EPM July/August 2018 by EPM Magazine

AT RISK? HOW TO PROTECT IP

DRUG DELIVERY DEVELOPMENTS

AUTOMATING CELL THERAPY PRODUCTION

july | august 2018

GO WITH THE FLOW Natoli Engineering details the importance of solving powder flow challenges before tablet production

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Contents

July/August 2018 | Volume 18 Issue 5 REGULARS 5 EDITORâ&#x20AC;&#x2122;S DESK Assessing the impact Amazon may have on the pharma space.

6 A SMALL DOSE A brief round-up of some of the developments in the industry including the revelation that many of us are taking too many NSAIDs and the latest on medical marijuana

10 ANALYSIS IDBS discusses the potential of big data and what barriers are left to overcome before its widespread use.

12 OPINION Looking at patient centricity in pharmaceuticals and how it may help with medication adherence.

15 REGULATORY AFFAIRS Here, we speak with Six Degrees Medical about the impact of GDPR on pharma.

16 COVER STORY Natoli highlights the critical issue of powder flow and how solving issues before production can reduce issues down the line.

42 TECH TALK This instalment sees the comparison between pharma and digital start-ups in the field of mHealth.

FEATURES 19 DRUG DELIVERY SUPPLEMENT In this special supplement several topics are considered, including how connected drug delivery can help with adherence, transdermal solutions and innovative method.

30 LEGAL â&#x20AC;&#x201D; IP Looking at why it is essential for businesses to insure their intellectual property and the proposal of the manufacturing exemption for SPCs in more detail.

34 STERILISATION Investigating the use of wireless dataloggers for autoclave validation.

36 ACHEMA REVIEW We speak innovations, present trends and what we should expect at the next event with five key manufacturing companies at the show.

39 EXCIPIENTS Summarising the benefits of an excipient GMP certification programme.

40 PERSONALISED MEDICINE Detailing why integrating and automating cell therapy production with MES will help sector growth.

So much more than a clean surface

Research & Development Technical Specialists Quality Built In Global Presence Complete Range Industry Experts Validation Innovation Experienced Collaborative It’s not just about the products. It’s more than just a clean surface. Contec prides itself on its longstanding technical expertise, innovation and commitment to quality. Continued improvements in lean manufacturing, safety initiatives, vertical global integration as well as Research and Development, drive our critical environments product range forward.

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To get to know Contec’s hidden depths, give us call on +33 (0) 2 97 4376 98 or drop us a line at infoeu@contecinc.com

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TAKING PRIME POSITION?

s we have recently witnessed the retail giant, Amazon’s, first real big push into the online pharmacy market, the question on most peoples’ lips is: Could this be the end of traditional pharma space as we know it?

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EDITORIAL

editor felicity thomas felicity.thomas@rapidnews.com deputy group editor dave gray david.gray@rapidnews.com

Delving into Amazon’s history, founded in 1994 it started as an online book retailer, selling to 50 states in the US and to more than 45 countries. Quickly diversifying the retailer now sells a vast array of products from video games to food and jewellery to nappies for babies.1

head of content, life sciences lu rahman, lu.rahman@rapidnews.com reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

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As the pharma market is rocked by the news of Amazon’s acquisition of PillPack — the online pharmacy — we briefly take a look at the history of the e-commerce giant and what impact its move into pharma may have on the traditional space.

Combine this with the unrelenting amounts of products the company makes itself, including hardware and software, and its business strategy, it’s easy to see why it has increased its market share consistently. It actually managed to surpass retail stalwart Walmart in 20152 as the most valuable retailer in the US by market capitalisation and currently controls five percent of total US retail sales. It is perhaps its data analysis that makes it the most terrifying

EDITOR’S DESK for the ‘bricks and mortar’ world of retail, whatever the market.3 However, this trait also makes it appealing to the consumer, as it offers a cheap, easy and reliable retail experience. So, what about its move into online pharma? Rumours and hearsay about various forays into this field have been rife for a little while, ranging from Amazon hiring a general manager to head up a pharma

sales department last year4 to its proposal to deliver drugs via unmanned drones in 2015 — Amazon Prime Air.5 Yet this latest news, the acquisition of PillPack,6 has yielded a serious response on the stock market and caused quite a stir within the field of healthcare. Through this acquisition, not only does Amazon now have an online pharmacy in its pocket it also has one with pharmacy licences in 50 states in the US, which means it has what it needs to launch a full-scale pharmacy business. Also, Amazon is expected to benefit from the PillPack acquisition with penetration of the over 55 market sector, something that has proved elusive for the company until now. At any rate, the pharma market is much more complex than simple delivery of pills so despite the immediate ramifications seen in share prices as a result of Amazon’s acquisition, a lot of experts anticipate this ‘up-ending’ of the pharma space to bottom out eventually with the market finding an equilibrium of sorts.7 REFERENCES:

1. https://en.wikipedia.org/wiki/Amazon_(company) 2. https://www.nytimes. com/2015/08/16/technology/inside-amazon-wrestling-big-ideasin-a-bruising-workplace.html 3. https://www.theguardian.com/ technology/2018/apr/24/amazon-jeff-bezos-customer-data-industries 4. https://www.epmmagazine.com/ news/is-pharma-ready-for-amazononline-store-reportedly-hires-exp/ 5. https://www.epmmagazine.com/ opinion/amazon-gets-closer-todrug-delivery-by-drone/ 6. https://www.epmmagazine.com/ news/amazon-confirms-entry-into-healthcare-with-pillpack-acquisition/ 7. https://investorplace.com/2018/06/ amazons-acquisition-pillpack-start-something-big/

A small dose

EYE ON… WET AMD Allergan and Molecular Partners have released two positive Phase III clinical trials for abicipar — a treatment for patients with neovascular age-related macular degeneration (wet AMD).

