EPM September/October 2020 by EPM Magazine

WHY SAFETY IS KEY IN DRUG DEVELOPMENT

HELPING THE NHS THROUGH LAB AUTOMATION

THE NEXT GENERATION OF MEDICINES

September/October 2020

SPI Pharma explores the advancements that are helping make drug dosage forms more patient-centric

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Contents Sept/Oct 2020 | Volume 20 Issue 5

REGULARS 5: EDITORâ&#x20AC;&#x2122;S DESK

How political meddling in pharma can harm the industry.

6: A SMALL DOSE

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

10: OPINION

How manufacturing systems can be improved for sustainability purposes in pharma.

14: IN THE NEWS

A short selection of stories from the world of science.

16: COVER STORY

SPI Pharma explores the advancements that are helping make drug dosage forms more patient-centric.

50: TALKING POINTS

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

FEATURES 8: PERSPECTIVE ON PHARMA

Why NHS Trusts must work together to meet the challenges facing their laboratories.

20: APIs/HPAPIs

Keeping operators safe from harmful compounds and the advancements driving new medicines.

24: ASEPTIC PROCESSING

Challenges in aseptic processing and why human interactions pose the biggest threat to sterility.

34: LAB AUTOMATION

How lab automation is helping streamline workflows and improve drug discovery.

QUALITY

LIFE SCIENCES LIFE INSPIRED, QUALITY DRIVEN

RELIABILITY

SGS Life Sciences' integrated network of laboratories offers extensive experience in novel vaccines, providing biosafety, biologics characterization and bioanalytical testing solutions to support the fight against COVID-19.

Our biosafety testing laboratory provides testing support for the biosafety and characterization of raw materials, cell bank and virus seeds for vaccines, cell and gene therapies, monoclonal antibodies and other recombinant protein based biological medicines, including a vaccine testing solution for coronavirus.

EXPERTISE

We provide established expertise and resources for all aspects of biopharmaceuticals characterization – from physico-chemical properties, to primary, secondary, and tertiary structures, as well as aggregation. Our characterization services include antibody testing and batch release testing for large number of doses. Our GLP/GCP compliant laboratories offer the expertise to both develop assays from scratch (including LC-MS/MS, immunoassays and cell-based assays). We support large-scale routine sample analyses, from regulatory pre-clinical (toxicology) to early and late clinical studies (Phase I to IV).

www.sgs.com/lifescience

www.sgs.com/LinkedIn-Life

5 HEAD OFFICE Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE.

POLITICAL SCIENTISTS P

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ULTIMATELY, IT’S SOCIETY WHO LOSES WHEN DIVIDES ARE CAUSED BY POLITICAL FEARMONGERING AND SCIENTIFIC ADVICE ISN’T TAKEN SERIOUSLY.

resident Trump’s recent rebuke of the FDA has solidified a growing consensus surrounding the public’s trust or rather mistrust of scientific bodies and the advice offered. It’s a sentiment that’s been growing for a number of years now as false information related to the likes of vaccines and viruses spread like wildfire across social media. Now, with Trump claiming the agency is out to hurt his re-election chances and pushing the FDA towards potentially dangerous Emergency Use Authorisations (EUAs), it’s clear that the president is completely disregarding the agency’s role of protecting public health in the US. This transition of political scapegoating can only be detrimental to how scientific advice is viewed by members of the public. Consider the outrage of those against wearing a mask to stop the spread of Covid-19 and the

EDITOR’S DESK parallel of Trump’s disregard of the pandemic. It doesn’t matter that at the start of the year Trump downplayed the threat of Covid-19, because he’ll take credit for any progress made towards a vaccine or treatment, or simply blame China. In some ways, the president’s political machinations match the rhetoric of our government

in the UK and its approach to Covid-19. In May, prime minister Boris Johnson said that the UK would have a ‘world beating’ track and trace system, a statement we can now clarify as false, given that government only just released a second, updated app in August, following a first failed attempt. We continuously see ministers like Matt Hancock get put on the backfoot in interviews concerning Covid-19, blustering on about the strides we’ve made, when cases are on the rise and stories of track and trace failures are rife. Thankfully, pharma has stepped up in regard to safety protocols, with nine major firms including Pfizer, AstraZeneca and GSK, pledging to uphold the integrity of scientific progress as they work towards an approval for a Covid-19 vaccine. The pledge affirms pharma’s commitment to making sure vaccines are made safely, through rigorous testing and clinical studies. The companies hope that the pledge ensures the public are confident in the industry’s ability to safely release a Covid-19 vaccine. It also flies in the face of Trump’s scientific overreach and his pressuring of the industry to release promising data for a Covid-19 vaccine. Yes, we’d all like to see a vaccine released so our lives can return to normal, but not at the expense of public safety. Ultimately, it’s society who loses when divides are caused by political fearmongering and scientific advice isn’t taken seriously.

A small dose Morphine capsules could give sense of freedom to chronic breathlessness patients

ow-dose, extended release morphine capsules may be able to help people with chronic breathlessness get back in the driver’s seat, according to new research from Flinders University.

SGS enrols ﬁrst patient into Covid-19 trial

GS has enrolled the first patient into its clinical trial designed to examine the safety, tolerability and efficacy of a potential drug candidate for people suffering with Covid-19 related respiratory failure. The testing laboratory was selected by French biotech Biophytis to conduct a clinical trial into the drug candidate Sarconeos (BIO101). The trial will recruit around 50 patients who have tested positive for Covid-19, as well as having developed severe respiratory symptoms in the previous seven days. They must have obvious Covid-19 symptoms – e.g. pneumonia and oxygen distress – but cannot have been reliant on high-flow oxygen use or assisted ventilation during the previous 28days.

Steven Thys, SGS’ director of Global Clinical Operations said: “As the whole world faces up to the challenge of finding effective treatments for Covid-19 we are pleased to announce the first patient has been successfully enrolled into the COVA Study. In the coming weeks, we may see more patients entering the study as more sites from different countries will join the study.” “Biophytis’ decision to choose SGS as its partner in the COVA Study is testament to our considerable expertise as a contract research organisation with proficiency in the field of infectious diseases. Together, we have worked intensively to set up this study in a remarkably efficient timeframe.”

Australia has become the first country in the world to approve regular, low-dose, sustained-release morphine capsules for the treatment of chronic breathlessness. A team at Flinders University connected to the Palliative Care Clinical Studies Collaborative (PaCCSC) interviewed chronic breathlessness patients and their caregivers to learn what activities they could pursue if their condition was better controlled.

A paper released by the researchers supports the use of regular, low-dose, sustainedrelease morphine to help people with chronic breathlessness perform tasks such as driving. The research found that the introduction of the capsules had no self-reported impact on driving. However, the team states that further work in regard to safety is still being conducted. The research could benefit the 300,000 people across Australia who suffer from the condition – especially the 75,000 who are housebound and limited in their daily activities. “Driving is a particularly valued part of most people’s lives and

helps to maintain a sense of normality and independence when there are lots of losses as people experience a life-limiting illness,” says professor David Currow, who leads PaCCSC. “Any therapy that could reduce the sensation of chronic breathlessness safely is beneficial in optimising such things as driving and will be very beneficial to these patients.” “As the population ages, more people will experience chronic breathlessness as a result of emphysema, heart failure and cancer. Finding ways to reduce breathlessness will help to reduce suffering across our community,” he says.

most inno Switzerla

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Liquid biopsy company raises funds for cancer detection technology

iquid biopsy company Mursla has raised over £400,000 to help it finalise technology that could detect cancer signatures in a much less invasive way for patients.

NORTH EAST BIOTECH AWARDED FUNDING FOR CELL TRANSPORT PROJECT 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

orth East-based biotechnology company Atelerix has been awarded funding to develop room temperature solutions for shipping therapeutic cells. The company was awarded funding under the UK Innovation and Science Seed Fund (UKI2S) Accelerator Programme from Innovate UK. Atelerix will put the funding towards its “BloodReady Project”, which is exploring scalable methods of cell preservation, transport and re-presentation for patient administration to offer cell therapy developers and manufacturers flexibility in workflows and remove the need for expedited shipments of frozen packages. Living therapies are short-lived outside

of their natural environments and whilst they can be frozen for storage, this can reduce the viability and potency of the cells when thawed or injected into the patients. More so, those that cannot be frozen often require complicated and expensive logistics to ensure their delivery to the hospital. Atelerix has developed a method that encapsulates cells in alginate gel for storing and transporting cells at room temperature. The company hopes this can help preserve and extend their functional viability and potency. The company has worked on small-scale research projects that have shown the technology to be effective with a variety of cell types. Atelerix is now looking to scale these

methods to enable larger volumes of cells to be safely transported while continuing to preserve their viability. Dr Mick McLean, CEO, Atelerix, said: “Cellular therapies offer the possibility of treatments for diseases and conditions that cannot be approached by conventional drugs. New capabilities enabling storage and transport of therapeutic cells are vital if these life-saving treatments are to be made widely available to many more patients.” We believe our innovative human cell preservation technology could be paradigm changing for cold supply logistics, and we are proud to have it recognised by such a highly respected grant funding body.”

The funding will be put towards the company’s ExoPheno platform, which is being developed to detect cancer signatures in plasma from solid tumours via exosomes. Exosomes are vesicles naturally released by all cells, and which usually carry biologically active molecules that can deliver their messages to local or distant targets. Liquid biopsies for cancer look at the nucleic acids or proteins circulating in the blood to determine if a patient has cancer. They are much less invasive than traditional biopsies

which require local anaesthesia, causing discomfort to the patient. Pierre Arsène, founder & CEO, Mursla commented: “The additional funding is a mark of confidence in our strategy from both the UK government and our existing investors in this currently challenging environment. It has allowed us to make up for lost time during lockdown and expedited our move to fully equipped lab space at Cambridge Science Park, which has been an extremely positive step forward. “Our next goal is to find VC partners to help us scale our assays and validate our own exosome-based biomarker panel for liver cancer detection.”

