DNA targets.

The potential to transform clinical decision-making

The key benefit of digital PCR can be summed up in two words: better data. It has the power to transform clinical decision-making, for example, in the following areas:

Pregnancy screening

Highly accurate testing for chromosomal trisomies, such as Down’s syndrome, by detecting traces of foetal DNA in maternal blood. Next-generation sequencing (NGS) is an existing alternative but has extremely complex protocols, including DNA purification, DNA library preparation, sequencing, data alignment, and analysis.

Cancer treatment

Pinpointing disease progression by detecting tumor DNA in liquid biopsies.

Organ transplants

Detecting DNA sequences leaking from a donor organ (a sign that the host immune system is rejecting it).

Virus detection

Increasing accuracy in treatment of HIV, hepatitis C, herpes, cytomegalovirus, and other infections.

Disease diagnostics

Quantification of bacterial species in stools due to digital PCR’s lower sensitivity to inhibitors.

Digital PCR could also deliver accurate quantification of levels of other infectious diseases such as respiratory viruses and sexually transmitted infections. This precision isn’t currently available but could be useful for clinicians to differentiate between different stages of infection.

How does digital PCR differ from quantitative PCR?

Digital PCR is a development of ‘standard’ PCR, using the same concept of exponential amplification of template DNA with DNA primers and a polymerase enzyme. It has two crucial differences: compartmentalization and end-point data collection.

Compartmentalization

Instead of performing a reaction on a whole sample, digital PCR splits the sample across a large number of separate compartments. ‘Compartment’ could mean a microfluidics chip, or a droplet suspended in an emulsion.

Each reaction is capable of detecting a single molecule of DNA. A larger number of amplification cycles are generally run, typically 60 versus 40 for standard PCR. Just one DNA molecule in a compartment is enough to initiate a PCR amplification reaction.

End-point data collection

Unlike quantitative PCR which reads after every amplification cycle, digital PCR just needs to read once when all the amplification cycles are complete. This is an important saving, as otherwise, all the thousands of individual compartments would need to be read every cycle, which would be a significant challenge.

Digital PCR overview

What’s stopping the mass adoption of digital PCR?

Though digital PCR has been around for 20 years and is mentioned in thousands of patents, only a handful of commercial products use the technology. The primary challenge innovators need to crack for it to go mainstream is optimal compartmentalization.

Cracking compartmentalization

Compartmentalization affects key performance parameters, such as the assay’s dynamic range, linearity, accuracy and ease of use; its cost; whether it’s run as a batch or on-demand; and how many samples can be run at once. The number of compartments in the assay must be high, relative to the concentration of input DNA molecules in the sample. But if the assay uses too few compartments, the accuracy of quantification will be too low, and the assay must be repeated using a diluted sample.

Why does compartment design matter?

Digital PCR’s randomly apportioned target molecules across a large number of compartments mean there will be some compartments with no targets, some with one, and a few with two or more. As it’s not known how many target molecules are in each positive compartment, the Poisson distribution is used to determine the most likely proportions of compartments with one, two, three, or more DNA targets. Using the Poisson distribution allows accurate quantification, but relies on two important factors:

  1. The input template being randomly spread throughout all the reaction chambers
  2. All compartments being the same size

These are critical parameters, and there are two main ways to achieve them. The first is passing the sample over a microfluidic flow cell containing microwells commonly filled using capillary action. The second is encapsulating the nucleic acid in a huge number of water droplets in an emulsion of oil, with each droplet containing a separate reaction.

Microfluidic droplet generator developed at CDP

The ideal compartmentalization system would retain the ease of use of current quantitative PCR systems and have a similar lab-bench footprint and costs. However, current approaches (typically involving microfluidics or droplets), require multiple complex disposables and sophisticated optics. If a new approach was developed with lower costs, clinicians and test centers may well convert to digital PCR for all their applications. The company that manages to crack this challenge has the potential to dominate the PCR market and provide huge advances to clinical decision making.

To talk to us about our current innovation in the field of digital PCR, get in touch.

Designing more sustainable electronics|||

Designing more sustainable electronics

September 14th 2022

From phones to laptops, home devices to watches, electronic devices – particularly smart devices – have become part of people’s lives, enabling better communication and access to information and making their day-to-day easier.