A spoonful of insulin... Pregnant women in the Thames Valley area (Berkshire, Buckinghamshire, Milton Keynes and Oxfordshire) are being asked to join up to a large screening study, aimed at identifying whether newborns are at high risk of developing type 1 diabetes.

a prevention study — Primary Oral Insulin Trial (POInT). In this trial, participants will be asked to give their child a powder daily from the age of six months until they are three years old.

The screening will be performed on blood that is already collected from newborns (for treatable metabolic and hormonal disorders) by researchers from the University of Oxford.

Half of those receiving the powder will have a real insulin version while the other half will be given a placebo. Neither the investigators or participants will know if they have insulin or placebo. The researchers will visit the families involved to monitor the health of the child.

If the child is found to have the high-risk genes that cause insulin deficiency, they will be invited to join

It is hoped that through spoon-feeding insulin to babies a tolerance will build up in the immune system that will enable

the body to cope with its own insulin and as such preventing the onset of insulin-dependent type 1 diabetes. “POInT is the first ever study aimed at primary prevention of type 1 diabetes, and in its approach represents an enormous breakthrough,” said Dr Matthew Snape, paediatric consultant at the University of Oxford and chief investigator for the trial. “Type 1 diabetes is a common, life long and challenging illness; preventing children and their families from having to live with diabetes and its threat of complications such as blindness, kidney or heart disease would be fantastic.”

WHAT IS ABICIPAR? Abicipar is an investigational drug that forms part of a new class called DARPin — being developed by Molecular Partners. WHAT DID THE TRIALS INVOLVE? The SEQUOIA and CEDAR trials were headto-head trials designed to demonstrate the eﬃcacy and safety of abicipar 12-week fixed dosing regimen with fewer injections versus ranibizumab. Treatment-naïve patients were included and the primary endpoint was taken as the proportion of patients who had received treatment and were stable at week 52.

AND THE RESULTS? Similar eﬃcacy was demonstrated in both trials after six or eight injections of abicipar compared with 13 injections of ranibizumab. Overall adverse events were shown to be similar for all forms of treatment and there was higher levels of intraocular inﬂammation in the abicipar groups. WHY IS IT IMPORTANT? This new treatment could lead to improved patient adherence as fewer injections would be required. “Abicipar could transform the way physicians manage AMD with anti-VEGF therapy,” said Dr Raj Maturi, Midwest Eye Institute & Associate Professor Ophthalmology, Indiana University School of Medicine. “Abicipar could be the first and only 12- week anti-VEGF treatment that improves visual outcomes in a real world setting for a large number of AMD patients.”

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Size matters Injecting drugs, rather than oral administration, can help to ensure they are delivered in a localised way and avoids the potential issues thrown up by the digestive system. Yet, hypodermic needles have their own set of distinct disadvantages. They cause trauma to the skin, produce biohazardous waste once used and many patients are frightened of them. Although not a new concept, technological advances have meant that microneedles are rising in the ranks for drug delivery solutions, commercially speaking. Now, thanks to advancements in microelectronics, microneedles less than 0.1 mm in diameter can be manufactured. Various materials can be used to prevent pain, tissue reactions and other traumas related to injections. Furthermore, recent research from a team at the University of Texas at Dallas, has seen microneedles that can painlessly administer drugs and then break off and dissolve underneath the skin. So, size definitely matters and none more so to a patient who undoubtedly would prefer a painless injection…

A STRONG LINK… A potentially viable avenue in reducing the risk of Alzheimer’s may have been conferred by epidemiologists in Taiwan, according to a commentary from scientists at the Universities of Manchester and Edinburgh.

With no current effective treatments available for Alzheimer’s, Itzhaki believes that using antivirals, which are safe and easily available, could increase the potential of disease prevention through a vaccination programme in infants.

The Taiwanese epidemiologists authored a study, published in Neurotherapeutics earlier this year, that demonstrated a reduction in the risk of dementia in patients with severe herpes infection who were treated aggressively with antivirals.

“Successful treatment by a specific drug, or successful vaccination against the putative microbe, are the only ways to prove that a microbe is the cause of a non- infectious human disease,” Itzhaki continued.

Combining this research with two others from different research groups in Taiwan, Professor Rith Itzhaki (University of Manchester) and Professor Richard Lathe (University of Edinburgh) have produced a commentary arguing the case that the research provides the strongest evidence yet that there is a causal link between herpes and Alzheimer’s. “This article and two others by different research groups in Taiwan provide the first population evidence for a causal link between herpes virus infection and Alzheimer’s disease, a hugely important finding,” said Itzhaki.

HSV1 it appeared to prevent the long-term damage in brain that results in Alzheimer’s.” It was back in the early 90s when it was discovered that in elderly patients infected with the herpes virus it can also be found in the brain, leading to further work during the decade that confirmed a risk of Alzheimer’s in people who have a specified genetic factor.

— a main characteristic of Alzheimer’s. “We suggested that the virus in brain is reactivated by certain events such as stress, immunosuppression and infection/ inﬂammation elsewhere,” she said. “So, we believe the cycle of HSV1 reactivation in the brain eventually causes Alzheimer’s in at least some patients.”

