EPM Jan/Feb 2021

THE COMPANY TARGETING UNMET NEEDS IN ONCOLOGY

THE LATEST IN DRUG DELIVERY

BRINGING BIOSCIENCE TO THE UK'S NORTH EAST

January/February 2021

THE RIGHT ROUTE TO TAKE Nemera explores how to manage drug overdosing through the use of a smart nasal spray device

Contents Jan/Feb 2021 | Volume 21 Issue 1

REGULARS 5: EDITOR’S DESK

The dangers of vaccine nationalism and the need for a unified global approach to Covid-19 vaccinations.

6: A SMALL DOSE

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

10: OPINION

How to achieve data integrity in pharmaceutical manufacturing.

14: IN THE NEWS

A short selection of stories from the world of science.

16: COVER STORY

Nemera explores how to manage drug overdosing through the use of a smart nasal spray device.

30: TALKING POINTS

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

FEATURES 8: PERSPECTIVE ON PHARMA

The company targeting unmet needs in oncology.

18: BIOPHARMA

The new methods bringing treatments to life and how a collaboration is bringing investment to the UK’s bioscience sector.

22: DRUG DELIVERY

The latest advancements in drug delivery.

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Volume 21 Issue 1 © Jan/Feb 2021

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s we head further into 2021 it’s fair to say that much of our focus is still placed on the ongoing Covid-19 pandemic.

Whilst much of 2020 saw governments and life sciences racing to stay ahead of the virus – to very mixed results – this year the spotlight is on the rollout of vaccines.

That there are three Covid-19 vaccines available in the UK is testament to the incredible efforts of the pharma industry, which has managed to bring to market therapies that would usually

take around a decade to research and develop.

And though in the UK at least millions of people have been given a dose of a Covid-19 vaccine, we can’t forget that much of the rest of the world still remains unvaccinated and will possibly remain this way for many years.

A major factor in this is that a lot of the Covid-19 vaccine supply has been bought up by wealthy countries, who have stockpiled exceedingly large numbers of doses far outweighing the needs of their respective populations.

EDITOR’S DESK The UK is just one example of this type of vaccine nationalism that prevents the equitable distribution of Covid-19 vaccines. For instance, the UK government has secured a portfolio of 407 million doses of Covid-19 vaccines, all in order to vaccinate a population of around 68 million.

At the same time, many developing countries

are having to depend on philanthropic efforts such as the Covax scheme, which has been designed to equitably distribute 2 billion Covid-19 vaccines by the end of 2021.

The Covax scheme is essential. Consider that as of 4 February, a total of 108 million Covid-19 vaccines doses had been administered across 67 countries. However, a mere 4.4% of vaccinations had been given in developing countries.

Quite frankly, there needs to be a better system in place to ensure that a larger spread of the global population is vaccinated against Covid-19. Efforts such as Covax are welcome, but without a global unilateral approach the risk of large swathes of the population being left unvaccinated for a long time is high.

Whilst it makes sense to vaccinate at-risk groups and essential workers, if we can’t do this on a global scale then we risk undoing a lot of the work that has gone into fighting this virus.

After all, we’ve already seen new variants of coronavirus spread throughout communities, causing governments and the pharma industry to rethink their approach to vaccines and lockdown measures.

The longer Covid-19 affects us on a global scale, then the longer we will have to endure a world without the luxuries we are used to.

The economy will continue to take a hit, but more importantly, families, friends and loved ones will be hit the hardest.

Until we’re all safe, none of us will be.

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A small dose

Sepha launches small batch packaging service

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harmaceutical packaging and machinery specialist Sepha has launched a contract packaging service to meet rising demand for small batch production.

The company’s new service is focused on providing cost-effective, low volume runs of blister and medical device packs within short turnarounds.

Sepha launched the service due to the rising demand for small batches of pharmaceuticals, due to an increase in the likes of personalised medicines and orphan drugs. The need to produce small batches in an economical manner has led to

manufacturers struggling to accommodate occasional low volumes on their high-speed production lines.

process parameter optimisation and analysis,” explains Paul Smith, managing director of Sepha.

“Customers were looking to us for support with small runs. Some were having to halt 24/7 high speed blister lines to produce a few hundred sample packs. This is not what these lines were designed for and cannot be justified in terms of line clearance and changeover times.

Sepha, on the other hand, is ideally placed to take on small runs, as we have all the knowhow we have built up over the years with our laboratory-scale EZ Blister packaging projects, consisting of design, manufacture,

The new contract packaging service is geared towards companies looking to outsource anything from 100 up to 10,000 packs per week, either as oneoff runs or longer-term contracts.

“We believe we have something unique in the marketplace. We have a breadth of experience – spanning pharmaceutical packaging equipment, leak testing, deblistering and packaging design – that is unrivalled in the small volume contract packaging space,” Smith added.

Gericke made partner in manufacturing collaboration

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harmaceutical equipment manufacturer Gericke has been made a partner in the Medicines Manufacturing Innovation Centre.

The Medicines Manufacturing Innovation Centre is a collaboration between CPI, the University of Strathclyde and founding industry partners, GSK and AstraZeneca with funding provided by Scottish Enterprise and UK Research and Innovation.

The Centre aims to address efficiency challenges within the pharmaceutical supply chain through a series of ‘Grand Challenges’.

Gericke has been made partner to help with the centre’s first Grand Challenge (GC1), which is focused on the development of an innovative continuous direct compression (CDC) platform, which will help enable oral solid dosage medicines

to be formulated more robustly and efficiently.

The partnership will build on Gericke’s existing contributions to Phase 1, which includes the provision of a highly modular and integrated system, suitable for both continuous and mini batch blending, making the machine suitable for a wide variety of products, market demands and supply chains.

Bernhard Meir, head of Continuous Manufacturing at Gericke, said: “We are delighted to have been introduced into this partnership with the Medicines Manufacturing Innovation Centre.

GC1 is a very exciting project, and the skills and experience we at Gericke can provide will help to guarantee its success. This unique opportunity will allow us to work alongside key industry players and contribute to the UK’s leading initiative to drive innovation in medicines manufacturing.”

most inno Switzerla

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CATALENT TO SUPPORT MANUFACTURE OF CELL THERAPY

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dvanced delivery technologies provider Catalent will support the manufacture of Trizell’s Phase 1 cell therapy for the treatment of micro and macroangiopathies.

Biotech company Trizell has developed an advanced therapy medicinal product (ATMP) that uses regulatory macrophages (Mregs), a platform technology developed in Germany.

The company’s therapy 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

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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

treats micro and macroangiopathies, a disease which affects small and large blood vessels respectively.

Catalent. Manufacture of the cell therapy will take place at Catalent’s facility in Gosselies, Belgium.

Initial development work will take place at the University Medical Center Schleswig Holstein (UKSH), Department of Anesthesiology and Intensive Care Medicine, the Clinic for Applied Cellular Medicine, and the Department of Cardiovascular Surgery, in collaboration with

“This is an important milestone for Trizell and the therapy for the treatment of macro- and microangiopathies,” said Sibille Engels, chief executive officer, Trizell GmbH. “I am delighted to enter into this collaboration with Catalent and to benefit from its outstanding expertise in cell and gene therapy

manufacturing.”

“Our relationship with Trizell will build on Catalent’s deep knowledge in immunotherapies, from the diagnosis and derisk stage all the way through to commercialready processes,” commented Manja Boerman, president, Catalent Cell & Gene Therapy. “Extending

into areas such as macrophages, allows us to stay on the forefront of emerging indications and cell types. The process development, manufacturing expertise, and the experienced production teams we have at Gosselies will enable a faster transition from development to manufacturing,” she added.

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

TABLETING TOOLS – QUALITY ENSURES SYSTEM HARMONY

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icrobiome therapeutics company MyBiotics has received €2 million from the European Union’s FS ® Technology Horizon 2020 Program.

The funding

Perfect harmony between machine, turret and tool from one single source.

The result: long service lifes, high tablet quality and higher output. www.fette-compacting.com

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PERSPECTIVE ON PHARMA

The company targeting unmet needs in oncology

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o-founded in 2018 between CTO Orlaith Ryan and CEO Sharon Cunningham, Shorla Pharma has quickly made a name for itself. The Irish company has been recognised as an emerging company in the oncology sector, being nominated for and winning entrepreneurial awards by the likes of The Irish Times and the Local Enterprise Office.

Back in June 2020, the company raised $8.3 million to help it advance its pipeline of therapies targeting women and paediatric cancers. Oncology may be a competitive sector within pharma, but Shorla is hoping that its approach towards treatments in the space will help it emerge as a serious contender.