But the increasing adoption of technology comes at an environmental cost. Electronic devices often have a significant carbon footprint because of the energy-intensive processes needed to produce printed circuit boards (PCBs) and integrated circuits.

Electronics production relies on mining and extracting dozens of different materials, including critical raw materials (economically important materials at high risk of supply shortage, such as lithium or titanium). Extracting these materials has a range of sustainability impacts, including the leakage of toxic chemicals such as cyanide into the environment, high levels of water use, and human rights abuses in the case of ‘conflict minerals’ such as gold and tantalum.

Waste electronic products, or e-waste, is the fastest-growing waste stream in the world, with over 53 million tonnes of e-waste produced in 2019. Most e-waste is disposed of incorrectly, ending up at waste dumps in developing countries. Hazardous chemicals, such as lead or mercury, that may be present in electronic components can leak into the environment, harming local ecosystems and damaging the health of people who live and work in the dumps.

Product sustainability has focused on the circular economy, particularly recycling. But there are fundamental limits to the impact recycling can have on electronics. Only 17% of e-waste is collected for recycling and, even if it’s collected, recovering materials from e-waste is particularly challenging.

Electronics contain trace amounts of rare metals, which are complex and expensive to separate. Only the most abundant materials, such as copper and gold, can be economically retrieved during e-waste recycling, and even if all e-waste was recycled in this way, the material recovered still wouldn’t be enough to meet the growing demands of the industry.

One way to tackle the environmental challenges presented by electronics is to remove the need for them in the first place, for example by detecting a temperature change using a color-changing chemical rather than a sensor. But, in some instances, electronics are necessary, so how can designers reduce the impact of the products they create?

Our sustainability team assessed a range of technologies and design techniques to determine their potential for reducing the environmental impact of electronic products and how difficult they are to implement. This article outlines a few approaches we’ve used in recent projects at CDP.

web_graph_designing-more-sustainable-electronics

Reducing complexity through connectivity

One of the best ways to reduce an electronic device’s environmental impact is by minimizing the electronics’ complexity, thereby reducing the number of integrated circuits needed as well as the surrounding passive components (resistors, capacitors and so on), connecting tracks, and PCB area.

An easy, effective way to do this is by pairing a product with a user’s existing device to provide the smart capability. Methods range from a simple QR code or NFC chip to a Bluetooth connection for transferring more complex data.

As well as reducing the electronics in the product, this allows for a degree of futureproofing, as software updates can be used to keep the product up to date. This idea isn’t new but is starting to be used more in applications from smart packaging to medical devices.

Important to note: Behind many of these software solutions are large data centers that need powering and should be considered in the product’s environmental impact.

Informed decision-making: Life Cycle Assessment (LCA)

Designers can optimize component choices and circuit designs during detailed design to reduce the overall impact of a product.

We recently used LCA to estimate the additional carbon footprint of adding an electronic module to a medical device. This step allowed our team to identify where to focus on reducing the impact of the design, such as replacing integrated circuits with a solution based on lower-impact passive components and optimizing the layout to minimize the total area of PCB required.

We identified several solutions that together had the potential to reduce the total carbon footprint of the product by up to 25% without compromising functionality. In many cases, this optimization also generates cost savings.

Optimizing electronics through additive manufacturing

Over the past two decades, additive manufacturing (such as 3D printing) has seen a surge in use in mechanical prototyping and manufacture, and its applications in the electronics sector are now starting to grow. In the context of PCBs, additive manufacturing refers to selectively adding conductive material to the areas required, as opposed to a more traditional approach which starts with a layer of copper and selectively etches away the areas where it isn’t needed.

These technologies can improve a product’s carbon footprint through reduced material usage and less energy-intensive manufacturing processes. A report published by the ECOtronics project found, “Changing from subtractive manufacturing (etching) to additive manufacturing (printing) has the potential to reduce environmental impacts by more than 50% across all impact categories.”

One additive manufacturing method is laser direct structuring (LDS), which allows you to construct circuits on the surface of device components. With this approach, you can remove the PCB entirely, dramatically cutting down on the material required.