Itzhaki and her team then went on to show that the herpes virus DNA can be found inside amyloid plaques

Lathe added: “Not only is the magnitude of the antiviral effect remarkable, but also the fact that — despite the relatively brief duration and the timing of treatment — in most patients severely affected by

…the herpes virus DNA can be found in amyloid plaques…

A small dose

Reviewing medical marijuana In June the US Food and Drug Administration approved the first drug containing a marijuana derived active ingredient — Epidiolex. This combined with the recent cases where children have had their epilepsy medication confiscated in the UK as it contains cannabis oil has led the government to re-assess laws around the use of medical cannabis. What does this mean? If, once reviewed, the government finds the medical and therapeutic benefits of cannabis and cannabis-based medicinal products outweigh the risk and potential harm posed to public health, then medicinal products containing cannabis may be prescribed and used in the UK. Government review process The government review is taking place in two distinctive parts. The first has already been completed and assessed the medicinal and therapeutic benefits of cannabis and cannabisbased medicinal products. Currently underway, the second part of the review will assess the balance of harms and public health needs of whether these products should be rescheduled

under the Misuse of Drugs Regulations 2001. This part is being conducted by the Advisory Council on the Misuse of Drugs (ACMD) and is expected to be completed soon. Expert opinions “There is clear evidence from highly respected and trusted research institutions that some cannabis based medicinal products have therapeutic benefits for some medical conditions,” explained Professor Dame Sally Davies, chief medical advisor for the government, who performed the first part of the review.

Professor Alex Stevens from the School of Social Policy, Sociology and Social Research at the University of Kent, and member of the UK Advisory Council on the Misuse of Drugs stressed that there are many children suffering as a result of the government’s refusal to allow the use of medicines derived from cannabis. “The government is clearly worried that the medical issue may be used as a wedge to drive through wider reforms on cannabis, as has occurred in other countries,” he continued. “But it should not force families and children to suffer just because it does not want to engage in open discussions of what this country’s laws on cannabis should be.”

There is clear evidence… that some cannabis based medicinal products have therapeutic benefits…

HITCHHIKER’S GUIDE TO DRUG DELIVERY Why did the drug cross the barrier of the gut? To get absorbed into the human system! But, what if those drugs would be destroyed by the stomach? This is the case for biological products such as recombinant proteins, vaccines and gene therapies. However, the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at the Wyss Institute and Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS), Samir Mitragotri may have a solution to this dilemma… Mitragotri and his team rapidly found that the answer may lie in blood cells themselves,

which are capable of performing the tasks that a nanoparticle may be used for without being removed by other organs of the body, such as the liver, which clears the blood from ‘harmful substances’. So, how can nanoparticles imitate blood cells? Mitragotri and his team quickly realised that they didn’t need to make the nanoparticles imitate blood cells as such, they just needed to let the nanoparticles ‘hitchhike’ on the blood cells as this allowed them to remain in the blood. Then they realised that the nanoparticles were sheared off the cells when they travelled to a capillary, so they found that by introducing the blood cells with the ‘hitchhiking’ nanoparticles attached just up-stream from the organ they were destined for they could control the delivery. This method has been demonstrated in mice, pigs and whole human lungs and has been published in Nature Communications, leading the team towards the brink of clinical studies…

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OVER-DOING IT? Many of us are taking too much ibuprofen and other non-steroidal anti-inﬂammatories (NSAIDs), according to a recent study published in Pharmacoepidemiology and Drug Safety.

A WIN FOR TRUMP? After extensive talks with President Donald Trump, Pfizer made the decision to defer on price increases until the end of the year or at least until the president’s drug pricing blueprint goes into eﬀect. “Pfizer is rolling back price hikes, so American patients don’t pay more. We applaud Pfizer for this decision and hope other companies do the same,” Trump tweeted about the news. “Pfizer shares the president’s concern for patients and commitment to providing affordable access to the medicines they need,” said Ian Read, Pfizer’s chairman and CEO. “The most fundamental way the biopharmaceutical industry creates value is by discovering innovative medicines that help people live longer, healthier, more productive lives… We are encouraged that the president recognises

the value our industry brings to society and our ability to fulfill our mission to discover and bring innovative new medicines to patients.” Shortly after this, Novartis followed suit, freezing its prices for 2018. In a statement the company said: “We work with governments and healthcare stakeholders in all the countries we serve, to support policies to ensure the development of and access to medicines that can improve and extend our patients’ lives.” Pharma companies have come under continued fire from Trump for increased prices and was a key topic for his presidential campaign. Perhaps these recent moves by two big pharma companies represents a win for the Trump administration and may help in the forthcoming midterms, happening later on in the year.

The researchers of the study, led by Dr David Kaufman from Boston University, looked at nearly 1,500 people who use ibuprofen who were asked to keep a diary of all medications they were taking over the course of a week. Looking at these diaries, the investigators found that 11% of participants took more than the recommended dose of ibuprofen in a day with another 4% taking more than the recommended dose of other NSAIDs that were included in the study. When exiting the study, participants were surveyed to determine some factors such as medical history,

demographics, knowledge of label instructions as well as attitudes to label reading and dosing behaviour. From this survey data it was found that more males exceeded the daily limit and other factors such as ongoing pain, poor physical function and daily smoking were factors that contributed to the excessive use of the over-the-counter products. Additionally, those participants who took more than the recommended dose tended to have an attitude of ‘choosing their own dose’ and not starting with the lowest dose as well as a poor knowledge of the recommended one-time and 24-hour doses.