PERSPECTIVE ON PHARMA

Embracing change

athology is involved in 70% of all healthcare diagnoses, meaning pathologists were facing increased pressure to cope with the UK’s growing and ageing population, even before the added stress of the current healthcare crisis. As life expectancy increases and people survive such diseases as cancer, they need support to manage living with chronic conditions. Supporting these patients means more testing for pathology services, meaning that in the future routine testing will constitute an ever-larger proportion of laboratories’ workloads. In order to keep pace with the increase in routine testing, laboratories will need to embrace greater automation provided by the latest technology platforms. These platforms allow laboratories to run several tests simultaneously, generate results faster and increase sample throughput. This in turn can reduce the need for manual work, the risk of errors, client turnaround times and costs. Innovative automation systems for processing lines also mean Penny Pinnock, sales manager – Healthcare & Public Sector for Siemens Financial Services (SFS) discusses why NHS trusts must work together to meet the challenges facing their laboratories.

information and workflows can be integrated and shared across various laboratory facilities, which can help to cope with peak volumes at busy times. Laboratory Information Management Systems (LIMS), for example, allow effective management of samples and associated data to improve lab efficiency through automated workflows, integrated

instruments and managed information. At the same time, the NHS is embracing personalised medicine which moves away from a ‘one size fits all’ approach to care and instead uses diagnostics, genomics, and data analytics to identify the underlying cause of disease. Through the 100,000 Genomes

Project, the NHS is building partnerships with academia and industry to decode the human genome in people with rare diseases and cancer. This aims to help to predict the future development of disease, to make a diagnosis where one has not existed previously and to identify treatments where possible. Advancements in this area have encouraged a

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In order to keep pace with the increase in routine testing, laboratories will need to embrace greater automation provided by the latest technology platforms.

wave of activity in the biotech sector, with several companies now offering a range of complex gene editing services. As personalised medicine becomes more prevalent, specialist genetic and molecular pathology laboratories are being created within the NHS. In order to meet these challenges NHS Trusts are working together to collaborate on laboratory services. In 2016, Lord Carter published an NHS report looking at operational productivity in performance of NHS acute hospitals in England. The report highlights that consolidated pathology organisations are the most efficient in the NHS and points to examples such as the consolidation of Ashford and St Peterâ&#x20AC;&#x2122;s pathology service into the existing joint venture

between Frimley Park and the Royal Surrey. The report notes that by sharing these services the Trusts could offer more training and development opportunities for staff, enhance recruitment and retention, and improve the quality of care through the sharing of clinical expertise. By pooling resources, the Trusts were able to introduce new technologies and take advantage of economies of scale. This shared services approach directly resulted in an annual saving of ÂŁ4m, and a reduction in posts of over 70 whole time equivalent staff members. This is an important example of how new technology can contribute to cost savings and improved outcomes. Despite the obvious advantages of these technological innovations, keeping pace with such advancements requires considerable capital expenditure. In many instances, however, the medical laboratory sector is caught in a predicament where budget limitations are impeding the ability to make essential investments. Medical laboratories sometimes retain outdated technology, as keeping pace with technological advancements requires considerable capital expenditure. This practice can, however, have a considerable negative impact on capability, productivity and efficiency. Harnessing technological innovations can not only result in cost savings, but can also help optimise processes, raise healthcare standards and increase productivity and efficiency of testing services. SFS works with technology vendors to provide cost effective financing solutions for a wide variety of medical technology and equipment, enabling healthcare

9 organisations to access the solutions they need without having to commit precious capital budgets. Intelligent finance solutions allow healthcare organisations to sustainably acquire new technology without having to commit large sums of capital. Such financing solutions spread the cost of the technology over an agreed financing period, with finance payments arranged to align with the expected benefits, such as greater operational efficiency, improved patient outcomes and enhanced access to healthcare services. Additionally, financing arrangements have the potential to incorporate other costs such as installation, as well as introduce the flexibility of future affordable technology upgrades, in line with technology developments. Such tailored financing packages tend to be offered by specialist healthcare financiers that have an in-depth understanding of medical technology and its applications. They understand the profound impact up-to-date equipment and technology can bring to the daily operation and can expertly evaluate any associated risks. They are therefore more inclined and more able to create customised financing packages that fit the specific requirements of each individual organisation. NHS laboratories are facing dual challenges of testing on a larger scale â&#x20AC;&#x201C; a crucial capability to have during this time of unprecedented demand - while also embracing a personalised approach to medicine. Fulfilling these briefs requires investment in technology and this is leading Trusts to pool resources. By combining this joint approach with sustainable financial solutions, Trusts have the best chance of embracing the technology required and reaping the benefits.

Opinion As pharmaceutical manufacturers continue to pursue efforts to reduce their carbon footprint, the need for energy saving solutions is now greater than ever.

WORKING TOWARDS IMPROVING SUSTAINABILITY Author: Angelo Giambrone - business development manager at Spirax Sarco UK The steps pharmaceutial managers can take to improve steam system eﬃciency, maximise process and ﬁnal product quality, and optimise overall productivity.

rom vitamins to vaccines, the pharmaceutical industry is fundamental to enhancing the world’s health by advancing cutting-edge, innovative solutions, and utilities like steam are vital in the manufacturing process. However, with reducing carbon footprint becoming an increasing focus for energy-intensive manufacturing processes, plant owners and operators are striving to reduce energy consumption and wastage. Heating, ventilation and air conditioning (HVAC) systems have always been an integral part of pharmaceutical manufacturing, with organisations such as AstraZeneca and GlaxoSmithKline estimating that HVAC demands accounted for 60-70% of their UK operations’ total energy consumption. In fact, operating costs of industrial HVAC in cleanrooms tend to be between 20 and 100 times larger per square foot than those employed in typical buildings. With such

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OPINION

large numbers in mind, it is understandable that reducing overall consumption and improving efficiency is an area of importance for plant managers and operators. Indeed, there has been considerable focus on ‘demand reduction’, and steam systems represent an interesting area where efficiencies could be identified and implemented. IMPROVING STEAM SYSTEM EFFICIENCY From the boilerhouse through to the distribution system and into the plant room, there are many areas pharmaceutical plant managers and operators can consider when looking to improve system efficiency. Some of these steps can be very simple – for example, ensuring that lagging is of a good standard is crucial in maximising system efficiency. The boilerhouse can present a number of opportunities to reduce fuel consumption. Controlling boiler TDS (Total Dissolved Solids) and using an associated heat recovery system is one such example. Another is to capture thermal energy in the boiler flue gases using an economiser, which is typically used to preheat feedwater going into the boiler. Fuel savings from each can typically be between 3% and 5%, lowering emissions while improving efficiency. ENERGY MONITORING SYSTEMS Another way to improve sustainability is through implementing energy monitoring systems. This technology is invaluable in identifying where services are being used and how much is being consumed, so key stakeholders know where and when they should take action. Those responsible for energy use in the boilerhouse often use burner efficiency to track overall efficiency, but this method does not take into account all aspects of the boiler operation. Factors such as fouled heat transfer surfaces, carryover, radiation losses and excessive boiler blowdown rates all impact on the overall boilerhouse efficiency. Considering just burner efficiency could lead to an overestimation of what the actual boilerhouse efficiency is. Through the use of technology that provides a complete overview of the system, such as Spirax Sarco’s B850 boilerhouse energy monitor, it is possible to measure overall boilerhouse efficiency and then target savings. Cost-

conscious boiler operators can utilise measured inputs from the fuel, feedwater, steam output, condensate return and blowdown to build a true picture, helping to yield energy reductions and increasing overall efficiency. THE IMPORTANCE OF AUDITS Although site engineers may be making progress with the steps detailed above, there will almost certainly be times when they need to engage with specialists outside of their organisation. Knowledge partners can provide expert consultancy and extensive resources to keep steam systems operating at peak performance. A key aspect of this service is the provision of steam system audits, which are a vital tool in identifying energy savings, carbon reduction and achieving best practice in system operation. These audits, which involve an on-site visit from an engineering team, can range from a checkup for a single plant room to benchmarking an entire steam system from the water treatment plant right through to process applications and condensate return. Whilst dealing with the challenges of Covid-19 and social-distancing, it has also been possible to conduct remote survey work with the use of video and images, to identify areas for improvement. TRAINING FOR BEST PRACTICE Optimising the skillset of boilerhouse operatives on site can also assist towards a more sustainable operation. Seeking out training centres that provide accredited courses, such as Spirax Sarco’s UK Steam Technology Centre, not only ensures safe working in line with BG01 (Guidance on Safe Operation of Steam Boilers) but also equips operators with the skills and knowledge required to maximise the efficiency and performance of the steam system. Again, as we adapt to a changing work environment, remote training and webinars are an increasingly effective way of ensuring that personal improvement can continue. To conclude, as pharmaceutical manufacturers continue to pursue efforts to reduce their carbon footprint, the need for energy saving solutions is now greater than ever. With a particular focus on steam systems critical to manufacturing processes, steam users in this sector should be reassured that there are several steps that can be taken to lower emissions whilst improving efficiency.

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14 ALMAC GROUP DONATES £250K TO SUPPORT CHARITIES DURING COVID-19

lmac Group has announced it will donate £250,000 to 33 charities to help support their work during Covid-19. The money is usually spent on the company’s summer “family fun day” at each of its locations, but Almac decided this year the funds would be better used as a charitable contribution. Employees across the company were given a chance to vote on which charities should receive the funds, with up to three charities being selected per each of Almac’s 11 locations across the UK, Europe and Asia. Charities inclduing childhood welfare, hunger and cancer support, were chosen as beneficiaries of the funding. Alan Armstrong, Group CEO, commented: “As a global organisation, Almac’s mission is to advance human health, and we recognise that this extends to supporting the health and wellbeing of our local communities, especially during a global pandemic."

IN THE NEWS

Industry calls on government to protect charity research

n open letter to the prime minister has been signed by over 30 life sciences companies urging the UK government to provide financial support for medical research charities. The open letter, led by the Association of Medical Research Charities (AMRC), urges the government to help stem a predicted £310 million funding shortfall caused by the Covid-19 pandemic. The letter asks the government to match the predicted funding shortfall by committing to a Life Sciences Charity Partnership Fund. The fund would provide three years of matched funding to protect the

contributions medical charities make to the UK’s health and economy. The Covid-19 pandemic has forced medical charities to cut their research spending, with the AMRC predicting it will take over four years for the sector to recover. The letter warns the shortfall in funding will have a knock-on effect on private R&D investment, threatening the government’s aim of increasing R&D expenditure to 2.4% of GDP by 2027. Aisling Burnand MBE, CEO of the Association of Medical Research Charities said: “The UK is fortunate to have a range of vibrant medical research charities that add

to the country’s life sciences R&D funding mix and this sector must be protected in the aftermath of Covid-19. Charity research provides the foundations for commercial research. You cannot support the latter without the former. “By investing in charity-funded research, Government can help medical research charities deliver a better future for patients across the UK, protect the UK’s research skills

and capabilities and contribute to economic growth.” Doris-Ann Williams, chief executive of BIVDA added: “The work of medical research charities is vital for promoting complex, early stage research into drugs, medical devices and IVDs that help to treat and diagnose patients. The Life Sciences Charity Partnership Fund would go a long way to support this vital work in the future."

Did you know?

UK life sciences generates around £74 billion in turnover every year.

Since 2008, charities have invested £14 billion in research in the UK.

Medical charities account for half of publicly funded medical research in the UK.

Almost 250,000 are employed across the life sciences sector in the UK.

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16 TAKING ORALLY DISPERSIBLE DOSAGES TO THE NEXT LEVEL In November 2019, it was heartening to read a New York Times article1 about the efforts of Cipla, an Indian drug manufacturer, to potentially save the lives of children living mostly in Africa. The simple switch of a combination HIV medication ritonavir– lopinavir–abacavir–lamivudine (Quadrimune) dosage into a strawberry-flavored, sprinklestyle form palatable for babies and toddlers, significantly improved compliance versus traditional tablets or an unpleasantly bitter syrup. Over the last 20 years, formulations with a pleasant patient experience have grown into a significant portion of marketed medicines. Adhering to the regimen is as important a factor as the efficacy of a given medication. Development of patient-centric dosage forms addresses the psychological hurdle in the adherence portion of the efficacy equation. Developing a positive consumption experience for the patient includes characteristics such as taste, mouthfeel, tablet robustness, shape, size and presentation. Such properties are critical for patient-centric or more aptly, patient-preferred platforms which encourage drug regimen adherence and reduce missed dosages of less desirable forms. A formulator must be mindful of these properties when designing an Orally Dispersible Dosage form (ODD). Other practical considerations for manufacturing need to be considered; for example, formula stability, compressibility, friability, flow and blending. SPI Pharma, along with academia and industry, have taken the approach of looking at this adherence challenge

COVER STORY

from the patient’s perspective to better understand the psychological obstacles and provide meaningful solutions in the ODD segment. PRODUCTS The increasing demand for patient-preferred forms such as ODTs has led formulators to focus on specially designed excipients, such as co-processed platforms that allow drugs to be formulated quickly, often with only the addition of a lubricant and flavours/sweeteners. SPI Pharma was a pioneer in this area with the introduction of Pharmaburst 500, a product which enables high drug loading in an ODT while retaining fast disintegration. Compendial excipients such as mannitol can also be tailored for these uses. Mannitol has long been associated with ODDs due to its desirable sweetness, smooth

texture, cooling sensation, and inertness. SPI Pharma’s Precious Gems Collection of mannitol allows significantly increased compressibility whilst still retaining its compendial status, pleasing palatability and fast disintegration. The high compressibility of such excipients is critical for direct compression processing, especially when a formula contains a significant portion of a poorly compressible drug. Furthermore, some drugs such as taste-masked versions or multi-particulate systems (MUPS) can cause segregation during processing due to higher particle size and/or density properties. SPI Pharma has addressed this with Mannogem XL Ruby, developing a high compressibility granular mannitol grade with similarly matched properties to overcome such issues.

PHYSIOLOGICAL SIMULATION Traditionally, oral disintegration testing has been measured by the USP Disintegration Test. However, this rather one-dimensional test has little in common with the actual physiological conditions that occur in the mouth after an ODT is administered. There are various methods designed to better simulate such conditions. An example can be found in our recent work with the University of London which outlined a simulated mechanical tongue and oral cavity. The authors concluded that this “model could have the potential to be implemented as a decisionsupport tool during the early stages of the drug design process to improve acceptability and further understand ODT disintegration behavior”2.

SPI Pharma explores the advancements that are helping make drug dosage forms more patient-centric.

Over the last 20 years, formulations with a pleasant patient experience have grown into a signiﬁcant portion of marketed medicines.

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preformulated flowable platform - can simplify development of these formulations. Flowable formulations can also find utility in larger sachet type packs or in applications where the finished formula may be sprinkled onto a foodstuff. This can increase palatability, especially in the case of bitter-tasting drugs, and allow easier administration to children or the elderly. Schematic of oral cavity model (OCM) (side view/sagittal plane). On the left is the initial position and on the right is full compression. This image is adapted from the original image included in citation.

TASTE-MASKING One of the main challenges for any formulation of ODTs is masking unpleasant drug taste. There exist a range of techniques to achieve this. Traditionally, these have consisted of applying barriers or pH-sensitive polymer coatings to drug particles or complexing the drug with other materials. However, these techniques tend to add significant bulk and increase mean particle size which limits the drug loading per dosage and can cause content uniformity issues. To improve this situation, we have developed an innovative aqueous coacervation technique that can add a minimal coating loading (<10%) while retaining good

taste-masking properties. This Actimask technology has been applied successfully to acetaminophen and ibuprofen for effective taste-masking with minimal (approx. 8%) coating load. STICKPACKS Stickpacks are gaining popularity in nutraceutical and pharmaceutical applications, partly for patient convenience, but they also enable formulators to utilise higher and more flexible drug dosages than ODTs. To be effective, such formulas need good flowability to both fill the package and subsequently pour- delivering a pleasant patient experience. Products such as Pharmasperse 416 - a granulated,

DRUG DELIVERY ODD formulas theoretically offer faster drug delivery by eliminating the stomach disintegration lag of traditional swallowed tablets. Depending on the drug properties, this can also open drug delivery via the oral cavity as an option with advantages such as fast drug uptake and potentially longer retention within the body (by avoiding hepatic first pass metabolism). FUTURE As patient awareness of available dosage options and changing regulatory emphasis grow, the demand for more patient-centric formats will intensify. The FDA has emphasised a shift away from syrups/suspensions due to concerns that include dosing accuracy, portability and stability of liquids, as well as

17 the Paediatric Investigation Plan requirement for new drug applications, all of which are driving manufacturers to consider all available solutions. With our long history of developing innovative patientcentric solutions, SPI Pharma has developed expertise in this area. Currently we are working on a directly compressible, sublingual platform with sub 10 second disintegration. The collective goal in pharmaceuticals is to make sick people well - requiring the right medicine be delivered in the right quantity throughout the prescribed timeframe. By building on current and future technology advances, we can improve the patient experience and make a difference in patientsâ&#x20AC;&#x2122; lives. REFERENCES (1)NY Times ref: https://www. nytimes.com/2019/11/29/health/ AIDS-drugs-children.html (2) University of London ref: Desai, N; Redfearn, A; MacLeod, G; Tuleu, C; Hanson, B; Orlu, M; (2020) How Do Orodispersible Tablets Behave in an In Vitro Oral Cavity Model: A Pilot Study. Pharmaceutics, 12 (7), Article 651. 10.3390/pharmaceutics 12070651.

Authorâ&#x20AC;&#x2122;s Bio: WAYNE CAMARCO Global Head of Technical Development Wayne Camarco joined SPI Pharma in 2019 as Global Head of Technical Development. Wayne brings broad-based excipient and API experience in the areas of formulation development and technical service. He has worked in a variety of technical, sales and business development roles at ACG Capsules, Juniper Pharma (Catalent UK), Ashland Specialty Ingredients in US and Rhodia in US & France.

GRAEME MACLEOD Global Head of Research and Development Graeme is a pharmacist and attained his PhD in Pharmaceutical Technology from the University of Manchester, England. His 25 years of industrial experience were gained in a number of positions within Industry in the fields of formulation development and drug delivery and Senior Technical Positions within Pharmaceutical Solid Form equipment and excipient companies. Graeme joined SPI Pharma in June 2017. His areas of experience include oral dose form technologies and processes, novel soft capsule technologies, and drug formulation.

CONTRACT MANUFACTURING

EPM speaks to Acino to learn about the world of contract manufacturing.

Choosing the right partner to manufacture your product is key for customers. What would you say is the most important attribute? It has to be a combination of attributes. Many contract manufacturing organisations (CMOs) have the technical capabilities to manufacture a product, but this alone is not enough. There are many other factors which define how well the transfer will go and whether the parties can work smoothly together.

Quick questions with Yuliyana Manolova, business development manager, Contract Manufacturing, Acino.

I once attended a manufacturing conference that was very technical, and the hosts had prepared a live poll asking which factor represented the greatest risk in new partnerships. There were over 200 people present in the room and the answer with the highest number of votes was “Cultural and organisational fit”. People are the driving force behind every successful project or company, and just as important are the technical capabilities and the technical know-how. Without solid expertise, scientific knowledge, a solid understanding of your customer’s needs and equally high-quality standards, it can be difficult to achieve great results. What changes have occurred for Acino Contract Manufacturing over the last six to 12 months? The last 12 months have been very dynamic for Acino Contract Manufacturing. In addition to the transfer activities at our Swiss and Estonian plants, we also implemented a new marketing and sales strategy, as it is important to find new ways of introducing our high-quality services to potential customers.

Again, producing high-quality products in state-of-the-art facilities is not enough; we have to ensure people are aware of what we can offer. Our efforts paid off and we received great feedback: so we know that we are on the right track. Covid-19 has enforced a diﬀerent way of working with customers. How has Acino responded to this change? We are lucky to be living in a digitalised world that allows us to continue working with our clients during the pandemic. From a CMO perspective, I would not say that there is a new way of working with customers, but rather that there were some temporary challenges we needed to address. There were active pharmaceutical ingredient (API) and excipient delivery delays, and sometimes-revised ordered quantities which had to be clearly communicated. There were also delays in launches due to the market uncertainty. We remained flexible and supported our clients during these difficult times. The experience allowed us to strengthen our partnerships and to gain trust as a reliable company. What new solutions are Acino oﬀering that perhaps incorporates a digital solution? As a result of the pandemic we could not schedule face-to-face meetings with our clients and organise site tours. This was a big challenge for us as we have a lot of projects in the pipeline. External visitors are still not allowed in our facilities for safety reasons and we had to find a way to help new partners visualise where their products could be produced. We introduced LIVE 360 degrees sessions with excellent

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audio connection that allow the participants to have full visibility in our facilities and interact freely with our colleagues in the production sites. As a result of this successful implementation we also used the technology to conduct our first virtual on-site audit. It was conducted by one of our biggest customers and we successfully passed it. Exciting success story. What is the roadmap for the next 12 months for Acino Contract Manufacturing and its customers? There are a lot of new transfer projects we have recently started, and we are hiring new colleagues

in the Quality Assurance, Quality Control, and Manufacturing, Science and Technology teams to support these activities. We are investing in technology and capacity increase and have started a project to assess the upgrade of our Liesberg bulk manufacturing plant to handle high potency products. It is an exciting time to be part of Acino and our management is leading us through remarkable growth despite the difficult Covid-19 context.

People are the driving force behind every successful project or company.

APIs/HPAPIs

How innovation in pharma is enabling RNA therapeutics’ rapid move to the clinic

Clinically signiﬁcant

I Author: DANNY GALBRAITH - head of New Services and Technology Management at Merck KGaA, Darmstadt, Germany

nnovation in the biopharmaceutical industry has always been rapid; however, this pace is accelerating with the global call to action to develop therapies to prevent and treat Covid-19. As the industry continues to look to novel modalities as a solution to Covid-19 and other diseases, a new class of therapeutic molecule is capturing attention -- nucleic acid, particularly Ribonucleic Acid (RNA). These molecules have demonstrated several clinical mechanisms of action in the treatment of a multitude of illnesses. For example, anti-sense or interfering RNA therapies have been used in oncology treatment and the use of the RNA to act as a means of gene delivery is showing promise. First described in 1961, RNA is the least developed of the biologically active molecules as a therapeutic. Compared with DNA delivered gene vectors, RNA has the advantage of being biologically active in both dividing and non-dividing cells and as

such would be the preferred tool to deliver expression of gene encoding proteins. They also have the advantage of no “foreign” genetic materials such as promoters on many DNA vectors. These molecules can be surprisingly easy to manufacture. Producer cells are transfected with an appropriate plasmid DNA and RNA polymerase, and these drive the production of RNA. The purification of the RNA away from the other host and manufacturing materials requires multiple steps but fortunately requires little in the way of the development of novel technologies, allowing a faster path to the clinic. A significant downside to RNA molecules, however, is their fragility in biological systems. The largest challenge with these drugs is the delivery system to achieve adequate survival of the biologically active molecule to the cells where the gene transfer and expression can be delivered. Many innovative compounds are being developed to enable these therapies to move to the clinic safely. The pharmacokinetics of naked RNA is well understood. With a half-life of around seven hours, this type of molecule is rapidly degraded in the extracellular space by a variety of RNase mediated mechanisms. If the molecule survives to reach a cell it requires to translocate across the plasma membrane into the cytosol where the protein can be translated and initiate its therapeutic target. However, these naked RNA molecules are negatively charged and compose a high molecular weight; both characteristics mean that passive movement across the charged cell

membrane is incredibly low. For these reasons naked RNA is no longer considered an option for drug developers. To combat these challenges, two strategies are used to create RNA therapy and delivery systems for the clinic. Firstly, modifications of the RNA molecule can increase stability during transportation to the cell. These modifications have included changes to the 5’ cap and 5’ and 3’ UTR regions to enhance stability and modification of the Poly-A tail. These modifications can enhance the potency of the molecule as well as reducing degradation. However, modifications in the genomic construct alone are seldom enough to improve the pharmacokinetics of the drug. One of the more interesting approaches has been the use of

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different formulation strategies to stabilise these products. The challenge of the dense negative charge of these RNA molecules can be overcome with the use of lipids or polymers that are used to encapsulate the RNA strand and mask the charge. Simple or complex polymer compounds such as Diethylaminomethyl dextran or polyethyleneimine have been proposed and some clinical work has been carried out, however safety issues have been described. A great deal of attention has been recently focused on lipidbased compounds such as lipidoids. Cationic lipids would appear to be the ideal polymer as they form a spontaneous, encapsulated complex with the RNA, thereby providing a mask to the charge and a protection to the degradative activity during transport to the cells. Cationic lipids are generally less toxic but do have some safety hurdles to overcome as pro-inflammatory responses have been identified. A solution to reduce toxicity is to complex neutral lipids with the cationic lipids, as this will also improve stability. These strategies

have already shown promise in clinical trials. The chemical flexibility of lipid compounds has seen innovation with ionizable lipids which switch charge depending on the surrounding pH values. Products are encapsulated at low pH and at physiological pH conditions the compound switches to a neutral charge, thereby reducing toxicity. In combination with glycols these lipid compounds are essential for RNA therapeutics to be viable in clinical trials. These compounds still must be evaluated long term and with multiple dosing regimens with respect to toxicity to understand if these novel lipids may have issues with patient tolerance in a long run. Appropriate testing of other characteristics of these lipids and the compounded end products, such as stability, is also required for safety assurance. Ultimately the lipids that can target specific cell types would be the ideal carrier. If, for example, T cells or tumour cells were able to be selected and RNA coding proteins expressed this would reduce the amount of materials needed to

treat a patient and thereby reduce any potential toxicity. Although at early stages, there are some groups investigating the ability of glycan markers on the cell surface to interact with lipids to enhance delivery to a target cell type. RNA based therapeutics could revolutionise how we deliver therapeutics. In the future it is possible that in place of a monotherapy, a population of different RNA substrates will code and cascade several proteins to trigger pathways to eliminate cancer cells. The primary obstacles of how to deliver these molecules to cells has seen progress recently, but with the innovations in lipid chemistry we are likely to see new products which advance this field. Reducing toxicity and better targeting of the RNA to specific areas or even particular cell types could be the next step in this journey. The part these drugs play in the treatment of Covid-19 remains to be seen but the information gained from these molecules used in large scale clinical trials that are going on currently will be invaluable.