These technologies present opportunities to fit electronics into new form factors, print onto a wide array of rigid or flexible substrates (the non-conductive part of the circuit board the metal circuit is added to) and increase the customizability of the design, all while reducing the product’s environmental impact.

As we’ve highlighted before, sustainability initiatives should always consider context, which is vital for electronics. In the absence of cost-effective recycling processes, designers must prioritize approaches that reduce the materials and energy required to produce electronics. As electronics continue to play a leading role in our lives, future designs should reduce our reliance on critical raw materials and consider how circular approaches to design can extend product lifetimes and prevent harm to people and the environment.

References

Connect with CDP

For more on how to reduce the environmental impact of your electronics through smarter design choices, contact Cambridge Design Partnership.

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Consumer Healthcare

Demystifying FemTech innovation: your questions answered

August 18th 2022
Sukie Whitehall

Sukie Whitehall 

Consultant Mechanical Engineer

In an exciting first half of 2022, our FemTech team attended and presented at conferences, including the Reproductive Health Innovation Summit in Boston and the Women’s Health Innovation Summit in Basel. We’ve enjoyed fascinating conversations at events like these, covering everything from whether ‘FemTech’ is a useful term to how FemTech can manage the gender data gap. In this article, we share our responses to some of those questions which stood out to us.

Is ‘FemTech’ the right term to use to discuss this space?

Yes – and no. The term ‘FemTech’ has been a valuable tool since Ida Tin coined it in 2016, but it can narrow the field of focus. FemTech gives investors a framework and ‘safe’ vocabulary to discuss women’s health issues – some people find “I’m investing in FemTech” easier to say than “I’m investing in a period tracker.” A Google search on the term shows that it has evolved into a rallying point for like-minded people in the industry to find each other and drive innovation. At CDP, we view FemTech as a design philosophy underpinned by inclusivity, experience-led design, and the smart integration of tech (or intentional absence of tech), which we overlay on wide-ranging areas of innovation.

How important is it that FemTech designs for the planet?

We can look at how FemTech has grown due to an increasing consumer focus on sustainability. Menstrual cups, for example, have been around for a long time but only recently become a mainstream product. In 2018, the global menstrual cups market amounted to an estimated US$1.2 billion – it’s expected to reach US$1.89 billion by 2026. This increase reflects a massive shift in consumer attitude towards prioritizing sustainability over the last few years. But it also shows the success of products that meet user needs. Menstrual cups generally need to be changed less frequently than conventional tampons, so they meet user needs and offer a sustainable alternative. [1] At CDP, our user-centered design approach means we design for people, first understanding what they are trying to achieve, before translating contextual insight into solutions.

How is FemTech managing the gender data gap?

Historically, medical studies have often assumed the male body as the default, ignoring that women have different physiologies and responses to disease. This has resulted in a lack of data focusing on women’s needs, which puts FemTech innovators at a disadvantage. On the other hand, it also presents an opportunity for the industry to create valuable proprietary data which can be shared to further the understanding of women’s health. Take the vastly under-researched area of female sexual pleasure – the first comprehensive anatomical study of the clitoris was only published in 1998. [2] For Goodness Sake is the parent company of OMGYes, an education app focused on female sexual pleasure. In partnership with Indiana University and Kinsey Institute researchers, it researches people’s most intimate and vulnerable experiences. The results are published in peer-reviewed journals and (to quote their literature) “turned into honest and friendly online products” – the best of both worlds.

What are some best practices when it comes to developing FemTech products?

The most important thing is not to treat each stage in the innovation journey as a discrete process but to communicate between disciplines and, critically, with consumers and patients – put them at the heart of the innovation process, and validating the new product or service experience. This will ensure that, for example, manufacturing decisions won’t negatively impact user requirements. Our advice is to apply our FemTech philosophy of inclusivity, user-centered design, and the smart integration of tech to a robust end-to-end innovation process, such as CDP’s Potential Realized. This comprises six steps: opportunity definition, concept creation, concept realization, product realization, manufacturing realization, and life-cycle management.

How should emerging FemTech companies approach regulation?