“NSAIDs are among the most commonly used medicines in the US and worldwide. These drugs can have serious side effects, including gastrointestinal bleeding and heart attacks and are often taken without medical oversight because many products are available over-the-counter,” stressed Kaufman to the New York Post. “The attitude that users can choose their own dose regardless of label directions, along with poor knowledge of dosing limits, is associated with exceeding the daily limit.” The study authors conclude that education really is key to reducing this worrying level of excess dosing of NSAIDs.

ANALYSIS

Some hurdles left to overcome

Big data has the potential to provide scientists with important insights but there are still some barriers to its widespread use that need to be overcome. In this article, Paul Denny-Gouldson from IDBS tells us more…

ig data can provide scientists with valuable insights that might otherwise be inaccessible, but it is crucial to capture the outcome of the analysis in a way that it can be reused. Choosing the right technology ecosystem is essential for scientists aiming to leverage big data analytics. The time-consuming task of aggregating and analysing data can disrupt scientists and engineers from focusing on highvalue tasks that require greater human input — meaning they spend valuable time copying and pasting data between applications!

Making big data analytics, machine learning and other algorithmbased AI techniques available to all is still a barrier that needs to be overcome.

Some of the obvious and perennial scientific questions present well known challenges — and they are automatically now attributed to the term ‘big data’. These tricky questions, for instance ‘is there a relationship between these two apparently disparate things?’, or ‘provide me with a data set that is an aggregation of all data we have collected from the past 15 years’ so I can do some analysis’ have been continually asked by scientists. They are starting to become tractable due to advances in storage (cloud based) and high-performance computing (HPC + GPU technologies) which can hold large sets of data in memory and then do high compute cycles/ second on the data, producing results tantalisingly quick — what took weeks just a few years ago now takes seconds.

ACCESSIBLE TO ALL? However, what is less talked about is how we initially access and integrate the scientific data, and how we make sense of the information that we gain from ‘big data analysis’ in a way that makes it usable by all. Currently, data sciences are a specialist function — and it may well stay that way — but the goal is taking what these specialists do and democratising it, making it accessible to all. Essentially, how we can make sure that the data aggregation and analysis process can be verified and repeated by all without causing the compute systems to overload and making sure that the data going in is of good quality? This ‘democratising of big data analysis’ is the next hurdle the scientific informatics community has to tackle. There are two parts to the hurdle — the historical data and the new data being collected going forward. With respect to historical data there are a number of approaches that can be used to ‘tag’ it to make it more accessible and consumable — retrospectively ingesting data and using ontologies and meta data tagging platforms to help give a view of the data landscape. Other tools then sit on these platforms and consume data, massage it and present it to analytics tools (visualisations, machine learning etc.). This type of data tagging is a step in the right direction but it’s important to note that tagging

does not capture the knowledge of the user — it is being inferred — so the ‘level of trust’ is lowered. IMPORTANCE OF DATA DESCRIPTION Working with ‘current data’ requires that all the data (contextual and structured) is captured and tagged as best as possible at the point of creation — getting the user to make sure that the data is fully described with meta data — or at least getting the user to confirm what is correct or not correct if algorithms are used. While this has the advantage of increasing the level of trust in the data, reaching 100% is unachievable. The same requirements exist for both the historical and new data — an organisational semantic taxonomy and ontology of data types and tags that describe the science being done in a way that allows both humans and computers to interrogate the data and consume it effectively (search, aggregate, analyse etc.). Whilst this sounds easy — it is not. Why? Because the science and the data landscape are continually evolving and so the systems that are being used to aggregate, tag and distil data need to do the same. These corporate scientific data ecosystems should be viewed as a living system — one that needs to be fed, curated and manged in the same way any other ‘live systems’ are.

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IT’S ABOUT WHAT DIDN’T WORK TOO… Successful R&D is not just being able to validate and defend results of experiments that worked — those published in journals. It is also about enabling other researchers to utilise existing findings and apply it to their research — and that includes those experiments that didn’t work. The knowledge that can be gained from those experiments that didn’t work is just as critical as the data about those that ‘worked’. This is why knowledge systems that are internal are so critical — because basing decisions on curated data of only experiments that worked (typically those published in journals) does not give the true picture of the scientific knowledge landscape.

BARRIERS STILL TO OVERCOME Using big data analytics, researchers can now begin to explore and expand their data sets and the types of analysis they use. A key to all of this however, is choosing the right ecosystem of applications, tools and data management infrastructures to manage these tasks. Making big data analytics, machine learning and other algorithm-based AI techniques available to all is still a barrier that needs to be overcome. We have seen similar hype over the years with other computational techniques and these are only just becoming ‘democratised’ and integrated into scientists’ working practices — 20 years after the initial push and introduction to the masses. We may see a similar trajectory with big data

analytics and AI in science — early adopters and pioneers are already looking at how to leverage these technologies and most large pharma and biotechs have programmes of work looking at problems. The majority of the problems people are tackling with big data and AI are in the clinical trials, drug repurposing and real-world evidence space — not so much in early research and development. But given the amount of investment and continual simplification of deployment it is almost inevitable that more and more case studies will be available showing how big data analytics and AI tools can be used to help research and development.

Big data can provide scientists with valuable insights that might otherwise be inaccessible, but it is crucial to capture the outcome of the analysis in a way that it can be reused.

