EPM Mar/Apr 2021 by EPM Magazine

A FOCUS ON DRUG DELIVERY

DIGITAL HEALTH AND THE PATIENT

HOW AUTOMATION IS DRIVING EFFICIENCY IN PHARMA

March/April 2021

Making a difference ONE COMPANY'S MISSION TO PUT SUSTAINABILITY AT THE HEART OF ALL IT DOES.

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Contents Mar/Apr 2021 | Volume 21 Issue 2

REGULARS 5: EDITOR’S DESK

One year later, Reece Armstrong offers thanks to those who’ve worked tirelessly to fight Covid-19.

6: A SMALL DOSE

A brief round-up of some of the latest developments in the industry.

10: OPINION

The tech advancements driving pharma manufacturing.

12: COVER STORY

How one life sciences company is making a change to the way it approaches sustainability throughout the industry.

20: IN THE NEWS

A short selection of stories from the world of science.

26: TALKING POINTS

Stories to consider and what to look out for in EPM in the coming weeks.

FEATURES 7: PERSPECTIVE ON PHARMA

The invisible work behind the Covid-19 vaccine rollout.

14: LOGISTICS

Why delivering Covid-19 vaccines is the logistics industry’s biggest challenge.

16: DRUG DELIVERY SUPPLEMENT Expert opinion and insights on the latest advancements in drug delivery.

22: CONTAINMENT AND CLEANROOMS

How the adoption of class II biological safety cabinets is helping deliver safe and effective medicines.

24: DIGITAL HEALTH

The digital technologies giving clinical trials more insights into the patient.

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A PERIOD OF REFLECTION

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MANY OF US ARE NOW IN A POSITION TO BREATHE A SIGH OF RELIEF WITH THE KNOWLEDGE THAT OUR CLOSE FRIENDS AND FAMILY ARE BEGINNING TO RECEIVE THEIR COVID-19 VACCINES.

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t’s now been over one year since the UK entered its first lockdown in the Coronavirus pandemic. The event was marked by a one-minute silence on 26 March, observed

by parliaments, healthcare workers and individuals in a display of remembrance for those that have sadly lost their lives due to Covid-19. There are many talking points, past and present, that can be levelled at Covid-19. The various industrial and political inner workings that are affecting global supply; the emergence of variants and what these mean for current vaccines; how the pharma supply chain needs to be diversified so shortages are less likely to occur. All these points require further consideration and analysis if

EDITOR’S DESK progress is to be made and so mistakes can be avoided in the future. Frankly though, those discussions can take place another time. Yes, governments will need to answer for their Covid-19 strategies, and we shouldn’t view the pandemic as something from which lessons can’t be learned. It’s understandable that after a year of Covid-19, a year in

which industry milestones have been weighed down by indecisive governments, international disputes and a global death toll of well over 2.5 million, many of us are now tired and saddened by the whole thing. That’s why instead I thought it fitting to remark upon the incredible work that has taken place within life sciences to get us to a point where millions of Covid-19 vaccinations are taking place around the world, every day. This is alongside the selﬂess work carers and healthcare staff have given around the world to those affected by the pandemic, not to mention the thousands of volunteers who are now helping ensure a steady roll-out of Covid-19 vaccines. The overall effort has been remarkable. As someone who hasn’t seen their family in over a year, but luckily still has their family to see, I’d like to thank each and every person who has worked on getting society back to a place where things like simply hugging a relative or loved one is once again possible. Of course, we’re not out of the woods yet. Vaccines are still yet to reach many poorer countries and the loosening of lockdown restrictions should be met with a sense of caution by the public. To do otherwise would show a staggering lack of appreciation for those that have worked tirelessly for over a year on our behalf. Many of us are now in a position to breathe a sigh of relief with the knowledge that our close friends and family are beginning to receive their Covid-19 vaccines. In doing so, reﬂect upon the global efforts that have gone into reaching this milestone and be thankful to those involved.

A small dose

DIGITAL HEALTH PARTNERSHIP TO USE GENOMICS TO IMPROVE RARE DISEASE DIAGNOSES

It's thought that there are over 300 million people living with a rare disease.

-based Sanford Health has teamed up with digital health provider Congenica on a project which will utilise genomic data in an effort to diagnose rare diseases. It’s thought that there are over 300 million people living with a rare disease. It can take considerable time and expense between a patient first meeting with a physician and receiving an accurate diagnosis. Congenica uses rapid genomic data analysis software to interpret

whole genomes in minutes, all in order to drive down the turnaround time for getting actionable information to patients as quickly as possible. Congenica is hoping that it can help improve patient outcomes through increased and more accurate diagnosis for those with rare diseases. Sanford Health is one of the largest health systems in the US and will use Congenica’s platform to analyse and interpret patient genomes to provide

information to clinicians to help identify the underlying causes of previously undiagnosed rare diseases. David A. Pearce, president of Innovation, Research and World Clinics, Sanford Health said: “This partnership between Congenica and Sanford has the potential to have a transformational impact on clinical outcomes for rare disease patients. We selected Congenica for this project as its platform has the capability of generating rapid and accurate analysis for patients who are currently the hardest to diagnose. The scalability of Congenica also offers scope for widespread integration across our network as we make clinical genomics and personalised medicine more accessible.” Christina Waters, SVP Genomics Insights & Solutions, Congenica said: “Sanford Health is one of the largest and most advanced hospital networks. This partnership further strengthens our position in the US and provides strong validation of our platform. We look forward to working with Sanford as we integrate genomic analysis into clinical practice to provide life-changing answers for rare disease patients and their families.”

Schott hits Covid-19 milestone for vaccine vials

ackaging supplier Schott has announced it has delivered enough vials to help provide over 1 billion doses of Covid-19 vaccines. The vials have been delivered globally to projects around the world, with a particular focus on the US, Europe and China. The company says that 90% of approved vaccines currently rely on Schott vials. As part of its 2021 goals, Schott is aiming to deliver enough vials for over 2 billion vaccine doses through 2021. “The reaction of the pharmaceutical community to Covid-19 is a testament to the power of scientific progress,” said Dr Frank Heinricht, CEO of SCHOTT AG.

“In just under a year, all previous records for vaccine development have been shattered by not just one, but several research groups. The entire industry is successfully working together to ensure an adequate supply. We’re also working with our government partners to evaluate ways to improve the supply chain and expand production capacity.” Schott’s Covid-19 response is supported by the company’s multi-year, $1 billion global investment in pharmaceutical glass and packaging facilities announced early in 2019 in response to rising worldwide demand for safer drug packaging.