Many FemTech products sit with one foot in healthcare and the other in consumer. Knowing which category your product falls into is key to avoiding unexpected regulation (our white paper on FemTech regulation has more information on this). Consider regulation early, as compliance is complex and expensive to retro-engineer. Negative PR following a regulatory oversight could be catastrophic for a new company or brand, which might otherwise have been successful. And even if you find your product is exempt from regulation, it’s good practice to take a risk-based approach to design to ensure your product remains safe and enjoyable for its end users.

REFERENCES

Connect with CDP

For more on how to design inclusive, experience-led FemTech products that meet the real needs of women, contact Cambridge Design Partnership.

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Women and maths|||

Women and maths: “I’ve gained so much confidence and resilience by going into this subject.”

July 19th 2022

Jayna Jogia 

Jessica Platt 

Sukie Whitehall

Sukie Whitehall 

Consultant Mechanical Engineer

UK government social mobility adviser and secondary school headteacher Katharine Birbalsingh recently caused a stir by suggesting that girls choose not to do physics at A-level because “There’s a lot of hard maths in there…”

Here, three of our consultants share a very different outlook on science, technology, engineering, and maths (STEM).

Jayna Jogia

Product Development Engineer

MEng, Mechanical engineering
International baccalaureate: high-level maths, physics, history

Jessica Platt

Associate Insights Researcher

MA, Social Anthropology
A-levels: biology, chemistry, English literature

Sukie Whitehall

Consultant Mechanical Engineer

MSc, Advanced Mechanical Engineering
A-levels: physics, maths, chemistry

When did you first realize you had a passion for maths? 

Jayna – The first time it occurred to me I was good at maths was when I was 11 and came top in a class Olympiad. Until then, maths was just a thing I could do and enjoyed. I always had encouraging maths and physics teachers, and doing maths was the norm in my household. My dad was an engineer and my first maths teacher. You often hear of female mechanical engineers who have been inspired by a direct relative to take up the subject. Outreach at schools is essential to encourage children who don’t have that. 

Sukie – I studied maths, physics, and chemistry at A-level. I’m a very logical person, and I loved that you could walk out of a maths exam knowing an exact score. Working things out rather than relying on memorized facts made me feel clever and gain confidence. 

Jessica – I was always celebrated for English – my head was always in a book, and adults would praise me for being ‘good’ at English – but I was also fascinated by science. I was obsessed with black holes. I studied A-level chemistry, biology, maths, and English literature.

Did you face any challenges or prejudices studying STEM? 

Sukie – There were very few female toilets on my degree course, and I lived my life running across the campus to the law building. Things like that make you lose your feeling of belonging. 

Jessica – When I had to take a month off A-levels with pneumonia, I asked my maths teacher what I should do to catch up. They said there was no point in carrying on because the highest grade I was expected to get was a B which they didn’t deem worth pursuing. I didn’t have the confidence to protest. I’m now working in technology, but I got there by a different route. 

Sukie – If I asked my tutors for help, they told me that a topic was ‘difficult to get’ and to move on. My female best friend and I were sure that our male counterparts weren’t getting the same brush-off, so we used to send her boyfriend to ask our questions for us.

What would you say to encourage younger women to get into STEM? 

Jessica – The comment that sparked this discussion was about girls not choosing to do physics. Dropping maths A-level wasn’t a choice for me; it was taken out of my reach. So, I’d say: “Don’t let anyone tell you that you can’t do maths or that it’s too hard. Make an empowered choice about what aligns with your vision, dreams, and values.”

Sukie – I’ve gained so much confidence and resilience by going into these subjects. Also, just because you’re good at one subject doesn’t mean you’re bad at another. Because I was good at maths, I became convinced I wasn’t good at languages (in fact, I was getting As). The same applies the other way round. 

Jayna – Even if girls are daunted by maths (which we’re not sure is true), that shouldn’t put them off. Why shouldn’t you rise to the challenge? Whatever path you take, you’ll get to a point that’s hard, but that’s not a reason to quit. At CDP, we invite complex problems. They can be exciting, interesting, and worth solving; sometimes, they’ve never existed before. Then, we get all the fun of exploring and creating solutions. I spend all day inventing healthcare products; it’s hugely rewarding. 

What do you enjoy most about using maths and physics at CDP?