Opinion

The industry is in the infancy of its patient centricity journey, but it is clear that with a focus on the patient, many tangible benefits are realised by drug companies

A W IN N I NG F OR M U L A Here, Justin Schroeder, senior executive director of Global Marketing and Design at PCI Pharma Services, looks at patient centricity in pharmaceuticals and how it may help with medication adherence.

here has been considerable discussion about the concept of patient centricity in the pharmaceutical community. The industry has taken a collective pause in an effort to re-evaluate and rethink longstanding approaches to drug development and commercialisation, with attention being recalibrated on the ultimate goal; making it easier for the patient to reach improved health outcomes. This perspective is underpinned by the recognition that what is best for the patient will lead to beneficial outcomes for all stakeholders, including the drug company, the healthcare provider and supporting community of associated service providers. Wide ranging studies have shown medication adherence rates for life threatening diseases can be as low as 30â&#x20AC;&#x201C;40%. With the benefit of interventional techniques and developing technologies, adherence rates have been shown to improve, however these programmes are not broadly adopted within industry with scale and have not had significant impact decreasing the overall cost of healthcare nor benefitted large populations. Patients may be non-adherent for a variety of reasons. Certainly, we are all admittedly forgetful when it comes to taking our medicine on time or being diligent about timely refills. Cost can also be a significant factor whereby patients will consciously stretch their medication supply or simply go off therapy.

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Other considerations may be unwanted side effects or a lack of understanding about how to optimally take the medication resulting in reduced effectiveness. Fear or general lack of understanding can also inhibit the path to improved health. Likewise, the patient may not physically experience the benefit of the drug, and in some instances may have a negative perception due to the unwanted side effects.

Conversely, when one evaluates the development of a unit dose adherence package they find that it may be a longer lead time for development and more costly to produce. If looking from a short-term perspective the choice leaves little room for debate. However, if taking a holistic approach with a focus on patient centricity, the broader economics absolutely point to use of a patient centric package.

FOCUSING PATIENT CENTRICITY IN CLINICAL TRIALS In addition to challenges with patient adherence to medication in clinical trials, sponsors and study organisers are also constantly faced with hurdles such as patient recruitment and patient retention.

Utilisation of a calendarised unit dose blister format, or compliance/adherence packaging, offers sponsor companies considerable benefit in both addressing the needs of the patient as well as positively impacting the desire for better data, more eﬃcient studies and lower total delivered cost. The use of this style of package allows patients to take medication exactly as prescribed and track their usage. Physicians can capture vital information on the package, including the specific date to start the therapy and any other pertinent notes for the patient.

As the industry is tasked with further expediting drug development and decreasing clinical study duration, the FDA is increasingly requiring additional studies and data to prove long-term safety and comparative effectiveness, including post-marketing studies once the drug is commercially available in the market. This trend is coupled with an increasing percentage of drugs being brought to market for very specialised disease states and narrow therapeutic indications. Clinical trial professionals are left to balance all of these demands and creatively identify initiatives to keep focus on the patient. PATIENT CENTRICITY IN PACKAGE DESIGN A practical example of patient centricity in action can be found in package selection for an investigational study. When looking to initiate a clinical study, a sponsor company may be evaluating various package designs. Looking simply at the short-term criteria of expediting material for study initiation the path of selecting a bottle would be a logical solution. It is a cost-effective packaging option, it is relatively ‘off the shelf’, it can be hand filled by a clinical packager with minimal start-up costs, as well as has an acceptable stability profile for barrier properties and is proven child resistant.

With the returned package, the patient can physically demonstrate to clinical providers that they have taken the product as prescribed. Furthermore, technologies are available that can provide real-time tracking of patient dosing, allowing for clinical interventions to ensure proper adherence while the study is in progress. These technologies and principles extend to other delivery forms. The ability to prompt, monitor and even track real time information is a powerful tool. Likewise, with the advent of Bluetooth and nearfield communication technologies, packages with integrated technology can capture real-time information about side effects or other vital information as patients take the medication over the course of treatment. It is estimated that in the industry, clinical studies on average have a 30% drop out rate. With more adherent investigational study patients, health outcomes are improved and better retention is realised, translating into reduced total delivered cost, more valuable data generated, and studies executed more eﬃciently.

13 PATIENT CENTRICITY IN CLINICAL SUPPLY CHAIN LOGISTICS Another area of focus for realising patient centricity in clinical trials is in the area of study design and administration. Considerable interest is being focused in direct-to-patient models. In this scenario patients are engaged by clinical trial or healthcare professionals in a home setting and study drug is physically delivered to their home by a trained specialist. Clearly this model is not applicable for all studies and disease states. PATIENT CENTRICITY IN A GLOBAL WORLD One of the increasing challenges in taking a patient centric approach to clinical study execution is the growth in multinational study execution. Often supplies are designed to pool so that multiple languages are provided and materials can be directed to individual countries as needed. This scenario forces sponsor companies to either manage a multitude of language specific supplies, or focus on common supplies where they condense information due to the shear amount of text being added, often squeezed into a multipage booklet. Careful consideration must be paid for graphics common to all languages and cultures. Rather than a traditional pooled supply approach, some companies have developed newer strategies for just-intime labelling or late stage customisation logistics whereby they label study materials according to country specific requirements at the time of drug dispatch. This can reduce the complexity of a scenario. PATIENT FOCUS YIELDS POWERFUL RESULTS The industry is in the infancy of its patient centricity journey, but it is clear that with a focus on the patient, many tangible benefits are realised by drug companies in their development and commercialisation of lifesaving medicines. With so many significant breakthroughs over the past decade, it is exciting to see where this patient focused journey will.