Testament to the power of scientific progress.

most inno Switzerla

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PERSPECTIVE ON PHARMA

The invisible work in the vaccine roll-out

W overtaken Germany as that Switzerland has across Europe – and delivery is accelerating innovation in drug highlights that Innovation Index from the Pharmapack Provisional findings shows. market, new research innovative drug delivery as Europe’s most overtaken Germany witzerland has

executives – notably according to industry ‘innovation potential’ Spain) saw increases in UK, France, Italy and (Switzerland, Germany, European markets states. All six major market, the research solutions entering the devices and packaging being driven by new Innovation is largely drug delivery market. Europe’s most innovative

in terms of FDA a remarkable few years Markets, said: “It’s been director at Informa Silvia Forroova, brand overall gains. showing the biggest and Switzerland (10%) United Kingdom (5%) year-on-year, with the has increased by 4% innovation potential leader. On average, States as the world closing on the United

ovative drug delivery market and overtakes Germany as

e are seeing incredible progress in the roll-out of Covid-19 vaccines. We are on track for all adults in the UK to have been offered the vaccine by July. Researchers and healthcare workers are rightfully being celebrated for all their work but if there is one thing the global pandemic has highlighted, it is how interconnected we are. Global travel, networks of research, and international support and PPE provision have been at the heart of keeping things ticking over and this is just as true in getting people around the world vaccinated. The UK is one country leading the way in vaccine roll-out but this brings with it the challenge of transportation. THE VACCINE SUPPLY CHAIN Like many vaccines, the Covid-19 vaccine is temperature sensitive. It would be easy to assume that the roll-out of the vaccine simply requires a scaleup of current infrastructure. After all, all vaccines need transportation from laboratories to health clinics, and the pandemic brought a surge in demand for refrigerated and frozen food deliveries. But this Jason Webb, director at Electronic Temperature Instruments (ETI) explores the work going into keeping Covid-19 vaccines at a stable temperature for transport.

vaccine has presented unusual challenges. The majority of vaccines require temperatures between +2 and +8 degrees Celsius. Frozen food deliveries typically require temperatures of around -20 degrees Celsius. In contrast, several of the leading Covid-19 vaccines will require ultra-low temperatures, in some cases as low as -80 degrees Celsius. Maintaining these temperatures requires the use of liquid nitrogen or dry ice. With many working

from home, the number of commuters around the world has decreased drastically. This means that demand for fuels such as ethanol has decreased. Naturally, providers have cut costs and reduced their production. However, carbon dioxide (CO2) is a key byproduct of ethanol production. It is captured and sold on to be used in the carbonation of food and drinks, but it is also used to make dry ice. Alongside this fall in production, the increase in

This vaccine has presented unusual challenges.

Monitoring is used as a vital safety measure.

home food deliveries has seen the demand shoot up. As such, the recent months have seen a shortage of CO2. KEEPING THE VACCINE STABLE This challenging cold-chain supply will require safety measures. If the vaccine is not kept at these cold temperatures, it will become ineffective. Those given an ineffective vaccine may believe they are immune and fail to take precautions. As such, monitoring is used as a vital safety measure. Indeed, the speed at which the vaccine is being distributed within the UK is a testament to the monitoring industry. Just a decade ago, safe effective distribution of vaccines on such a scale would have been virtually impossible even at standard vaccine temperatures. Until recently, temperature monitoring was carried out manually every few hours. Someone would have to enter the insulated container, opening the doors and letting in potentially damaging amounts of heat. If something went wrong between measurements, a few hours was more than enough time for many of the vaccines to be lost before the next measurement was taken. However, measuring any more regularly would slow transit, ultimately increasing the demand for the resources such as dry ice that are required to keep the vaccines cool. Vaccines also have a limited lifespan so more time in transit

limits their shelf-life once they arrived at the medical centre. The World Health Organisation estimates that over 50% of vaccines worldwide are wasted each year. A great number of these are lost due to ineﬃcient delivery and storage. Wireless data loggers have revolutionised the market. They monitor and record the temperatures in both storage and transport facilities and relay it in real-time. Access to real-time data is vital. WiFienabled data loggers transmit data via the cloud to be stored on local devices. They allow for immediate action to be taken if any issues arise with cooling equipment. ADDITIONAL CARE To further reduce risk in these systems, a level of redundancy is built in. All recordings are backed up and operators will receive live data at regular intervals. This means that if one sensor fails to provide a result or gives an unreliable readout, the issue will be picked up on as quickly as possible. Many loggers also utilise two sensors in a single device so that imprecise read-outs are obvious. These loggers are designed to be user-friendly as well as reliable. After all, supply chains rely on wellmanaged partnerships and vital technology should be accessible throughout the industry. Cost also plays a part in making this technology accessible. The overall cost of

the data logger may be more than that of the device itself as software and batteries will all need to be accounted for. While these may seem like small elements, at the level of worldwide distribution, offering competitive costs for reliable hardware will be incredibly valuable. The World Health Organisation has reported that 65%-70% of people will need to be immune to Covid-19 to break the chain of transmission. Transporting vaccines to 70% of the global population is an unimaginably vast task. Many people live in rural and inaccessible areas, and one fifth of children globally are still not protected by even the most basic vaccines. 2020 was a year that brought challenges but also demonstrated that we are innovative and creative in the face of such a challenge. 2021 will be a year of scaling up this innovation. Working in supply chains is a challenging but immensely rewarding place to be as we have the opportunity to see this innovation as it takes place. The continuous development and falling cost of technology is opening doors that many would have thought impossible only a few years ago. Certainly, the speed at which this vaccine was developed is a demonstration of that. Now, as this technology becomes streamlined and user-centric, it is becoming accessible to those that need it. Thanks to such processes, an end to the pandemic is in sight.

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Opinion

The pandemic has disturbed the equilibrium and Pharma 4.0 is well underway.

THE TECH ADVANCEMENTS DRIVING PHARMA Author: RICHARD PORTER - pharmaceutical director at AspenTech

How automated technologies can help manufacturers prepare for the new world order.

or pharmaceutical manufacturers, one of many issues that Covid-19 has highlighted is the need to be ready to quickly meet demand spikes. The requirement for vaccines to be brought to market and production scaled up at a much higher velocity is shaking up traditional research & development (R&D), clinical trials, and the supply chain, with their well established and often protracted processes. In recent months the profile of drugs in demand has changed significantly. Some drugs have seen spikes as a result of induced or panic buying, others have seen troughs, along with shortages due to supply chain disruption. While legislative compliance and process control remain critically important, the rapid development of Covid-19 vaccines has set a positive precedent and the ongoing expectation that drugs will continue to come to market faster than in the past. The pandemic has disturbed the equilibrium and Pharma 4.0 is well underway. FINDING A SOLUTION When a pharmaceutical manufacturer discovers a new drug, in most markets they typically own its patent for 20 years. Many factors can affect the duration of a patent, however, and in addition, exclusivity laws depending on drug and market, mean actual market exclusivity from generic competitors