Jessica – I’m passionate about telling the stories that emerge from large datasets. When we run quantitative research projects, I use maths, particularly statistics, to understand what we’ve found and communicate that to my audience.

Jayna – Physics isn’t merely a classroom subject; it’s a perspective. It’s a way of understanding the world around us: how things interact in a system; how to see something on an atomic scale and a galactic scale; how to define assumptions to draw conclusions. This approach is instrumental in my work. Recently, I’ve been looking at how to make a product more sustainable without compromising its performance. I’m doing this by evaluating how material changes affect strength, flexibility, wear, interaction forces, and manufacturing. Then I can see how the product could be redesigned to incorporate that material. I couldn’t do this without Newton’s Laws, which I learned in high school!

Women in STEM

Not adding up

The percentage of female students taking physics A-level has hovered at around 23% for the last four years. Meanwhile, the percentage taking maths has stayed at approximately 39%.

Balancing the equation

There are several initiatives in the public and private markets to encourage girls and women to pursue STEM. Here are just a few examples: 

Every February 11, the UN celebrates International Day of Women and Girls in Science.

The UK Mathematics Trust runs a Mathematical Olympiad for Girls to encourage them to tackle advanced problems. 

The AAUW (American Association of University Women) advocates for gender equity for women, through research, education, and advocacy. It provides research and teaching materials to encourage girls into STEM. 

Stemettes is an award-winning social enterprise working to inspire and support young (from five to 25 years old) women and non-binary people in STEM careers.

In January 2022, the UK Foreign Secretary and Equalities Minister launched a task force to boost the representation of women in STEM jobs. One of its objectives will be to establish whether to introduce targets to increase the percentage of women in STEM jobs.

Technology Due Diligence||||||||

Seven principles of successful technology due diligence

June 7th 2022

The Theranos story is as avoidable as it is dramatic. The company claimed its desktop technology could rapidly perform multiple disease-detecting tests simultaneously from just a few drops of blood (while large vials of blood and lab testing would usually be needed). The possibility of addressing needle phobia, reducing healthcare costs, and increased convenience attracted hundreds of millions of US dollars of investment – only for it to be revealed that the technology didn’t work as promised and its failings had been covered up. The exposure of false claims begs the question: what happened to credible technology due diligence before making a significant financial commitment?

At CDP, we’ve been performing technology due diligence for decades, helping our clients assess target technologies for potential rights acquisition, or investing in the company that owns the technology. Our due diligence provides an independent view of how far away these target technologies and companies are from managing their risks, opportunities and milestones.

For technology due diligence to be successful, we apply seven principles, which I’ll share with you in this article. They could certainly have helped Theranos’ investors – but are useful for other, less dramatic acquisitions, too.

Take a wide view

Investment and acquisition risk of a technology can exist in many places, depending on if it’s in development or on the market.

 

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Figure 1: Potential assessment areas for technology due diligence

With time and effort for due diligence activities being limited, it’s understandable that choosing not to focus your investigation on areas that appear less risky might feel sensible. But we’ve found that success stories such as granted patents, regulatory approvals, great PR, and high sales figures don’t always lessen the risks in those areas.

The key to managing the risk perceptions and defining the correct plan for due diligence is seeking input from a multidisciplinary team, working collaboratively to explore the importance and probability of issues and strike the right compromises to fit the assessment work into the allotted time.

Although due diligence activities can flex as you go along depending on your findings, an initial plan should be in place that defines the areas and depths to explore.

Mind the skills gap

Building the right due diligence team means keeping clear of a couple of hazards.

The first is assuming that, because you might only lightly explore some areas, you just need generalists who can cover many bases. The problem with this approach is that sometimes the findings of your investigation compel you to go deeper, or your generalist may not even realize that you need to go deeper because of their limited expertise.

The solution is investing time in finding specialists for the different areas – either to give their input from the start or to be brought in as needed. Depending on the target technology, your team might consist of engineers (mechanical, electronic, software, human factors, manufacturing), scientists, market researchers, and IP attorneys – and, ideally, individuals who are experienced in the sector in question. For example, in the case of Theranos, a pathologist could have sense-checked the evidence for the claim you can run so many tests on a few drops of blood.