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REGULATORY AFFAIRS

As we are now a couple of months in after the enforcement of GDPR, we ask Robin Kerbel, CEO and co-founder from Six Degrees Medical* what the impact on the pharma sector is and what may be the wider implications of the regulation changes…

Data protection — it’s personal! Q. COULD YOU BRIEFLY RUN THROUGH GDPR AND HOW IT IMPACTS PHARMA? A. GDPR applies to all organisations that provide goods and services to people in the European Union (EU). EU member states also have the ability to maintain or introduce further conditions, including limitations, regarding the processing of genetic data, biometric data or data concerning health. The objectives of the GDPR are to harmonise data privacy laws throughout Europe, and to safeguard individuals’ privacy. It applies to Personally Identifiable Information (PII), so, a US company conducting a trial in an EU member state must adhere to all aspects of the GDPR in protecting the PII of data subjects. Similarly, trials conducted in an EU member state that will be transferred outside the European Economic Area (EEA) must be protected in accordance with the GDPR. There are a number of rules stipulated by the EEA that data practices must adhere to, the ones listed below represent the most pressing steps for pharmaceutical companies: � Personal data are to be kept no longer than necessary to carry out the intended purpose. � Data processed must be up to date, adequate, relevant and not excessive in relation to the purpose of use. � The purpose of processing cannot be altered unless a change of purpose is explicitly outlined by internal rules. � All data subjects must have access to their data.

*www.sixdegreesmed.com

� �

Data transfers are subject to conditions depending on the status of the recipient. Data controllers must notify the EEA of their processing operations.

Q. WHAT MAY BE THE BIGGEST AREA WITHIN PHARMA THAT IS AFFECTED? A. Clinical trial sponsors must carry out a Data Protection Impact Assessment (DPIA), which includes: � A description of the processing operations and purpose of processing. � An assessment of the necessity and proportionality of the processing. � An assessment of any risks to the rights and freedoms of subjects. � The measures in place to protect those risks. The DPIA is less a matter of capturing the exact information being processed, and more a matter of recording all the reasons for processing, and the measures being taken to prevent the risk of breach.

Q. IF THERE IS A DATA BREACH WHAT STEPS SHOULD BE TAKEN? A. Most importantly, organisations conducting clinical trials must be maintaining proper documentation from the very beginning. In the event of a breach, the controller must report it to the authorities no later than 72 hours following the discovery of the breach. They will be required to supply documentation as evidence of the responsible handling of all processing, and attempts at mitigating risk. Q. WHAT PROACTIVE STEPS CAN BE TAKEN BY COMPANIES TO ENSURE THEY ARE PREPARED FOR FUTURE CHANGES? A. Given the wide-reaching scale of the data protection initiatives taking place across the globe, many organisations have begun partnering with consultants who have an indepth knowledge and continuing eye on upcoming legislative changes. Data protection is a unique knowledge set that requires focus. Delegating the responsibility of data protection assurance to a specific individual or team (whether internal or third party) is key to ensuring that it remains a priority. Q. WE WILL SEE STRICTER GLOBAL GUIDELINES FOR PERSONAL DATA PROTECTION? A. To a certain extent, the GDPR has already affected global change. Companies conducting any level of processing on the data of subjects in the EU must still abide by the regulations, regardless of their country of origin. Further, as the media continues its focus on privacy risks, citizens will likely continue to press for greater enforcement of data protection laws.

COVER STORY

Go with the flow A perfect active pharmaceutical ingredient is one that performs well from R&D through tablet production. However, in real-world situations challenges are inevitable. Here, Jonathan Gaik, director, Natoli Scientific, looks at the critical issue of powder flow and how solving issues before production can reduce product performance issues later down the line.

he ideal active pharmaceutical ingredient (API) is one that flows well, is stable, self-lubricates, compacts well and is not strainrate sensitive. While all the listed properties are important, the one that continues to be critical is powder flow. Most challenges in the tabletting process initiate with or can be traced back to flow.

FIGURE 1. PARTICLE SIZE AND DENSITY VARIATION WITHIN A HOPPER

Product flow challenges become more apparent when scaling up to full production. A seemingly minor product fault during R&D can become unmanageable during production. Conducting studies on a formulation during R&D and scale-up can help identify and solve potential powder flow issues before moving into commercial production. STORAGE CONDITIONS Humidity within storage or production areas can affect a powder’s properties and thus how it flows. Additional moisture can increase a powder’s potential to form hydrogen bonds that may cause a more cohesive powder that will restrict flow. Hold time studies during R&D are crucial to determining the effects of storage conditions on the formulation. Maintaining an environmentally controlled storage and production area is vital to a formulation’s flow characteristics. BLENDING Flow difficulties at the blending step often manifest as slow/no discharge or ratholing. These issues are most likely due to improper storage, a poorly selected binder

that is too cohesive with the API, lack of glidant, improper order of addition, or an incorrect blending procedure.

give formulators clear evidence of whether a formulation is within specification before moving to the next step.

The best way to establish flowability is to compare flow on a Flodex powder flow tester with the tablet configuration to determine whether the powder’s intrinsic flow is close or equivalent to the crosssection of the die. For example, a Flodex may show a neat API powder has flowability of 26 mm, with a round tablet design of 12 mm in diameter. The formulator needs to look at the concentration and types of glidants and binders to achieve a target intrinsic flowability of 12 mm or less. Once that has been achieved, lubricants can be added and evaluated for flow.