“We concentrate on indications where existing treatments are limited, in shortage or inadequate for the target population,” CTO Orlaith Ryan says whilst discussing the company’s approach to treatments.

Shorla currently has three treatments within its pipeline EPM speaks to Shorla Pharma’s CTO ORLAITH RYAN about how the company is aiming to be a strong contender in the oncology market through therapies designed for women and children.

We concentrate on indications where existing treatments are limited, in shortage or inadequate for the target population.

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and has been working with the US FDA towards new drug applications. The first to be launched in the US market is a treatment for children with T-cell Leukemia, (SH-111). It has also created a drug for treating breast and ovarian cancers (SH-105), which it hopes to have filed with the FDA for approval

by Q1 2022. The last to move down the pipeline will be an oral solution that was developed to treat children with glioblastoma (SH-110) who have trouble swallowing, launch for which is planned in 2023 The competitive nature of the oncology market isn’t lost to Ryan and it’s the company’s strong intellectual property and solid regulatory strategy that she believes will help Shorla gain a foothold within the industry.

The fact that rare cancers “are often overlooked by larger companies and the market in general,” Ryan explains, allows Shorla to “address areas of unmet need [and] apply applicable strategic aspects from a market exclusivity perspective.”

Of course, whilst a strong commercial strategy is needed if success is to be had within pharma, Shorla was launched because Ryan and Cunningham want to develop treatments that can have a significant clinical impact on patients.

For instance, the company’s oral solution to treat Glioblastoma (SH-110) has been designed to reduce the treatment burden of patients suffering from this cancer. The oral solution has been made to be palatable for patients having to take it, with Ryan saying how a “simple change can really have a significant impact” on patients.

“This treatment is the standard of care so it’s the first therapy given for most treatment regimens. The treatment is effective but ultimately can’t be taken properly by the patient because it’s difficult to swallow, patients in this case can be very young children. Really it’s not an effective process and we need to alleviate that treatment burden for patients. We believe having a palatable treatment vs a very difficult to swallow treatment is significantly impactful,” Ryan says.

The decision to set up Shorla in Ireland stems from Ryan and Cunnigham’s previous careers at EirGen Pharma – a company which they saw grow from a very small start-up, to one employing 200 people and which later was acquired by US multinational Opko for $135 million.

“We saw that company grow and succeed from the very early days. That really motivated us to do something meaningful and purposeful, and ultimately have a wider impact.”

Whilst being based in Ireland allows Shorla to draw upon the country’s strong network of pharmaceutical talent, the company is largely looking towards the US market in terms of where it will initially distribute its products.

However, a need to understand that market when setting up the company led Shorla to engage key stakeholders throughout the healthcare setting in the US. All of this was “to ensure that our products were screened and would ultimately be products that would have an impact and be used by clinicians alike, once they got to market,” Ryan explains.

And it’s this key engagement with voices across the US healthcare market that Ryan thinks will help Shorla’s pipeline of therapies succeed.

“We’re very confident. It’s the engagement that we bring into the very early stage of our product development to ensure that they will ultimately be used in a clinical setting and to explore the payor landscape to ensure that they will be covered and ultimately get to the patient,” Ryan says.

With Ryan and Cunningham at the head of Shorla Pharma, the pair could be seen as an example of those who have successfully managed to break through pharma’s glass ceiling.

Whilst Ryan has never found being a female entrepreneur to be an obstacle, she does state how “female-led start-ups get much less capital investment,” but that the reality is “there are far less women seeking such investment.”

9 “It might not always be the problem that women are being overlooked, it’s also that more women should come forward,” she says.

With the pharma industry still experiencing a gender gap, particularly amongst those in leadership positions, Ryan stresses how important it is that systems of support are put in place for underrepresented parties. For Ryan, nowhere has this been more evident than in Ireland.

“Our own Irish government agency, Enterprise Ireland, saw the underrepresentation of women and put in support to encourage it. That is really encouraging because it ensures that to support females coming forward there are supports in place and that can be the first step in getting there,” she says.

That system of support is crucial, Ryan believes, when it’s applied to a company’s own personnel.

“The most successful teams, whether they’re executive teams or technical teams, have a variety of perspectives.

But it’s not enough to have a diverse team; you also need to support the members of the team,” she says.

That level of support is something Ryan says she’s been lucky enough to receive throughout her career and in turn she now feels responsible for passing on that mentorship to the members of Shorla Pharma.

“It’s encouragement to not only establish a career but to build it, so they too get to the C-suite position or to a level where they’re on the executive team, because I think that’s really important,” she says.

Opinion

In recent years, the focus around data integrity has continued to intensify.

THE KEY TO ACHIEVING DATA INTEGRITY IN PHARMACEUTICAL MANUFACTURING Author: PETER ZIPFELL, product marketing manager at Thermo Fisher Scientific

How better software can help pharmaceutical manufacturers keep their data accurate

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very day in pharmaceutical manufacturing, countless decisions are made which have the potential to directly impact public health. At the core of these decisions lies the constant monitoring of carefully selected parameters with known or potential consequences on product safety or efficacy. The degree to which data is complete, consistent, and accurate across its entire lifecycle is referred to as ‘data integrity’ and is monitored by regulatory agencies. While adherence to data integrity guidelines indicate good practices, incomplete or inaccurate records can reflect poor data management systems, human error, or intentional data falsification.

As failure to ensure data integrity contributes to compromised product quality, pharmaceutical manufacturers are required to keep an audit trail; a secure electronic system that maintains an accurate record of events to enable a historical reconstruction of the data. However, audit trails are challenging;

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maintaining a meticulous record of complex processes across multiple sources can be difficult for manufacturers, while audit trail assessments represent an onerous and multifaceted task for reviewers.

Having appropriate software is, therefore, essential for implementing practices necessary for compliance and easing the burden for both parties. The functionality of this software should not only support audit trail maintenance and review; streamlined systems are also critical to enhancing productivity.

TRENDS SHAPING AUDIT REQUIREMENTS In recent years, the focus around data integrity has continued to intensify, following an increasing number of warning letters, notices of concern and statements of non-compliance. Authorities are now striving to reduce incidents of poor data integrity by encouraging transparency and updating regulatory guidelines related to pharmaceutical manufacturing and global clinical trials. As part of the shift towards greater transparency, electronic data systems are now encouraged over paper, making data increasingly searchable, accurate, and difficult to falsify.

The enforcement of ever-evolving audit trail regulations is driven by one underlying factor: the demand for highquality products. To this end, the US Food and Drug Administration (FDA) is considering novel strategies for incentivising mature quality management systems, especially after the findings from a 2019 report on drug shortages. Of 163 drug shortages in the US between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality problems. Consequently, the FDA has suggested introducing a rating system, whereby pharmaceutical companies could disclose a rating indicative of their commitment to establishing quality management systems that help anticipate problems before they arise. Such a move would provide companies that demonstrate strong quality management maturity with a competitive advantage, potentially enabling them to grow their market share.

In this context, robust audit trails are not just tools for achieving data integrity, compliance and product quality; when used to their fullest, they can become a competitive advantage under greater demands for transparency. The report also recognised that simple adherence to cGMP standards doesn’t necessarily mean a company is investing in improvements; manufacturers are now expected to take greater responsibility and demonstrate quality maturity.

THE CHALLENGES OF CREATING AND REVIEWING AN AUDIT TRAIL Not only are audit trails a record of the “date and time of operator entries and actions that create, modify or delete electronic records”; manufacturers are also required to “track actions at the record or system level” – as written in the FDA’s Data Integrity and Compliance with cGMP Guidance for Industry. Specifically, any attempt to access the system, or rename or delete a file, must be recorded. Without the right software systems in place, it is impossible to track these actions.

Audit trail reviews are laborious and multifaceted; experienced users must be able to review available data to determine whether the recorded actions can be justified based on the ‘who, what, when, where and why’. Without appropriate filtering and grouping features, it is difficult for the reviewer to quickly identify relevant information among the hundreds of potential entries. In addition, the global nature of pharmaceutical manufacturing and increasing uptake of continuous manufacturing only adds to the challenge of maintaining comprehensive and easily accessible audit trails. Overall, there is a growing need for secure and streamlined software reporting tools.

FORWARD-THINKING CHROMATOGRAPHY DATA SYSTEM (CDS) SOFTWARE PROVIDES AN INVALUABLE SERVICE A software that affords full traceability is a strong deterrent to malicious intent, so it is imperative that a CDS captures all actions in the audit trail. With Thermo Scientific Chromeleon 7.3 CDS software, for example, the ability to change specific settings or perform certain actions can

11 be restricted to select users. If these settings were changed, the changes would remain visible to all. Every deleted, modified and added event is documented electronically, thereby addressing any concerns around traceability. Even failures and errors that may cause a run to abort are recorded as a significant system event with an accurate date and time stamp.

Throughout the workflow, a number of features are being added to CDS software to simplify compliance and audit trail reviews, for example: • Single user identity and password authentication for maximal traceability.

• A clear record of activity allows regulators to easily view any changes.

• A highly searchable interface that enables reviewers to query events and extract more information from the data.

• Use of ‘standard comments’ to assist with action verification or reasoning, i.e. a predefined list of the most commonly accepted answers for routine actions or amendments.

• Sequence-centred storage of all associated components related to the dataset, keeping everything in one place for completeness.

• A self-notification system where the software alerts the reviewer to specific high-risk audit trail events, e.g. a manual change to a chromatogram.

COMPLIANCE AND WORKFLOWS MADE EASY WITH ADVANCED CDS SOFTWARE The pharmaceutical industry is experiencing significant pressure to demonstrate greater transparency and data integrity to ensure a reliable supply of high-quality pharmaceutical products. Meticulous and evolving audit trail regulations reflect the need to safeguard public health and represent a major challenge for manufacturers. To remain compliant, manufacturers require software systems capable of handling larger and more complex datasets without compromising on productivity.

Ultimately, implementing a more modern and advanced CDS platform is an opportunity to achieve compliance, simplify audit trail reviews and enhance workflows.

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AN INSIDE LOOK

AN INSIDE LOOK

at Spirax Sarco EPM speaks to Spirax Sarco to understand the role steam systems play in pharma and how the company can help improve sustainability throughout the industry.

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ith over 100 years of experience, Spirax Sarco not only stand proud in the FTSE 100, they are a constituent of the FTSE4Good Index, meeting globally recognised corporate responsibility standards. This is built on a long and successful history of providing steam solutions to customers across multiple industries, including food and drink, healthcare and of course pharmaceuticals. The company’s range of products and services include solutions for the efficient use of steam in applications such as heating and sterilisation. Their service capabilities extend from audits & surveys to training in one of its 59 training facilities across the globe.

“Wherever we operate, we strive to exceed our sustainability targets, helping our customers to do the same. Our ability to provide engineered solutions that improve our customers’ operating efficiency, reduce their environmental impacts and increase their sustainability is at the heart of what we do, and is where we have our greatest, and most positive environmental impacts” says Angelo Giambrone, healthcare business development from Spirax Sarco.

In a global effort to reduce

carbon emissions and embrace more sustainable operations, companies the world over are implementing sustainability plans.

GlaxoSmithKline (GSK) has recently set targets on having a net zero impact on climate and a net positive impact on nature by 2030.

AstraZeneca has also launched a similar ‘Ambition Zero Carbon’ programme: committing to having zero carbon emissions from global operations by 2025.

However, every company within the supply chain has a role to play too. Spirax Sarco has set its own plans in motion to achieve netzero greenhouse gas emissions by the end of 2040, alongside other sustainability goals such as sourcing 50% of its electricity from renewable sources by 2030, and also designating board accountability for greenhouse gas emissions. It is also one of over 20 UK companies that has committed to a biodiversity net gain by 2030.

Spirax Sarco isn’t simply looking inwards towards its own operations though. The company estimates that in 2019, its products, services and solutions helped its customers reduce an estimated 7.2 million tonnes of carbon emissions.

That’s the equivalent of taking around 3.7 million new cars off the road or planting over 300 million mature trees.

Through the correct installation, monitoring, testing and management of plant and pure steam systems, manufacturers can maintain exacting standards of product quality.

So, where does steam fit within the pharmaceutical industry?

Steam plays a fundamental part in delivering controllable thermal energy across a range of applications and it ensures that process equipment used in the manufacture of medicines is kept sterile and free from contamination.

“Steam plays a fundamental part,” explains Angelo Giambrone, healthcare business development manager at Spirax Sarco.

“There are strict rules governing validation, but through the correct installation, monitoring, testing and management of both plant and pure steam systems, steam helps achieve the exacting standards of product quality.”

What steps can be taken to improve the effectiveness of existing systems?

In order to understand how systems are performing and may be improved, Spirax Sarco can

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conduct Steam System Audits (SSAs) and Steam Quality Testing (SQT). These are vital to help identify energy savings and operational improvements, all in order to meet environmental and efficiency objectives. Spirax Sarco works with pharmaceutical companies to assess anything from a single plant room up to an entire steam system. “Our customers increasingly rely on our expertise to deliver unique engineering solutions to achieve enhanced and sustainable operating efficiencies,” adds Giambrone.

Spirax Sarco can help companies gain a better understanding of their energy use through monitoring and measuring.

This can reveal opportunities to target improvements in efficiency.

Not only does this apply to the pharmaceutical production process, but also to utilities such as hot water and heating throughout the plant. Whether plant or process, both areas are of importance. Improving systems, whether plant or process, can help overcome “issues with system reliability, quality, maintenance or even natural product obsolescence,” Giambrone states.

How is the pharmaceutical industry adapting to the challenges of reducing fossil fuels?

“Plant steam is a large contributor to overall energy consumption of a pharmaceutical plant. A high proportion of the energy consumed in pharmaceutical manufacturing is in the heating and ventilation of the facility,” Giambrone explains. There is a drive to reduce the use of fossil fuels and to lower carbon emissions. The way this impacts on the thermal needs of industry is a problem that is challenging engineering minds, particularly where there are large instantaneous thermal loads required by the process.

Typically an energy centre uses gas as the primary fuel, which then distributes thermal energy in the form of steam to the plant.

The steam has very high energy content when compared to a typical circulating hot water system (26 times more energy per kg than a water circuit working on 80-60oC flow and return). Steam is also very easily distributed, without the need for circulation pumps to move large volumes of water.

However, in the long term the pharmaceutical industry will still need to consider the primary fuel source. While the world currently strives to find an alternative to burning natural gas, there is much development taking place to seek a fuel that can flow through our national infrastructure. “We may find that a breakthrough is achieved in the use of bio-gas or maybe hydrogen – we read and

watch with anticipation as these developments progress,” says Giambrone.

One answer may be through increasing electrification by using electric steam generators.

The electrical power can be obtained from a renewable ‘low/ zero carbon’ source and this may solve some of the issues; many sites are also investing in their own solar capabilities. However, the high thermal requirement of a plant would place a significant demand on any existing electrical infrastructure.

A solution to help overcome potentially high electrical loads is to use a steam accumulator, which can store the thermal energy produced by the generator. This can then be released in the form of steam, as and when the process demands it. In effect, it acts like a buffer, reducing the peaks on electrical load, whilst satisfying the peaks of the steam demand.

Energy storage is receiving increasing focus, as engineers endeavour to harness energy from intermittent renewable sources like wind and solar. Spirax Sarco is using its global expertise to produce innovative solutions relating to storing and delivering thermal energy. This may well pave the way in the future, not only for the pharmaceutical industry, but for many other industries that require heat for their processes. As challenges in the pharmaceutical industry evolve, so do the products and services of Spirax Sarco. Whether it be improving the quality of steam or identifying energy savings and process improvements, the company’s steam engineering know-how, combined with a global presence and an ongoing commitment to innovation, ensures that its customers have the support and technical solutions needed, now and in the future.

AN INSIDE

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IN THE NEWS

Oxford/AstraZeneca Covid-19 vaccine less effective against South African variant

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he University of Oxford and AstraZeneca’s Covid-19 vaccine only provides minimal protection against the South African variant of Covid-19, according to data from a small-scale study.

Researchers from the University of Witwatersrand and others in South Africa worked alongside the University of Oxford to analyse how effective a two-dose regimen of the ChAdOx1 nCoV-19 vaccine is against a mild-moderate infection from the South African variant of Covid-19.

The study consisted of approximately 2,000 volunteers with an average age of 31 years old. Mild disease was defined as at least one symptom of Covid-19.

The study did not analyse protection against moderatesevere disease, and the low risk of the target population meant that hospitalisation or death could not be assessed.

Whilst the vaccine was found to have high efficacy against the original coronavirus strain in South Africa, protection was substantially reduced when tested against the B.1.351 coronavirus variant.

The University of

Oxford has said it has begun working on a second generation of the vaccine which has been adapted to target variants of the coronavirus with mutations similar to B.1.351.

The researchers says

that these early data confirm theories that mutations in the virus seen in South Africa will allow Covid-19 to spread through vaccinated populations.

Shabir Madhi, professor of Vaccinology and

Director of the Vaccines & Infectious Diseases Analytics (VIDA) Research Unit at University of the Witwatersrand, and chief investigator on the trial in South Africa said: “Recent data from a study in

Did you know?

Viruses are more likely to mutate as the number of human and animal infections rises.

The UK is thought to have 147 cases of the South African Covid-19 variant.

The UK has secured a portfolio of over 400 million Covid-19 vaccines.

South Africa sponsored

by Janssen which assessed moderate to severe disease, rather than mild disease, using a similar viral vector, indicated that protection against these important disease endpoints was preserved.

“These findings recalibrate thinking about how to approach the pandemic virus and shift the focus from the goal of herd immunity against transmission to the protection of all at risk individuals in population against severe disease.”

Sarah Gilbert, professor of Vaccinology at the University of Oxford said: “Efforts are underway to develop a new generation of vaccines that will allow protection to be redirected to emerging variants as booster jabs, if it turns out that it is necessary to do so.”

“We are working with AstraZeneca to optimise the pipeline required for a strain change should one become necessary.

This is the same issue that is faced by all of the vaccine developers, and we will continue to monitor the emergence of new variants that arise in readiness for a future strain change.”

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Ebola outbreak declared in Guinea

A SLOWER TRIALS A POSSIBILITY IN 2021, CRO WARNS

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he newly formed Scientific Advisory Board (SAB) of clinical research organisation (CRO) Europital has warned that a clinical knowledge deficit amongst smaller biotechs will potentially slow trials in 2021.

Europital’s SAB was formed to address many of the complex targets and biologies that now proliferate pipelines within drug discovery.

Europital predicts that investment communities – backing many earlystage development programmes – will look holistically at biotechs and their partners to ensure that deep therapeutic expertise is available.

“The drug discovery pipeline is increasingly made up of smaller and more nimble innovators with limited clinical experience in-house.

Yet, with many of the low hanging fruit already

having been developed, molecules and biologies are becoming ever more complex. The challenge for small and medium pharma and biotechs is how to access appropriate high-quality clinical knowledge – and this clinical deficit over the next few years is set to be a critical factor in any candidate's advancement,” said Dr Mohamed El Malt, chief medical officer of Europital.

“It’s no secret that unlike the larger pharma companies that can pull in the best resources from the largest CROs, smaller companies must increasingly compete to ensure they can access the best clinical knowledge, as this can be the difference between delays due poor trial management and planning, and even, a project’s potential success or failure,” added Dr El Malt.

new outbreak of Ebola has been declared in Guinea after three cases were found in the rural community of Gouéké in N’Zerekore.

The country’s national laboratory confirmed the cases, marking the first time the disease has been reported in the country since the last outbreak ended in 2016.

On 28 January 2021, a nurse from the local health facility died. Following her burial, six people who attended the funeral reported Ebola-like symptoms. Since then, two of them have died whilst the other four have been admitted to hospital.

“It’s a huge concern to see the resurgence of Ebola in Guinea, a country which has already suffered so much from the disease. However, banking on the expertise and experience built during the previous outbreak, health teams in Guinea are on the move to quickly trace the path of the virus and curb further

infections,” said Dr Matshidiso Moeti, the World Health Organisation (WHO) regional director for Africa. “WHO is supporting the authorities to set up testing, contact-tracing and treatment structures and to bring the overall response to full speed.”

Staff from WHO have already been positioned in the area to help prevent infections from spreading and to also convey with health facilities and other parts of the community to ensure they play a key role in the response.

The current outbreak’s epicentre borders Libera and Sierra Leone and WHO is already working with health authorities Since the epicentre of the current outbreak is in a border area, WHO is already working with heath authorities in Libera and Sierra Leone to increase community surveillance and strengthen their capacity to test for cases.

16 CONVERGING TRENDS IN NASAL DELIVERY The intranasal route of administration is commonly used to treat various therapeutic areas. As a matter of fact, nasal delivery is an attractive option for locally acting medications as well as for systemic therapies which may vary from benign to serious health conditions. The nose anatomy allows us to administer the medications systemically or locally by targeting the right area for drug deposition in the nose to eventually treat certain conditions.

For instance, a nasal spray could be used to manage several chronic or acute pathologies topically such as allergic rhinitis, sinusitis, and nasal congestion. Indeed, the dynamic number of pipelines via the nasal route for systemic or nose-to-brain applications has grown over the years, as the nasal route is not invasive, and does not require healthcare professionals’ intervention.

With the advantage of nose physiology, even emergency and crisis could be addressed with nasal delivery.

Considering this, for instance, patients who experience breakthrough pain due to their chronic conditions such as cancer could opt for a nasal route treatment delivery. In such a case, systemic acting drugs are administered through the nostrils to relieve the pain, as a complementary option to pills.

NASAL FOR PAIN MANAGEMENT There is a wide range of drugs that are used for painkillers. As an example, opioid treatment is used to relieve pain with its rapid onset of action through unit-dose or multidose nasal drug delivery: opioids are

COVER STORY

THE

RIGHT ROUTE TO TAKE

Nemera explores how to manage drug overdosing through the use of a smart nasal spray device. a class of drugs including prescription painkillers such as fentanyl. Due to their pharmacological effects, they can cause difficulties with breathing, and opioid overdose can lead to death1. Worldwide, about 0.5 million deaths are attributable to drug use. More than 70% of these deaths are related to opioids, with more than 30% of those deaths caused by overdose. In the USA, the number of people dying from opioid overdose increased by 120% between 2010 and 2018, and two-thirds of opioid-related overdose

deaths in 2018 in the USA involved synthetic opioids, including fentanyl and its analogues2.

Indeed, fentanyl is a potent drug, used to treat severe pain that has become the main driver of recent increases in synthetic opioid deaths. The fentanyl painkiller is used on a regular basis by patients with cancer.

For multidose nasal spray presentations, this may lead to opioid overdose when it is not used according to the treatment posology. Given this, it is crucial to consider the mode and way

of administration to ensure the patients’ safety.

OUR SOLUTION: SAFE’N’SPRAY On that account, Nemera developed a smart electronic concept device with childresistant, dose counting and locking features, Safe’n’Spray, which offers solutions to prevent overdosing on potent drugs. It is an integrated device with a reusable electronic locking unit and fingerprint identification, to monitor drug dose delivery in a defined period of time to ultimately ensure patient’s safety. The device is intuitive, thanks to its interactive and animated user-interface which helps patients use the device correctly through audio and visual feedback. It has a simple display indicating the number of doses left and the remaining time for the next dose.

Moreover, with reusable and disposable parts, Safe’n’Spray offers a unique possibility to reuse the “SAFE” electronics for sustainability once the “SPRAY” part with the drug content is empty; of course, this is both economic and eco-friendly.

The fingerprint sensor feature for patient unique identification prevents any abuse of use by other people than the one(s) pre-determined, as the device is personalied for specific individuals (e.g. patient, relative, healthcare professional, etc.).

Besides, this acts as an easy and intuitive child-resistant feature, without the need for adding any secondary packaging with a smart child-resistant function.

Opposite to fully integrated devices, Safe’n’Spray does not change the manufacturing process of primary packaging on existing filling lines, as another module will deal with assembling Safe’n’Spray around primary packaging.

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Safe’n’Spray™ usage sequence customized to each drug posology

With a growing tendency of self-administration as well as digitalisation, Safe’n’Spray is designed as a connected device, linked to e-Nemera Cloud Solution, Nemera’s cloud platform. With a customised development fitting each customer need, it can offer access to patients, healthcare professionals, and pharmaceutical companies for data exploitation. Patients could be able to manage and track their treatment history, whilst healthcare professionals could also follow patients’ treatment management closely and evaluate their conditions with unbiased information.

On the other hand, the pharmaceutical companies may for instance use the statistical analysis generated from the available data. Ultimately, thanks to its innovative concept, key features, and benefits for better chronic treatment management, Safe’n’Spray bagged two awards in PharmaPack 2020 as the “Best Innovation in Drug Delivery Device” and CPHI Festival of Pharma 2020 under the category “Excellence in Pharma Drug Delivery Devices”.

OUR WAY OF WORKING: DEVELOPING PRODUCTS WITH PATIENTS IN MIND As mentioned earlier, in order to treat a specific condition, it is important to reach the right targeted areas using the right device for drug deposition, which is adapted for a certain patient population. This with both performance and usability perspectives in mind.

Therefore, it is important to understand the patient journey from the beginning of the device concept to correctly address their painpoints to answer their needs.

As a world-leading drug device combination solutions specialist, Nemera’s purpose of putting patients first enables the company to design and manufacture devices that maximise treatment efficacy.

Through human factor studies, we ensure that the device features and parameters are set to ease patients’ life therefore improve their quality of life.

Nemera’s expertise within the device development ecosystem for nasal route delivery allows a thorough endto-end understanding of the

combination-product solutions.

Patients are on-board with us since the beginning of the device conception.

Nemera is the utmost holistic partner and helps its customers succeed in the sprint to market.

From early device strategy to state-of-the-art manufacturing, Nemera is committed to the highest quality standards. Agile and open-minded, Nemera works with its customers as partners. Together, they go the extra mile to fulfill their mission.

Authors: AUDREY CHANDRA - Category project manager at Nemera PASCALE FARJAS Global category manager for the ENT (ear, nose, and throat) segment at Nemera

* Safe’n’Spray is a registered trademark by Nemera REFERENCES 1) “Opioid overdose. Who.int.

2021” 2) CDC WONDER (2020).

National Center on Health Statistics

The dynamic number of pipelines via the nasal route for systemic or nose-to-brain applications has grown over the years.

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BIOPHARMA

Frankenbodies: How (mad) scientists are bringing new treatments to life

O

ver the past 35 years, biologic therapeutics have revolutionised the way we treat disease.

Monoclonal antibodies (standard mAbs) have predominated in recent years as therapies for treating cancers and autoimmune diseases.

While there are many more applications where mAbs can excel, researchers are finding better, smarter ways to expand beyond the limitations of these biologics. Intelligently designed antibody variants often referred to as “Frankenbodies” such as bi-specific and multi-specific mAbs, bi-specific T-cell engagers (BiTEs), peptibodies and nanobodies are showing promise.

HIGHER PERFORMANCE ALTERNATIVES Because of monospecific binding sites, standard mAbs can only interact with a single target on the cell surface. Their large size also hinders access to solid tissues and prevents them from crossing the bloodbrain barrier. Frankenbodies are designed to overcome these limitations by including multiple binding sites and/ or using specific fragments of conventional antibodies to provide greater in vivo stability, access to more targets and greater efficacy via multiple target binding. For example, one alternative to standard mAbs in cancer immunotherapy

has been CAR T-cell therapies.

However, multi-specific antibodies may provide a bigger advantage by being able to engage two or more antigens at once.

MERGING EXISTING TECHNOLOGIES Many of these new, more specific treatments are being generated by merging various components of existing biologic structures. These mAb variants can be divided into two major classes: immunoglobulin (IgG)like and non-IgG-like.

IgG-like Frankenbodies include bi- and tri-specific antibodies, antibody-drug conjugates (ADCs), Fc-fusion proteins and more exotic types such as dual variable domain IgGs. They have at least one Fc region up to three Fab regions for binding multiple targets.

Non-IgG-like molecules do not have an Fc region. They include small fusion proteins, referred to as single-chain variable fragments (scFvs) or peptibodies, nanobodies, BiTEs, bi- and tri-specific killer-cell engagers (BiKes/TriKEs), and antibody fragments (Fab, F(ab)2).

GREATER ANALYTICAL CHALLENGES When Frankenbodies are manufactured, even the smallest changes in process conditions can impact the

Author: SAHANA MOLLAH - senior manager, Global BioPharma Collaboration & CE Tech Marketing at SCIEX

resulting product structure.

Often many different variants – more than 15 in some cases – of the desired product are obtained in each batch, of which only one or two are therapeutically relevant. In addition, titers can be much lower (10–50%) for multi-specific Frankenbodies produced compared with those for mAbs.

mAbs and Frankenbodies face many similar challenges; however, these challenges are exacerbated for the Frankenbodies. The diversity and greater complexity of Frankenbody structures combined with the production of numerous variants and low titers create significant analytical challenges and thus

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a higher analytical burden, beginning at the clone selection stage through process development to commercial production. It is necessary to distinguish molecules with minor structural differences at low concentrations. Additional sensitivity and separation resolution are therefore essential when developing analytical methods for Frankenbodies.

OPTIMISATION OF TRUSTED METHODS To overcome these challenges, existing trusted methods are being adjusted for Frankenbody assays. Off-the-shelf mAb methods such as capillary

19

electrophoresis (CE) and liquid chromatography-mass spectrometry (LC-MS) are being optimised for the development of effective solutions.

The major challenge is to adjust standard mAb methods for variants during assay development, which requires having the right sample preparation, the right separation method for analysis such as purity testing, and the correct method for glycan sequencing.

For instance, analytical systems that can run multiple characterisations for mAb assays such as CE-SDS (sodium dodecyl sulfate) for

purity/heterogeneity, capillary isoelectric focusing (cIEF) and capillary zone electrophoresis (CZE) for charge heterogeneity and fast glycan analysis for micro heterogeneity, can be very helpful. These methods can be optimised and extended for mAb-variants by increasing the percentage of reagents in the sample, using different reagents, lowering the pH, or changing the temperature and time of the analysis.

Additionally, CE can provide information on the purity and structure (disulfide hinges and chain mismatching).

LC-MS is another technique that is popular for characterisation of standard mAbs and can also be optimised for mAb-variant assays. One such example is the characterisation of multispecifics on the subunit level, using SCIEX’s TripleTOF 6600 LC-MS/MS System with SelexION differential mobility separation (DMS) technology. This technique enables separation of protein subunits and unambiguous characterization of each chain with a single injection and without the need for chromatographic separation, making data collection and analysis simple and reducing the overall time required to complete studies.

NEW ORTHOGONAL METHODS The industry has been working towards alternative orthogonal techniques

(instead of just modified mAb methods) that can address the specific complexity of the variants and impurities in Frankenbodies. For example, in the development and manufacturing of nanobodies, which are approximately 10–15 kDa, intact protein analysis offers the overall picture of the protein product even offering the discovery of features as small as one–two Daltons. Unfortunately, even the ability to discriminate mass differences as small as one– two Daltons is insufficient for unambiguous identification of the actual molecular feature.

Hyphenated techniques such as CE paired with mass spectrometry (CE-MS) can be ideal in these cases. Consider a two-Dalton mass shift, it could be due to a break in a disulfide bond or two deamidations.

Charge variant separation via CE followed by online MS analysis can easily and unambiguously differentiate these isobaric modifications.

As advances in the space continue, companies are focused on collaborating across the biopharma, academia, and analytical sectors to find the best ways forward. These collaborations are crucial to continue innovating new applications and workflows to overcome analytical gaps and bring life-changing drugs to market faster.

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BIOPHARMA

EPM learns about a new partnership set up to stimulate investment in the North East’s bioscience sector. purpose to give every invention the best chance of becoming a successfully marketed product.

The Northern BioAccelerator Partnership (NBioP) is a close collaboration between CPI, Fujifilm and Teesside University – through its National Horizon Centre – with a focus on promoting the North East – specifically Tees Valley and Darlington Central Park – as a key area for companies to access research, training and manufacturing excellence for bioprocessing in the UK.

Quick questions with SOPHIE WALTON, Group Director of Academic Engagement, CPI Could you introduce CPI and the Northern BioAccelerator Partnership (NBioP) please?

CPI is a UK-based technology innovation centre and is one of the founding members of the High Value Manufacturing Catapult. We have a vision for the creation of a healthier society, a cleaner environment and a more prosperous UK economy; and a

The North East has a long history of industrial, chemical and biological manufacturing. While there are other areas of the UK that focus on certain aspects of biotechnology and life sciences research and development, we believe that this partnership is located where these more applied and industry-focused skill sets can be leveraged. This is being accomplished through the specialist skills provision and research taking place at the National Horizon Centre, through innovation and development at CPI, and development and manufacturing at Fujifilm.

Through this partnership we have ambitions to generate significant inward investment, creating and augmenting a strong bioscience cluster in the North East, ultimately accelerating economic growth in the Tees Valley and beyond.

What are the reasons behind the decision to partner with Fujifilm and Teesside University?

The partners have a long history of working together on individual technology-based projects and programmes. We knew the strength of Fujifilm as an ambitious and innovative global biologics manufacturer. Similarly, we understood Teesside University’s

ambitious plans for the National Horizon Centre at Darlington Central Park, providing industryspecific expertise, training and workforce development in bioprocessing. Combined with CPI’s leadership in biologics innovation and its ability to create powerful public and private partnerships, this seemed to lead naturally to the creation of a long-term partnership with broad, ambitious and strategic goals.

Do you think the North East is an unexplored region in terms of its potential for life sciences and pharma?

I think that the North East has a unique offering for bioprocessing and bio-pharma. The strong industrial heritage, particularly

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within large-scale chemical and biochemical manufacturing (bioreactors, fermentation, etc.), gives the people and organisations here a different perspective when compared to many other areas of the UK. I think the expertise here is very pragmatic and applied, used to develop processes and products that can be readily and rapidly scaled up and manufactured, with experience spotting potential pitfalls and technology challenges early in development.

Within the North East there is already a strong bioscience cluster to tap into. In addition, good regional networks – supported by organisations such as NEPIC – can drive collaborations, helping to deliver new technology

through to manufacturing. A range of different spaces are readily available for companies to expand into, dependent on an individual company’s requirements. The area is also surprisingly well connected, with good road links and direct trains to London in two and a half hours. Teesside airport is now offering new flights and destinations, whilst Newcastle and Leeds Bradford airports are also only one to two hours away.

What does CPI hope to achieve through the NBioP? The NBioP helps CPI to continue strengthening its relationships with the partners themselves, helping to leverage the capabilities of the founders in support of thirdparty companies and SMEs

that we, in turn, support. It also helps us to highlight our own strengths and offerings to the region, which can enable us to find new regional and national partnerships and opportunities.

The new bioscience ecosystem around Darlington Central Park can increase the number of innovative SMEs calling the region home and accessing support from the partnership.

Ultimately, this can help deliver our own ambitions of supporting job creation and a more prosperous economy within the Tees Valley, benefitting the region, and the UK life science industry as a whole.

The North East has a strong academic presence within life sciences. How important is the link between academia and industry so graduates can find work within their field?

The link between academia and industry is critical in several ways. In terms of graduates, it can help them find industry positions more easily, and work experience with companies can introduce them to different jobs within the life sciences industry. In addition, close ties between academic providers and industry – such as the NBioP – help ensure that graduate courses are kept relevant. This can be done through both opportunities for placements and industry input to course content, creating students that are more ‘industry-ready’. Schemes like Innovate UK’s Knowledge

21 Transfer Partnerships can also help new graduates find positions between industry and academia, supporting their education while sharing expertise with companies.

Links between academia and industry are also critical to ensure research is driven by real industrial challenges and that the research performed can be easily translated and scaled directly into manufacturing.

What are you excited about the most from the NBioP? The opportunity to realise significant inward investment for the Tees Valley, which will help to support our region and create opportunities for our people, is one of the most exciting parts of this partnership. I can see how the three founding organisations, collaborating across interrelated areas such as skills, technology development and economic growth, have the potential to drive significant investment from both the private and public sector. I also love seeing small companies and micro-SMEs being supported on their journeys, which we hope we will be able to do more of through this partnership. Hopefully in a few years’ time we will see some of these SMEs move their ideas and technologies into manufacturing on Teesside, bringing exciting new jobs and opportunities to the region.

The North East has a long history of industrial, chemical and biological manufacturing.

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DRUG DELIVERY

Caring THROUGH A cross-examination of the connected drug delivery device industry.

T Author: GEORGE I’ONS - head of Product Strategy and Insights at Owen Mumford Pharmaceutical Services

he current health crisis highlights the value of migrating some healthcare procedures beyond the confines of the hospital. In some areas, this is already well-developed, notably remote patient monitoring for chronic respiratory conditions and diabetes. Other areas are now playing catch-up; according to our own analysis, the global market for connected drug delivery devices (injectables and inhalation devices specifically) is projected to reach $706 million by 2025 – that is to say a CAGR of over 25% from its $225 million value in 2020. This projected pace will however depend on a number of key stakeholders and their attitudes towards the development and adoption of these devices. Given the potential of increased digitalisation in improving the efficiency of health services, a careful examination of the healthcare landscape and the factors driving new forms of patient monitoring is constructive.

BENEFITS FOR KEY STAKEHOLDERS Connected drug delivery devices use embedded electronics and sensors to report on information such as the time, volume and site of the dosage self-administered by the patient, allowing clinicians to remotely monitor adherence. In cases where a patient’s response to therapy and eventual outcomes are not as anticipated, this may make the clinician's job much easier by providing them with some of the necessary data to understand why. By potentially helping to deliver better health outcomes for their patients, increased connectivity may play a part in alleviating some of the

pressure on clinicians, especially as health services globally are suffering from staff shortages.

For payers, a decreased reliance on healthcare services, especially in the acute care sector, lends itself to a reduction in overall healthcare costs. Using new data channels provided by connected devices, patients can be monitored without having to visit the hospital or clinic as often. Correct dosage and administration timing and frequency are essential factors to the success of a treatment, and connected devices may help patients comply with the prescribed regime through reminders and adherence trackers as well as providing training, information and support.

Ultimately, this increases the chances of a treatment being successful and may reduce escalation to further interventions in the long-term, as well as the burden on healthcare services.

Many increasingly prescribed injectable biological therapies are costly, so the opportunity to reduce waste is also welcomed by pharmaceutical companies and those payors providing reimbursement. A growing number of pharmaceutical companies offer wider services in addition to supplying the drug itself, such as training and support, and these can now extend to adherence monitoring and benefit tracking.

Connected devices will most likely play a key role in the delivery of these services and in demonstrating value for money as well as providing patient benefits.

From the perspective of the patient, being able to step away from the typical clinical setting

and take parts of their medication regime into their own hands makes the day-to-day of living with a chronic illness more manageable and easier to assimilate with their personal lives. More than that, patients are given access to their own treatment data which may help to solidify their understanding of their own condition. Training can also be provided to patients through connected technologies which offer guidance and information on best practice

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ECTIVITY for self-injection as well as additional support for their condition. Connectivity also means that treatments may be able to be tailored to patient indicators, potentially making them more effective. The amount of information that is shared with the patient and the frequency of notifications are important considerations in the development of these products and may impact patient adherence both positively

and negatively if not properly understood. In fact, ease-of-use and patient comfort will need to be prioritised from the very beginning of the device design process. Manufacturers must carry out mandatory Human Factors (HF) studies with that objective: to mitigate any risks and improve product usability.

Ultimately, devices are no longer to be designed solely for healthcare professionals and developers must instead

keep the variety of patient types and demographics in mind throughout the design process.

ADHERING TO REGULATORY REQUIREMENTS AND SUSTAINABILITY OBJECTIVES A hurdle in the development of connected devices and the aim of improving adherence is the requirement from insurers and payors that they produce measurable outcomes. This may turn out to be challenging to prove without first deploying the products on the market.

Device manufacturers will also need to ensure that devices are interoperable with standard clinical information systems and are robustly protected from the risk of data breaches.

This will require collaboration between regulators and market players if data security is to be guaranteed. Finally, device designers will need to consider the sustainability of the connected devices they are bringing to the market. As electronic components often contain rare-earth metals which are largely not recycled properly, making disposable connected devices may have a damaging impact and would be costly to produce.

With environmental concerns high on the world agenda, finding a sustainable hybrid approach will be crucial in the development of connected drug delivery devices. The ability to reuse parts of the device would be a good starting point.

For instance, some designs may opt to offer disposable injection devices but coupled with a reusable connected ‘shell’ section containing the electronic components.

As the world continues its battle with Covid-19, the potential efficiency benefits of connected drug delivery devices for healthcare systems is more apparent than ever. These benefits should help unite stakeholders to collaborate and overcome any hurdles together. The specific benefits for each involved party are numerous, and challenges such as environmental concerns, data security issues and regulatory considerations will be easier to tackle collectively.

The growth of the connected device industry is inevitable, but the extent of its largescale deployment and the success of this will depend on collaboration between parties.

Increased connectivity may play a part in alleviating some of the pressure on clinicians, especially as health services globally are suffering from staff shortages.

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DRUG DELIVERY

EPM speaks to Lonza to learn how to ensure good bioavailability across compounds and which therapy areas are benefitting from targeted drug delivery.

bulk-sparing methodologies that allow each technology to be evaluated in vitro. This approach is based on learnings gained from screening thousands of molecules and progressing hundreds to clinical development or commercial production.

Quick questions with DAN DOBRY, director, head of Commercial Development, Small Molecule Drug Product at Lonza How do you ensure good bioavailability across such a differing range of compounds in pharma?

The key to improving bioavailability across a range of compounds with differing physical-chemical properties is to strategically choose the best technology for each compound. At Lonza, we use a science-based approach to determine the mechanism of poor bioavailability along with

What are the most common causes of poor bioavailability?

The primary causes of poor bioavailability are encompassed in the biopharmaceutical classification system quadrant II (BCS II). The two most common reasons for poor bioavailability for compounds in this quadrant are slow dissolution rate (DCS IIa) and low solubility (DCS IIb). These two causes constitute around 50%-70% of poorly bioavailable compounds.

Additionally, some 10%-20% of the compounds are poorly permeable.

These compounds fall into either BCS Class III (high solubility/low permeability) or BCS Class IV (low solubility/low permeability).

What technologies are pharma companies using to improve bioavailability?

There are myriad technologies that have been developed for improving bioavailability. However, the three most common technologies used for commercially-viable compounds are particle size reduction (jet milling), lipidbased formulations (SEDDs) and amorphous solid dispersions (ASDs). ASD formulations are manufactured using either spray drying or hot-melt extrusion depending on physical-chemical properties. Jet milling/particle size reduction increases bioavailability of compounds that have slow

dissolution rates while keeping the compound in the crystalline state.

In contrast, SEDD formulations enhance solubility by dissolving the compound in a lipid solution or suspension encapsulated in a capsule or softgel format.

The SEDD then forms into nanometer-sized droplets when the drug is administered to the patient. ASDs trap the compound in an amorphous form that is more readily dissolved than the crystalline state, and also often provides sustained solubility via use of colloidal polymers or surfactants.

How ineffective can a drug become when the compound displays low solubility, bioavailability or dissolution?

A compound that has a slow dissolution rate or poor solubility can become completely ineffective if absorption in the gut is minimal.

Most often the consequence is high variability, especially

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lipid multiparticulate (LMP) for taste-masking, the patient’s needs are always a priority.

for therapies with a narrow therapeutic window. This outcome can lead to failed efficacy in some patients or requirements for restrictive labels such as foods or antacid therapies. In a worst-case scenario, a poorly bioavailable/ unabsorbed drug can have a negative impact on the patient due to off-target toxicities of the unabsorbed drug in the gut.

In terms of targeted drug delivery which disease areas are benefitting the most from this method?

Oncology and inflammation are two disease areas that are benefitting from targeted delivery. This is primarily because compounds being developed are often not specific to a single biological target in the oncology or inflammatory cascades, leading to potential off-target activity.

Targeted delivery directs the

drug to the desired biological target, increasing its efficacy.

In addition, local targeting such as inhaled delivery by particle engineering, or lower gastrointestinal (GI) targeting with modified release formulations can ensure the drug is physically placed at the desired point of action.

Do the products used for targeted drug delivery or to increase bioavailability affect the way patients take their drugs?

Generally, methods for increasing bioavailability or targeting do not change the way patients take their drugs.

In pharma drug delivery, the oral route remains the preferred route of administration.

Amorphous solid dispersions, which are used in over 25 commercial products, are generally delivered via the oral route as a tablet or in a capsule.

More so, what considerations does Lonza take about the patient when developing new products or methods to improve drug delivery?

Patient-centricity is central to Lonza’s approach in developing and deploying drug delivery technologies. It is one of the first factors accounted for when developing the target product profile (TPP) for a new medicine. Whether it is minimising tablet size by using our high-loaded dosage form format for amorphous solid dispersions (ASD) or a coated

Biologics are currently limited to intravenous delivery only due to the sensitive nature of the gastrointestinal (GI) area. Do you anticipate this changing towards oral routes as therapies progress?

Biologics, due to their large size/high molecular weight, are poorly permeable in the gut and can be readily degraded by the low stomach pH or gut enzymes. While there are a number of ongoing efforts to deliver biologics orally and even a recent product approval (Rybelsus, semiglutide) the current efforts remain plagued by low oral bioavailability, generally in the low single digit range. Other exceptions can be found in local targeting.

Some biologics are intended to act in the lower GI or the lung, enabling potential formulation with oral or inhaled forms.

While it is a noble effort to deliver biologics orally, most biologics will likely remain injectable products for the foreseeable future to maximise cost effectiveness and patient compliance.

Oncology and inflammation are two disease areas that are benefitting from targeted delivery.

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DRUG DELIVERY

MADE TO MEASURE The advances being made to reduce medical error with improved infusion drug delivery.

I Author: DR TRACY BROWN, head of Life Sciences and Healthcare at TÜV SÜD National Engineering Laboratory

nfusion is the most common form of therapy in a clinical setting, but its widespread use in critical healthcare settings means errors are often made. Whilst the monitoring of a patient’s vital signs can indicate potential dosing errors, they cannot be relied upon as they only indicate the error after it has occurred, and it is too late.

patient groups, e.g. neonates.

Techniques will be developed for generating and measuring the response or delay time of these devices and examining the influence of fast-changing flow rates and innovative approaches to make these challenging measurements, for example, optical methods.

Growing focus on personalised healthcare brings with it a commensurate impetus for greater metrological understanding.

Precision medicine is expected to change fundamentally the delivery of medical treatments and is predicated on the idea that different sizes of dose can be delivered accurately. The journey towards therapeutic and prophylactic interventions tailored to individuals that take into account their genetic blueprint, environment and lifestyle is underway. Intrinsically, this will require enhanced measurement capability to ensure the accurate dosing of infusions containing novel complex therapeutics designed to treat niche illnesses.

The research programme will also investigate how mixtures of liquids with different viscosities mix and flow in multi-infusion systems and how this affects the therapeutic drug concentration over the course of an infusion. It is intended that such rigorous metrology will prevent harm to patients arising from inappropriate mixing such as therapeutic failure or toxicity.

We are part of a consortium of European National Measurement and Designated Institutes, universities and manufacturers that is conducting a three-year project aimed at improving dosing accuracy and enabling the traceable measurement of volume, flow and pressure of drug delivery devices used in infusion therapy.

The research project will develop traceable calibration procedures for medical flow devices such as infusion pumps, down to very challenging low flow rates in the nanolitre (nL) per minute range necessary for infusions in certain

The primary infusion devices used for administration have a significant impact on metrology.

In the case of intravenous administration, for example, various devices with different purposes may be used (syringe pumps, peristaltic pumps, insulin pumps). Each method must be capable of delivering traceable, accurate and reproducible metered doses of drug.

Understanding the sources of, and minimising, measurement uncertainties attributable to the operation of each device is key to achieving this and is a fundamental aspect of the work being undertaken in this multi-partner project where uncertainties of one to two per cent are being targeted.

The Coronavirus pandemic has created unprecedented conditions and challenges for hospitals - bringing accurate, traceable flow measurement for drug delivery more acutely into

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focus. These extraordinary times have seen new measures being implemented in some healthcare settings, including the use of drug delivery devices outside the patient’s room and the postponement of maintenance and calibration schedules. In response to these changes, the consortium published a document highlighting specific metrological and clinical physics guidance on newly-adopted Covid-19-related measures implemented in some European hospitals for patients receiving drug therapies through infusion pumps. These provide clinicians and nursing staff with practical solutions which can be implemented easily to safeguard confidence in the use of these drug delivery devices during these challenging times. This Metrology for Drug Delivery project has received funding from the EMPIR programme co-financed by the Participating States and from

the European Union’s Horizon 2020 research and innovation programme.

Organ On A Chip (OOAC) microfluidic devices are evolving rapidly and present exciting opportunities across the drug discovery pipeline from candidate identification to efficacy, toxicity and safety.

These microscale in vitro human physiological models are efficient and cost-effective with their added potential to reduce the use of animal models offering an ethical alternative to conventional pre-clinical drug discovery approaches.

Moreover, OOAC technology can be used as implantable drug delivery devices capable of producing continuous, noncontinuous or pulsatile delivery patterns by less painful means.

Fluid flow measurement has an integral role to play in the translational journey of these novel microfluidic applications from bench to clinic. For

example, the interconnection by microfluidic flow of single organ models enabling the study of biological interactions between organs.

The burgeoning adoption of technologies such as OOAC in healthcare will necessitate the development of a metrological infrastructure to validate their accuracy and reproducibility.

Accordingly, a further aim of the collaborative European metrology project is the development of a proof-ofconcept microfluidic microchip flow pump for use as a moveable traceable transfer standard for the calibration of drug delivery devices used in drug discovery and OOAC for ultra-low flow rates (below 100 nL/min).

Regulatory compliance underpins every innovation or innovative methodology within the medical device sector; an obligation which is set to increase when the new Medical Devices Regulation (MDR 2017/745) and In Vitro Diagnostic Regulation (IVDR 2017/746) come into full effect in May 2021 and May 2022, respectively. Conformity leads to CE marking of devices enabling them to be sold within the EU. Additionally, with the UK having left the EU as of 1 January this year, device manufacturers will also be required to comply with the new UK Conformity Assessment

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(UKCA) from July 2023 if they want to sell their device to the UK market.

The move towards greater regulation and increased innovation and complexity of drug infusion systems will inevitably see metrology form an essential part of the regulatory approval process for these medical devices. Not only will this entail the development of existing standards, it will also require the creation of new ones to address their diversity and increasing complexity.

Whilst at an embryonic stage, microfluidic technology is progressing apace. In parallel, work is needed to define measurement standards for microfluidic devices covering areas such as the control and quantification of fluid flows.

Developing microfluidics measurement standards will facilitate their uptake across the pharmaceutical and health sectors by providing the necessary accuracy and reliability in their manufacture and performance.

The advantages of microfluidic devices as drug discovery and delivery platforms cannot be underestimated; they are quick, inexpensive, portable and effective. Developing a robust flow metrology infrastructure to validate their quality, reduce dosing errors and ensure efficacy and safety will be key to unlocking their potential.

Precision medicine is expected to change fundamentally the delivery of medical treatments.

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PACKAGING

PROTECTING THE PAYLOAD How tracking technologies support supply chain monitoring ensuring the protection of pharma payloads.

S Author: ADAM TETZ - director of Worldwide Marketing for Peli BioThermal

ophisticated supply chain monitoring advances are increasingly being deployed to ensure the protection of pharmaceutical payloads in transit.

Remote and real time tracking technologies help track and trace high-value pharma shipments, delivering cold chain compliance.

These new advanced software systems and the integration of information technologies (IT) within the pharma supply chain are increasingly playing a vital part in protecting pharmaceutical shipments, helping to combat counterfeiting of drugs on route to their designated destinations.

Maintaining end-to-end pharma supply chain integrity is critical to mitigate risks within the pharmalogistics cold chain and better ensure the safe and secure transportation of health-giving and life-saving pharmaceutical products.

Transparency of the status of the shipment is an increasing demand from the lane owners for pharmaceutical shipments.

Transparency of location, transparency of temperature history and transparency of circumstance of each access to the payload space are all of great interest.

The global life sciences industry faces several complex challenges, including protecting the integrity of their temperature-sensitive high-value payloads during transportation. This must be done while mitigating costs, managing and tracking the assets within a complex cold chain closed loop logistics system, meeting stringent global regulatory standards and

navigating complicated global shipping lanes and unforeseen challenges.

With pharmaceutical companies developing ever more complex and temperature sensitive drugs, there’s growing demand to integrate IT solutions within the supply chain, balanced alongside the established requirements of providing improved packaging performance and efficiency within cold chain logistics. It’s vital to ensure there’s a secure, compliant cold chain from deployment of shipments from the packaging factory line, to the distribution center and, finally, to last mile delivery.

Innovation, IT integration and new technologies to enhance supply chain monitoring and remote tracking are proving pivotal to support adherence to GDP (Good Distribution Practice) regulations within cold chain logistics. These technologies are crucial in addition to the continuous evolution of smart temperature controlled packaging protecting pharmaceutical payloads globally.

The industry is also seeing a growing trend to deploy reusable systems coupled with asset management SaaS (software as a service) and reaping the associated benefits. These systems can automatically collect and analyse data from company smart data logger outputs. These monitoring devices are increasingly being used in cold chain as they become more affordable and thus more accessible to pharmaceutical companies. These lane owners are excited about the prospect of

offsetting the costs of these new technologies with savings, based on reduction of lost drug products and fine tuning distribution models based on efficiencies proven by data from the smart devices.

A key development includes real time monitoring of payloads, via smart loggers and devices which are interconnected to the Internet of Things (IoT), making it possible to access and assess the condition of the payload at anywhere across its journey.

Being alerted about a temperature excursion within the shipped package before it reaches destination allows preventive or corrective supply chain actions earlier than would have otherwise been possible.

Real time monitoring devices can be helpful to get precise data on a payload, at its exact location, but they have downsides as well, such as size, cost and limited battery life due to their reliance on two way communication technology, essentially a mobile phone.

Another class of smart devices is also used to track location and temperature throughout the journey when exact location and condition is not needed. These just in time (JIT) devices often use other methods of communication when passing through a physical IoT gate or providing a download of data via Bluetooth, QR code, bar code, USB connection or others.

This information can be assessed at the end of a journey for logged temperature throughout the trip, as well as location, number of opens of the payload space and more.

29

ANALYSIS

Depending on the location, condition and temperature data needed by shipping lane or even individual shipment, real time or JIT devices can be an ideal fit when weighing urgency of data need versus cost and reduction in payload size to accommodate the device.

Data retrieved and shared can help the pharmaceutical manufacturers make more informed choices on the most appropriate packaging systems to deploy depending on specific shipping lanes and routes their

payload needs to navigate.

Increasingly, both passive and active bulk systems are incorporating IoT devices to track the temperature, location and other data throughout the course of the trip.

Issues can arise for the temperature in the payload space, if the shipper is opened during a customs inspection or tampered with, the IoT device can track or warn when the shipper has been opened, for how long and if there is a risk

to the payload’s temperature requirements.

Alternatively, IoT device devices can be attached to a specialised container to ship a pallet of products providing an isolated monitoring option to pick up data, which can be saved to the Cloud via Bluetooth or RadioFrequency Identification (RFID).

If payloads are intercepted, lost or get delayed en-route, the pharmaceutical company can take steps to intervene and recharge or replace coolants,

so the package or the bulk system gets delivered before expected temperature duration is exhausted. This presents a strong case for using IoT devices and their supporting software and technology to mitigate a temperature excursion caused by a delay.

Any deviations in temperature, beyond the range specific pharmaceutical products are required to be stored and shipped at, could have a devastating effect on the payload, damaging the container’s contents and impacting the efficacy of the products being transported for use by patients.

Therefore, temperature monitoring is becoming more commonplace, due to the cost of IoT devices and the capture of the data becoming both affordable and accessible.

Packaging companies are frequently utilising advanced asset management software systems, which are in place specifically to ensure drug products are shipped to the right place, at the right time and, critically, arrive in the right condition.

The use of and sharing of that data between packaging providers, logistics providers and pharma companies themselves is an area of increasing interest enabling the development of better, more effective solutions to meet the challenges that are now better understood through that data.

Data retrieved and shared can help the pharmaceutical manufacturers make more informed choices.

30

www.epmmagazine.com

Talking points

OUTSIDE EPM

SUPPLY OF COVID-19 VACCINES BEING ARTIFICIALLY RATIONED, ALLIANCE WARNS UK SIGNS PARTNERSHIP WITH CUREVAC TO TACKLE COVID-19 VARIANTS

T

he UK government has signed a partnership with vaccine manufacturer CureVac in order to rapidly develop new vaccines for Covid-19 variants.

UK expertise on genomics and virus sequencing will be utilised to allow new varieties of vaccines based on messenger RNA technology to be developed quickly against new strains of Covid-19.

The UK has already placed an initial order for 50 million doses of new vaccines, which will be delivered later this year if needed. To date, the government has secured a portfolio of 407 million doses of Covid-19 vaccines. This is in order to vaccinate a population of around 68 million.

The vaccines developed through this partnership will largely be variants based on an existing jab by CureVac which is currently undergoing Phase 3 clinical trials. The development process is similar to the method used to update flu vaccines each year. The new mRNA technology will be used to and update vaccines that can be reformulated against variants more quickly than older vaccine technologies.

T

he supply of vaccines is being artificially rationed due to the protection of exclusive rights and monopolies of pharmaceutical companies, the People’s Vaccine Alliance has warned.

The People’s Vaccine Alliance highlights how purchasing agreements between rich countries and the developers of Covid-19 vaccines are resulting in a much lower coverage rate around the world.

Indeed, as of 4 February, a total of 108 million Covid-19 vaccine doses had been administered across 67 countries. However, only 4.4% of these vaccinations have been given in developing countries.

The People's Vaccine Alliance says that the limited supply of approved vaccines means that unless action is taken only one in 10 people will be vaccinated by the end of the year in many developing countries.

The People’s Vaccine Alliance is now urging governments

and the pharmaceutical industry to scale up production of Covid-19 vaccines. The People’s Vaccine Alliance is calling for the removal of artificial barriers, including suspending intellectual property rules, sharing technology and ending monopoly control, so that everyone has access to a vaccine as quickly as possible.

Anna Marriott, Oxfam’s health policy manager said: “People out there would be forgiven for thinking that every major vaccine company is working flat out to vaccinate the world, but this is simply not the case.

We need every company on earth who can make safe and effective vaccines for Covid-19 to be making them right now.

We urgently need to lift the veil of corporate secrecy and instead have open-source vaccines, mass produced by as many vaccine players as possible, including crucially those in developing countries.”

N

eeraj Shah, from the Health Tech Alliance examines how policymakers can truly transform the landscape for medtech innovation post-pandemic.

Make sure to read the full article on www.med-technews.com

BE SURE TO LISTEN TO The MedTalk Podcast returns with new episodes examining the Covid-19 vaccine landscape and what the future of medicines manufacturing looks like in the EU. Subscribe to The MedTalk Podcast on Soundcloud and iTunes.

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