The second pitfall is cutting corners on the team make-up, either because you don’t have the expertise in-house, or the team doesn’t have the time to investigate the technology with the attention needed. The solution is to purposefully ringfence your in-house experts and consider bringing in external specialists who can add other perspectives. For example, one of our clients was considering making significant investments with several technology companies. With only in-house financial and market experts on hand, they took the step to commission our technologists and engineers to carry out comprehensive due diligence – resulting in more informed decisions on where (and where not) to invest, and great returns.

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Figure 2: Potential technical experts required for technology due diligence

Engage to establish trust

With confidentiality agreements in place, it’s a plus when the company which owns the target technology is willing to open up its books for detailed scrutiny of its assets – it makes your work easier, shows they’re keen, displays trust, and is a sign of what your future relationship might be like.

Often, though, you might not get all the information you want – the answers don’t exist, work is unfinished, it’s messy, or enveloped in positive spin. It’s understandable that the target company might be nervous about being under the spotlight and needing to secure investment. To see through this, you need to create the conditions that increase trust to foster transparency. Often, trust is increased by establishing a personal connection with the target company. Meeting face-to-face, COVID-19 restrictions allowing, is one step, but a more effective approach is understanding the technical, organizational, and commercial challenges the company had when developing the technology, so your expectations are realistic, and your communication is empathetic.

Work around confidential information

Even given your best efforts to establish trust, target companies still might choose not to disclose everything, because unintended leakage of trade secrets can cause significant business harm.

How can you assess if you can’t see everything? What if the thing being hidden isn’t a trade secret but a fundamental flaw or gap in the offering?

This is where your subject matter experts come into play. They should be able to formulate investigative questions that don’t force secrets to be disclosed – such as asking about the precepts behind the technology, associated engineering principles, methods of test, or quality and regulatory requirements.

Black-box testing (testing a system without knowing how it works) is another approach which helps navigate confidentiality. In the case of Theranos, the potential investors could have asked for the machine to be tested in front of them with provided samples to see if the results were as expected. If a product is on the market, you can try to get hold of a sample of it for technical testing, market testing or tear-down (disassembly to study how it works and is made).

Remember other information sources

A client commissioned us to estimate the production costs for a product to figure out the potential profit and risk areas. This needed to be done without speaking with the company that owned the target technology to avoid alerting other suitors.

Starting out with just one photo given to us by our client, we researched publicly available information such as patents, scientific papers, conference presentations, and other marketing material to estimate the product’s construction, material type, material content, and manufacturing processes with reasonable accuracy. Similarly, we found critical risks that informed questions we went on to ask the company later.

Admittedly, public domain information can be dated and fragmented, but it’s a source worth considering. It might be able to fill in gaps when information finding is restricted, and potentially find other risks and opportunities you may want to ask the target company about.

Don’t ignore the fundamentals

We recently performed due diligence on a target product that had been approved by regulators, used by other companies, and created a stir with its solid intellectual property.

We were told the technology was sound but that there were challenges around manufacturing it in high volumes. Despite assurances from our client and the target company, we still chose to scrutinize the core technology, especially around a novel critical feature which the whole product hinged on.

Working against the clock, we discovered a fundamental flaw with that critical feature that no one had caught before, shocking our contacts at the target company. It threw their concept and the robustness of their intellectual property into question and found a risk that the product could cause serious harm.

The finding was so significant with such a low chance of resolution that our client stopped the potential acquisition process and the target company aimed to restrict the product’s use.

The lesson: ask yourself, “Imagine there was a potential problem in this one area; how impactful would that be compared to another failing in another area?” This line of thinking should prioritize your efforts. Usually, the area where the cost of modification is highest is the technology’s fundamentals.

Be balanced

Looking back to the example above, you might think finding an investment-stopping flaw in the technology that no one else had caught is a sign of good due diligence. It is – but good due diligence isn’t about seeing how many negatives you can collect.

Good due diligence is about a solid process and approach – knowing you were thorough, applied the right experts, were equally motivated to find the positives and negatives, and sized the risks and opportunities with impartiality – leaving the decision to invest to the client, based on their appetite for risk.

In other words, it’s just as important that due diligence enables you to identify fantastic technology for potential acquisition as it is that it helps you avoid making a bad investment.