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is often far less. This, coupled with the high probability that it will take the manufacturer some time to bring a new product to market means the race is on. The speed with which manufacturers can bring a drug to market can directly impact the time they then have to drive up return on investment. So, a faster time to market translates to far-reaching commercial benefits to manufacturers. But how can improved velocity best be achieved? The timeline required for clinical trials is often the key element. Product development can be a factor but typically only if the company concerned is not confident they will get approval, and therefore does not parallelize the requisite scale-up component. That said, we would expect the industry’s experience with Covid-19 to permanently reset expectations, including the belief that innovation may compress the clinical trial timeline and put increasing pressure on product development to accelerate processes and ensure parallelization. Coupled with all this, rapid batch release requires electronic batch records to be verified instantly. Analytical techniques need to be fast enough to allow corrective actions before quality is affected. Clean data allows for faster, better insights. That equates to faster, better decisions to be made. However, in a world where workﬂows remain heavily manual and paper-oriented and much time is taken processing, checking and cleaning data rather than making timely decisions based on it, that’s a massive challenge. The latest digital technologies can help by eliminating non-value add processes, giving decision-makers visibility on product quality and consistency faster than before, but also providing them with deeper insights that would previously have been out of reach. This can allow them to reduce time taken and number of iterations to get the manufacturing process correct and validated, enabling them to reduce costs and improve public health. The effect on the time to market will depend on whether this important data access is on the critical path to product launch, but at least this increases the robustness of the manufacturing

process and reduces the risk of the product launch being subject to delay. In addition, process simulation tools can be used to help select and deploy the right processes and assets to scale up from pilot to full scale manufacture. Simulation tools will allow users to look across their supply chain for the right asset, or to understand that with some tweaking or re-engineering of their existing processes, they will be able to manufacture a new drug product in their existing plant. Another trend helping manufacturers is the increased use of multipurpose plants. Historically, plants were built for specific drugs, even if global demand was tiny, in some cases to the extent that such plants ended up mothballed when annual drug production was complete. As a result, there is a growing trend toward multipurpose and continuous plants, which can streamline drug throughput, reduce capital expenditure and save money and time through better use of resources. However, there are challenges to overcome too. There may be demand from multiple different drug lines for the same equipment. Manufacturers therefore need to consider when they can fit processes in, and where and when they have the necessary bandwidth or time in the day to do so. HOW AUTOMATION DRIVES EFFICIENCIES The use of electronic batch records (EBRs) can be another key factor driving reduced ineﬃciencies and delays in the manufacturing supply chain. Traditionally, plants would create paperbased batch records, and the majority of pharmaceutical plants still run on paper. Manufacturers end up producing reams of paper per batch record. Each record then has to be manually checked three times for errors. As a result, for example, a manufacturing process taking three weeks to complete might then be bookended by a paper-checking process taking months. During that time, the drug would remain stored, gathering dust and racking up warehousing and demurrage

11 charges. By automating the batch release process, highlighting only exceptions, EBR can take months out of the process. In addition, the EBR creates a wealth of easily accessible data, from which further analysis can be applied and an EBR solution that is integrated with enterprise information systems improves compliance by providing industry required, high levels of control, transparency and traceability. Process analytical technology (PAT) is now starting to come of age. Although regulatory bodies such as the FDA have long advocated the use of PAT, widescale practical applications have been relatively slow to take up, primarily due to the availability and complexity of technologies and infrastructure. Many manufacturers now have the sensors in place and the right data systems to carry out multivariable processing; manage feedback online in real time and close the loop. These technologies are allowing the sector to produce high-quality product in greater consistency. They help reduce bad batches, ensuring the market gets the quality product it needs. COLLABORATING FOR SUCCESS Solutions that enable technology transfer and collaboration are increasingly prized in the development and manufacturing process. Simulation tools provide organisations with a common vocabulary. Project stakeholders can work on theoretical processes from the outset and pass work forward to those who have to fit it into the manufacturing workflow. It is a process that promotes collaboration and is far more efficient than traditional approaches. This collaborative approach is one further example of how the Covid-19 pandemic and the subsequent vaccine roll-out has reset the parameters. Technology can help drive faster time to market, improve quality consistency, reliability and capacity in the manufacturing process, ultimately helping guarantee an effective and efficient drug supply chain. That will clearly be the direction of travel for the pharmaceuticals industry in the years to come. Manufacturers wedded to traditional and paper-based processes need to take action now to avoid being left behind.

FRONT COVER

One company’s mission to put sustainability at the heart of all it does.

Making a difference INTERVIEW BY REECE ARMSTRONG - EDITOR OF EUROPEAN PHARMACEUTICAL MANUFACTURER

n April 2019, the Life Science business of Merck launched a four-year initiative that was aimed at improving its sustainability efforts when it came to packaging. For a global business shipping around 30,000 packages every day, the task was enormous. From reducing the overall amount of packaging it was using, maximising recycling, improving plastics sustainability and even targeting zero deforestation, the initiative was a statement of intent by the business to begin to understand its environmental impact – and do something about it.

Now, the business is increasing its ambitions with a new initiative that looks to make sustainability a core focus throughout its entire network of research and development (R&D). Ambitious is certainly the word when it comes to its Design for Sustainability (DfS) framework. The Life Science business of Merck supplies more than 300,000 products and has more than 1.6 million customers working within the science and technology sectors. Applying a sustainable thinking framework to an R&D network within a company this large is something Whitford says can cause sleepless nights.

“Invariably we know there are opportunities to decrease the number of resources we use,” Jeffrey Whitford, head of sustainability & social business innovation at the Life Science business of Merck tells me. “SMASH Packaging was really to say we understand and recognise this is something that will require further effort, that we are focusing on it and that here is the framework so you can see exactly what we’re doing.”

As an internal initiative, DfS started at Merck’s facility in Molsheim, France, in 2014, where the programme was used to provide a metric for what resources were being used and potentially saved throughout product development. Looking back, the initiative was certainly worthwhile, but it wasn’t something that was going to make a large difference to the way the company operates. Launching it across the entire global business has been a gargantuan task, with Merck testing out the system from 2016 to 2018 and oﬃcially launching it in 2020.

Whitford admits to SMASH Packaging being a long-term project. Since 2019, the Life Science business has been collecting data and working on ways to reduce its environmental impact through projects such as a recyclable cooler for the transportation of products and the reduction of wasted space within packages.

BUT HOW DOES IT WORK? DfS takes into account seven areas that are indicative of the Life Science product portfolio – materials; suppliers & manufacturing; packaging; energy & emissions; water; usability & innovation, and the circular economy.

Trust is at the centre of all of this. If there isn’t trust and transparency, we don’t have a chance of doing this successfully.

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Since the product portfolio is so large, DfS had to be developed to provide the business with “a ﬂexible framework that allows us to address something that is a piece of equipment but that in another area is a chemical or a biologic product,” Whitford says.

Seeing what materials are being used throughout a product’s development, how it is then transported across the globe or how much water or energy is used throughout that product’s lifecycle, enables Merck to look at each product from a sustainability perspective and ask if it could be doing a better job.

“Every product isn’t going to come out being sustainable but what we have done is we’ve included it as part of the checklist process,” Whitford says. “It could be that we were able to significantly reduce water usage but then something else went up because of that. But we need to be clear about it so the customer can then understand how we did it and why we did it.”

A recent example of this was the development of two laboratorybased filtration systems, which were designed with the DfS framework in mind. Previous products were used with the media being poured in through a top container, going through a filter, before coming out into a bottom container. Using a usability innovation approach, Merck was able to remove the top container to allow bottles to simply be screwed onto the filter unit – resulting in the reduction of up to 47% of plastic, less emissions due to a smaller product and other beneficial, sustainable savings.

Some would argue that there’s an inherent level of reputational risk that comes with a company being this transparent about its environmental footprint. Whitford though says that these are the conversations we need to be having.

These metrics are released by Merck in a DfS scorecard for each product or service, which really highlights just how transparent the company is being with this initiative. “Trust is at the centre of all of this. If there isn’t trust and transparency, we don’t have a chance of doing this successfully. That means you have to have a semi-radical level of transparency you have to give to customers,” Whitford tells me. Of course, with such a large product portfolio, the company has to be realistic about its chances of successfully making sustainable savings across its entire R&D network. JEFFREY WHITFORD head of sustainability & social business innovation at the Life Science business of Merck

“The differentiator is to know what your [environmental] footprint looks like when you do business with us. I hope that more companies, regardless of their industry, take that into mind and think about giving people more information about the choices they are making, because it does have an impact on the long term.” Within life sciences, the ultimate gauge for success has been whether or not products are providing a benefit to people’s lives. Whitford argues that that goal can still be the main target, but it can be achieved in a manner where people ask questions as to how it was achieved in an environmentally sustainable manner. Throughout our conversation, Whitford stresses that the DfS framework, much like SMASH Packaging, is a long-term focus. Merck now has its framework set up, but gathering the data and digging deeper into its larger supply chain is a task that won’t be accomplished overnight. “The message here though is that this is going to be a process. This is an ambitious and tough project. Having taken that step with the framework, now it’s about educating people about it, getting them comfortable with it, getting them thinking about usability. So, one step done but we’ve got a lot of steps ahead of us.”

LOGISTICS & DISTRIBUTION

Safe travels

Why delivering Covid-19 vaccines is the logistics industry’s biggest challenge.

he sheer speed of developing and gaining regulatory approval for effective vaccines against Covid-19 has been unprecedented. Transporting them rapidly and safely from manufacturing sites to vaccination centres and doctors’ surgeries across the world is possibly the biggest challenge the logistics industry has ever faced.

and in some cases temperaturecritical product on such a huge scale creates considerable operational challenges. Many pharma companies and global carriers have turned to supply chain technologies including sophisticated parcel transportation management software to help ensure vaccines get to where they need to be in good time.

More than a dozen different vaccines have now been authorised for use in various countries, with several more in Phase 3 trials anticipating roll outs in 2021. Pfizer has stated its intention to produce up to 1.3 billion doses of its Covid-19 vaccine in 2021, whilst Moderna projects between 600 million and 1 billion doses in the same period. A total predicted capacity of 10 billion doses globally in 2021 means the magnitude of the task is clear. Managing global distribution strategies for a time-sensitive

Planning for such an immense logistical undertaking started as early as April 2020. Since then, Logistyx Technologies has worked with a number of pharmaceutical and life sciences customers and their carrier partners to help them plan ahead for the challenges of distributing vaccines worldwide. It was essential to kick off the process early, so they would be ready to go as soon as regulatory approval was granted. The preparations included choosing the right carriers to handle the specific requirements of different

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vaccine shipments, as well as planning for the bulk storage and return of valuable bespoke temperature controlled ‘cooling boxes’ (with multiple sensors), which some companies are using to distribute shipments. Temperature control and the mass quantities that need to be rushed across the globe have stretched existing medical supply chains’ capabilities and volume.

and electronic data produced are compliant with the specifications required by the carrier. In international shipping, each carrier has its own quirks when it comes to data, and the verification of this is critical, especially if this is the first time that hazardous materials, such as dry ice pods for example, are being shipped. If the data is incorrect, you get errors and delays which you just can’t afford.

AGILE LIBRARY OF CARRIERS Any organisation that wants to manage the distribution of the vaccine needed to rapidly build an agile library of carriers - each with the capability to provide the specific services required - to cover all destinations. In many cases, shippers had to quickly identify and go-live with multiple new carriers who specialise in specific geographic locations, and who themselves needed updated documentation and labelling to support the delivery of vaccines - with back-up carriers ready to go in case of carrier capacity issues, or if the first choice did not perform as required. It simply is not an option to throw away vaccines because they were spoiled in transit due to delays or an inability to effectively manage extreme cold temperatures (as low as -70˚C). To gain approval for shipping with a new carrier, it is necessary to prove that the labels

DATA VERIFICATION The data verification process involves a sequential ﬂow, starting with processing a few orders in a test environment with real data. Having tested the data, the next step is to check that the physical label meets all requirements. Is the ink black enough to be easily read by the carriers’ systems? Is there the right amount of shine on the labels? Are all the right codes being used? A seemingly simple 2” x 6” label with a 2D barcode contains vital and complex data, including routing codes, information on hazardous materials and payment terms that must be accurate. You do not want a time and temperature sensitive shipment to go astray because the routing code sends it to the wrong hub. To ensure that vaccines can be shipped as a matter of urgency, this process was reviewed with

Transporting them rapidly and safely from manufacturing sites to vaccination centres and doctors’ surgeries across the world is possibly the biggest challenge the logistics industry has ever faced.

various vaccine producers, to ensure that millions of shipments are ready and labelled with carrier compliant information to enter the supply chain as soon as regulatory approval is given. PROACTIVE SHIPMENT MANAGEMENT Of course, the preparation for shipping is just one piece of the puzzle. Another important part is complete, real-time visibility of shipments from the point of departure to final delivery. This can be achieved through the Business Intelligence function of a Transportation Management System (TMS) designed for shipping parcels globally and where necessary, partnering with internet-of-things (IoT) providers who deliver deep metadata for truckload visibility. Having the information of the exact whereabouts of any shipment and the possibility of any delays, enables the supply chain leaders who are coordinating the distribution of the vaccines to proactively manage shipments in transit, even potentially diverting them, in order to avoid vaccine degradation. Using a digitised, cloud-based supply chain system that records every delivery event on a shipment’s journey can also provide the data and analytics required to detect sub-par logistics performance and uncover opportunities to optimise execution for even better outcomes. Everyone is hoping that a successful global roll out of vaccines in 2021 will bring a return to normality. By building ﬂexible and agile supply chains to meet the specific requirements of the various vaccines, with real-time visibility of shipments, the logistics industry is helping to play its part by ensuring that each delivery is right first time, on time, every time.

Author: KEN FLEMING - president at Logistyx Technologies

DRUG DELIVERY SUPPLEMENT

A FLEXIBLE DELIVERY PLATFORM The increasing complexity of molecules in the drug development pipeline calls for ﬂexible and patient-centric drug delivery platforms. Multiparticulate technology offers many advantages over conventional tabletting methods. These drug delivery systems provide the ﬂexibility to design complex oral solid dosage (OSD) formulations that require controlled or extended release.

TALKIN'

ABOUT AN

MATERIAL CHARACTERIZATION The foundation of a robust manufacturing process is an indepth characterization of input materials to understand any lotto-lot variability and potential impact on critical to quality attributes (CQA) & downstream manufacturing.

Multiparticulates are discrete drug-containing particles that together make up a single dose. Preparation methods are varied and can be adapted according to target drugrelease profiles. Extrusion-spheronisation as a technology platform accommodates a wide range of drug loading with the process ﬂexibility to deliver immediate release, extended release, or combination products. It has the added advantage of dose ﬂexibility that can be achieved by changing capsule fill weight without altering the manufacturing process. In addition, multiparticulates eliminate dose dumping, a challenge often observed with single-unit dosages. From a patient perspective, multiparticulate dosage forms are more desirable as they can be adapted to a once-daily, extended-release dosing, are easier to swallow, and can be coated for taste-masking.

ROBUST AND RELIABLE From a manufacturing perspective, extrusionspheronisation is a highly robust, reliable, and predictable technology platform achieved by an integrated process design approach: • Characterization of material inputs and variability; • In-depth process understanding; and • Process modelling and control.

At Pfizer CentreOne’s facility in Newbridge, Ireland, advanced characterization of inputs and fingerprinting of different lots of active pharmaceutical ingredients (APIs) and critical excipients using Process Analytical Technology (PAT) are completed to ensure optimised, controlled, and consistent manufacturing processes.

How drug delivery methods have evolved to deliver complex formulations using multiparticulate technology - with a focus on extrusion-spheronisation coated bead technology.

PROCESS UNDERSTANDING Robust processes are designed and developed using development data from small-scale manufacturing to establish normal operating ranges and to understand process inter-dependencies and intricacies, thereby reducing the risk of unexpected challenges during scale-up and commercialisation. PROCESS MODELLING & CONTROL The resulting manufacturing processes can be modelled to allow seamless scale-up from development through

Author: JACINTHA GRIFFIN - Site Lead for Technical Services, Operational Excellence & Innovation at Pfizer CentreOne

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The spaghetti-like extrudate is fed into the spheronisation unit where, extrudate characteristics, rate of extrusion, spheroniser setup, spheronisation time, speed, and load will determine the quality and consistency of pellets for downstream drying and coating processes.

to commercial manufacturing. Critical process controls are established and monitored as part of an integrated process control strategy.

• process control strategy includes granulation endpoint and intermediate hold times which are established as part of the process design.

A MULTIPARTICULATE PROCESS USING EXTRUSIONSPHERONISATION An example of a multiparticulate process that has successfully performed for over 20 years at the Newbridge facility is the extrusion-spheronisation process. This consists of a sixunit operation – dry blending, wet granulation, extrusion, spheronisation, pellet drying, and, if required, pellet coating. Each unit operation is optimised to ensure seamless transition from one operation to the next downstream process.

EXTRUSION AND SPHERONISATION The next two-unit operations – extrusion and spheronisation – begin with feeding the wet mass through an extruder screen. -The critical parameters include: granulate moisture level, impeller and feeder speed, screen thickness, and diameter of perforations, and extrusion force.

DRY BLENDING Optimisation of dry blending to achieve a homogeneous blend is established during process design. Critical parameters include: the order of addition of APIs and excipients, the optimum batch size, blender fill level, mixing action, speeds, and blending time.

From a manufacturing perspective, extrusionspheronisation is a highly robust, reliable, and predictable technology.

At Pfizer CentreOne, a multivariate design of experiments approach is used to optimise these processes to ensure high pellet sphericity for subsequent coating.

At Pfizer CentreOne’s Newbridge facility, PAT is used to develop blending end point as part of a process control strategy. One example of PAT is near-infrared (NIR) spectroscopy.

PELLET DRYING AND COATING For pellet drying and coating, process parameters and equipment set-up must be carefully controlled and thermodynamically balanced to achieve consistent and uniformly coated pellets. Key process parameters to ensure uniformly coated pellets include: • Incoming pellet characteristics, e.g., size and shape; • Batch size; • Coating solution characteristics; e.g.; viscosity; • Equipment set up, e.g., nozzle design; • Process parameters including spray rate, atomising air pressure, inlet air temperature, and volume and product temperature. The resultant pellets can be filled into hard gelatine capsules, sprinkle capsules or sachets, ﬂexibility being the hallmark of a multiparticulate process. FINAL THOUGHT Extrusion-Spheronisation is a highly ﬂexible multiparticulate technology platform that can deliver increasingly specialised medicines.

WET GRANULATION This process forms liquid and solid bridges between the particles which coalesce to form granules. The critical process parameters for a wet massing granulation process are: • the rate of addition, quantity of the granulation solution, nozzle design, mixing action, and granulation time; and

With the appropriate technical expertise, robust, predictable, and scalable processes can be designed that enable seamless transfer from development through commercialisation.

DRUG DELIVERY SUPPLEMENT

EASY ACCESS L OF A NEW MODE D IN H E B K R AND THE WO UG DELIVERY R D L A S A N NS A INTR FORMULATIO R O F S N A E WHAT IT M ARD. GOING FORW

ntranasal delivery has always been a tantalising target for topical and systemic drug delivery due to ease of dosing, highly vascularized epithelium, and direct access to the central nervous system. Delivery is relatively painless, the onset of drug action can be rapid, and formulations can be easily administered in emergency situations.

As with all methods of drug delivery, the development of new intranasal formulations and treatments can only advance as fast as the existing models allow. The reconstituted nasal epithelium (RNE) model is one of the latest models available to de-risk and expedite intranasal delivery – giving a competitive edge to those developing formulations for this route of delivery.

TRADITIONAL NASAL DRUG DELIVERY MODELS The epithelial surfaces of the nose can be divided into four general regions: the nasal vestibule, nares, nasal cavity, and the olfactory bulb. The main target regions are the nasal cavity and the olfactory bulb. The nasal cavity is characterised by the presence of broad, rigid, highly vascularised structures called turbinates. Droplets from sprays or particulates from powders will enter the nasal cavity, encounter these surfaces and adhere to the mucosal surface, where they gain access to the vasculature. Drug delivery is complicated, however, by the presence of tight junctions, active ciliated epithelial cells, and a protective layer of mucus on the epithelium. The olfactory bulb, located above and behind the nasal cavity, is a section of specialised tissue that acts as the olfactory sensory organ. Due to its location and underlying structure, this patch of epithelium allows for direct and rapid access to the central nervous system, bypassing the blood brain barrier entirely. Historically, one of the common in vitro models used to screen various formulations for nasal delivery is excised animal nasal mucosa mounted on a Franz cell. Formulations are applied to the apical side of the tissue, and receptor solution is sampled from the basolateral side to determine formulation performance. This model has proven successful in the development of nasal drug formulations for decades and it has been used for the development of several drug products. However, like all models, this model has some limitations. Although passive barriers such as basement membrane and matrix binding remain intact, the

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active components such as tight junctions, mucus production, cilia, and other metabolic-dependent activities are lost. A NEW MODEL FOR INTRANASAL DELIVERY To build and improve upon the existing ex-vivo model, we have developed a reconstituted nasal epithelial (RNE) model. This model system uses primary human nasal epithelial cells, harvested from the mucosa at the turbinates, regrown on permeable inserts, and stimulated to develop into a welldifferentiated nasal epithelium. Nasal epithelial cells are harvested from a donor using a nasal swab and resuspended in a gentle proteolytic media bath. Resident immune cells and fibroblasts are removed, and the remaining epithelial cells are expanded in monolayer culture using specific epithelial growth media. Cells are then seeded onto porous membranes, supported over a bath of similar growth media. Over the course of about a week, cells expand and become fully conﬂuent, beginning the differentiation process. At this point, the media is changed, and the apical surface is kept dry to promote full differentiation, which occurs over the span of three-four additional weeks. Over this time, the epithelial cells adopt a pseudostratified columnar compound epithelial layer. Upon full differentiation cells exhibit mucus production, ciliary activity, and tight junctions. This architecture typically persists for approximately four weeks, and the integrity of the barrier can be monitored throughout the process by transepithelial electrical resistance (TEER). In addition to being a closer approximation of nasal mucosal barrier than traditional excised

animal tissue models, RNE cultures allow for additional analyses that are not possible using ex vivo tissue. This can include assessing the irritation potential of a formulation or drug or studying how mucus and ciliary action can impact the permeation of a formulation. This model can be extended to include nasal infection. The advent of the Covid-19 pandemic has highlighted the role of the nasal epithelium in infection and viral propagation and subsequently the importance of good models of infection. Modelling infection in RNE instead of cell lines (such as the more classical HBE4 and A549 cell lines) bypasses many of the well-known shortcomings associated with cell lines in general. Well-differentiated primary cells more closely mimic in vitro physiology, cell signalling, and architecture. This has special importance in viral infection models, as the conditions in the host cell (such as protease and receptor expression) can generate artificial selection during propagation and infection. This selection can cast doubt on results from such work. Although the use of RNE does not eliminate this effect, it can reduce it. The RNE model can also be easily adapted for bronchial epithelium, allowing for the testing of a host of new formulation types, such as those for the treatment of asthma, COPD, and cystic fibrosis. In the case of cystic fibrosis (and other genetic diseases), epithelial constructs can be grown from cells collected from the affected patient population during routine medical care. FINAL THOUGHT The applications of RNE and other airway epithelial models can be further expanded using co-culture systems. Co-culture with

inflammatory cells can be used to compare the performance of anti-inflammatory and antibiotic drugs. Reconstructed airway tissue can be co-cultured with airway smooth muscle to compare the efficacy of drugs treating airway hyperresponsiveness in asthma. Due to the long-term viability of these constructs, remodelling effects from irritants such as smoke, diesel exhaust particles, and other environmental particulates can be monitored, and recovery from insult compared.

Authors: DR JON VOLMER - senior director Research Biology and Innovations and DR JON LENN chief scientific oﬃcer at Medpharm

It is always the goal to develop the next more useful model, and thereby advance drug development. This RNE model achieves this by increasing the utility of available models for intranasal delivery and allows companies to de-risk their development programmes.

As with all methods of drug delivery, the development of new intranasal formulations and treatments can only advance as fast as the existing models allow.

IN THE NEWS

New Covid-19 vaccines could be needed in less than a year

pidemiologists from across 28 countries believe we may have less than a year before the SARS-CoV-2 virus mutates to the extent that first-generation vaccines are rendered ineffective or new vaccines are needed. The warning comes from a survey of 77 epidemiologists, carried out by The People’s Vaccine Alliance, in which two-thirds believe that we may running out of time before new vaccines are required to combat SARS-CoV-2 mutations. A third of those surveyed gave a timeframe of nine months or less and fewer than one in eight said they believed that mutations would never render the current vaccines ineffective. The majority (88%) also said that persistent low vaccine coverage in many countries would make it more likely for vaccine resistant mutations to appear. The People’s Vaccine Alliance warns that at the current vaccination rate, it is likely that only 10% of people in the majority of poor countries will be vaccinated in the next year. Currently, the daily vaccination rate across the globe is estimated at slightly below 15 million, but the majority of these are taking

place in wealthier countries. Now, three quarters of those surveyed are calling for the open sharing of technology and intellectual property (IP) so that manufacturers can boost Covid-19 vaccine supplies. Echoing this, The People’s Vaccine

Alliance is asking for pharmaceutical companies working on Covid-19 vaccines to share their technology and IP with the World Health Organization Covid-19 Technology Access Pool. Devi Sridhar, professor of Global Public Health at the

University of Edinburgh, said: “The more the virus circulates, the more likely it is that mutations and variants will emerge, which could make our current vaccines ineffective. At the same time, poor countries are being left behind without vaccines and basic medical

Did you know?

Israel has vaccinated over It’s been over one year 60% of its population since the ﬁrst lockdown against Covid-19 with at was announced in the UK. least one dose.

Sadly, there have been over 2.7 million deaths related to Covid-19.

supplies like oxygen. “As we’ve learned, viruses don’t care about borders. We have to vaccinate as many people as possible, everywhere in the world, as quickly as possible. Why wait and watch instead of getting ahead of this?” Covid-19 variants have been of concern for pharmaceutical developers for some time. Moderna has said it is looking at a revised version of its own vaccine targeting the B.1.351 variant, which was first identified in the Republic of South Africa. Studies show that Moderna and Pfizer’s Covid-19 vaccine are less effective against the South African strain compared to the UK variant. Anna Marriott, Oxfam’s Health Policy manager, added: “In many rich nations, vaccinated people are starting to feel safer, but unless we vaccinate all nations, there is a huge risk that the protection offered by vaccines will be shattered by fresh mutations. “This survey highlights that we need a people’s vaccine, not only to protect people in the world’s poorest countries, but to ensure that people all over the world who’ve already been vaccinated aren’t put at risk again.”

DRUG DELIVERY SUPPLEMENT

FLIP THE Biosimilar interchangeability: EU and FDA approaches to device switching.

n Europe, a fifth of the total spend on biologics (€12 billion) is already exposed to competition from biosimilars. Meanwhile, in the US, just under a fifth of the biologics market (worth $211 billion dollars) is exposed to biosimilar competition, and three fifths of the market has the potential for biosimilar development. Manufacturers of originator biologics are taking various measures to defend against this competition, such as reformulating drugs, making dosing improvements, or changing drug delivery devices. Similarly, biosimilar manufacturers must differentiate from other producers, to be able to secure suﬃcient market share. DEVICE INNOVATION Manufacturers can choose to differentiate through their choice of delivery device. Patients are used to brand changes for their drugs and so may not react adversely if their pharmacy changes provider, but a device that improves their experience may help to retain patients in the long-term. Ease of use tends to encourage patient adherence, and is especially important now that many treatments for chronic illnesses are administered outside of the healthcare setting and often without the support of a healthcare practitioner. However, pharmaceutical manufacturers may be concerned about the regulatory implications of making device changes for combination products.

THE EU APPROACH Guidance from the European Medicines Agency (EMA) separates the drug from the delivery device, which makes the approvals process easier. Moreover, the guidance makes it clear that differences in the administration device may be allowed if there is no impact on safety and eﬃcacy. Manufacturers can therefore gain a competitive advantage by improving device usability or even changing the mode of delivery. To provide a recent example, one manufacturer developed a biosimilar suitable for subcutaneous administration, for a reference biologic that is usually administered intravenously. The formulation allows for three administration options and may even improve the effectiveness of the treatment. FDA GUIDANCE Unlike the EU, the US FDA has a dedicated approval pathway for combination products, where both the drug and device are assessed together. The FDA’s final guidance document titled “Considerations in Demonstrating Interchangeability with a Reference Product” is not clear on the scope for device changes. At first, the document seemingly advises against submitting an interchangeable product with a different ‘presentation’ – i.e. the device component – from the approved reference product. However, the guidance then suggests that sponsors considering this option should nonetheless

approach the FDA, allowing the regulator to determine whether the proposed changes could support a demonstration of interchangeability. TAKING INITIATIVE Despite the ambiguity in the FDA guidance, the organisation’s increased emphasis on human factors suggests that more patient-centric devices would be welcomed, and as more organisations take the initiative to engage with the FDA, it is likely to inform future advice on this issue. Biosimilar development is highlighting the opportunity to make the administration experience more positive, and the resulting improvement in patient acceptance would be beneficial for all stakeholders, from pharmaceutical businesses to healthcare providers. Finally, optimised devices can also help encourage long-term product confidence among patients who have never used the originator biologic, further incentivising manufacturers to explore device enhancements.

Author: DARREN MANSELL - Regulatory Affairs manager at Owen Mumford

Pharmaceutical manufacturers may be concerned about the regulatory implications of making device changes for combination products.

CONTAINMENT AND CLEANROOMS

IMPORTANCE OF How the adoption of advanced Class II BSCs in cGMP environments is helping to to deliver safe and eﬀective medicines.

P Author: DR DAVID PHILLIPS - senior global product technology specialist – clean air at Thermo Fisher Scientific.

harmaceutical manufacturers have a responsibility to consistently deliver safe and effective medicines, and this can be achieved by complying with the Food and Drug Administration’s (FDA) current Good Manufacturing Practice (cGMP) regulations. To meet the stringent cleanliness and containment requirements set out in the regulations, manufacturers largely rely on Class II Biological Safety Cabinets (BSCs). However, until now, regular monitoring of air cleanliness and quality within cabinets has been a key challenge. The latest advances in Class II BSCs address this issue, and these systems can be easily integrated into facilities, enabling manufacturers to fully comply with cGMP standards and deliver highquality, safe products. A NEED FOR GOOD MANUFACTURING PRACTICES cGMP-regulated environments are essential for the manufacture of drugs, ensuring a clean and safe setting with no risk of contamination. Indeed, poor cGMP conditions at a manufacturing facility could ultimately pose a life-threatening health risk to a patient. As such, the manufacture of sterile products is subject to special requirements as set out in the FDA’s cGMP standards and EU Guidelines for Good Manufacturing Practice. Quality Assurance is a particularly important aspect of these regulations, and pharmaceutical manufacturers must strictly follow carefully established and validated methods of drug preparation

and manufacturing procedure to comply and ensure product safety. Where terminal sterilisation is not possible, the drug manufacturer commonly uses aseptic processing, whereby the products and containers are sterilised separately and then brought together in an extremely clean environment. Guidelines for aseptic workﬂows state that air cleanliness in the immediate proximity of exposed sterilised containers/closures and filling/ closing operations should be ISO Class 5 (Class 100) and routine particle monitoring should be performed during each production shift. However, this presents a challenge for traditional Class II BSCs. While they are capable of providing highquality clean air with containment, they historically have limited monitoring capabilities. LIMITATIONS OF TRADITIONAL BSCS Class II BSCs are an essential component of pharmaceutical manufacturing workﬂows,

providing a carefully controlled environment that safeguards therapeutic products from airborne impurities, as well as protecting operators from the materials they are working with. However, the systems were originally designed as safety devices for use in research environments where there is a low requirement for monitoring. The ability of Class II BSCs to provide four types of protection — personnel, product/sample, environmental and protection from cross-contamination — is a major advantage compared with other types of device, such as laminar flow cabinets. Class II BSCs use controlled airflows and high-efficiency particulate air (HEPA) filters to provide protection through a precise balance of clean downflow inside the cabinet and inflow drawn from outside the cabinet. However, as the HEPA filters collect more particles, they resist the airflow and associated velocities can decline over time. This degradation in performance is an issue for pharmaceutical

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cleanliness alarm system to alert the manufacturer when there have been changes in standard operating conditions and attention is needed.

manufacturers needing to demonstrate that their cabinets provide the appropriate level of protection during the entire drug manufacturing process. Advanced Class II BSCs are designed to overcome these challenges, and meet the cleanliness and containment requirements of pharmaceutical manufacturers. ADVANCED CLASS II BSCS FACILITATE COMPLIANCE WITH CLEANLINESS AND CONTAINMENT REQUIREMENTS Pharmaceutical manufacturers need to produce evidence of a clean work area and of containment. Therefore, a Class II BSC intended for use in cGMP applications requires two capabilities at a minimum. First, a sampling capability to monitor air cleanliness in the BSC work area/sample chamber. Monitoring air cleanliness can be easily achieved with a particle counter and most Class II BSC manufacturers offer a

modest customisation inserting a sampling tube or sampling probe holder to meet this need. The second capability is to monitor containment. Using the criteria validated in accordance with the NSF International/ American National Standards Institute (NSF/ANSI) 49 standard on “Biosafety Cabinetry: Design, Construction, Performance and Field Certification”, containment can be monitored by checking the inflow and downflow velocities to assure they stay within the acceptable range. The design of Class II BSCs has advanced to provide the level of monitoring required so manufacturers can be safe in the knowledge they are complying with regulations. Many advanced Class II BSCs have been designed with innovative features, including intelligent motor/fan systems that automatically adjust to changes in resistance to maintain a constant flow. They also have an airflow monitoring/

Class II BSCs now incorporate separate downflow and exhaust fans to monitor and maintain inflow and downflow separately rather than as an aggregate totaled value. This has two key benefits for delivering superior containment. It maintains the balanced inflow and downflow needed for containment and does not overlook potential problems due to uneven filter loading between downflow and exhaust. Additionally, it allows for the monitoring of the pressure difference across downflow and exhaust fans separately, giving the benefit of looking at the overall flow without being as affected by differential filter loading. The latest Class II BSCs even record an exportable log of all airflow measurements and operator activity. Many of the advanced features built into modern Class II BSCs are also designed to ensure these systems maintain certified performance for longer. As a result, if air velocity does decline over time, pharmaceutical manufacturers

can quickly access detailed logs to determine when conditions deviated from specific operating parameters and by how much. If these parameters are known to have no effect on the safety or performance of therapeutic products, manufacturers are better placed to demonstrate to regulators that products are still safe to be released to the market. CONCLUSION cGMP environments require clean and safe workspaces for the manufacture of drugs. In addition, the manufacturing process needs to be carefully controlled and validated. Clean air that is contained and regularly monitored is critical for both protection of the product and personnel, and this can be achieved easily by integrating modern Class II BSCs. The ongoing advances in the design of cabinets and inclusion of novel features, such as intelligent motor/fan systems and alarms, means the latest Class II BSCs are facilitating and simplifying compliance with FDA and EU regulations. Manufacturers using these systems can improve their workﬂow eﬃciency, and are better placed to deliver safe and effective medicines.

Until now, regular monitoring of air cleanliness and quality within cabinets has been a key challenge.

DIGITAL HEALTH

THE BIGGER PICTURE How harnessing digital platforms and remote solutions can give the broadest picture of patient response.

Author: PAUL O’DONOHOE, Scientific Lead, eCOA and Mobile Health at Medidata

PATIENT BURDEN – A CONTINUOUS HURDLE Patient burden in clinical trials remains one of the biggest challenges for the life sciences industry to address. Patient retention and adherence are crucial in the clinical trial process and can dramatically impact the outcome of the trial. Dropout rates are sometimes over 30%, leading to trial delay, additional costs, risk to the validity of the study, and potential failure of the trial. By lessening the burden on trial participants and ensuring they are engaged in the study, dropout rates can be significantly reduced, and patients can generally have a more positive experience. It’s therefore essential that trials are designed with patient centricity in mind. The concept of patient centricity is not new and has been a topic of much discussion in the life sciences industry over the last decade. During this time, we’ve seen the industry begin to engage with patients during the protocol development of a trial. This has had a truly meaningful impact on how studies are designed and conducted, as it gives patients an opportunity to voice what is realistic, viable and important to them. Alongside this, we are also starting to see technologies emerge as key tools in improving the patient experience. While cutting-edge technologies have always been used in clinical trials, the industry is beginning to embrace the potential impact these can have on reducing

patient burden and, in turn, delivering the best quality data and broadest picture of patient response to a new drug or treatment. We repeatedly hear from patients that the most frustrating aspects of clinical trials are the day-to-day burdens - time spent on-site, cost of travel, days off work, stress of finding childcare and the list goes on. The negative impact these significant burdens have on patients’ ability to remain engaged with trials are well known and has been a key driver towards using remote tools that move engagement away from physical trial sites and into patients’ homes. Patients can now complete questionnaires and surveys at home or do physiological tests in their living room or at their local GP/pharmacy, thus providing greater ﬂexibility to patients. TOOLS BEING DEPLOYED TO MAXIMISE ADHERENCE Electronic clinical outcome assessments (eCOA) are to date the most commonly used digital tools to provide insight into the patient experience in a clinical trial and have become the mainstream method for capturing this kind of data in pivotal trials. These measures (usually in the form of questionnaires) are designed to explore how a patient is feeling or functioning and are used to provide better insight into how patients are responding to a treatment. Having historically been captured on paper, this electronic shift has brought significant

benefits in regard to data quality, as well as simplifying the whole experience for patients and clinicians. Another tool that is growing in prevalence is the use of electronic informed consent, or eConsent. Consent forms have traditionally been full of dense language more focused on providing legal protection, rather than to truly educate patients with the information they need before joining a trial. Today, rather than being a box-ticking exercise, eConsent engages and educates patients on the clinical trial they’re about to join. It uses interactive components like video, infographics, and audio

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components, as well as the ability to look up definitions and ﬂag up areas of uncertainty. This gives patients the opportunity to be truly informed on what they are signing up for, and by receiving consent forms electronically they can review and deliberate at home with their families before proceeding. The process builds trust and means that patients who may

have been concerned by the jargon now feel comfortable with the trial and the process. And by allowing patients to electronically sign their consent, they can be recruited and on boarded onto a trial remotely and far more quickly. Wearable devices, ranging from medical grade sensors to commercial wearables

The increased use of digital and remote solutions is certain to persist beyond the pandemic.

like Fitbit, are also attracting intense interest in the clinical research space. These devices hold the promise of providing an additional datastream alongside the more established eCOA measures to provide a deeper insight into the patient experience. It also opens the possibility of performing assessments which might traditionally have needed to be completed at a site under the supervision of a clinician in the patient’s own home (e.g. the 6-minute walk test). We are only just starting these conversations and the next step for wearables will be to determine what the data is really telling us and how it can translate into something meaningful for the trial. Once we are able to determine the full potential of these technologies, the patients may not even have to think about doing specific tests – the data will be captured automatically in real-time. FLEXIBILITY BY DESIGN AND WHAT’S TO COME One of the key strengths of these technologies is that they can be scaled up and down to meet the needs of a specific study and patient population. At Medidata, we call this the ‘Trial Dial’ - the amount of trial virtualisation can be easily adapted to meet the specific needs of the study. For example, in an oncology study where patients are often receiving a significant amount of additional treatment support, it may make sense to do more on-site activity so the patients can be monitored carefully and receive the care they need. But in a trial looking at a rare

disease, where patients are scarce and likely located far from the trial site, it may make sense to use remote solutions to improve access and remove geographical restrictions. While some digital technologies, such as eCOA, are already in widespread use, the adoption of some digital and remote solutions still face headwinds. Wearables are still new, some clinicians favour traditional methods and, most significantly, regulators tend to have a conservative and careful approach when adopting new technologies. This is why educating the industry on these tools and demonstrating their true value is imperative. The Covid-19 pandemic has significantly accelerated the industry's reckoning with these tools. We saw clinical trial sites shut down overnight and study teams were suddenly unable to capture the stream of data needed for their trials. Regulators advised companies and investigators not to be afraid to harness the power of technology to keep trials moving. The industry saw an increased interest and uptick in digital platforms and remote tools to allow trials to continue virtually. The increased use of digital and remote solutions is certain to persist beyond the pandemic. By normalising these patientcentric technologies and increasing patient engagement, clinical trials will obtain better, broader and more complete data, ultimately leading to better outcomes.

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Talking points

OUTSIDE EPM

GUIDANCE RELEASED FOR THE RESPONSIBLE USE OF ANTIBIOTIC TREATMENTS NOVAMIND PARTNERS WITH MERCK ON TREATMENT FOR DEPRESSION

ental health company Novamind has been selected to work alongside pharmaceutical company Merck & Co on a clinical trial focused on treatment-resistant depression (TRD). The company’s subsidiary, Cedar Clinical Research (CCR) will act as a key research site for a phase II study assessing the eﬃcacy and safety of Merck’s new drug for TRD. TRD is thought to affect approximately 30% of people who suffer from major depressive disorder. The clinical trial will assess Merck’s MK-1942 drug when added to a stable antidepressant therapy for participants with TRD. It will recruit up to 140 participants and assess the safety and eﬃcacy of MK-1942 compared to a placebo group on a stable course of antidepressant therapy. The primary outcome of the trial is to see whether the treatment of MK-1942 is superior to that of a placebo. The trial will use the MontgomeryAsberg Depression Rating Scale (MADRS) score to assess how participants' depression is affected.

framework has been released so that treatments targeting antibiotic-resistant bacteria are used responsibly and that the spread of antibiotic-resistant bacteria is minimised when new products are launched onto the market. The Stewardship and Access Plan Development Guide has been developed by international collaborators working across industry, government and philanthropic efforts. The document provides companies with guidance on strategies and activities that help support stewardship and access for developers bringing new antibacterial products to market. The framework sets a new benchmark for the responsible use of antibiotics and other therapeutics such as vaccines and diagnostics

that target antibiotic-resistant bacterial infections. It’s hoped that the guide will also make governments and product developers become more proactive in integrating stewardship and access principles into their activities. “Antibacterial innovation must go hand-in-hand with responsible use and access. Otherwise, innovative drugs that are meant to help patients risk contributing to the global burden of antibiotic-resistance,” said Kevin Outterson, executive director of CARB-X, which is investing $480 million in 2016-22 to accelerate the early development of innovative antibacterial products including antibiotics, vaccines and rapid diagnostics. “We all must do our part to see that antibacterials are used responsibly and that patients who need them have access to them. From a public health, health security and economic perspective, it is the right approach.” Companies that receive funding by CARB-X will need to develop a Stewardship and Access Plan for when their product reaches clinical trials. This will outline what strategies will be deployed to ensure responsible stewardship and access in low-and middle-income countries.

r John Payne, consultant transplant cardiologist and clinical safety advisor at InterSystems, outlines what should be provided to patients who expect digital health services. Make sure to read the full article on www.med-technews.com

BE SURE TO LISTEN TO This episode of The MedTalk Podcast sees EPM speak to Richard Daniell, head of commercial at Teva Europe about what the future of pharma manufacturing looks like in Europe.

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