HOPPER DESIGN AND POWDER SEGREGATION After blending, the powder will be discharged to the hopper, where the formulator must ensure adequate flow properties to successfully enter the gravity or force feeder. Difficulties when discharging a powder blend can be due to improper hopper design. Studies are conducted in R&D to calculate measurements like angle of repose and wall friction based on the powder properties. This information can be used to design the hopper’s shape and determine the best material of construction and surface finish for encouraging powder flow.

Material interactions will guide the order of excipient addition and blending procedures. For example, if a glidant is needed, consider a preblend step to maximise the interaction between the glidant and the poorly ﬂowing materials. A preblend step usually lasts between two and eight minutes, and the length of this step can be determined using a Flodex. Blend uniformity (BU) studies ensure APIs are adequately blended with excipients and can

Powder segregation within the hopper may result from formulation design or improper transfer. One type of segregation, called sifting, occurs when gravity or vibration from the tablet press causes larger

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particles to separate from the smaller particles. Smaller particles filter to the bottom while the larger particles rise to the top (Figure 1). Researchers can conduct studies according to ASTM International Standards to help understand whether segregation is occurring and by what mechanism. Segregation happening at this point in the process can affect tablet quality, possibly causing capping, lamination and high ejection forces. Conducting content uniformity (CU) studies, which should follow the guidelines set forth by the US FDA under 21 CFR 211.110, can help determine whether the batch is consistent and within specification. TABLET PRESS CONSIDERATIONS Flow challenges on the tablet press can cause tablet quality issues such as weight variability, content uniformity and/or tablet defects. Weight variability can be driven by a poorly flowing powder or agglomeration by a material within the powder. Each die sits under the opening in the feed frame for a small amount of time, usually milliseconds. Therefore, the flow rate must be calculated and tested to ensure the powder can keep pace with the feeder and turret speed and adequately fill the dies to the correct weight. Agglomeration might not be detected in flowability studies. However, it can become a

localised flow event that randomly causes weight variability. Turret and feeder speed must also be matched to the flow rate of the powder to prevent overblending, which can result in segregation or excessive lubrication and thus can lead to poor tablet quality in terms of CU or compactibility. To identify these issues, CU samples are typically collected in set intervals as tablets are produced on the tablet press. Figure 2 shows an example CU assay at 15-minute intervals during tablet production. CU1 shows tablets within the acceptable content uniformity range. CU2 shows an example of sifting segregation, while CU3 shows irregular, non-uniform tablet content due to overblending. CU samples can help identify specific problems based on the results; however, unless they are paired with BU studies they will not be able to isolate where the issue is occurring. Changes in hardness can be identified with the same CU studies. Finally, poor powder flow can result in tablet defects such as sticking and picking, which may be caused by entrapped air within the die. Formulation design, engraving, tooling material, or coating can improve powder flow during the compression cycle and thus reduce tablet defects. Gentle curvature in engraving cuts result in more laminar and less turbulent powder flow. Tooling material and metal coatings should be selected to decrease the coefficient of friction while increasing release characteristics, to improve powder flow. ENSURING GOOD POWDER FLOW A poorly flowing powder can affect tablet quality at every step in the process.

Key factors to consider when encountering a powder that doesn’t flow well are formulation design, storage conditions, tablet design and mechanical design of processing equipment. Powder rheology studies, such as shear strength and wall friction, which can be conducted on a Freeman FT4, and flowability on a Flodex, can be performed throughout the R&D process to help demonstrate a powder’s flow characteristics. A thorough process development, including conducting BU and CU studies and determining turret and feeder speed, helps optimise production and reduce time involved in troubleshooting. Minor powder flow issues during R&D can turn into major headaches once scale-up to production begins. Conducting studies throughout R&D and scaleup can help identify and isolate where in the process a formulation issue began. Powder flow can also vary from lot-to-lot, which needs to be understood during R&D. Most problems that manifest on the tablet press start with the powder and its flow properties, so it’s important to understand how a powder will perform under every circumstance. Working with a trusted partner, such as Natoli Scientific, can help identify and address potential formulation concerns before moving into production to reduce product performance issues.

FIGURE 2. TABLET CONTENT UNIFORMITY ASSAY STUDIES

Studies on a formulation during R&D and scaleup can help identify and solve potential powder flow issues before commercial production.

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EYEING UP ADHERENCE Nemera explain how connected solutions for drug delivery in the opthalmic space may help with patient adherence

MICROBUBBLE TECHNOLOGY TRANSDERMAL SOLUTION ANTIBIOTIC RESISTANCE

DRUG DELIVERY SUPPLEMENT

In this article, Felicity Thomas, EPM editor, discusses connected solutions for drug delivery in the ophthalmic space and how this may help with patient adherence among other things with Fanny Sellier, global category manager for ophthalmic devices from Nemera.

EYEING UP ADHERENCE

ith an ageing population and increasing numbers of patients suffering from chronic eye conditions that require regular topical treatment, effective drug delivery and patient adherence to treatment regimens are important considerations within ophthalmology. Conditions, such as dry eye and glaucoma, can require the patient to administer eye drops consistently over a long period of time. However, according to multiple studies, medication adherence for glaucoma — a leading cause of irreversible blindness worldwide — is commonly found to be low.1–4

There are several factors that can attribute to this low adherence rate, such as a lack of understanding by the patient about the condition and the necessity of following a strict

treatment schedule, uncomfortable side effects of the medication as well as diﬃculty in administering the treatment, to name a few. Although the ophthalmologist can help the patient to understand the gravity of their condition and as such the importance of taking their medication, the latter two issues need to be addressed by the drug and delivery device manufacturer(s). Nemera — a developer and manufacturer of drug delivery devices — has looked into improving patient adherence of ophthalmic treatments extensively discussing the issue with both patients and doctors. “The quality and success of a treatment depend on the patients’ adherence,” said Sellier. “Underdosing, because of either poor adherence or poor performance, means that patients

are not receiving the prescribed medication. Overdosing, as seen in a 2009 American Medical Association’s study, has the potential for several problems, including systemic or ocular adverse events and a more rapid use of the medication.”5 AN EASY SOLUTION WITH LESS SIDE EFFECTS? “Our objective was to come up with an innovative system to deliver eye drops easily into patients’ eyes and limit negative side effects, in order to improve their compliance to treatment,” Sellier added. Working on a suitable solution, the company is developing a connected eye dropper for multi-dose preservative-free formulations. “Our multi-dose closing tip system, Novelia, avoids the need for preservatives in the drug and

CONNECTED SOLUTIONS

prevents bacterial contamination over the duration of treatment,” she explained. “Rather than relying on the antimicrobial properties of preservatives to kill any bacteria that enter the bottle, the ideal approach is to prevent any entry of bacteria into the bottle in the first place, thanks to a non-return valve system used in conjunction with a silicone membrane to filter the returning air.

Our objective was to come up with an innovative system to deliver eye drops easily into patients’ eyes and limit negative side eﬀects

“The one-way valve ensures that no contaminated liquid can be re-introduced to the container after the drop has been dispensed, completely removing the need to filter the liquid,” Sellier continued. “The intake of air into the dispenser takes place via a separate venting system with a silicone membrane called the PureFlow Technology.” Being able to use a formulation without requiring preservative should help improve adherence as potential side effects will be reduced. Preservatives can cause allergic reactions/irritations in some patients and in some extreme cases can cause a toxic response.5 ELECTRONIC ADD-ON TECHNOLOGY “Digital enhancement can assist with drug delivery through aiding the patient with administration while also being able to give them reminders about when their next dose is due and enabling more detailed information to be gathered,” stated Sellier. Using smart add-on technology, the patient benefits from digitalised and interactive instructions via their mobile device as well as an on-device screen. Patient awareness can be increased with reminders of when to take a dose as well as when to replace their medication. Additionally, it is possible to store information like expiry date, dosage and batch number on a smart device and feedback along

with guidance can be given to the patient on how to use the device in the correct way to ensure the correct dose is administered. Obviously, there have been issues in clinical studies when trying to evaluate the relation between patient adherence and eﬃcacy of topical treatments as once at home, patients cannot be monitored other than what they record themselves. Through a smart add-on device, a more thorough collection of data can be collated and used by the healthcare professional as well as drug manufacturer. “The electronic add-on collects the number of drops delivered via the system and when exactly they have been delivered (date and time). It compares the actual intake with the posology and therefore calculates the patient’s compliance,” revealed Sellier. “It can also retrieve if the device has been shaken off if required. By recording the system’s inclination it

is possible to ensure the right drop size is being administered.” USEFUL FOR ALL! Connected technology is finding use in many areas of life and, with rising numbers of people using smartphones or smart devices, are becoming a more routine development with far reaching possibilities and applications. “Not only will our new technology (and connected drug delivery devices) be useful for patients, but will also be so for the entire industry,” Sellier concluded. “Healthcare professionals will benefit from dose tracking analysis and as such will be able to adjust the treatment if required; researchers will be able to perform more eﬃcient clinical studies; the pharma companies will also be able to use the data collection to launch better performing drugs; and the payers will be able to check if the patients comply with their prescriptions.”

21 REFERENCES: 1. https://bmjophth.bmj.com/ content/3/1/ e000114 2. https://www. ncbi.nlm.nih. gov/pmc/ articles/ PMC4274150/ 3. https://www. nature.com/ articles/ eye2012294 4. https://www. ncbi.nlm.nih. gov/pmc/ articles/ PMC3038505/ 5. https://jamanetwork.com/ journals/jamaophthalmology/article-abstract/423345 6. http://www. tearfilm.org/ dewsreport/ pdfs/TOS0502-DEWSnoAds.pdf

Smartphone app connectivity to allow real-time tracking and care management

Mechanical Dose Counter

Introducing the next generation MDI For more information contact H&T Presspart: www.presspart.com eMDI@presspart.com

H&T Presspart are pleased to introduce the first market-ready, fully-embedded, intuitive and connected metered dose inhaler (eMDITM) established to optimize care of patients ensuring from asthma and COPD. The eMDITM integrates seamlessly with BreatheSmart from Cohero Health, the only respiratory disease management platform that enables tracking of both controller and rescue medications, along with clinically accurate lung function measurement, in real-time.

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STEPWISE

TO FUTURE RESPIRATORY CARE More than 500 million people worldwide suffer from Asthma and COPD. These major chronic decisions lead to more than 3 million deaths per year. Also, the associated cost burden is significant and exceeds €150 billion in the USA and Europe taken together. A major driver for this disastrous status is insuