EPM October 2019 by EPM Magazine

SUSTAINABLE ANTIBIOTIC PRODUCTION & AMR

OUR SPECIAL GUIDE TO CPHI WORLDWIDE

THE WORLD OF CONTRACT MANUFACTURING

October 2019

FEELING GOOD

SPI Pharma guides readers through the bioavailability challenges facing CBD medicines.

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Visit us at CPhI Worldwide While you’re in Frankfurt, discover why we’re the small molecule company with end-to-end capabilities. Meet the experts you’ll enjoy working with at Booth 41C10, November 5-7.

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Contents October 2019 | Volume 19 Issue 7

REGULARS 5: EDITOR’S DESK

Reece Armstrong writes about Brexit one last time and looks ahead to CPhI Worldwide.

6: A SMALL DOSE

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

12: OPINION

What artificial intelligence brings to pharma.

14: IN THE NEWS

A short selection of stories from the world of science.

16: COVER STORY

With the emergence of CBD-based medicines, SPI Pharma guides readers through the bioavailability challenges facing this sector of the industry.

FEATURES 8: PERSPECTIVE ON PHARMA

Why environmental sustainability is key for stopping antimicrobial resistance (AMR).

18: CONTRACT MANUFACTURING

Features from the world of contract manufacturing.

31: CPHI WORLDWIDE PREVIEW

Ahead of the world’s biggest pharma tradeshow, EPM takes a look at what CPhI Worldwide has to offer visitors this year.

50: FROM THE FACTORY

How augmented reality was used to validate the design of a new pharma manufacturing facility.

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After all, innovation is a global phenomenon and advances in medicines, wherever they are made, ultimately benefit patients – and that’s what’s most important.

ith news that the UK government has banned exports on some 24 drugs to avoid shortages, patients are once again cast into uncertainty surrounding what will happen when the country finally leaves the EU come Halloween. The news should at least be welcome to patients who depend on some of the potentially lifesaving medicines, but the announcement – described as an ‘unprecedented move’ by the BBC – does little to stem worries over concerns about medicine shortages. Industry leaders called for a temporary ban on drug exports earlier in March after they feared wholesalers would be more tempted to sell overseas if the pound dropped in value. With less than a month to go until the UK leaves the EU, the temporary ban now appears to be either desperate or a reckless shot in the dark to ensure no patients come to harm. Let’s hope the idiom of ‘better late than never’ holds up in this case.

EDITOR’S DESK Of course, medicine shortages do often occur, but the rhetoric surrounding Brexit and the UK’s preparedness for managing a potential ‘no-deal’ situation is comparable with verbal firefighting. Our government is so concerned with stemming any worry around

leaving without a deal, that no one has any idea what’s going to happen – not least the Conservatives. Here in the office we’re coming up to one of our busiest periods; jetting off to international tradeshows where industry players from all around the world meet to share ideas, network and do business – you know, all the typical jargon you’d expect from an industry event. For the EPM team that tradeshow is CPhI Worldwide, the world’s biggest pharma event and one which I’m particularly looking forward to, even with the shadow of Brexit threatening international collaboration between the UK and EU members. Despite Brexit, CPhI Worldwide is set to highlight the current world of pharma with all of its offerings, challenges and trends. With sessions on the latest innovative medicines, advances in continuous manufacturing and the rise in digital technologies, CPhI Worldwide offers so much across every sector of the pharma supply chain. As editor, it will be my first time visiting the tradeshow and I’m excited to learn more about the industry from some of its biggest and brightest players. And whilst my return to the UK may be met with a raft of announcements about the downsides of Brexit to pharma, it won’t be the end of the world. After all, innovation is a global phenomenon and advances in medicines, wherever they are made, ultimately benefit patients – and that’s what’s most important.

A small dose New facility opens in UK to support pharma start-ups

new facility has opened in Alderley Park to support the UK’s growing community of biotech and life sciences start-ups.

VELESCO EXPANDS CLINICAL MANUFACTURING

harmaceutical development and clinical manufacturing expert, Velesco Pharma has announced it will triple its clinical manufacturing capacity through a new state-ofthe-art facility. The new building will feature expanded processing suite space to provide enhanced current good manufacturing practice (cGMP) clinical trial material capabilities. The new facility, which is set to be opened at the end of the year, will be supported by Velesco Pharma’s existing quality control (QC) release and stability testing laboratory. Dave Barnes, Velesco Pharma’s CEO said: “This investment in new space and increase in our capacity will enable

us to meet growing client demands for cGMP clinical manufacturing services while still maintaining our sciencefocus and flexible approach to client projects. “Our team forged their careers in big pharma R&D and bring a wealth of expertise to the table. This experience combined with our personalised and agile approach makes us an ideal choice for clients in the critical early and later stage drug development phases. "As a business we have always placed great emphasis on adding scientific value to the drug development process and this continues to be central to our ethos as we expand and move forward.”

Pharmaceutical solutions provider Origin will open its second UK facility in Alderley Park to support the pharmaceutical industry. The company has invested heavily in its New Product

Development and Innovation Department at its headquarters in Melton over the past two years. The new facility in Alderley Park will specialise in the latest digital pharmaceutical packaging products. Biotech and life sciences start-ups will have onsite access to Origin’s packaging technologists who specialise in digital secondary packaging, compliant primary

packaging and childresistant design. Origin has said its long-term aim is to become the packaging innovation office for the site, promoting innovative thinking in the community and supporting the next generation of UK pharma talent. Pharmaceutical start-ups will be introduced to the latest digital products at the new facility, including Smart-I, one of the world’s most advanced anti-counterfeiting solutions using patented perennial encryption technology to prevent the duplication of data and heighten security. Rich Quelch, global head of marketing at Origin said: “Alderley Park was the natural choice for Origin to open its next strategic UK office, helping us to create strong partnerships on the ground with emerging UK pharma start-ups, in addition to our ever-expanding global network of clients. It’s a fantastic opportunity to support the next generation of UK pharma companies and create accessibility for them to drop in and engage with our packaging technologists.”

most inno Switzerla

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New standard for handling pharmaceuticals at Copenhagen Airport

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

Batavia Biosciences to develop anti-Zika therapy with collaborators

nfectious disease company Batavia Biosciences has announced it is to produce a potent Zika virus neutralising antibody. Batavia Biosciences has signed a license agreement with Horizon Discovery to deploy the company’s GS knockout CHO K1 cell line expression system, which will be deployed to produce high yield antibody-expressing cell lines. Batavia Biosciences will work alongside Vanderbilt University Medical Center (VUMC) and IDBiologics to develop the antibody for

the Zika virus neutralising antibody. VUMC researchers discovered the Zika virus neutralising antibody three years ago when working with colleagues at Washington University School of Medicine in St. Louis. The VUMC antibody, dubbed ZIKV117, binds to an epitope or “part of” the Zika virus in a way that no other antibody has to date. The mosquito-borne virus can cause a condition in which children are born with unusually small heads and other congenital malformations. Currently, there is no way to prevent Zika virus infections or its

aftermath. Menzo Havenga, CEO, Batavia Biosciences, said: “We are thrilled to now have access to Horizon’s expression system to complement our existing STEP technology for recombinant protein production and to have VUMC and IDBiologics as collaborators on the development of a much needed Zika virus medical countermeasure.” “We’re excited to work with Batavia to move this promising Zika antibody therapy one step closer to the clinic,” added James Crowe Jr, director of the Vanderbilt Vaccine Center.

new facility at Copenhagen Airport has set a new standard for the handling of pharmaceutical products.

biomedical shipments for many years to come,” he told guests attending the ‘ribboncutting’ ceremony.

The new facility opened by Worldwide Flight Services (WFS) provides end-to-end handling in a temperaturecontrolled environment for pharmaceutical products requiring conditions between 2-8°C.

Dan Parker, SVP commercial cargo – EMEAA at WFS, added: “We see significant potential in Copenhagen by investing in the facilities and solutions our customers need to grow their businesses. Pharma is a big focus because both Denmark and Sweden have important pharmaceutical production sites located in or around the Oresund region and Copenhagen is a natural international gateway for these products. By increasing our commitment, we also hope pharma volumes still being trucked to other airports will now see WFS is offering a more local, high quality and costefficient solution and this will also contribute to the continued growth of the airport.”

The expansion by WFS plays into Copenhagen Airport’s “Grow Pharma” strategy, according to Morten T Mortensen, the airport’s director of airline sales and route development. Speaking at the ‘ribboncutting’ ceremony in the facility, Mortensen said: “With the opening of this facility, WFS has set a new standard for the handling of pharmaceutical products in Copenhagen Airport and has ensured the capability to handle pharmaceutical and

PERSPECTIVE ON PHARMA Tackling AMR through sustainable antibiotic production A

ntimicrobial resistance (AMR) is the biggest health crisis of this and the next generation. By 2050, AMR is predicted to cause 10 million global deaths per year, more than obesity and all cancers combined and it is anticipated to cost the global economy more than 100 trillion USD per year in lost GDP. Without effective antimicrobials for the prevention and treatment of infections, the success of critical medical procedures such as organ transplantation, chemotherapy and major surgery will be severely compromised. Antimicrobial resistance occurs naturally over time but misuse and overuse are seen as the core problems accelerating the process of AMR. One area that is frequently overlooked is the environmental impact of antibiotics, including its production. The production process of active pharmaceutical ingredients (APIs) and antibiotics naturally creates wastewater, which contains residual levels Author: Alba Tiley - head of sustainability, Centrient Pharmaceuticals

of antimicrobials. Sustainable production processes then see this wastewater treated, so that it is considered safe to release into the environment. However, this is not always the case and if not treated correctly or effectively, then antibiotics are released into the waterways, accelerating AMR through the environment. This is a particular issue in Asia (China and India produce the vast majority of antibiotic APIs and finished dose antibiotics), where regulations of pollution and antibiotic effluents are not as advanced as in Europe. In the extreme, a study in Hyderabad, India, found concentrations of antibiotics in treated wastewater higher than those found in the blood of patients being

treated with antibiotics. The concentration of the most abundant drug, ciprofloxacin (up to 31,000 Îźg/L) exceeded levels toxic to some bacteria by over 1000-fold. Until recently, this contributor to AMR was severely overlooked. The World Health Organisationâ&#x20AC;&#x2122;s (WHO) global action plan on AMR makes only brief reference to the issue of unsustainable antibiotic production. If we are, as a global community, going to tackle AMR and the devastating health impacts it will cause we must act collaboratively and decisively. Simply put, this can be achieved in two key ways: MAKING antibiotics in a sustainable way

by adopting emission targets and BUYING antibiotics and antibiotic ingredients only from responsible sources to ensure a clean supply chain. When it comes to sustainable production, progress has been made by industry. The AMR Industry Alliance, one of the largest private sector alliances, formed of 100 life sciences companies and associations, have joined together to work towards a common goal of tackling AMR. The Alliance was crucial in the development of emissions targets outlined

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in the Antibiotic Manufacturing Framework which looks to reduce the amount of API content in wastewater. Similarly, efforts are being made to improve sustainability of supply chains, most notably through the Pharmaceutical Supply Chain Initiative (PSCI) which requires members to complete five supplier audits each year. This data is accessible in a shared database, exposing suppliers who are using unsustainable production methods, promoting sustainable practice. As part of Centrient Pharmaceutical’s Sustainable Antibiotics Program, we’ve implemented methodologies to detect remaining antibiotic activity in our wastewater. This way, we are sure none of our operations add to the growing threat of AMR. We have developed a wastewater

treatment and discharge test to detect the presence of antimicrobial activity in effluent and are updating our methods to reach the newest target limits. Lastly, but perhaps most importantly, is the need for buyers of antibiotics to ensure they are procuring antibiotics that are sustainably produced. Because antibiotic production and usage is global, efforts to establish international regulations have been unsuccessful. Therefore, incentivising sustainability is a critical way forward and environmental criteria should be included in the procurement process. Since 2010, for example, Swedish County Councils have been co-operating on a national level to use environmental

criteria in the procurement of pharmaceuticals in an attempt to phase out products which are deemed to be environmentally hazardous. These environmental standards are setting the nation on its way to meeting national and international targets and it demonstrates the effective use of public purchasing power as a tool to reach non-economic targets. In Norway, a similar stance has been adopted with suppliers now rewarded for their environmental efforts. The preferred pharmaceutical procurement criteria in Norway includes the supplier’s environmental and supply chain policies, comprising 30% of the overall procurement score criteria. More organisations are beginning to take similar responsibilities. Most notably, the United Nations aims to use environmental criteria on its decision making regarding the procurement of medicines, widely referred to as ‘green health procurement’, and believed to be a major contributor to the attainment of the UN Sustainable Development Goals. This good practice now needs to be adopted by nations and organisations worldwide. Together, we can secure the future of antibiotics, but it requires a collaborative global effort, and sustainable production must be a key component in the fight against AMR.

AMR:

WHAT YOU NEED TO KNOW

Antimicrobial resistance is listed by the WHO as one of the top 10 threats to global health. It’s estimated that one in ﬁve antibiotic prescriptions in the UK is unnecessary. Without antibiotics, a range of medical procedures such as organ transplants and chemotherapy won’t be possible.

Antimicrobial resistance (AMR) is the biggest health crisis of this and the next generation.

EVENTS

Can’t Stop the Future C

ontinuous manufacturing has been a hot topic within pharmaceutical manufacturing for a number of years now, but widescale implementation is yet to be seen. To help increase the industry’s understanding of the technology and its benefits, IMA Active’s ‘Can’t Stop the Future’ event ran across two days in September. Hosted at the beautiful Palazzo di Varignana resort in Bologna Italy, the event saw over 200 pharmaceutical executives learn about the benefits and latest developments surrounding continuous manufacturing within oral solid dosage forms. Introducing the event, Alberto Vacchi, IMA’s chairman and CEO said: “We are very pleased to host numerous pharmaceutical customers from all over the world in the elegant structure of the Palazzo di Varignana and at one of the Group’s facilities. For the IMA Group, the world of “Pharma”, with its increasingly demanding challenges, represents an extraordinary accelerator to which we are responding with a huge innovative effort in terms of digitisation and automation. Discussing with our customers and hearing their requests helps give direction to our strategic decisions.”

Whilst solid dosage forms are still the most common form of medicines, there haven’t been any real changes in the last 50 years, with the event highlighting how far other industries, such as food and automotive, have come compared to pharmaceutical manufacturing. However, with many pharmaceutical players now starting to focus on continuous and with regulatory bodies across the world offering encouragement, global companies are beginning to show more interest in continuous technologies. Indeed, IMA Active state that the ‘switch from batch to continuous manufacturing could represent the most important evolution since the advent of the validation and qualification system.’ Speaking at the event Bernhardt L. Trout, professor of chemical engineering at MIT and director of the Novartis-MIT Centre for Continuous Manufacturing spoke about some of the ways in which continuous technologies can benefit pharma. “Continuous manufacturing technologies have the potential to produce medicine in a matter of days

as opposed to months or even close to a year,” Trout said, highlighting the technology’s ability to help tackle drug shortages and stockpiling of medicines. The issue is that whilst we’ve seen an influx of innovative new therapies such as CAR-T and Kymriah, innovations in manufacturing have struggled to keep pace. “While we have made a lot of progress over a decade plus, I think the consensus in the continuous manufacturing community is we can do a lot more,” Trout said. BUT HOW DO WE DO THIS? Moheb B Nasr, principal at Nasr Pharma Regulatory Consulting (NPRC) and formerly of the FDA, believes trust may be an issue that needs addressing, During his talk, Nasr mentioned how often, the conversation surrounding the implementation of new facilities or processes was on the cost impact, and rather how pharma companies may be perceived to always be trying to cut costs. Instead, the focus should be on quality. What benefits does continuous manufacturing for instance bring to a drug’s quality and how this will impact the patient in a positive way.

Opinion The standout value that AI can currently provide to the pharmaceutical industry is in removing the bottlenecks around data identiﬁcation, extraction, quality, harmonisation and integration.

THE AI SWEET SPOT FOR PHARMA Artificial intelligence (AI) has been trumpeted by many in the pharmaceutical industry as the magic bullet to the issues they face in drug discovery and other research. However, expectations need to be tempered because although it’s easy to get excited by the potential of AI it’s important not to get too carried away with the reality of what’s possible today – at least at low cost and at virtually no risk.

T Author: Barley Laing UK managing director at Melissa

he standout value that AI can currently provide to the pharmaceutical industry is in removing the bottlenecks around data identification, extraction, quality, harmonisation and integration. These are all issues that have plagued the pharmaceutical industry for a long time. And in an age of digitisation where researchers are increasingly facing a proliferation in the types and variations of data, including drug doses and molecular structures in many forms, such as text, numbers and images; it’s AI that can play a vital role in helping to make sense of it all.

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SEMANTIC TECHNOLOGY A relatively new AI technology that has data quality, integration and analytics at its core called semantic technology, which is also called the semantic web and “semtech”, is well positioned to solve the issues that face researchers in pharma. Where it really stands out is in its ability to associate words with meanings and understand the relationships between them. By building relationships between data semtech can deliver machine reasoning, allowing computers to understand data objects in meaningful ways; helping researchers to make connections, uncover hidden relationships and deliver greater learnings from their data. Even better, semantic technology can do this in real-time, accelerating research and discovery, for example in assessing drug efficacy, detecting toxicity during drug development, or testing hypotheses. As a result, it not only helps to drive efficiency during the research process, but also uncover hidden insight within the data, which cannot be delivered via any other method. A further important plus for semtech is it can deliver universal data interoperability. This means data sets that are relevant to each other but exist in other formats or locations can be securely and reliably exchanged; something that’s very beneficial for research. Additionally, when researchers upload new data into the system semantic technology can update and deliver learnings quickly and cost effectively. Looking at the bigger picture, this technology can redefine concepts and relationships as new information becomes available – increasing its value as a flexible and powerful tool that evolves in step with data. It’s this evolution in AI and its ability to automate and streamline the process of data capture and integration, which will help researchers in the pharmaceutical industry to move away from time consuming manual work and focus their efforts on making learnings, quickly and cost effectively, during drug and clinical trials, and other important research.

DATA ACCURACY AND INTUITIVE PLATFORM It’s important for the pharmaceutical industry to bear in mind that for semantic technology to successfully deliver insight it requires access to accurate data. This can sometimes be hard to come by in a sector that has a reputation for having poor data because of its complexity, which can result in critical errors and inefficiencies. To solve this problem the industry needs to prioritise investment in data quality operations. This means continually cleansing, standardising, and enhancing their data. Ideally those in pharma should source semantic technologies optimised for healthcare which include built-in, in-depth knowledge of drugs, genes, and diseases that recognise and validate drug names, variants, dosages, and spellings. This will help prevent confusion and mitigate errors generated by busy researchers and physicians in a very complex field as well as aid data enrichment. In a world that can be made increasingly complicated by new technology, it’s vital the frontend interface to access semantic technology is easy to use by non-IT personnel. To this end it must enable straightforward visual exploration and data analysis across numerous internal and external databases – with no coding knowledge required – to uncover insight securely. This should include the ability to perform detailed semantic queries easily and interact with third-party applications for analysis. Semantic technology hits the sweet spot for AI in pharma. It opens up a wealth of opportunity to improve efficiency in drug trials and medical research alike, by extracting the relevant information to deliver insights and outcomes, costeffectively, and in real-time. It’s time for the industry to investigate its wide-ranging benefits.

Where it stands out is in its ability to associate words with meanings.

14 Self-translating labels to be rolled in across pharma in 2020

onsumers may be able to read pharmaceutical packaging in any language according digital marketing specialist Dave Chaffey. Chaffey, who leads the augmented reality start-up Third Aurora, believes the technology will be rolled out across the pharmaceutical industry in 2020. By combining artificial intelligence (AI), AR, and a smartphone, Third Aurora was able to develop a solution which can translate over 100 languages. The opportunities for pharmaceutical manufacturers are tremendous, Chaffey believes, though he states there’s still a lot of work to do before the product launches. More so, the company is using AR to deliver a range of other information and services directly from packaging labels.

IN THE NEWS

NICE rejects migraine prevention drug

harma company Novartis has expressed disappointment over the National Institute for Health and Care Excellence’s (NICE) decision to reject the use of its chronic migraine prevention drug Aimovig on the NHS England. Though NICE recognised the clinical effectiveness of Aimovig, it stated the drug wasn’t cost effective compared to current treatments of Botox; which require patients to undergo several clinical visits to receive injections to the head and neck. Aimovig on the other hand can be selfadministered at home and doesn’t result in any side effects which are currently experienced with existing oral medicines for chronic migraine.

THE MEDTALK PODCAST TALKS HEALTHTECH

T Haseeb Ahmad, Novartis’ UK president said: “Clearly this is not the result we’ve been working towards; with chronic migraine patients in England who could benefit from Aimovig being denied routine access to this important treatment option, whilst it is NHS funded in Scotland.” Charities too have expressed disappointment over the decision, with The Migraine Trust

expressing concern over the lack of treatment options available for patients. “My main worry is that I’m yet to find a neurologist who doesn’t want to have the option of being able to prescribe these new types of preventive drugs when they and their patient think it is likely to be in the patient’s best interest,” Gus Baldwin, chief executive of The Migraine Trust said.

his episode sees the team speak to Dr Ian Jackson, medical director and clinical safety officer at digital communications company Refero. Their chat takes them through all things healthtech; from the appointment of Matthew Gould at NHSX to the digital technologies and investment solutions taking place within the NHS. Lastly, Dr Jackson gives his thoughts on the plans for an NHS artificial intelligence laboratory and why the name might be a bit of a misnomer.

Did you know?

“We’re creating a future where the product is the source of its own information. Conveniently delivering meaningful content to consumers right from the label,” exclaims Chaffey.

There are over 190,000 migraine attacks in the UK every day.

Migraines affect three times as many women compared to men.

Migraine is ranked as the seventh most disabling disease in the world.

Migraine is the third most common disease, affecting around one in seven people.

Contract Manufacturing

Last year we produced enough packs to reach the International Space Station twice!

Launch your next product with Acino Contract Manufacturing... acino.swiss/our-business/contract-manufacturing

COVER STORY

FEELING GOOD With the emergence of CBD-based medicines, SPI Pharma guides readers through the bioavailability challenges facing this sector of the industry. Author: Sarath Chandar â&#x20AC;&#x201D; chief scientific officer, SPI Pharma

annabidiol, or CBD, is one of more than 100 different derivatives of Cannabis. CBD is produced from both synthetic and natural sources. It is nonpsychotropic and is being increasingly promoted for its potential therapeutic benefits in pharmaceutical, nutraceutical, cosmetic, food and beverage applications. Companies and consumers are following benefits such as treating pain, nausea, anxiety, schizophrenia, epileptic seizures, and more. There are currently only two pharmaceutical products with clinical data that have been approved by regulatory agencies. There are multiple clinical studies in progress in various phases and for different indications. The number of studies has more than doubled in 2019 over the previous year. Based on some of the early results, an outlook of strong growth is projected for CBD formulations in the pharmaceutical sector. Market research data indicate global market projections for sales of CBD ranging up to $22bn by 2022. While there may not be consensus on the actual size of the market, the one thing researchers seem to agree on is the strong growth rate of up to ~30% per year that is forecast to continue well into the next decade. Limited clinical data and efficacy issues associated with CBD have resulted in few approved pharma products. GW Pharmaâ&#x20AC;&#x2122;s epilepsy drug, Epidiolex is the only FDA approved product in the US. Despite an explosion of nutraceutical and cosmetic products that have hit the US market in the last two years, none of them have been subjected

to the rigorous FDA approval process. Instead, they fall into a regulatory gray area that allows CBD from hemp having less than 0.3% THC to be sold in certain states as consumer products, while being restricted at the federal level. Regulators are debating the necessary requirements for classification and approval of CBD-based therapies. At the same time, consumers are becoming more discerning and educated, demanding higher quality and consistency in CBD products. Regulations will become more stringent and consumers will demand new products. The debate will likely continue until safety and efficacy claims are proven with clinical studies and reliable finished product testing to determine dosing range. Ultimately, CBD products will require proof of safety, efficacy and appropriate dosing for each indication, in addition to being convenient to transport, store, administer and take. With this background in mind, it is important to understand CBD from a pharmaceutical perspective. Characterising the solubility, bioabsorption and dosing range are challenges that formulators face when developing new CBD products. CBD is lipophilic and highly susceptible to first pass metabolism, meaning that in its natural state, only about 8 to 12% of the CBD ingested by oral route is capable of being absorbed into the bloodstream and delivering targeted therapeutic benefit. In addition, CBD made from natural source can result in batch-tobatch variations in composition

and concentrations of the active with different levels of impurities making proper API dosing extremely challenging. Many consumer products on the market today are liquids in oil or tincture form, which inherently carries a higher risk of micro-contamination, inaccurate dosing, poor taste, and higher transportation costs. The lack of convenience and cost effectiveness could result in a lack of compliance. A significant body of work has been conducted in the last 10 years to overcome the challenges of limited oral bioavailability, the variation of CBD from natural sources, and the ability to test accurately for impurities. However, successful pharmaceutical product launches have been few and far between and the current IP landscape presents its own set of challenges in overcoming these obstacles. Purisys, LLC, a new business spun off from Noramco, and SPI Pharma are working together in a phased approach to tackle these challenges. Purisys manufactures and supplies controlled substance active pharmaceutical ingredients, produces ultra-pure synthetic CBD that meets the strictest regulatory requirements of health authorities around the world. SPI Pharma manufactures and supplies functional excipient platforms and drug development services, brings significant experience in formulating patient friendly dosage forms, which are particularly useful in 505(b)(2) regulatory pathways. The goal of the collaboration is to generate unique, efficacious CBD dosage forms that deliver

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improved bioavailability, consistent stability, faster onset of action, lower cost of manufacturing, and that are convenient to carry and take. So far, the efforts (Phase 1) have focused on the following, which are critical to understanding the basics of formulating with CBD: • Identifying compatible APIexcipient combinations that will provide the functionality required to develop the desired dosage forms without generating unwanted impurities. • Developing and testing various bioavailability enhancing techniques, some that are established technologies and some novel approaches. • Establishing a multi-phased formulation strategy based on the outcome from a recent study that examined more than 75 samples of high-purity. • CBD with various excipients and platforms by stressing the samples and measuring chemical decomposition over time. Phase 1 is being completed using some of the more commonly published techniques for increasing bioavailability of CBD. Patient-friendly forms like orally dispersible powder and/or tablet prototypes are on schedule to be placed on ICH stability and evaluated for functionality by Q4 2019. These prototypes are expected to deliver therapeutic effects similar to other orally ingested products but in a more convenient delivery format. Phase 2 work has also begun and focuses on improved bioavailability through multiple, innovative, techniques that will enable lower dosing regimens and administration through more efficacious routes, (e.g. sublingual). If successful, the major benefits of this approach will include reducing

the amount of the API (and as a result, the cost), lowering the impact of potential side effects, while delivering faster onset of therapeutic action. The initial results for improved bioavailability have been very encouraging, and the goal is to have proof-ofconcept prototypes available by mid-2020. Phase 3 will focus on getting the formulation into the clinical trial process and will depend on identifying potential licensees for the technology. The work is intended to expand the understanding and utility of CBD by creating innovative formats and enabling the process to make it a more accepted therapy that can make a difference in enhancing patients’ lives.

Ultimately, CBD products will require proof of safety, efficacy and appropriate dosing for each indication, in addition to being convenient to transport, store, administer and take.

CONTRACT MANUFACTURING

LEADING THE WAY Felix Faupel, head of contract manufacturing at Acino talks to EPM about the biggest challenges of being a contract manufacturer. Felix Faupel, head of contract manufacturing, Acino

The only things that must not be flexible is your quality, your word and your integrity.

As a leader in advanced drug delivery technologies, specifically oral modified release and dispersible forms what are the current challenges for contract manufacturers? I strongly believe that it is a question in which field you are working in. Things are going great for companies that produce or process biologics. The more complex it gets, the more power technology driven contract manufacturing organisations (CMOs) have in negotiations, which directly translates into revenue and profitability. In this field I sometimes have the feeling that it is maybe more challenging for a pharmaceutical company to find a reliable partner. For oral solid dosage forms it is a completely different picture. We see worldwide overcapacities and very strong international competition, even though European manufacturers can still profit from high market entry barriers, good quality systems and more reliable supply chains. Especially for products with higher margins in the market, e.g. specialty pharmaceuticals, European manufacturers are still the best choice for pharmaceutical companies. But these products are often smaller in volumes and difficult to handle. As a manufacturer, this needs to be addressed with a flexible contract manufacturing offer. So how does Acino’s offering set it apart from other manufacturers in such a highly competitive field? Even though we see ourselves as

a best-in-class manufacturer of oral solid dosage forms, we know that the technology we offer has existed for many years or even decades. There are few companies in Europe that can offer the technologies we have. So, when we started to think about what we can do differently, we quickly came to the point where we realised that we have to adjust our offering towards the actual market demand and as I already mentioned, for me this is flexibility. Flexibility is a word that might be very vague, but it gives us guidance on how we must operate in our daily business. It means we need to show flexibility in our technology set-up, e.g. to be able to offer all kind of different oral dosage forms in different scale and our equipment allows us to do exactly that, it also means that we must be able to adjust to the market conditions of our customers, because if they are not able to sell their products in their markets, we wouldn’t participate as well. There are many other things that CMOs must show flexibility on, e.g. how you handle unusual customer requests or when you work out transfer projects with customers, but it shall be an overall and integrated way of flexible working. I have seen many customers complaining about feeling unimportant with larger CMOs, but with our company size, I think we can work for all kind of differently sized customers, with different demands and desires, care about each single customer as well as

possible and still be flexible in our daily work. The only things that must not be flexible is your quality, your word and your integrity and with that approach, I firmly believe that we can make a difference for our customers and set ourselves apart. In the end CMO business is always a partnership and not a classical provider/customer relationship and both partners must realise that in the first place and live up to it. What are the beneﬁts and challenges to outsourcing partnerships and how can we overcome the challenges? I think the benefits and challenges are well known to all players in the outsourcing world for quite a long time and therefore I find it utterly surprising that the challenges were not yet fully removed upon today, after decades of outsourcing activities and the rising of the CMO industry. Of course, we see real ambitions to overcome the existing challenges, like the current supplier consolidation activities at almost every major pharmaceutical company to reduce complexity and costs in external manufacturing, but for me this is not enough and pharmaceutical companies and manufacturers could do more. In which way? Supplier consolidation is often a one-sided approach that does not work without integration of the manufacturer in business processes. It requires a lot transparency and trust, but I believe integrating your CMOs into your business process earlier and better can only help to improve

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the supply of the goods. After risk sharing and commercial agreements, both partners need to work as if they are one company without any prejudice and reservations towards each other and this can only function in an open and transparent environment. For me, establishing such an environment is the most difficult task of our entire industry. Everybody can request quotations and construct a profitable business case around consolidation, but only the daily work with your partner defines if your ambitions will pay off, because itâ&#x20AC;&#x2122;s a relationship driven by humans and not machines. So integration of both partners is key? Yes, it can start with sharing folders between both parties and end with CMOs managing the customerâ&#x20AC;&#x2122;s

demand planning. In addition, our industry will be heavily influenced by the digitalisation and the newest developments of service providers like SAP, Microsoft and Google. These developments will also help partners to facilitate their relationships in manifold ways, we will have endless opportunities and it will be a challenge to choose the right among them. With regards to digitalisation, how do you integrate Industry 4.0 into your operations? From our daily business as a commercial role we are well equipped with the abovementioned tools to integrate ourselves, but to be very honest, Acino started to look into digitalisation of our technical operations just recently. But we are now really accelerating our digitalisation activities also within

our facilities. We started with our QC department, which will become paperless in the future and for which we implemented a digital planning schedule that is connected to SAP. We will use RPA (robotic process automation) to reduce process times for different processes from several hours to a few seconds, which will clearly give us an advantage in the market. But we also have identified areas in our production that can be digitalised or integrated and we will be working on them in the near future. The interesting thing is, our entire industry just accomplished a huge step that I would consider as a digitalisation & integration project: Serialisation. We have seen our and our partnerâ&#x20AC;&#x2122;s engineers and project managers working together very closely to meet the deadline earlier this year and they succeeded. So almost everybody has made experiences now and I hope we can take this a good example on how digitalisation and integration can work out properly, if our data is well maintained and everybody works together. We would all benefit from that.

TOP 5 BENEFITS

Supply risk mitigation Product cost savings Access to (niche) technology Access to free capacity Avoiding major investments

TOP 5 CHALLENGES

Communication & cultural hurdles Mismatch of expectations Increasing dependency with increasing complexity Pricing for commoditised products Missing CMO market transparency

CONTRACT MANUFACTURING

STRAIGHT TO THE SOURCE

What beneﬁts does an embedded CDMO model bring and how Pﬁzer CentreOne operates within one of the world’s premier biopharmaceutical companies.

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harma companies often need to access specialised manufacturing resources, facilities and capabilities to progress a drug from development through to commercial production. The outsourcing landscape is very fragmented and highly competitive, with a wide range of full service and niche contract development and manufacturing organisations (CDMOs) to choose from, as well as pure play and embedded CDMOs. THE EMBEDDED CDMO MODEL The embedded CDMO is a unique option within the pharma and biopharma outsourcing space. Although it is not new, there is still a lack of understanding about it in the market. An embedded CDMO operates as a self-contained organisation, within a larger biopharmaceutical company. Through this embedded model, the CDMO can offer access to technologies, capabilities, and expertise of the parent company while simultaneously protecting the IP of the prospective customer. One advantage of the embedded model is that it can often implement scale up in a reliable way as embedded CDMOs have been through the process many times through their parent company’s own development work. By having access to experts who can anticipate issues that may occur during scale up before the process begins, embedded CDMOs can offer their partners reassurance. Many CDMOs strive to offer a full suite of services from development through to commercial manufacture to simplify the supply chain for prospective customers. In order to provide that service, CDMOs must have experts that understand what it takes to go from lab or small scale to larger, commercial production scale. The CDMO must have expert

knowledge of the container system, the drug substance, the excipients, the equipment and the conditions needed for tech transfers and scale-up to run smoothly.

accordingly. Embedded CDMOs will often invest the money needed to do this, as they will need to ensure that their own products also meet the necessary requirements.

With embedded CDMOs, it is often much clearer in which areas they have a stronger offering, having built up specialist expertise through their parent company and invested in the appropriate technology over time. Other CDMOs may base new technology investments to keep up with market trends without having built the right expertise, potentially adding greater risk to customer projects.

PROTECTING INTELLECTUAL PROPERTY Understandably, pharma companies are fiercely protective of their intellectual property (IP) and other forms of sensitive data. There is a current misconception in the industry that embedded CMDOs cannot protect important IP from the larger companies in which they work.

With extensive experience through their own development work, access to global manufacturing expertise, world leading technologies and contemporary facilities, embedded CDMOs are ideally placed to implement effective tech transfers and scaleup. REGULATORY DEMANDS AND COMPLIANCE Businesses operating in a heavily regulated industry, such as pharmaceuticals, are very likely to know about the regulations that may apply to the geographical location they will market their medicine in, and they need to ensure that their CDMOs are just as knowledgeable. By understanding the regulations that apply to each step of the development and manufacturing process, embedded CDMOs can often anticipate questions that might arise and help avoid costly delays. Good practice (GxP) requirements are ever changing, and they can vary from location to location. Pharma companies and their CDMOs need to remain up-todate with any challenges and changes they may face and invest

Embedded CDMOs will not risk the legal repercussions and the damage that failing to protect a customer’s IP would do to their reputation and their business. Because the embedded CDMO will usually implement the strict policies and procedures of the parent company it operates within, in order to protect IP and other forms of sensitive data. This means that partners can rest assured, knowing that important information such as trademarks, copyrights, patents, process and other pieces of proprietary information will be kept entirely confidential from development through to commercialisation. IN CONCLUSION There is clearly a lot to think about when it comes to choosing the right CDMO. While standalone CDMOs can work well for many pharma companies, the embedded model is becoming a strong option. By having constant access to the expertise and capabilities of big pharma, embedded CDMOs can advise on changing regulations, scale up effectively, protect partner IP, provide access to ‘in demand’ technologies and work in collaboration to deliver personalised service. Going forward, it is likely that the embedded CDMO model will continue to grow.

Author: JoyL Silva – general manager, Pfizer CentreOne

CONTRACT MANUFACTURING

Contractual obligations EPM speaks to a number of key players in contract manufacturing to get their thoughts on the sector’s changing landscape.

The CMO market has been predicted a CAGR of over 7.75% between 2019 and 2024, what do you attribute the anticipated trajectory to? Why are companies outsourcing more of their manufacturing requirements?

Authors: Mark Quick, executive vice president – corporate development, Recipharm Bobby Sheng, CEO, Bora Pharmaceuticals Manuel Leal, director of business development, Idifarma Vincent Dunne, CEO, The Wasdell Group Tom Wilson, VP, global contract manufacturing leader, Pfizer CentreOne Andrew Henderson, sales and marketing director, Sterling Pharma Solutions

Quick: There are a number of reasons why outsourcing is a popular option. Put simply, it allows drug developers to access expertise and capabilities they may not possess in-house, as well as generating time and cost efficiencies in many cases. For example, many big pharma companies have divested their manufacturing facilities often to CDMOs, particularly those using more traditional technologies, and have turned to outsourcing their manufacturing. This allows them to focus on R&D and developing the next round of pharmaceutical innovations. In addition, as drugs become more complex, the need for specialist skills is increasing and outsourcing is a good option to access these. With this forecasted growth, where you do see investments needing to be made in the future? And do you have any in the pipeline? Leal: There's demand for contract manufacturing of highly specialised drugs for cancer and other treatments. As such drugs require niche and complex skills to develop and manufacture, the outsourcing industry has thrived as companies look to partner with specialists for their product.

We identified that around 40% of all new chemical entities (NCEs) have low solubility. At Idifarma, we believed it was a necessity to have a strategy for improving poor bioavailability, hence why we invested in GMP spray drying capabilities to support the development of these drug products. Consolidation has been a hot topic in the contract service market, how has it impacted your organisation? Do you think it’s aﬀecting market competition? Sheng: Our industry is a relatively small community, so with each acquisition there is a lot of shuffling of resources, humans and capital. This makes it an interesting time for CMOs and encourages growth and change. I think it’s healthy for CMOs and the industry benefits as a whole, as it forces companies to be more competitive in their offerings when other CMOs are scaling up and pooling resources with every M&A. However, I believe quality, customer service and reliability will prevail for a company’s overall competitive value. Alongside technical capability, these factors are at the forefront of considerations as they will always be critical to the success of their product or project. There is always a risk that the larger an organisation becomes, the more siloed and inefficient it will be, which ultimately impacts the quality and speed of product delivery.

How are CMOs oﬀering added value to the market in 2019? Wilson: CMOs should serve as reliable partners for their customers, offering expertise that is not available in-house to guide a drug securely and efficiently from development to commercial manufacture. There are many challenges faced during drug development, including scaling up and optimising processes for commercial volumes. CMOs with both small and large scale capabilities are well equipped to guide their customers. In addition, as the regulatory landscape becomes more complex, CMOs with a global reach can help biopharma companies navigate the requirements and achieve compliance. It is Pfizer CentreOne’s belief that many minds are better than one. Collaboration and knowledge sharing in a successful CMOsponsor relationship can add significant value to a drug development project. Does the CMO market diﬀer from region to region, or are we seeing these trends on a global scale? Dunne: Trends within the CMO market are fairly similar on a global scale, with outsourcing needs increasing on an annual basis. However, there are some regional differences, for example in Europe companies need to choose an outsourcing partner who is well equipped for navigating the specific regulatory landscape and

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requirements of each country. Choosing an outsourced partner who is not only focused on product delivery, but on market access and distribution allows for seamless product and market entry, supporting ongoing commercialisation requirements. Do you think CMOs are riskaverse or pushing innovation in the pharma supply chain? Henderson: We launched our Technology and Innovation Programme over 4 years ago designed to allow us to explore new and emerging technologies that could benefit the pharmaceutical supply chain. By working with our partners at local universities we are able to access the viability and commercial potential of some of these new technologies with the ultimate goal of developing these into solutions

for our customers. At Sterling weâ&#x20AC;&#x2122;re committed to continuous progression so we can provide the best service for our customers and their products. How are contract manufacturers preparing for niche drug pipeline? How will the move from large scale manufacturing aďŹ&#x20AC;ect the CMO landscape? Leal: As the industry becomes more focused on such complex treatments and smaller-patient populations, specialisation amongst the CMO market will become more important as each organisation looks to differentiate itself and demonstrate its expertise. The industry is also continuing to consolidate and bring a vast range of niche requirements under one roof. However, despite this trend, smaller independent CDMOs will

be better placed to support on these highly-complex projects, as they have been built on agile manufacturing methods that are prepared to handle smallervolumes and the nuances that come with that.Â Idifarma is an example of this, as our focus is to manufacture niche and highly potent products and we have specifically designed our facilities to do this.

This makes it an interesting time for CMOs and encourages growth and change.

CONTRACT MANUFACTURING

Triangulating factors Understanding the factors related to outsourcing mAbs projects.

ver the last decade, emerging biotechnology companies have played an increasingly critical role in the development of new drugs. According to a recent IQVIA report, emerging biotechs, (defined as companies with less than $500 million in revenue) patented more than 60% of the 59 new drugs that launched in 2018 (up from 50% in 2010). Furthermore, these organisations account for more than 70% of the current assets in the late-stage pipeline (up from 61% in 2008). Contract manufacturing organisations (CMOs) and contract development and manufacturing organisations (CDMOs), together

Authors: Daniel Dussault, Merck Manuel Kretschmer, Merck Stella Chen, Merck JeďŹ&#x20AC; Tsao, Merck

with their partners in the emerging biotechnology sector, play an integral role to support the swift and cost-effective development of novel drugs as they can help reduce the need for large upfront capital expenditures to build infrastructure. Suppliers of equipment and consumables for process development and manufacturing of monoclonal antibodies (mAbs) play a special role in this ecosystem, since they often serve both parties. In an attempt to understand the interactions between emerging biotechs and CDMO/CMOs better, Merck, together with Ipsos, conducted a double-blinded

global online survey in Q1 of 2019. The campaign surveyed ~130 participants that are affiliated either with a CDMO/CMO or an emerging biotech from the US, Germany, China, Japan and South Korea. THE KEY RESEARCH FINDINGS CAN BE SUMMARISED AS FOLLOWS: The majority of emerging biotechs seek to engage CDMOs early in the development process to mitigate risk and save cost According to the research, in most world areas approximately 40% of biotechs engage with CDMOs/ CMOs during Phase 1. In China,

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CONTRACT MANUFACTURING

The primary motivation for outsourcing early-stage assets is managing risk, thereby ensuring a smooth manufacturing process. this occurs more frequently during Phase 2. The primary motivation for outsourcing early-stage assets is managing risk, thereby ensuring a smooth manufacturing process. Cost savings is nearly equally as important for emerging biotech, as it reduces the need for large capital expenditures necessary for setting up in-house facilities, instead preferring to seek a partner to take on this responsibility for them. Becoming a preferred vendor pays oﬀ for CDMOs, but a strong network is helpful The survey also focused on the process for selecting CDMO/ CMO partners. Findings indicated that emerging biotechs in all surveyed countries rely heavily on preferred vendors as well as informal networks. This highlights the importance for CDMOs to focus on building a strong network in the industry and ideally aim for preferred vendor status. Formal RFP processes seem to play less of a role in Western markets, however, this does not extrapolate to China, where they appear to be quite common, potentially driven by the absence of strong networks given the market’s lower maturity. Cost matters everywhere, but other preferences vary by geography Regardless of the process used— preferred vendors, an informal process or request for proposal

(RFP) — there is a consensus across geographies that cost competitiveness is a prime attribute for CDMO/CMO selection. Beyond that, however, there is again a geographical divergence. A CDMO’s track record and reputation are very important criteria in the US and Europe. In these markets, emerging biotechs seem keen to establish stable relationships with CDMOs/CMOs so they can grow together and develop an asset together in a true collaboration. The track record is less important in China. Instead emerging biotechs prioritise the availability of specific capabilities (e.g. regulatory, quality, etc.), again reflecting the different maturity stage of this market. CDMOs are gatekeepers for selection of equipment and consumables making them an important partner for consumables and equipment suppliers Following CDMO/CMO selection, emerging biotech firms were asked about the guidance they provide related to protocols and equipment/consumables during the asset transfer. The research indicated that two separate decision-making processes seem to exist. On average, approximately 30% of the emerging biotechs recommend protocols, most often for cell lines, chromatography, and cell culture media. However, only about 20% provide recommendations related to equipment or consumables. It is interesting to note that of the emerging biotechs that provided recommendations, 50%-60% believe that their recommendations are being followed. These findings prove the reliance on CDMO/CMO partners to develop a robust manufacturing process and demonstrate

that there is an opportunity for suppliers of equipment and consumables to drive a part of their business through engagement with the emerging biotechs. To triangulate these findings, similar questions were asked to the CDMO subgroup and the research showed that only one third of CDMOs at least sometimes follow the recommendations they receive and 45% do not even consult their partner. The main reason to deviate from the received guidance is incompatible infrastructure, followed by a different preferred supplier. These findings highlight the powerful and critical role of the CDMO in the process and make it abundantly clear that the suppliers have to focus on this stakeholder group to drive their business. When examining the nature of the relationship between the suppliers and the CDMOs, the research revealed that only 15% of CDMOs avoid switching suppliers, whereas the rest evaluated on a project-byproject basis which supplier to use. Suppliers have several levers they can exploit to increase loyalty. When selecting suppliers, >80% of CDMOs indicate quality as a main attribute in the selection, rendering this attribute table stakes. There is a series of attributes that a large percentage of participants deem important and are therefore potential leverage points to drive differentiation. In summary, the research furnished important insights for each stakeholder in the ecosystem that suppliers can leverage to better serve this market and increase efficiency in the drug development process.

#TheContiTruth #GoingConti

Immerse Yourself … in the Real and Virtual Worlds of Continuous Manufacturing At the heart of this year’s CPhI Worldwide, GEA (stand 110C70)

For real-world learning opportunity, GEA is also hosting a

will be presenting a selection of equipment for the batch and

free-to-attend pre-CPhI event on 4 November in Wommelgem,

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products, as well as containment solutions, separation technologies

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and equipment for materials handling, homogenization and

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freeze drying. Back at CPhI, our experts will be happy to meet you and talk In the on-stand Continuous Experience room, attendees will

about Quality by Design (QbD) for oral solid dosage production,

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CLINICAL TRIALS

THOUGHTS ON CLINICAL TRIALS

Aiden Flynn, founder of analytical solutions company Exploristics answers some of the most pressing questions relating to clinical trials.

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What are some of the major barriers currently facing clinical trials? The clinical trials industry suffers from a very poor record of success. One of the major barriers facing clinical trials today is poor trial design, which can lead to incomplete data sets, an inefficient or costly trial process and ultimately contribute to a trial’s failure. The increasingly complex clinical questions that are being asked in trials that focus on precision medicine or rare diseases demand an optimised study design from the outset. Statisticians should be brought in at the design stage to ensure that studies are designed to deliver statistically significant and clinically meaningful answers. Many case studies are not planned like this and statisticians are only involved at the end of the process to recover value from incomplete data sets, which isn’t always possible. How digitised is the clinical trials industry? The industry has been reluctant to employ new approaches and software but is beginning to recognise the benefits. Cloud computing, for example, can facilitate the electronic data capture (EDC) of the large volumes of data routinely collected as part of a clinical trial. We are also seeing the emergence of cloud-based solutions in other stages of a clinical trial. Researchers are starting to employ simulation software to improve their design with the advent of new data types, such as biomarkers and wearable technology. With server-based software, statisticians are constrained

by processing power and the time required to generate and repeatedly amend programming code to change parameters and run multiple simulations. Cloudbased simulation tools allow the user to investigate the design and analysis options through a web browser and run hundreds of parallel processes at one time. Clinical development teams and regulators are starting to acknowledge the advantages of cloud-based software. As such, we are starting to see growth in requests and the application of simulation to optimise clinical trials and programmes. How can patients beneﬁt from the use of tech within clinical trials? Software technologies that facilitate the clinical trial process will enable drug developers to deliver medicines faster to the patients who will receive a marketed drug following approval. As the clinical trial process becomes more efficient and effective at evaluating a treatment, it means that a treatment is more likely to be approved by regulators and be accepted as a marketed medicine. The better we get at designing clinical trials, the better we will understand which patients are more likely to respond to new treatments. The result will be the right drug to the right patient first time, meaning huge cost savings to organisations like the NHS, which can avoid paying for drugs that aren’t very effective. How can clinical trials use cloudsoftware to improve study time and results? Failure to optimise a clinical trial design often results in unnecessarily lengthy timescales,

inefficient recruitment strategies and ultimately inadequate results, which could lead to failure. The ability of cloud software to use sophisticated statistical algorithms and synthetic data sets to reveal probable clinical trial outcomes before any time or money is spent in the clinic has the potential to revolutionise clinical research and the rate at which life-saving innovation is enjoyed by patients.

Author: Aiden Flynn – founder, Exploristics

Does the emergence of cloudsoftware coincide well with the rise of wearables in the healthcare sector and what does this mean for clinical trials? Wearable devices have proven invaluable in some clinical studies, particularly those on neuro diseases, as they allow key patient measurements such as heart rate, gait and sleep pattern to be taken 24 hours a day and provide a more detailed picture on why some people may respond to a treatment and others don’t. Wearable technology also allows huge numbers of subjects, not enrolled on specific clinical trials, to generate data relating to their baseline activity and other simple physiological measurements. If we harness these data intelligently in the future, we have the possibility of understanding patient behaviour and disease progression in greater detail enabling more effective trial designs having understood more about the subjects.

The industry has been reluctant to employ new approaches and software but is beginning to recognise the benefits.

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EDITOR’S COMMENT A swathe of high stakes mergers and acquisitions between various pharma players this year has shown that the industry is far from stagnant, and the need for global cooperation is key if the industry is to survive without repercussion. More so, it’s evident that while advances in technology are driving other industries such as food and automotive, pharma is still behind the curve due to a highly regulated environment and uncertainties surrounding costs. That’s why as an event CPhI Worldwide is so important: bringing together the pharmaceutical world to share ideas, collaborate and ultimately advance the industry. I look forward to being there!

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Showtime

ur guide to CPhI Worldwide will have you prepared for the biggest pharmaceutical exhibition taking place this year.

CPhI Worldwide is set to unite our industry once again as the world’s largest pharmaceutical exhibition returns to the Messe Frankfurt Germany on 5-7 November. Running across three days, CPhI Worldwide covers all aspects of the supply chain – from ingredients and finished dosage to machinery, packaging, outsourcing and biopharmaceuticals. This year over 45,000 attendees and 2,500 exhibitors are expected to walk through the doors to CPhI Worldwide, meaning visitors will be hard pressed if they want to maximise their time at the show. WHAT’S ON For those wanting to expand their knowledge of the industry, CPhI Worldwide’s Pharma Insight Brieﬁngs feature over 60 seminars across the show’s three days. Three theatres ensure visitors have enough content to absorb throughout the show; from artificial intelligence (AI), drug delivery devices, the latest cell & gene technology and more. From the emergence of cell and gene therapies, digital healthcare and constant updates surrounding regulation, the pharmaceutical

industry is constantly moving. That’s why this year, CPhI Worldwide has opted to include a new podium titled World of Pharma to help visitors wrap their heads around the everchanging pharmaceutical landscape. Expect updates on Brexit, the latest therapeutic innovations and how to navigate markets in Africa and the Middle East. With the industry currently excited by the rise in biopharmaceuticals, CPhI Worldwide has made sure to dedicate an entire zone to the sector.

The BioProduction Agenda will feature speakers from BristolMyers Squibb, Bayer, GSK and more to discuss the opportunities, strategies and latest innovations for biologic and cell and gene therapies manufacturing. Don’t miss the session’s keynote speakers set to focus on the challenges and opportunities in biomanufacturing; what to expect from next generation bioprocessing technologies and how patients can benefit from effective data management.

EPM PICK GEA – Stand C70, Hall 11 At the heart of this year’s CPhI Worldwide, GEA will be presenting a selection of technologies for the batch and continuous granulation, tabletting and coating of pharmaceutical products, as well as containment solutions and equipment for materials handling, homogenisation, separation and both spray and freeze drying. Discover GEA’s portfolio of single units, modular systems and complete production lines, create new opportunities to get your product to market faster with our efficient and reliable process solutions, experience the 3D virtual world of continuous manufacturing and discuss the developments and technological breakthroughs that will help to define the future of the industry.

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EPM PICK Chargepoint Technology – Stand 110G02 ChargePoint Technology will be showcasing its new Single Use Multi-Site solution, which offers manufacturers a high performance and cost-effective way to transfer high potency and sterile material.

Use Multi-Site solution provides a method of contained powder transfer within facilities and can also be used as a product’s primary packaging and container closure for transport between sites.

This new development, which utilises new and existing technology, allows users to take advantage of the benefits of disposable technology without compromising performance. ChargePoint Technology’s Single

Even better, the solution’s standardisation enables it to be used off the shelf and lets pharmaceutical companies deploy a pre-qualified system without significant delay or set up for new production.

WHERE AND WHEN The CPhI Pharma Awards take place on 5 November at The Forum, Congress Centre Messe Frankfurt. Business attire only!

For the latest advancements in pharmaceutical technology, CPhI Worldwide is the place to be for any industry professional.

n a bid to grow, this year saw pharmaceutical companies turn to other industry players to acquire new technologies and pipelines. Major moves - evidenced by the likes of Bristol-Myers Squibb’s acquisition of Celgene – shook the industry but concerns around a shrinking market and the role smaller companies have to play still remain. CPhI Worldwide’s M&A Forum will outline the current landscape for mergers and acquisitions, giving attendees a chance to listen to in-depth discussions on what’s driven the deals of 2019 and what 2020 has in store for pharma. Don’t miss this event which runs on 6 November! INTERESTED IN INNOVATION? For the latest advancements in

Make sure you register for a free Innovation Tour to get an expert-led guide around what’s on show.

pharmaceutical technology, CPhI Worldwide is the place to be for any industry professional. The show’s Innovation Gallery is set to showcase the very best and latest pharmaceutical products and solutions, giving visitors a unique insight into the hottest trends and topics in the industry. WOMEN IN LEADERSHIP FORUM Focusing on a how to build a future-fit workplace, the Women in Leadership Forum will feature executive speakers from the likes of Bayer, Merck and Pfizer to discuss a range of issues that challenge

current workplace dynamics and guide companies on being more inclusive. Men are encouraged to attend with a diverse audience needed if we are to understand the issues women face in the industry and how best to challenge the status-quo. WHERE AND WHEN The Women in Leadership Forum will take place 6 November at the Frankfurt Marriott Hotel, Hamburger Allee, situated directly opposite the main entrance to CPhI Worldwide. The event runs from 15:30PM – 18:30PM and will conclude with

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a cocktail reception and networking. Bear in mind the Women in Leadership Forum costs €40 to attend. AWARD TIME Once again, the CPhI Pharma Awards return to recognise the amazing innovation that takes place across the industry every year. Taking place since 2004, the awards have celebrated the great work conducted within pharma and biotech, bringing together the companies and individuals paving the way for innovation and driving the industry forward.

This year, pharmaceutical companies involved in the design, development, manufacture and distribution of large and small molecule drug products will compete for awards across 12 categories. Those attending can expect an evening of celebration which brings together an echelon of pharmaceutical executives.

attendees, doing so can often be harder than you think. That’s where the show’s Live Pharma Connect Match & Meet Service can help. It’s an online portal that allows both visitors and exhibitors to pre-arrange beneficial meetings ahead of the event. Make sure to make the most out of this service.

NETWORKING Obviously CPhI Worldwide is the ideal place to network with peers from across the pharmaceutical industry, but with a such a big show and so many

EPM PICK Wasdell Group - Stand 121A11 The Wasdell Group is a leading outsourcing partner for the pharmaceutical industry. With multiple sites across Europe, the group offers an impressive range of technical, manufacturing, packaging and storage/distribution services. The company opened doors to its new

90,000 sq.ft. stateof-the-art European headquarters in Dundalk, Ireland in July of this year, a facility that acts as a stepping stone into the European market and responds to the growing demand from companies that wish to outsource their entire product life-cycle from clinical services to EU launch.

Bring business cards Six product zones including APIs, custom manufacturing, fine chemicals & intermediates, excipients, integrated pharma and natural extracts ensure visitors can find exactly what they’re looking for.

With attendees and exhibitors visiting from over 150 countries CPhI Worldwide is the place to be for anyone looking to expand into other markets.

Co-located with five other events: ICSE, P-MEC, InnoPack, Finished Dosage Formulation (FDF), BioProduction Congress – CPhI Worldwide brings together companies from the entire pharmaceutical supply chain.

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Faster formulation at CPhI Being showcased at this year’s CPhI Worldwide, Colorcon’s StarTab has been designed to simplify the tablet formulation process. Here, gain an exclusive look into StarTab’s manufacturing benefits before you visit CPhI Worldwide - Colorcon Stand 102B70. SIMPLER FORMULATION TO SPEED YOUR PRODUCT TO MARKET Pharmaceutical manufacturers prefer excipients that are easy to use, functional and provide benefits for the drug product while maintaining safety and efficacy. Colorcon’s Starch 1500, partially pregelatinised starch has been proven in-use in the marketplace for over 40 years, with the company’s manufacturing facility in Indianapolis, USA, producing millions of kilos of starch excipient products every year that subsequently go into billions of tablets and capsules used around the world. CHOOSING THE RIGHT EXCIPIENT Through the addition of innovative products, the starch product line enables the formulator to reduce the number of excipients needed, thereby lowering costs and complexity. StarCap, superior flow maize starch product has been developed specifically for high speed capsule filling. Whilst the latest addition, StarTab, directly

PRODUCT PREVIEW

compressible starch, brings superior compaction properties and simplifies formulation development for tablets. Starch 1500 has a proven track record and is trusted for performance and versatility. In addition to its effectiveness for low dose drugs to promote content uniformity, it helps stabilise moisture sensitive drugs. It has no known active pharmaceutical ingredient (API) incompatibilities and meets global regulatory requirements. ACTIVE PHARMACEUTICAL INGREDIENT (API) COMPATIBILITY Unwarranted moisture sorption by either APIs or excipients can result in unstable oral solid formulations. In solid oral dose development, API compatibility will drive the selection of the excipient, which in turn determines the necessary manufacturing process; with an impact on long term production costs and resulting profitability. Through inclusion of starch excipients to preferred excipient lists, pharmaceutical companies have realised the benefits of using these most effective ingredients

that do not contain reactive species for possible incompatibility. STABILISING MOISTURE SENSITIVE DRUGS The stability of moisture-sensitive products depends on many factors including choice of excipients used in the formulation and their concentration. Although careful control of the manufacturing environment and the use of protective (and often expensive) packaging can reduce the exposure of a drug, to improve the stability of the final dosage form it is advisable to select excipients that have low water activity. Excipients that possess low water activity, such as pregelatinised starch, are preferred in the development of moisture sensitive formulations because they can protect actives from hydrolytic degradation by tightly binding moisture on storage. One common misconception surrounding choice of materials is the level of excipient moisture content. In reality, water activity, not absolute moisture content, is the trigger for unwanted reactions. Loss on drying (LOD) or total moisture content of pharmaceutical products can include both bound (e.g. water of hydration) and free water. It is the free water that is responsible for degradation of moisture sensitive materials resulting in poor stability profiles. Starch 1500 has a relatively high moisture content ranging from 6-14% LOD, while its low free water content means that water FIGURE 1: Moisture content and water activity of common tableting excipients. Moisture content encompasses all water present, while water activity discerns free and bound water.

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activity is equal to, or lower than, other excipients of lower moisture content (see Figure 1). Multiple studies have been performed showing that the low water activity of Starch 1500, and now StarTab, improves product stability and reduces formation of degradants on moisture sensitive actives. Moisture barrier coatings with low water permeability, such as Opadry PVA-based film coating systems, applied to a final dosage form can further improve the stability of water-sensitive drugs on storage. The moisture uptake of the core during aqueous film coating processes is minimised through correct selection of process parameters such as drying step (pre-warming the tablets), airflow, inlet air temperature and spray rate. BLEND HOMOGENEITY FOR LOW DOSE DRUGS Achieving blend homogeneity is an important criterion for formulating micronised drugs, as they tend to segregate during blending due to their increased surface area and particle agglomeration. Blending of micronised low-dose drugs may be challenging and cause content uniformity issues and physical instability.

FIGURE 2 – Weight Consistency in High Speed Encapsulation

The choice of filler in a formulation, for a low-dose micronised drug, may assist uniform dispersibility of the drug throughout the blend with no segregation during compression. Fillers with irregular surface characteristics (such as Starch 1500) may provide favourable adsorption for micronised particles and behave as a carrier, rendering content uniformity. The potency of both new and currently used drugs necessitates doses as low as 0.025 mg. During the development and manufacturing of a low dose tablet, content uniformity is the principal technical challenge. Starch 1500, and now StarTab, directly compressible starch improves formulation flow properties, resulting in good tablet weight uniformity which is demanded for high-speed direct compression. INNOVATION The many advantages and application successes of Starch 1500 have been built on through the development of two new products. STARCAP – SUPERIOR FLOW MAIZE STARCH StarCap is an inert excipient with a unique particle morphology that provides free flow and ensures good compactibility. Ensuring weight uniformity and enhancing powder flow are essential for effective capsule filling operation. StarCap demonstrates smooth operation on high-speed production scale, continuous movement, dosator encapsulation equipment at 100,000 capsules per hour. In a case study, capsules were filled, and weight measurements taken every minute, for 30 minutes. Low weight variation demonstrates that StarCap is highly applicable for high-speed capsule filling operations.

STARTAB – DIRECTLY COMPRESSIBLE STARCH Recently launched, StarTab is designed especially for direct compression to simplify tablet formulation and process, providing excellent flow and superior compressibility; resulting tablets have low friability, ideal for film coating and packaging. StarTab alone provides excellent tablet hardness and very low disintegration time compared to other directly compressible excipients. Formulation is simpler by removing the addition of flow aid, compression aid and disintegrant; and by limiting the number of ingredients, there is less potential for interactions with the API. With just one main material needed for the direct compression process, the formulator can think “Less is More”.......less complexity, more efficiency. Colorcon continues to innovate with specialty excipients and film coating systems, providing pharmaceutical manufacturers with improved convenience marked by speed and efficiency, cost savings and dependable performance.

Through the addition of innovative products, the starch product line enables the formulator to reduce the number of excipients needed, thereby lowering costs and complexity.

Think Direct Compression,

Think StarTab

From Core to Coating, Your Supplier of Choice®

www.colorcon.com

LAB AUTOMATION

Smarter working How modern automated systems are enhancing the accuracy, speed and efficiency of endotoxin testing workflows.

E Author: Alan Baines, director, Testing Solutions at Lonza BioScience

ndotoxin testing is an important quality control (QC) measure that is used across the medical and bioscience sectors to ensure the safety of parenteral drugs, medical devices and other raw material products that are used in these markets. A range of methods are employed by QC laboratories to perform endotoxin testing, including the limulus amebocyte lysate (LAL) test and the recombinant factor C (rFC) assay.

Given the large volume of samples that must be processed by QC laboratories, endotoxin testing workflows must be fast and effective to avoid costly delays in the manufacture and release of products. However, with patient safety dependent on the quality of data generated by these routine tests, the need for speed and efficiency must not come at the expense of measurement accuracy. Regardless of the type of assay used for endotoxin testing, these workflows typically involve multiple liquid handling and data transfer steps for a large number of samples, which must be performed reliably, consistently and with the utmost precision. Despite this, many laboratories still operate manual endotoxin testing workflows, which are often very

repetitive and labour intensive, making them vulnerable to human error, leading to the development of repetitive strain injuries (RSI) amongst operators and causing data reproducibility issues across multiple technicians. Fortunately, recent advances in robotics and laboratory automation platforms are helping to streamline and improve performance in the QC laboratory. AUTOMATED PLATFORMS FOR ENDOTOXIN TESTING ARE ENHANCING DATA QUALITY Manual endotoxin testing workflows present a number of challenges for QC laboratories, including the accuracy and consistency of the data that is obtained. Even when performed by the most skilled personnel, the pipetting steps used in these

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LAB AUTOMATION

Automation platforms are not only enhancing the quality of the data generated by endotoxin testing workflows, they’re also improving laboratory efficiency too. labour-intensive workflows are inherently vulnerable to human error. Small deviations in the volumes of samples and reagents that are used can have a detrimental impact on the reliability and reproducibility of endotoxin measurements. Manual workflows may also involve multiple manual data recording and processing steps, which may be affected by inconsistencies in the way individual operators perform tasks. Moreover, accidental errors in transcribing data into spreadsheets or databases can have significant consequences for patient safety. Although many laboratories look to mitigate some of these issues through the application of data validation and verification steps, these additional workflows are tedious and time-consuming, and can take trained team members away from other tasks that add more value to laboratory operations. Furthermore, personnel performing all of these manual steps run a high risk of sustaining RSI, which can have a significant impact on their performance as well as on their personal life, while making businesses liable to claims. Recent advances in automation technologies designed specifically for endotoxin testing workflows eliminate many of these challenges. The latest automated, plate-based platforms significantly reduce the requirements for manual intervention in endotoxin testing, enhancing measurement reproducibility and improving the consistency of results. These

systems can automatically perform all of the necessary steps required to complete workflows, including sample mixing and dilutions for a range of sample types. Through highly precise, robot-controlled liquid handling steps, these systems are delivering extremely accurate measurements, day in and day out. It’s not just improvements in robotics that are supporting enhanced performance and data quality — some of the latest platforms, such as Lonza’s PyroTec PRO Automated Robotic Solution, integrated with the WinKQCL Endotoxin Detection Software, are also able to improve the relevance and timeliness of key information through improved reporting, integrated trend analysis and flagging of errors or out-of-specification results. As these systems automatically read microplates and save the results directly to a data management solution, like a laboratory information management system (LIMS) or a corrective action and preventive action (CAPA) system, they also eliminate errors associated with the manual transcription of data. By improving the precision of liquid handling and taking human error out of the equation, these sophisticated platforms are helping to boost confidence in the data that’s ultimately used to facilitate the release of products onto the market. BOOSTING EFFICIENCY IN ENDOTOXIN TESTING WORKFLOWS Automation platforms are not only enhancing the quality of the data generated by endotoxin testing workflows, they’re also improving laboratory efficiency too. The latest automated systems are capable of processing large volumes of samples with unprecedented speed, enabling the delivery of results and the clearance of products in an accelerated timeframe.

A key advantage of robotic testing platforms is that they are able to operate continuously, with minimal or no manual intervention. Once a run is initiated, these systems automatically execute transfers in and out of the reader at the appropriate times for incubation, extending walkaway times and enabling experienced team members to perform other skilled tasks, such as results analysis. Capable of running 24/7, modern automation systems for endotoxin testing workflows can significantly increase sample throughput and operational efficiency, ultimately reducing the cost of performing each test. The increased simplicity and convenience offered by modern automation platforms also extends to system set-up, with the latest run-control software applications eliminating the need for complex and time-intensive robot programming steps. Other software features, such as the availability of microplate templates that provide operators with a layout of the robot deck, allow operators to quickly duplicate runs or apply common parameters and reduce the need to repeat tedious tasks. By making these efficient systems intuitive and easy to use, modern automation platforms and run-control applications are helping to deliver highly accurate results faster and more efficiently than ever before CONCLUSION With precise and efficient endotoxin testing essential for the delivery of safe parenteral medicines and medical devices, growing numbers of laboratories are recognising the benefits of automated testing protocols. Thanks to the latest advances in robotics and run-control software, modern automated endotoxin testing platforms are enhancing the accuracy, speed and efficiency of these important workflows.

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APIs/HPAPIs

A potent cocktail How can containment valves and wireless monitoring mitigate risk in HPAPI manufacture?

Author: Michael Avraam - head of solutions engineering, ChargePoint Technology

Analysts estimate that the oral solid dosage (OSD) market will reach the trillion-dollar mark in the next decade, having rocketed to nearly US $21.5bn in 2018[1]. Similarly, the highly potent API (HPAPI) market is expected to rise, reaching $26bn by 2023 [2]. Further knowledge of existing compounds is one of the forces behind this momentum â&#x20AC;&#x201C; as new toxicity data is produced, some of these compounds are reclassified as HPAPIs. In addition, there is increasing demand for more effective, better-targeted medications; hence manufacturers are handling more and more HPAPIs. However, containment strategies are required to protect

both operator safety and the drug product itself. As OSD forms such as capsules and tablets continue to make up almost 50% [3] of the total pharma products market, the industry is seeing an increase in regulatory pressures and quality demands in this area and the need for efficient, flexible and modular processes. Working with highly potent substances in a complex manufacturing environment poses a significant challenge for manufacturers. During material transfer, effective engineering controls are crucial as employee safety is the primary

focus, however companies also aim for minimal disruption to the manufacturing process. Because of this, new and re-classified HPAPIs present a challenge for existing manufacturing facilities, which are increasingly looking to outsource to specialists with the necessary controls and equipment. CONTAINMENT DURING PRODUCTION Whether a manufacturer is using an established containment solution like a rapid transfer port (RTP) or an isolator, or a more versatile solution like a split butterfly valve (SBV), or disposable technology, materials transfer during solid dose manufacturing can be complex. Materials must

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be transferred from one process to the next in a contained manner. Closed transfer valves such as SBVs are continuing to replace traditional open transfer techniques. This technology is made up of a passive unit attached to the mobile container and an active unit attached to the processing equipment. Both halves of the valve are combined during powder charging, enabling contained and efficient materials transfer. Transferring material from one closed system into a separate closed system is one of the key difficulties in powder transfer. Itâ&#x20AC;&#x2122;s important to ensure that the design specifications of the technology or device used in this process will meet the required accessibility, batch size and containment performance. Regardless of the process, containment integrity remains the key challenge, requiring effective performance testing and maintenance programmes. PERFORMANCE TESTING Performance testing is usually assessed in line with the ISPE (International Society for Pharmaceutical Engineering) SMEPAC (Standardised Measurement of Equipment Particulate Airborne Concentration) guideline before a manufacturer can implement a new control device within its process. Users generally perform analyses and compare different technologies using SMEPAC as a guide for containment performance testing. It has been adopted by containment equipment manufacturers to appraise and benchmark the performance of equipment capabilities and is often utilised to influence the selection process of containment devices. However, the guidance only demonstrates how a device performs in theory in a laboratory setting â&#x20AC;&#x201C; qualifying the testing in an environment as

close as possible to real world parameters is still necessary. TESTING WITH PLACEBOS Results obtained during performance testing are influenced by the type of placebo used. The placebo of choice most commonly used by equipment manufacturers is lactose. This is readily available, is non toxic and is supplied in varied micronised grades. Itâ&#x20AC;&#x2122;s important to consider the best match to the API in terms of particle size and bulk density, which will affect levels of detection, airborne characteristics and consequential results. Preparation and dispensing of the placebo batches are critical operations due to the risk of contaminating the outside surfaces of bags or bottles, which could compromise the test. Consideration needs to be taken to wipe down, and batches should be stored carefully as differing temperature, light, humidity and length of storage could all have a bearing on the result. In addition, using differing sampling devices to test the same equipment, with the same placebo, under identical test conditions, will give variable results. Understanding how each batch has been tested and how the performance results have been obtained helps manufacturers to interpret the results and understand any potential variations. TRANSFER PERFORMANCE Multiple transfers will improve statistical understanding and offer greater assurances of the capabilities of containment equipment. This will allow for a superior continuity of results. The guide indicates that recovery of all potential material from the sampler should be achieved, to ensure that as much of the particulate material captures, is analysed. Most performance results will be obtained from the analysis

Working with highly potent substances in a complex manufacturing environment poses a significant challenge for manufacturers. of combined filter and cassette arrangements, however, there will be test data still available and present on promotional literature covering only filter analysis. Indepth research into containment figures published must be done to check data and the criteria by which it has been produced. The technology in this field is evolving and new single use, one piece samplers have been developed to avoid any risks involved with handling of the device and also standardising on the analysis. Furthermore, operator training and equipment familiarity is necessary to avoid wide ranging operating methods, resulting in potential variations in performance. MAINTENANCE AND ONGOING MONITORING As well as testing equipment before it is introduced to a process, maintenance and ongoing operational performance monitoring are vital parts of a containment strategy. For example, wireless technology can record usage data and provide insights into the health status of SBV, giving safety and compliance teams the necessary information to make informed choices about required maintenance. Decontamination and cleaning of process equipment also needs to be undertaken in a contained manner. As disposable technology continues to be adopted within the industry, manufacturers are starting to look to this as an inexpensive alternative to conventional containment equipment.

REFERENCES

[1] https://www. prnewswire.com/ news-releases/oralsolid-dosage-contractmanufacturing-marketis-estimated-to-growat-a-high-cagr-of-5-8percent-by-2017-2028persistence-marketresearch-884554975. html [2] https://www. marketwatch.com/ press-release/ high-potencyapishpapi-2018-2023global-market-analysisby-type-synthesismanufacturer-andtherapy---market-toreach-2684-billion--researchandmarketscom-2018-04-26 [3] https:// resultshealthcare. com/wp-content/ uploads/2017/01/ Results-Healthcare_ Pharma-Biotech-2017Review-of-outsourcedmanufacturing_ Whitepaper.pdf

TECH TALK

GOING PRO How smart technology is influencing and ultimately improving clinical research.

he growing capabilities of data collection using personal computers, tablets, and smartphones paired with direct data capture platforms — like electronic patient-reported outcome (ePRO) systems — are bringing new efficiencies to the clinical research process. The level of convenience for patients, clinical research organisations (CROs), and sites, for example, all rise when ePRO solutions are deployed using a patient’s personal mobile device. Compared to a paperbased diary approach, studies show data quality and compliance from ePRO technologies deployed in a bring-your-own-device (BYOD) capacity can increase as much as 97%. However, a CRO interested in adding ePRO technology to its portfolio has limited options: build its own solution, acquire an ePRO company, or work with a partner. Each of these alternatives has its own shortcomings. And, regardless of which solution a CRO chooses to use, it will take some time before the CRO sees its investment generate business, benefit patients, and earn financial returns. This article outlines an alternative solution that includes time and cost savings for CROs. TAKING CONTROL Choosing any one of these methods for delivering an ePRO solution can create silos that make it difficult to access and mobilise data efficiently. Additionally, by adopting an electronic approach, a company may lose revenue that it had previously earned through the implementation and support of its paper-based PRO tools. However, there is another solution: a consumption-based

business model — one that also flexibly moves control over the deployment, delivery, and support of ePRO from the vendor to the CRO. If structured appropriately, this approach can enable CROs to implement, manage, and support an ePRO solution in-house by licensing an ePRO technology, purchasing support services à la carte, and ultimately creating a new revenue stream. Successful transfer of ePRO technology requires a delivery model where vendors are willing to price their services separately and charge customers according to their use. In this way, CROs can configure a custom combination of ePRO technology and services that leverage the vendor’s existing resources for support while enabling the CRO to bill for the services it can provide itself, which might include some combination of project management, help desk, configuration, hardware procurement, inventory management and shipping, and support. GENERATING REVENUE This approach enables CROs to reduce costs, accelerate study startup, develop an additional revenue stream, and maintain complete flexibility and control over its ePRO deployment. The key to success is finding a partner that offers a cloud-based, enabling technology and an à la carte process that includes a configurable interface. The CRO must also make sure the vendor provides full-bodied, compliant ePRO functionality as well as support, such as with copyright licensing, software, and training. When managing the technology transfer, it’s a good idea to

deploy a well-managed, stepped process customised according to the CRO’s internal capabilities, capacity, and resources. For example, the ePRO vendor initially should perform the work while training the CRO. Then, as the CRO shadows and becomes comfortable, it would gradually assume responsibility, configuring its internal capabilities and resources to manage deployment of the entire end-to-end process. The well-trained and well-prepared CRO would then license the technology and offer ePRO as its own service offering. CONCLUSION The latest ePRO technologies are poised to solve some of the most pressing patient-centric study design needs in the industry. As such, it’s important that CROs find a way to make them efficient, profitable, and easy to adopt. Now is the time for CROs to look ahead and consider the benefits of a consumption-based business model that supports adding a technology transferable solution to their service offerings.

Author: Kyle Hogan, director, eClinical Solutions, Clinical Ink

REFERENCES

1: Applied Clinical Trials. ePRO vs. Paper. http://www. appliedclinicaltrialsonline. com/epro-vs-paper. 2019.

LABELLING

Get smart Find out how the pharmaceutical industry can benefit from labels with RFID and e-paper technology.

Author: Frank Jäger, managing director at Faubel

SMART LABELS SPEED UP THE SUPPLY CHAIN Over the centuries, the complexity of the supply chain for pharmaceuticals has grown steadily. In addition to conventional labels, the label specialist Faubel also produces labels with (radiofrequency identification) RFID and e-paper technology or enhances its labels with temperature sensors or tamper-evident features.

The accessible data flow provided by smart labels leads to greater transparency.

“These smart labels can save time and money as well as lead to improvements,” says Frank Jäger, managing director at Faubel. The accessible data flow provided by smart labels leads to greater transparency. “The pharmaceutical industry already uses temperature sensors or RFID tags, but it is limited to certain applications which only take one part of the

supply chain into account without being holistically structured”, explains Jäger. INVENTORY MANAGEMENT BASED ON REAL-TIME DATA Pharmacists and contract manufacturing organisations (CMOs) often operate a large number of production sites, depots and locations in different

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countries. Individual medicines or entire batches, or pallets of them, labelled with a smart label featuring RFID tags will feed data into inventory management platforms. Each RFID tag has a unique identification number. This UID (Unique Identification Number) can be located at any time, making it theoretically possible to trace the entire life cycle of a product. In concrete terms, smart labels can be used in inventory management to keep a sensible balance between shortage and surplus. Inconsistencies, such as incorrectly placed products, can be promptly identified and appropriate action be taken to enhance picking efficiency. For quality management purposes, a comprehensive test documentation is available that has been stored on the platform in a summarised form. Thanks to their UID, smart labels also increase the level of security in the packaging of drug kits. Jäger is convinced of the benefits: “Inventory management based on real-time data can help to significantly reduce operating and administrative costs.” MONITORING AND PROTECTION With smart labels, freight forwarders, wholesalers, clinics, pharmacies and even patients can take part in tracking and provide pharmacists with key data on the whereabouts of the medicines. RFID and NFC technologies – and the mobile and/or stationary readers that go with it – comply with standards. “Investing in readers and IT infrastructure pays off quickly. Using NFC tags has another advantage: NFC-enabled smartphones can be used as readers,” adds Jäger. Smart labels can improve brand protection because pharmacists or their supply chain managers are in a position to identify where a shipment went missing and see whether the drug or its packaging

has been stolen. As highlighted by Jäger, “Weak links can be subsequently eliminated, the risk of product piracy will decrease.” Smart labels are also used to prevent drugs from being removed from their original packaging and replaced by counterfeits. Like sealing labels, smart labels with NFC tags are applied across the opening area of the original packaging. Once the seal is broken, the NFC tag immediately registers that it has been tampered with and even patients are now able to figure out how intact the packaging of a drug is. AUTOMATIC UPDATING OF IMPS At the beginning of each clinical trial, the shelf life of investigational medicinal products (IMPs) is a factor which is difficult to quantify. During trials, new findings on the stability data of IMPs frequently emerge. If, for example, the shelf life of IMPs increases, this also impacts IMP labelling and therefore the entire supply chain. “Whenever stability data change, typically a re-labelling process is initiated where IMPs receive new labels that carry updated expiry dates,” explains Jäger. Re-labelling takes time and can lead to delays in regular supply chains as well as to budget extension. IMPs may need to be shipped from the site to the depot where they are relabelled before being returned to the site.” The complete re-labelling process does not only mean time and cost, but compliance requirements for manual relabelling are also high.” Since 2010, Faubel and Merck Sharp & Dohme have regularly exchanged ideas on how to completely replace re-labelling with smart labels when stability data change. An extensive benchmarking of possible technologies lead to the decision to focus on a combination of a label, an RFID tag and an e-paper

display. “Fortunately, these smart labels have been marketable since spring 2017 after proving their worth in a variety of mock-up studies. It has been carrying the registered trademark of FaubelMed Label since December 2014,” says Jäger. During the entire seven-year development phase, the whole challenge was about combining digital elements such as hardware and software with analogue components such as packaging in a way that is both user-friendly and operational for all stakeholders in the supply chain. The Faubel-Med Label features a segmented bistable display which is able to show simple texts and numbers as well as 1D or 2D barcodes. This e-paper display is powered by electric induction without using any battery. In the Faubel-Med Label, the segment showing the stability data of the product can actually change. In other words, the expiry date of the product can be updated by receiving data from the RFID tag. All it takes is to place the product concerned on a reader. The Faubel-Med Label complies with Annex XIII guidelines. Beyond this, it allows expiry updates to be performed with a sealed kit that does not need opening, therefore supporting the implementation of Annex VI requirements. “This smart label brings about considerable savings to international clinical trials in terms of time and cost management. In addition, clinical trials can start earlier than in the past, and it is even possible to conduct trials involving limited stability data for the first time ever,” concludes Frank Jäger.

This smart label brings about considerable savings to international clinical trials.

FROM THE FACTORY

King of the castle How GSK embraced augmented reality (AR) to validate the design of a new aseptic manufacturing facility at Barnard Castle.

hen GlaxoSmithKline (GSK) began building a new aseptic manufacturing facility at Barnard Castle in County Durham, it needed to be certain that the equipment and plant being installed was a direct match for the design they had created. GSK needed the validation and assurance that the completed facility could secure the future of aseptic filling of vials and syringes and the handling of cold chain products for the next 10-20 years. And, they needed to be sure that such a heavily serviced and highly complex facility complied with an equally complex set of industry standards. The project’s lead designer, BakerHicks, found the solution in AR, creating a customised AR app which could be viewed using Microsoft’s HoloLens technology to quite literally bring the facility to life.

By exporting a live construction model onto the app, BakerHicks was able to project the 3D building information modelling (BIM) design model onto the plant space within the facility. When viewing through the HoloLens, the team could view an AR model overlaid onto the real-world environment to easily identify any issues with the facility’s build. A walkthrough by BakerHicks identified a number of areas where the installed elements differed from the 3D design. By capturing this information, the project team was able to work with the contractor to rectify these quickly and easily early on in the process. The BakerHicks team returned a month after the initial walkthrough to carry out a second installation check to ensure the issues had been resolved satisfactorily. Once

the facility is complete the team will conduct a further walkthrough to validate the as-built model against the finalised construction installation, providing GSK’s facilities management team with accurate data to help automate their processes. Had standard detailed installation check methods alone been relied upon, with a facility of this complexity, it is possible that some of the issues may not have been picked up, causing delays or further problems later on. AR technology offered the GSK team the ability to be confident that the services, even those located in areas difficult to access had been checked against the design and that the construction could progress to programme. The use of this technology may still be in its infancy but

its use on GSK’s new aseptic manufacturing facility at Barnard Castle has been a great success. The validation process was made quicker, easier and smoother, ensuring everything was constructed as per the design. And, on a project where the design team’s priority is ensuring complex multidisciplinary designs integrate seamlessly into one cohesive facility, this is invaluable.

The validation process was made quicker, easier and smoother.

5 – 7 November 2019 | Frankfurt, Germany

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