To combat these challenges, two strategies are used to create RNA therapy and delivery systems for the clinic.

APIs/HPAPIs

SAFETY GUARAN How a fully integrated isolator and process equipment solution oﬀers high safety, eﬃcient control and cleaning features as well as full compliance in terms of manufacturing regulations.

Author: GABRIELA MIKHAIEL marketing manager at Dec Group

he pharmaceutical industry is developing at a faster pace than ever before. New drugs and forms of therapies, persistent market growth, Industry 4.0 and the current Covid-19 pandemic are synonymous to enormous challenges for manufacturing companies. Due to the high potency of certain active pharmaceutical ingredients (APIs), machine operators have to be protected. At the same time, humans are a high source for product contamination and the key to a successful operation lies in reliably engineered technologies that bring forth equipment capable of offering suitable containment solutions to protect people and products from each other. In pharmaceutical manufacturing facilities, isolators are becoming increasingly important as they can achieve the desired level of protection and security. HIGH CONTAINMENT TRAY DISCHARGE, MILLING, MIXING AND PACK-OFF ISOLATION SYSTEM For a recent project with the aim to replace parts of an existing thyroid hormone production facility, a new high containment fully integrated isolation system for several interlinked process stages was designed and implemented. The new facility guarantees closed product handling and achieves a very low Occupational Exposure Limit (OEL < 400 ng/m3).

The plant accommodates two distinct process phases starting with the introduction of trays from an adjoining process room

through a transfer door into the conditioning chamber which is equipped with an ergonomic lift system. The conditioning chamber is connected to the rear of the tray oﬄoading and milling chamber. MILLING AND BLENDING Equipped with a tray oﬄoading rack and situated at right angles to the conditioning chamber, this chamber collects the product into an integrated discharge hopper able to de-agglomerate the product and connected to feed the cone mill. After the milling, the product is then collected into a suction hopper and automatically transferred to an integrated PTS Batchmixer system where it is homogenised and from which samples from two to 10 grams can be collected. This mixer is a novel system and offers the advantage of working without rotating tools. The substances are thus mixed or homogenised very gently. With limited circulation speed, particles are not damaged. The system operates under inert conditions and handles hygroscopic, oxygen sensitive or explosive materials. Powders can be transferred automatically from drums, bags or directly from process equipment like a granulator. It operates on recirculating a single or several products via two circulation lines using a PTS (Powder Transfer System) which is mounted on top of the blender. To ensure a contained closed transfer the PTS Batchmixer is mounted directly above the pack-off isolator chamber discharging the product into a 50 l feeder hopper. PACK-OFF AND DISCHARGE

The pack-off isolator consists of two chambers, of which the upper chamber is fitted with an integrated weigh scale mounted on a slide rail system. This allows the scale to be moved to the side when direct bulk discharge into the lower chamber is required. In the upper chamber, the homogenised APIs are filled into bottle containers and stored on a rack before leaving through the

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NTEED rear wall into the final transfer chamber. The lower chamber permits the direct discharge of APIs into bags using an EziDock containment valve system. The final transfer chamber serves for the initial empty clean container transfer into the isolator prior to commencing the batch and for the contained transfer of the filled containers

prior to exiting the chamber through a Rapid Transfer Port continuous liner system providing high containment. SECOND PROCESS PHASE The second process phase encompasses reactor charging from bags and previously filled Ezi-Dock bags and the filter dryer discharge, after the product has gone through the pressure filtration, crystallisation, washing and drying processes. To maintain security and high containment, the material is transferred into a filter dryer discharge isolator before it is milled and transferred to the blending

process. In this second phase, PTS Batchmixer discharge is set to deliver the product in trays again to be reintroduced in the isolator conditioning chamber for equilibration purposes where humidity is added to the material. Once more the product repasses into the blender for homogenisation and the automated collection of samples as small as from 1g upwards. The product is finally accurately dosed into 1kg containers with a tolerance of +/- 1 g. Reactor charging with PTS allows for oxygen elimination during the charging process

23 and therefore excludes any explosion risks. PTS is an exceptionally effective and reliable method for transferring and dosing both dry and wet powders. Its unique filtration concept with a flat membrane prevents filter clogging thus avoiding operation failures. The system uses vacuum and pressure to convey materials and can be used in sterile operations as well. FULLY INTEGRATED CONTROL AND IN-PLACE HYGIENE FEATURES The plant is controlled by using an integrated PLC system controlling both the isolators and the complete process system. The facility is designed for clean-in-place with integrated fixed and rotating spray nozzles as well as manual hand guns. Equipment providers to the pharmaceutical manufacturing industry play an important role in supporting manufacturers. Which legal requirements have to be observed and which regulations will be changed in the coming years? How will changing conditions affect the production process and what technologies are required to be immediately and seamlessly integrated into the overall process offering enough flexibility in case of process changes? These are some of the questions to be considered during the preliminary design phase. Manufacturers should not focus exclusively on individual technologies and machines but rather on complete system integration capabilities and process linkage competences as well as the benefit of receiving advice, in-depth industry knowledge and aftersales services.

ASEPTIC PROCESSING

The challenges faced in aseptic processing

A GAME OF RISK A

Author: MICHAEL ARTHUR WICKHAM LABS

lthough we may not realise it, every single person in the world could be affected by the use of sterile products. This may include the use of needles to inject vaccines, administering lifesaving prescription drugs such as Insulin or Epinephrine or in a hopefully rare, but very real situation for 2020, the insertion of a ventilator tube to enable a patient suffering from Covid-19 to breathe. Many parenteral or sterile products may be produced in a clean but non-sterile environment, then terminally sterilised, however there are also many other parenteral or sterile products for which terminal sterilisation cannot be performed. Commonly used sterilising activities may include wet heat (i.e. autoclaving), dry heat (i.e. depyrogenation ovens), using Hydrogen Peroxide Vapour, application of Surface Action Chemicals commonly known as surfactants (e.g. 70% Isopropyl Alcohol [IPA] or Sodium Hypochlorite [Bleach]), or Gamma Irradiation using a Cobalt 60 isotope. Use of these methods in some cases can potentially cause damage, degradation or inactivation of the final product. The cost of these methodologies will also have a heavy influence upon sterilisation methods chosen, as the manufacturer must consider the effect this will have on the cost of the final product. For example, a competitor may be able to undercut the production value of a product and therefore will be able to subsequently sell at a

lower price. This is not to say that use of such sterilising techniques must not be in place where aseptic processing is used, but this will bring about new challenges. The first challenge in aseptic processing is the facility in which the product is to be produced. The facility must be constructed in such a way as to minimise occluded surfaces, be well ventilated using High Efficiency Particulate Air filters (known as HEPA) and be easily cleaned, maintained, and decontaminated. The second challenge is that the equipment used in the room to produce the components, intermediates or final products must also be easily cleaned, maintained and be non-shedding (releasing particles through interactions with items or airflow). In ever improving industries, when innovations are made there will be a cost benefit balance as to whether you should buy the newest equipment or stick with older technologies that have proven efficacy. As equipment ages, it may be prone to damage, breakdowns, leaks of lubricant or shearing of parts (even microscopically), which could cause potential contamination of the facility. This is why it is of vital importance to have a regular maintenance and requalification regime as these issues can be minimised and contained more readily if equipment is installed and maintained correctly. Further challenges are then produced through the introduction of specific equipment such as tools for maintenance or

extraction of materials and also the component materials necessary for the manufacture of the finished product. All of these items must be transferred into the aseptic production environment from an originally open and uncontrolled environment, for example the delivery vehicle, a storage warehouse, or a preproduction facility. To do this, the aforementioned decontamination method must be utilised upon the materials prior to packaging for entry into the aseptic processing

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area and again upon the outer layer of packaging immediately prior to entry. Again, the method of decontamination may cause damage to the item being passed into the aseptic production facility or may be cost prohibitive. Such examples may include heat sterilisation of active pharmaceutical ingredients (APIs), which could denature proteins or molecular bonds rendering the compound inactive. Use of irradiation is vastly expensive, when wet heat sterilisation would be a faster and more cost-effective option for non-porous materials. Each method must be routinely re-evaluated for effectiveness and robustness in its action, routinely known as re-validation.

The largest challenge of all is that the processing will involve human interaction at some stage. This may be minimised through the use of barriers such as glove ports or by the use of mechanisation, but even if there is intended to be complete isolation of the process, any errors or faults will require the intervention of humans. Humans routinely carry vast amounts of bacteria on their bodies, with the average human reportedly composed of 1-3% bacteria. In fact, the number of bacteria outnumber the number of human cells by a ratio of around 10 to 1.1 Due to the ubiquitous nature of bacteria on the human body, it is not possible to purge them entirely. The body also sheds skin continually when moving, through

abrasion and also passage of air currents. This can amount to around 35kg over the course of a lifetime.2 All shed skin and bacteria pose a large threat of contamination during aseptic processing and must be controlled by minimising interaction with the process as far as practically possible, maximising shielding through the use of barriers and nonshedding clothing. The human body itself is by far the weakest factor in the chain of control of contamination. As such it is necessary to impose restrictions on the number of people involved in aseptic activities and also to monitor environmental trends seen in microbial contamination in the production areas. Alongside effective cleaning and disinfecting procedures this helps to maintain a relatively low level of bioburden in the aseptic processing area and allows for early intervention if any â&#x20AC;&#x153;spikesâ&#x20AC;? in contaminants arise. In conclusion, as far as practicable, there are many possible actions that can be made to reduce the risk of contamination entering the aseptic processes. These actions range from controlling and monitoring the environment, maintaining the facilities and machinery used, sanitising input materials and having precise instructions for the process flow. There are many other controls including use of pressure differentials to move air, particulates and bacteria away from the production process areas, which have not been mentioned here but the interaction of humans will cause the biggest concern for a breakdown in contamination control. Therefore, regardless of what processes are put in place, continual monitoring will always be required, along with a continual review of the controls in use to ensure that critically ill patients will continue to have access to a safe, regulated supply chain of aseptically manufactured products.

The largest challenge of all is that the processing will involve human interaction at some stage.

1) https://www.nih. gov/news-events/ news-releases/nihhuman-microbiomeproject-definesnormal-bacterialmakeup-body 2) https://www. sciencefocus.com/ the-human-body/ how-much-skindoes-a-human-shedin-their-life/

SPONSORED CONTENT

Planning for Brexit A case study on the strategic role CDMOs can play for their customers.

hortly after the 2016 Brexit referendum, it became clear that Brexit’s impact on the pharmaceutical industry would be intricately complex. As the situation unfolded, Kindeva Drug Delivery (then 3M Drug Delivery Systems) acted with a sense of urgency to develop Brexit preparedness plans and ensure continuity of supply for its customers. Planning for Brexit has proven to be an exercise in dynamic project management, navigating uncertainty, and rapid adaptation. It has also proven to be a powerful case study in the leadership and advisory roles that contract development manufacturing organisations (CDMOs) can play in service to their customers. Scenario Planning Brexit planning is a formidable challenge not just because it involves massive change and complexity, but because there have been multiple layers of uncertainty. When a vote of noconfidence in the Theresa May government was tabled in January of 2019, there were at least four feasible outcomes and multiple ways of arriving at each result (Figure 1). While we leveraged internal and external sources to estimate the probability of each outcome occurring, we did not want to merely plan for the most likely outcome. It was important to work with customers to establish playbooks for all feasible outcomes. A fundamental ingredient in confidently preparing for different scenarios is knowing what questions to ask. These questions should be comprehensive, ranging from transportation to taxes to regulatory filings. We relied on our subject matter experts, customer

Figure 1 – Flowchart of possible outcomes before January 2019 vote of no-confidence in Theresa May’s Government.

input and external advisors to fully understand each potential scenario’s impact. As the situation evolved and negotiations progressed, we continued to work with customers to refine these scenario plans.

Authors: CARL BROOKES - vice president of Manufacturing & Supply Chain operations at Kindeva Drug Delivery & FRANCIS MACKIN - product commercialisation manager at Kindeva Drug Delivery

SPONSORED CONTENT

Planning for Brexit scenarios in the pharma industry has been a landmark activity. Act Early with a CustomerOriented Mentality Scenario planning is especially useful when it reveals actions that need to be taken urgently, even before a final outcome is known. Before the 2019 vote of no confidence, Kindeva had already proactively worked with many customers to develop strategies to mitigate the impact of a no-deal Brexit. This included starting the long processes of updating Quality Agreements, identifying QC testing sites in the EU, updating product packaging to show the new name of MA holding and testing site, and planning for worst-case port/airport delays. Why bother acting before the outcome was even known? A singular goal was guiding us: maintain continuity of supply for our customers that were selling products into the European market. With that goal in mind, preemptive actions were often necessary – particularly for activities that have long lead times or high risk of delay. The need to start early is especially pertinent for CDMOs that focus on complex drug products since actions such as identifying alternate test sites can be more complicated for complex dosage forms compared to simpler dosage forms.

There were times in our Brexit planning when we determined it was necessary to increase inventories before ramping back down. In some cases, we instituted a redesign of supply chain sampling processes to brace for a no-deal scenario. Today, we are prepared to initiate testing and QP release if there is no deal by the end of the year. Importantly, these were decisions made in collaboration with our respective partners, with all parties supportive of the direction taken. Some of these actions may prove to be unnecessary or premature, but they are jointly viewed as the course most likely to ensure continuity of supply. Tailor Made CDMOs can play unique roles in Brexit planning, with expertise that allows them to act as valuable advisors. But the customer needs to own the decision. In Kindeva’s case, each of our customers has different product portfolios, global footprints, and strategic priorities. Naturally, they each had different approaches for confronting Brexit. With quality testing, some customers were more risk-averse and asked to work to set up alternate testing sites in the EU. Other customers preferred to delay the EU site set-up until more information was known. Both approaches are justifiable and come with their own set of challenges and advantages. As a CDMO, Kindeva’s job was not to provide a blanket strategy to all customers but to meet each customer’s individual needs. In the case of some customers, Kindeva initiated and drove the Brexit planning forward. Frequent communication with the customer allowed us to inject urgency into the process. Collaboration also allowed us to exchange lessons learned throughout the industry and to bring our domain expertise to the table. For example, Kindeva

has a deep understanding of the elaborate quality and regulatory considerations surrounding metered-dose inhalers and other complex dosage forms and we were well-positioned to share that differentiated perspective with our customers. Most importantly, frequent communication enabled the creation of a plan that was well-tailored to each customer’s situation and needs. Moreover, correctly identifying who should participate in the collaboration was invaluable in co-developing Brexit playbooks. Kindeva fostered communication at a function-to-function level, organising and encouraging Quality-to-Quality, Regulatoryto-Regulatory, and Key Account Manager-to-Key Account Manager collaboration. For some customers, we hosted planning workshops on specific topics which enabled cross-functional collaboration. Due to the complexities of the challenge, we could not pin the responsibility for Brexit planning on a single person or even a single function. We needed to engage expertise at every functional level and encourage customers to do the same. Conclusion Planning for Brexit scenarios in the pharma industry has been a landmark activity, representing a multi-dimensional challenge with rapidly evolving assumptions. But the work is still ongoing. In the remaining months and years, CDMOs can still bring value to their customers by implementing the best practices described in this article. Beyond Brexit, pharma companies should look to their CDMOs to be more than just transactional business partners. CDMOs can act as critical advisors, leading customers to make wellinformed, data-driven decisions about their products and supply chain.

Could your drug substance use a dose of our innovation? Ever since the CDMO industry began, we have been developing and manufacturing pharmaceuticals for markets around the globe. For the past twenty-five years we have been developing solutions of the highest quality, to the exact specifications of our customers. Find out how we can do the same for you at recipharm.com. Join our live webinar ”Tomorrow’s medicines with today’s drug substances,” on September 15, Time: 3pm London/10am New York. Register at recipharm.com/events

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AN INSIDE LOOK

at ONFAB The company striving to make the manufacturing of drugs safe for everyone involved.

hen you think about pharmaceuticals, you may picture tablets, capsules or liquid drugs that are used to safely treat illnesses and save lives every day. It’s easy to forget that the people developing, manufacturing and dispensing these drugs are in danger of being exposed to harmful, sometimes deadly, chemical compounds, particularly with the increase in the use of high potent ingredients for cancer and other treatments. Yet their work is essential to the steady supply of ever more complex medicines that keep many of us healthy. We sat down with Mark Arnold, managing director of containment specialist ONFAB, part of Envair Technology, to understand more

about the business of keeping people and drugs safe throughout the manufacturing process. “At ONFAB, we work with pharmaceutical manufacturers (CMOs) and drug development companies (CDMOs) who need to handle high potent active pharmaceutical ingredients (HPAPIs) safely within their existing non-contained manufacturing process. We design, manufacture and install single-use flexible isolator systems to achieve containment performance levels below 1μ/m3 (OEB 5). These are bespoke to the site and each process,” he tells us. ONFAB protects users from the dangerous effects of exposure to hazardous potents, whilst also

avoiding cross contamination of the drugs, by designing isolators which house the compounds in an enclosed controlled space. These systems might cover one or multiple parts of the process, ranging from weighing, mixing, milling, spray drying to packaging. Negative or positive pressures are used to create different environments inside the isolator, such as low humidity, low oxygen, aseptic or ATEX; this provides protection and GMP conditioning for both the product and process. The operator then safely handles the ingredient through a glove sleeve from outside of the containment unit. SO WHY CHOOSE A FLEXIBLE SYSTEM? ONFAB’s impressive growth over the last 16 years has been driven by clients’ requirements to reduce cleaning validation time and cost, plus avoid large capital expenditure on rigid isolator systems. As Arnold notes, “cleaning validation in pharma is very expensive, it can run into thousands of euros per day. If you can encapsulate that process within a flexible isolator, you can reduce that cost significantly or in some instances, eliminate it altogether.”

AN INSIDE

Mark Arnold Managing director of containment specialist ONFAB

AN INSIDE LOOK

It allows for simple engineering change out and has been shown to improve productivity - more batches can be carried out due to less downtime. Rigid isolators are more suited to circumstances when a manufacturer is making the same product continuously.

For me, as leader of the business, I think it’s vital to listen to my staﬀ, create a positive company culture and always look for the best in my team. “It still surprises me how few companies understand that upgrading their existing noncontained equipment is a possibility, particularly when they’re under pressure to quickly become HPAPI-ready. This is especially true for those with newer super-potent oncology, cardiovascular and diabetes medicines, and where a GMP compliant environment is essential. Instead, the market has seen an influx of single-use products alongside rigid containment measures.” To put it into context, Arnold mentions that the cost difference between a contained rigid system and flexible system is about tenfold. “If you were to build a rigid process isolator costing about £100,000, an equivalent retrofitted in-process flexible isolator would typically cost you around £10,000 and achieve the same containment levels,” he says. “And over the years, we have learnt that we are able to retrofit around 98% of all existing process equipment.” Flexible isolator technology arguably also offers a better solution to contract manufacturers, simply due to how adaptable it is.

A flexible isolator can be used for a number of months and when no longer needed, put away for storage after the single-use glove bags have been safely disposed of. If the contract manufacturer wins another urgent project requiring high containment, then the system can be rolled out again, keeping the original frame and control system and needing just a new glove bag and HEPA filtration. SUCCESS THROUGH TAKING PRIDE Founded in 2004, ONFAB is a fast-growing company which has recently made a number of business acquisitions to help it expand. In 2017, the company received investment from London based private equity managers Foresight, which was followed by the acquisition of UK market leader in rigid isolators, Envair. This led to the formation of parent company Envair Technology and this summer’s further acquisition of industrial fume cupboard specialist TCS, to enhance the group’s positioning as the global leader in contained clean air solutions. Throughout our conversation Arnold comes across as someone who is especially passionate about the work he and his staff do throughout the pharma industry. I ask him what he puts the company’s success down to. “For me, as leader of the business, I think it’s vital to listen to my staff, create a positive company culture and always look for the best in my team. I lead by example and roll my sleeves up to support every department, switching from

planning future growth strategy to working on site,” he tells me. The conversation shifts to the Covid-19 pandemic and sustainability within pharma. Arnold mentions how ONFAB has been fortunate, given that pharma manufacturing has continued as usual and drug discovery work has expanded in Europe and the USA. He forecasts further growth for the business in 2020. On sustainability, Arnold is aware that it is a particularly tough industry to affect change in and though he isn’t convinced that single-use products are always more environmentally friendly, as some of the industry argue, he is convinced of the necessity for action. The company has just appointed a quality and environmental manager to assess all of its processes and identify where ONFAB can improve, which shows it is looking towards the future not only from a business sense, but also from an ethical one. As we finish the conversation, Arnold offers one last thought. Earlier in the chat, he paused at a question on what the culture of ONFAB is like. On reflection, it seems to him that it all comes down to pride in what you’re doing. “We do genuinely care, that comes from the top. I go on about this a lot but simply you need to care about what you do, whether you sweep the floor or build a sophisticated low humidity, nitrogen enriched isolator.”

LAB AUTOMATION

STREAMLINED TRANSFORMATION The challenges of drug discovery and how advances in lab automation are bringing developers closer to streamlined workﬂows.

D Author: OLIVIA HUGHES - life science writer and digital marketer at Sphere Fluidics

rug discovery companies are under ever-increasing pressure to speed up biologics discovery and manufacture by streamlining processes and timelines, in order to meet the surging demand for new therapeutics. However, the discovery process remains complicated and inefficient, extending timelines and development costs. In the broad range of contributing factors, the time -and labourintensive aspect of screening large cell populations during drug discovery for rare antigen-specific, antibody-secreting cells, can cause major delays. Traditional hybridoma-based approaches involve time-consuming screening steps that pose significant obstacles in identifying leading candidates for antibody optimisation (Figure 1). Barriers to the adoption of new technologies is another important consideration. To avoid implementation hurdles, manufacturers need to design instruments that fit seamlessly into current workflows, while providing evidence that they outperform the benchmarked traditional methods and ensure authentication for registration purposes.

Figure 1. The main challenges faced in the traditional workflow of hybridoma screening.

INCREMENTAL IMPROVEMENTS IN THE DRUG DISCOVERY PIPELINE With the onset of automated, high-throughput screening technologies, drug discovery processes have been improving gradually. For example, screening purified B cells directly with flow cytometry bypasses traditional hybridoma fusion, and phage display approaches. But this technique only partly surmounts the limitations of hybridoma technology for producing monoclonal antibodies. Flow cytometry has the advantage of being very high throughput, allowing the detection of potential drug candidates by screening millions of antibodies. Antibodies secreted by B cells can be screened using cold capture, a strategy utilised to trap antibodies at the cell surface. This technique, however, only provides a representation rather than a direct measurement of the profile of antibody secretion by a single cell. This screening approach has many other drawbacks, such as altered cell function and decreased cell viability. Alternative screening approaches include ELISA and Elispot; although, these strategies involve manual execution and consequently, the study of large populations becomes too expensive and time-consuming (1).

Following several iterative screening and selection rounds, the positive cells must then be sub-cloned into monoclonal populations (lead panels) using semi-automated methods such as cell-in-well imagers and cell sorting. Yet, this multi-step approach adds even more complexity and slows the discovery process even further (2). FULLY INTEGRATED THERAPEUTIC DRUG DISCOVERY SOLUTIONS With the development of picodroplet microfluidics and the integration of these approaches with robotic automation, and AI-supported image analysis technologies, scientists can now identify and isolate rare antigen-specific B cells from large heterogeneous populations in just two days. These capabilities are revolutionising the current drug discovery process. Picodroplets are small aqueous picolitre volume droplets in which individual cells, or multiple cells in pools, can be encapsulated for high-throughput analysis. Picodroplets compartmentalise cells and facilitate growth, eventually trapping secreted molecules such as antibodies, making them easily accessible for characterisation (3). Using this approach, researchers can conduct complex multi-step assays with high reliability, costefficiency, and throughput. Emerging fully integrated picodroplet systems present a unique opportunity to enhance the antibody-drug process, from target selection and validation, through to bioanalysis and bioproduction. Such technologies not only simplify the screening of one- to tens-of-millions of encapsulated

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cells and their components, but also incorporate the subsequent selective sorting, cell isolation, imaging, and single-cell dispensing phases into a single, automated platform that easily integrates into existing workflows. The combination of automated picodroplet systems, image recognition, and analysis tools ensures researchers quickly collect reproducible and quantitative data. These capabilities facilitate high-throughput research to interrogate more extensive repertoires and find more functional properties in just days (4). For example, researchers can use a fully integrated platform to analyse whole B cell repertoires (up to 40 million cells) for antigen-specific antibody-secreting B cells in a two-day process (each picodroplet will contain approximately 30 cells in the first of a two run protocol). The two-step screening approach involves using a bulk assay to enrich for B cells that present the antibody of interest, then using an antigen detection assay to screen for antigen-specific antibodies. The isolated antigen-specific antibodysecreting cells are then dispensed as pooled population or as single cells into 96- or 384-well microtitre plates for further analysis.

Figure 2. High-throughput screening workflow Notably, during the discovery process, these platforms maintain the cells in a highly viable state. Picodroplets provide a specific protective environment to preserve cell integrity during incubation and shield cells from shear stress as they pass through the microfluidic channels. The miniaturised format also uses much lower sample volumes and allows the rapid accumulation of molecules secreted by the cell. This enables a more sensitive and precise measurement of antibody secretion levels to identify clinical candidates with optimal properties at a dramatically

reduced cost per-test. Using this streamlined process, researchers can automate the entire antibody drug discovery workflow to quickly identify cells that secrete antibodies and isolate rare cells that secrete antigen-specific. State-of-theart picodroplet microfluidic technology offers an innovative and accessible method to transform labour-intensive and inefficient therapeutic drug discovery processes, facilitating lower operating costs, increased success rates, and decreased time to market.

Advances in picodroplet microfluidics and imagerecognition technology has enabled researchers to ‘mine’ the rarest cells naturally occurring in a heterogeneous population to identify valuable antibodies with the highest antigen-binding affinity and specificity. A process that can take several weeks if following a conventional, multi-step discovery workflow (Figure 2). REFERENCES

1. Zhang, H., Wilson, I. A., and Lerner, R. A. (2012). Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries. Proceedings of the National Academy of Sciences, 109(39), 15728-15733. doi:10.1073/pnas.1214275109. 2. Streamlining Lab Processes for Faster Antibody Discovery. https://www. contractpharma.com/issues/2020-05-01/view_features/streamlining-labprocesses-for-faster-antibody-discovery/ 3. Josephides, D. et al. (2020). Cyto-Mine: An Integrated, Picodroplet

System for High-Throughput Single-Cell Analysis, Sorting, Dispensing, and Monoclonality Assurance. SLAS TECHNOLOGY: Translating Life Sciences Innovation. https://doi.org/10.1177/2472630319892571 4. Matuła, K., Rivello, F., and Huck, W. T. (2020). Droplet Microfluidics: Single Cell Analysis Using Droplet Microfluidics (Adv. Biosys. 1/2020). Advanced Biosystems, 4(1), 2070012. doi:10.1002/adbi.202070012. 5. The Future of Antibody Discovery and Cell Line Development. https:// www.genengnews.com/magazine/december-1-2018-vol-38-no-21/the-futureof-antibody-discovery-and-cell-line-development/

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FILLING IN: HOW STEVANATO GROUP IS SUPPORTING CORDENPHARMA'S EXPANSION.

It started as an innovative solution, but now it has become standard in the industry.

ersonalised medicine has been one of the main trends in the pharmaceutical sector over the past few years. While the increased demand for tailored therapies is a great opportunity, it also poses new challenges.

container to another. Also, their high CAPEX and large footprint can make it difficult to build a business case for entering new market segments, with smaller volumes initially, and the intention of scaling up later.

Unlike the classic top-down approach, where drugs are produced in large volumes, personalised medicine requires smaller batches and different formats. For manufacturers, this creates the need to be more flexible with their production and the ability to move efficiently between different projects and packaging.

A MORE FLEXIBLE SYSTEM The solution was SG EZ-fill® by Stevanato Group, a long-standing CordenPharma partner and market leader in the manufacturing of cartridges for insulin pen injectors, glass vials and syringes.

THE LIMITS OF TRADITIONAL FILLING TECHNOLOGY That was exactly the challenge CordenPharma - a full-service CDMO for the integrated supply of APIs, drug products and packaging services - was facing when it decided to expand its portfolio of primary packaging for anaesthetics. CordenPharma’s growth and evolution from filling generics in bulk containers to value-added treatments using fill & finish multiformat lines for ready-to-fill vials and syringes, increased the need for flexibility and a faster rampup. With traditional technology, however, this expansion would have been problematic. Filling lines are typically designed to take care of the end-to-end process - from washing, to depyrogenation, to filling - and produce large volumes efficiently. Their limitation, however, is the lack of flexibility when it comes to moving from one type of glass

SG EZ-fill® is a primary packaging

platform that supports different types of formats. Its glass containers are ready-to-fill and can be used in two configurations: nest-and-tub and trays. CordenPharma adopted SG EZ-fill® in its CordenPharma Caponago facility, near Milan, IT. For Fabio Stevanon, Director of Global Injectables Platform at CordenPharma, Stevanato Group’s platform has been crucial to expanding the company’s offering and shortening the path to commercialization: “Thanks to SG EZ-fill®, we are able to use

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the same fill & finish technology for early-phase drugs, typically during clinical trials, up to the final product. For us that means enabling our pharma customers to shorten time to market by up to 10% or even 15%”. SG EZ-fill® helps to achieve these results by saving manufacturers time on non-core activities. In a traditional filling line, changing format - for example, moving temporarily to a different container to produce a smaller batch for phase II of a clinical trial - would take days. With the SG EZ-fill® platform, the changeover can be completed in a matter of hours. Additionally, SG EZ-fill® containers are ready to use and require no washing or sterilisation. The other main benefit for CordenPharma was a lower Total Cost of Ownership (TCO), thanks

to SG EZ-fill®’s higher output, reduced footprint, and the ability to scale up production fast. QUALITY AND SAFETY Central to the container design and engineering is the patient safety factor. Through the separation of all containers in the secondary packaging, SG EZ-fill® ensures maximum integrity of the container during the transportation phase and in the buffering/in-feeding operations, while maintaining no glass-to-glass contact. This mitigates the risk of breakages, cosmetic issues and particle generation and brings significant mechanical and performance advantages, as it dramatically reduces production stop and rejects during inspection. FROM INNOVATION TO STANDARD CordenPharma’s successful experience comes at a time when developing drugs and vaccines more rapidly is more important than ever. SG EZ-fill® is highly compatible and can work with eighty equipment models. This compatibility is the result of Stevanato Group’s collaboration with several manufacturers during the early development stages. In the 12 years since its launch, the system has been installed in 250 filling lines. “It started as an innovative solution, but now it has become a standard in the industry,” says Fabio Sartore, Head of Regional Sales EMEA, Stevanato Group. “It’s a perfect example of how suppliers, when working in partnership, can introduce innovation that will make a positive impact on the growth and success of a customers’ business.”

One of the reasons for its success is the positive knock-on effect on other cost areas: • The tubs can fit on a pallet perfectly, saving storage room and making transportation and shipment easier. • The nest-and-tub and tray configurations avoid any glass-to-glass contact during transportation and the buffering/ in-feeding operations. This reduces breakages, cosmetic issues and particle generation. • SG EZ-fill® containers maximise filling efficiency by allowing different combinations of filling nozzles. THE NEXT STEPS IN A LONG PARTNERSHIP After 20 years of successful partnership between Stevanato Group and CordenPharma, the two companies are already looking at what comes next: “We are going to expand our collaboration to injectable new reference drugs, especially autoinjectors and medical device applications,” says Stevanon.

To ﬁnd out more information visit: www.stevanatogroup.com www.cordenpharma.com/technology-platforms/injectables-platform/

LOGISTICS & DISTRIBUTION

KEEPING TRACK How smart software solutions can speed up crucial delivery operations.

T Author: NATASHA JONES European Channel manager at SmartFreight

When it comes to delivery, certainty is everything.

he current public health crisis has provided a challenging scenario to the healthcare and pharmaceutical sectors, from firefighting the coronavirus pandemic to delivering the numerous life-saving drugs, medicines and medical devices that are vital for patients. Health facilities and retailers want short delivery times and precise timescales. Meeting these expectations often means juggling different transport providers and their various systems, which is not an easy operation to do manually. Consolidating all transport providers into a single platform improves the distribution process and delivers an efficient method of connecting fulfilment and shipping.

but provides an automatic choice of transport provider best suited to the client’s requirement, along with the flexibility to manage a dip or spike in volumes during a crisis, whether it’s for ventilators, PPE equipment or hand sanitisers. When it comes to delivery, certainty is everything. Due to the critical nature of pharma goods, a supplier needs to select a service from transport partners knowing they comply with all the regulations relating to the nature of the goods and how time critical it is to deliver. A lack of shipment visibility can lead to customer frustration.

Shipping software solutions specialists have seen increased enquiries from pharmaceutical companies looking to reduce transport spend and the amount of time keying in orders manually. As one of our recent clients told us: “It’s all about providing a more hassle-free service.”

Tracking deliveries enhances trust between provider and customer. From processing and dispatch through to delivery, it’s easy to track a shipment every step of the way. When orders are dispatched, customers receive a branded email from their supplier with all the details they need to track their items on desktop or mobile devices, regardless of transport provider.

However big or small a business is, streamlining the despatch operation using the latest shipping solutions not only frees up staff

Pharma businesses that don’t have an integrated shipping solution are likely to be manually processing the same data multiple

times through different systems, with the potential for human error, while shipping orders on suboptimal routes or services causes delays, additional costs and a poor customer experience. Businesses also need to consider customers who place numerous orders, not necessarily at the same time, but are anticipating receiving them on the same day. Why despatch multiple consignments to one address when an integrated system will consolidate all the orders placed in one day to send out as one consignment, reducing shipping costs, product miles and helping the environment? That’s the beauty of an integrated shipping solution, businesses can slice and dice their distribution pie any way they like to suit specific needs. It’s all about making a decision based on customer requirements. The best software solutions will also automatically reconcile transport providers’ invoices, saving time and the laborious task of doing so manually and reducing the risk factor of human error. Pharmaceutical companies with their own fleet can still access a cost-effective delivery tracking system comparable to the UK’s best transport providers. This allows track and trace capability from a smartphone and app, giving the fleet tracking and Proof of Delivery (POD) capability without the need to deploy costly hardware in each vehicle. To keep up with increasing demands and challenges, automated shipping software solutions with delivery tracking technology should be your first consideration.

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First time’s the charm How to ensure your formulation strategy goes to plan every time.

FORMULATING FIRST TIME RIGHT Developing a new solid oral dosage form involves many decisions, including excipient and film coating selection, potential interactions and desired release profile. It’s best to keep the formulation strategy simple by minimising ingredients and process steps; this is less likely to cause downstream problems and results in the most cost-effective option. Complicated formulations and processes are more likely to lead to complex questions from regulators and could lengthen the approval process. FIRST TIME RIGHT When formulating tablets, wet granulation involves multiple steps and the use of moisture, which can cause the active pharmaceutical ingredient (API) to degrade. Therefore, industry specialists typically prefer the simpler dry method, involving direct compression, which also works well at a large manufacturing scale. There are numerous excipients available for use in direct compression although many require additional ingredients for the formulation to be practicable. However, over complicating the formulation and process creates the risk of interaction with the API and creates manufacturing complexity. To overcome this and reduce the potential risk, Colorcon’s newest excipient, StarTab directly compressible starch is designed specifically for tablet manufacture; simplifying both formulation and processing. StarTab is a single excipient

designed for direct compression and provides improved flow during manufacture, due to its unique particle shape and size. The use of super disintegrants can also be avoided by using StarTab, reducing costs and further simplifying the formulation and process, while helping to support product stability. AVOID COMPLEXITY AND ENSURE CONSISTENCY By choosing the most appropriate core excipients and selecting the right film coating system, manufacturers can positively improve the stability of the API and reduce the risk of degradation. In addition to providing an aesthetically pleasing finish that improves patient adherence, film coatings also provide a barrier that reduces uptake of moisture to the tablet core, further helping to support stability for sensitive APIs. For many companies, the final manufacturing location for the product may not be known, so selecting a film coating that can be used across a range of conditions and equipment is critical. Colorcon’s Opadry QX has a wide processing latitude which means it is suitable for use on all types of coating equipment – which is beneficial if the final coating equipment and manufacturing location is not defined. As a one-step fully formulated film coating system, Opadry QX also provides batch-to-batch coating consistency, reduced inventory management and is backed by Colorcon’s global regulatory and technical support network.

FORMULATING FOR EARLY SUCCESS It’s easy to go for the same tried and tested approach, used for previous product development, but it may not be the best strategy for your new project. Colorcon provides a complementary formulation service through HyperStart; providing pharmaceutical scientists with options to accelerate the development process and reduce costs. The easily accessible online service takes the basic information (confidentially, of course) related to the API, release profile, preferred dosage form and the manufacturing process being considered, then recommends a starting formulation. The result is a higher likelihood of successful tablet design, with a reduced need for multiple formula trials and iterations.

Author: JASON TECKOE technical director EMEA at Colorcon

Contract Manufacturing

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FORMULATION

Driving FORWARD

How proteomics studies are helping bolster the next generation of medicines.

roteomics defines the methodologies used to characterise the proteome - the entire protein complement of a cell, tissue, or organism under a specific set of conditions. The foundation for this area of study comprises fractionation of a protein mixture, identification of the individual proteins and bioinformatics to analyse and compile the data. The first protein studies that may be considered under this definition began in the mid 1970’s with the introduction of two-dimensional gel electrophoresis. While protein identification was not possible, this advance in separation technology led to the first attempts to catalogue all human proteins. Further advances in this field however, were only possible after the development of sensitive and reliable methods for identification. The first techniques were based upon N-terminal, Edman sequencing and have been refined to allow microsequencing from trace amounts of electroblotted proteins. This technique has now largely been replaced as a result of developments in mass spectrometry. Since the early protein characterisation work by “FAB-mapping” in the mid 1980’s (1), the application of MS to protein analysis, including identification, has become ubiquitous. Significant improvements in sensitivity, accuracy, speed and automation of mass spectrometric techniques have been made this, the primary method of choice for protein identification.

Concomitant to the development of modern-day proteomics has also been the evolution of other disciplines such as glycomics, genomics, transcriptomics, lipodomics and metabolomics, each with a particular focus on understanding specific cellular functions and processes (2). There has also been a movement towards data-driven diagnoses and personalised therapies based on data obtained from such omic studies. Data from both genomics and transcriptomics have demonstrated only limited ability as predictors of cellular phenotype while proteomics, although more challenging, appears to offer much greater relevance for precision

medicine directed at a particular phenotype. Today, a typical experiment in proteomics comprises three phases. Firstly, isolation of a protein fraction from a desired source which may range from whole cell / tissue extracts to single cell organelles. Secondly, the acquisition of structural information, primarily sequence data by MS-based technologies driven by automated software interpretation. Finally, database utilsation, where the application of bioinformatics has improved the identification and quantitation of proteome data.

Author: MARK ROGERS - global scientific director, Life Sciences, at SGS.

www.epmmagazine.com

Today, a typical experiment in proteomics comprises three phases.

The field of proteomics may be separated into three categories: Expression Proteomics, in which analyses are performed to identify and quantitatively determine the differential expression of protein(s) within the proteome in response to an event. This application has been facilitated by the development of techniques such as isotope-coded affinity tags (ICAT), stable isotopic labeling with amino acids in cell culture (SILAC), and isobaric tags for relative and absolute quantitation (iTRAQ). Structural Proteomics, in which data is used to identify and map the protein content within specific cellular locations. It is hoped that this will eventually lead to a greater understanding of cellular architecture and the influence that specific proteins provide to each cell’s distinctive characteristics. Functional Proteomics, a term broadly applied to proteome studies that do not fall within the previous two categories and includes studies into protein-ligand binding and protein signalling. Since its inception, the field of proteomics has continued to improve and expand both in terms of technology and application. To date, approximately 10,000 proteins have been studied from human tissue alone, which has expanded our understanding of signalling, regulatory, and metabolic pathways. However,

the majority of these studies have been performed with large cell populations such as cell lysates, negating the ability to provide cell type specific data. The term “nanoproteomics” was introduced almost 10 years ago but it has only been recently that advances in technology have allowed this idiom to become a reality (3). Today, very low number cell populations and even single cell proteomics are possible and can reveal critical information related to rare cell populations, hard-to-obtain clinical specimens, and the cellular heterogeneity of pathological tissues. The last two decades has seen the growth of proteomics-based technologies for the molecular characterisation of pathogen-host relationships and insights into the biological basis of infectious diseases (4). Specifically, proteomic studies have had a role in defining the physical interaction between host proteins, viral proteins and nucleic acids and have been influential in the monitoring of host cell responses, including changes in protein abundance upon viral entry, and during the course of infection. MS-based proteomics have been used to help define the molecular structure and composition of viral and bacterial pathogens and have supported the development of diagnostics and therapies in the emerging field of multi-omics, which can provide a holistic view of pathogen-host relationships. For many years the identification of bacteria and yeast pathogens by MS-related technologies has been a widely accepted as a clinical diagnostic tool while more recently, PCR– electrospray ionization mass spectrometry (5), has emerged as an approach that is capable of identifying nearly all known human pathogens either from microbial isolates or directly from clinical specimens.

It seems inevitable that the future applications of proteomics will become part of broader studies involving data from other omics techniques. The integration of genomics and proteomics with disease phenotypes, for example, has the potential to establish disease or individual-specific proteotypes, which may aid in making therapies more specific to the disease or individual. As the multiplicity of omics studies increases, the challenge will not be in which system to apply these methods, but rather how to properly integrate, visualise, and interpret the complex outputs. Flexible yet comprehensive platforms for integrating largescale data sets will become a vital component in such investigations. 1) Analysis of polymeric protein and protein products, US Patent US4701419A (1985) H.R. Morris 2) Integrated Omics: tools, advances and future approaches, J. Mol. Endo. (2019) B.B.Misra et al 3) Nanoproteomics comes of age, Expert rev proteomics, (2018) Y.Zhu et al 4) Novel applications of mass spectrometry and proteomics to Infectious disease diagnostics, (2017) NIH CLC Res Grant, J. Dekker 5) PCR–Electrospray Ionization Mass Spectrometry: The Potential to Change Infectious Disease Diagnostics in Clinical and Public Health Laboratories (2012), J. Mol. Diagnostics, D.M.Wolk et al 6) Proteomics in commercial crops: an overview, (2017) J.Proteomics, B.C.Tan et al

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FORMULATION

EPM speaks to Kindeva Drug Delivery to learn about changes in formulations and how patients are being put at the centre of development.

Quick questions with Steve Wick, vice president of R&D and chief technology officer at Kindeva Drug Delivery How are drug delivery systems changing to become more patient-centered? Over the past decade, there has been a transformation within the pharmaceutical industry surrounding the integration of drug delivery system technologies and devices. Historically, the

pharmaceutical industry focused on the drug and how to most effectively and safely deliver this drug to the patient. Although safety and efficacy remain paramount, healthcare providers and patients are increasingly interested in an improved overall patient experience. Weâ&#x20AC;&#x2122;ve seen a focus on factors such as dosing regimen, remediation of sideeffects, human factors, ease of use, and form factor convenience. Within this transformation, numerous technologies have been developed to improve the overall patient experience: sustained release technologies, implantable technologies, pen-injectors, selfregulating systems, and mobile health/wearable technologies. The future of drug delivery will incorporate expanded patientcentric technologies such as bio-feedback systems, tissue targeted drug delivery, longterm drug delivery (months), and an expansion of mobile health solutions. While the exact nature of innovation is difficult to predict, the next generation of drug delivery innovation will come through aligning technological solutions to patient needs. With respect to inhaled medicines, how do you anticipate formulations will evolve over the next ďŹ ve to 10 years? The delivery of higher doses (multiple milligrams and higher) is the challenge that limits the future of inhalation therapies. I suspect that expansion of the dosage limits will continue to be an area of focus over this five-10 year time horizon. The development of novel Dry Powder Inhalation (DPI) technologies and devices will likely play a significant role in our ability to deliver higher doses to the lungs. DPI technologies with higher efficiency in terms of

respirable dose or carrier-free formulation technologies will enable higher doses. The delivery of higher doses from a pressurised metered dose inhaler (pMDI) using conventional valve technologies is extremely challenging. The attainable dose is limited by pMDI valve capacity (typically limited to 100 microliters or less) and drug solubility limitations in propellant systems. In the future, we will start to see new valve systems and new propellant systems which both will enable higher doses from pMDI systems. Certainly, worth noting is that future active pharmaceutical ingredients (APIs) are likely to become more complex with unique chemical properties and increasingly challenging solubility characteristics. These complex APIs will likely require complex formulation technologies to achieve stability. The use of surfactants or suspending agents along with stabilising agents is likely to become routine. As we move from monotherapies to drug products containing two or three APIs, the formulation challenges become exponentially more complex, requiring novel formulations and world-class scientists to deliver stable product performance profiles. Sustained release inhalation dosage forms achieving less frequent dosing regimens is also an area of interest. Recent product launches have routinely achieved once-per-day dosing requirements and this is likely optimal from an inhalation perspective. Dosing less frequently than daily will require a combination of increased residence time in the lung and sustained release formulation technologies. Although perhaps

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The future of drug delivery will incorporate expanded patientcentric technologies.

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achievable, the therapeutic value of such a solution must be carefully measured against the risks in terms of potential lung toxicity. ReďŹ&#x201A;ecting on the Covid-19 pandemic, is there value in exploring alternative formulations or delivery systems for vaccines? First, consider the route of administration. Vaccines are often delivered intramuscularly. However, there is reason to believe that vaccines will elicit an enhanced immune response when delivered intradermally. Historically, there have not been reliable devices that can reproducibly and consistently deliver to the intradermal layer. With more of these delivery systems in development, I believe intradermal delivery can play an important role in the delivery of certain vaccines. Moreover, vaccines can be effectively delivered through the inhalation route â&#x20AC;&#x201C; both via the lungs and the nasal cavity. Most of the work reported in the literature focuses on single dose DPI delivery systems. Single dose systems are cost-effective and enable the introduction of innovative approaches to achieve a stable drug product. Vaccines are deactivated through denaturing and conventional particle engineering technologies often result in vaccine deactivation. If a respirable particle size can be achieved without deactivation of the vaccine and the vaccine itself is stable, then achieving a stable formulation with either a DPI or a pMDI system should be possible. So, the bottom line is depending on the stability profile of the vaccine itself, the dosage requirements, and the dosing regimen, cost-effective, selfadministered vaccine systems

could be achieved for Covid-19 to enable rapid distribution and repeated self-administration. How can the industry apply data, analytics, and predictive modelling to formulation and product development? The drug delivery industry is already applying data analytics and predictive modelling to the development of both formulations and novel device technologies. In-vitro modelling has become a routine tool in the development of formulations for inhalation drug delivery and advances in predictive modelling have dramatically improved our ability to predict in-vivo performance of a formulation. This same approach has recently been taken by Kindeva within the development of novel device technologies including breathactuated systems, nasal delivery systems, and intradermal delivery systems. This approach requires a fundamental understanding of the underlying route of administration, experience with multiple drugs, and the drug-device interaction expertise to properly design and utilise predictive modelling. This expertise is typically developed only by leveraging decades of drug delivery experience. When your customers approach you with their formulation and development challenges, what are the factors that increase the degree of technical diďŹ&#x192;culty?

The most frequent challenge we encounter is a customer looking to achieve higher doses. The primary consideration in addressing this challenge is solubility of the API. If the API has limited solubility in the propellant, adhesive, or formulation, the drug product can be assembled as a suspension. However, achieving a stable suspension can be problematic and may require more complex formulations with cosolvent systems. These complex formulation excipients can in turn lead to increased stability challenges. Beyond the technical challenges with formulation, another challenge in the development lifecycle is understanding the regulatory requirements for approval. There are country-specific and regionspecific requirements and they can often evolve quickly. For novel products, these pathways are often more complex and require a greater degree of coordination and communication with the regulatory bodies. CDMOs will be more successful if they maintain in-house regulatory expertise and engage them early and often in the development process. In the end, experience with a multitude of APIs combined with a thorough understanding of the drug-device interaction and regulatory capabilities enables Kindeva scientists to tackle these complex formulation and development challenges.

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AN INSIDE LOOK

at ARRALYZE The journey an established technology company is making into the life sciences market to improve drug screening.

he journey of drug development is a long one, taking 10 - 20 years, costing billions in funding and offering less than 10 % of success when entering phase I of clinical trials. Even finding a drug candidate in the pre-clinical phase is a tedious screening process in which hundreds of thousands of compounds are tested against potential disease targets. Now, an established technology company is looking to make the process for drug screening less intensive for those working in the lab. Entering a new market is never easy, but that’s exactly what LPKF is doing with its foray into life sciences under the brand ARRALYZE. A supplier of laser-based solutions for the technology industry, LPKF recently developed a new technology which can introduce microfeatures into glass. Called Laser Induced Deep Etching Technology (LIDE), the solution caught the attention of the life sciences sector due to its applications in the lab. For instance, LIDE processes glass, which allows for a range of optical techniques in that it’s inert and can be used without the worry of it influencing the experiments, as in some plastics, and its variety of surface chemistry enables the binding of anchor molecules easily to the surface. “So even though glass has these great properties there were no processes available

that allowed to introduce microfeatures with very small volume in the picoliter to nanolitre range with high quality or in an economical manner for high volume production. This unique combination of characteristics is what made customers in the life sciences interested in our LIDE technology,” says Dr Robin A. Krüger, head of Product Management and Innovation ARRALYZE at LPKF Laser & Electronics AG. Indeed, ARRALYZE is making microarrays manufactured with LIDE the centrepiece of its platform, a customisable workstation which is able to precisely print living cells, reagents and the like into glass wells. The platform has been designed to carry out high throughput single cell screening experiments and Krüger explains to me how the ARRALYZE arrays “can provide hundred thousand or even millions of individual wells on the footprint of a microscope slide – a number no human can scan through manually.” The reason this is important, Krüger tells me, is that for experiments such as drug screenings, it’s necessary to control the composition of each glass well very precisely. Certain materials can absorb drugs, making the experiment useless since it then affects the drug’s concentration and how much for instance a tumour type might be exposed to. Glass is the perfect material then, Krüger says, as researchers can

be sure they’re not being misled during experiments, as the material doesn’t take up drugs or other reagents. In ARRALYZE’s case, researchers benefit from being able to run hundreds of thousands of experiments at the same time at a much lower cost due to the platform requiring a lower number of conventional labware. ARRALYZE is an open platform, which makes sense when Krüger starts talking

about the democratisation of scientific techniques that can help foster innovation throughout the industry, particularly in academia. “Enabling for example PhD students to just buy small numbers of glass arrays that they load randomly for their experiment with cells, without the need to buy the workstation or allow our customers to downsize their assays with the chemistry that they prefer, will lead to much more innovation

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over time than a fully closed ecosystem.” ARRALYZE, which is entirely customisable through its workstation, the arrays that are used and the chemistry involved, will also be available as an out-of-the-box product, something which Krüger thinks larger pharmaceutical organisations will appreciate more than those experimenting in academic environments. Of course, entering a new market is never easy, even for a company as established as LPKF, but doing so in the middle of a pandemic is almost unthinkable. Krüger though was surprised at how fast LPKF managed to adapt to the safety measures put in place due to Covid-19. “I personally was quite concerned that this will

paralyse us for many months to come since the collaborative interaction within LPKF was always a huge part of how we worked,” he says. “But my concern was pretty much unfounded. Actually, very quickly the company as a whole - not only individual people found a way to synchronise with each other and figured out how to interact sufficiently with each other.” For ARRALYZE the situation was made even more challenging. The life sciences industry has seen countless exhibitions cancelled or postponed and travel restrictions have stopped companies from meeting up with potential clients. The removal of such events and opportunities meant that LPFK’s “marketing plans vanished into

thin air,” as Krüger describes. Like many companies though, LPKF adapted to the changing circumstances and has managed to stay in touch with existing customers, and has also utilised remote technologies to compensate for some of the “missed opportunities that would have been available without Covid-19,” Krüger says. And if Covid-19 did affect LPKF’s working operations, it hasn’t changed the company’s plans for the rest of 2020. “A huge portion of our efforts with ARRALYZE will focus on discussing with collaboration partners and lead users the final details of features we should implement into the workstation – mostly as software features and automated routines,” Krüger says. The reason the company wants to focus on this is due to all labs having very different ways of working, through routines, infrastructure and needs, so LPKF wants to make ARRALYZE as accessible as possible. The company is now looking for partners to work with to assess the pros and cons of the platform’s various features. So, a stressful 2020 for LPKF but one which should, if all goes well, lead to fruition in a new market for the company. And whilst the pandemic has meant a change to working lifestyles, Krüger thinks that the skills learned during this time will be beneficial once the pandemic is over. “We will take many tools and habits that have proven to be helpful into the time after Covid-19. But I am really looking forward to the time when things go back to normal and our work days are only controlled by the needs of our developments and the projects we are working on.”

AN INSIDE

Dr Robin A. Krüger ARRALYZE.

Sanoﬁ to acquire Principia Biopharma for $3.6bn

anofi is to acquire a US-based late-stage biopharmaceutical company in an effort to strengthen its research and development (R&D) capabilities. Sanofi will acquire Principia Biopharma for $3.68 billion and its portfolio of Bruton Tyrosine Kinase (BTK) inhibitors focused on treating autoimmune diseases. The acquisition on Principia and its BTK portfolio will add to Sanofi’s efforts to accelerate and build a range of treatments for autoimmune diseases. BTK is found in the signalling pathways of key innate and adaptive cell types of the immune system. By blocking or disrupting these signalling processes, it’s thought that this can help stop inflammation and tissue destruction related to autoimmune diseases and perhaps target some of the underlying pathophysiology. "This acquisition advances our ongoing R&D transformation to accelerate development of the most promising medicines that will address significant patient needs,” said Paul Hudson, Sanofi CEO.

TALKING POINTS

Talking points

OUTSIDE EPM

UK GOVERNMENT CRITICISED FOR ANIMAL TESTING

n his first editor’s column, Ian Bolland highlights the importance of the UK’s diagnostics industry to the country’s economy, having been at the forefront of the Covid-19 testing programme.

he UK government has been criticised for not doing enough to reduce the number of scientific experiments taking place on animals. Statistics released by the Home Office show that 3.4 million procedures involving animals took place across the UK in 2019, representing a decrease of 3% from the previous year. While the figures do represent the lowest number of animal procedures since 2007, a number of charities have argued that not enough is being done to truly represent a significant and consistent decrease in animal experiments. The government is being called upon to revise its 2010 research policy and focus on replacing animal procedures in science with new non-animal techniques based on human biology.

For instance, the pharmaceutical industry is pursuing technologies such as organ-on-chip and digital twins of the human body which can help replicate how drugs function within patients. Dr Lindsay Marshall, the UK’s biomedical science adviser for the Humane Society International said: “The UK cannot expect to have worldleading science innovation whilst we rely on failing animalbased research methods that are rooted in the past. “In drug discovery, pharmaceutical safety, chemical testing, cancer research, the data shows that animal models are really bad at telling us what will happen in a human body. “As well as sometimes being dangerously misleading, animal approaches typically take a very long time to produce results, sometimes years, are very expensive, and of course cause enormous animal suffering.”

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

COMING UP ON EPM

PM editor Reece Armstrong sits down with Marc Howells, VP and head of Global Talent at AstraZeneca to find out about how the pharma giant ensures its staff are constantly learning.

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EPM September/October 2020

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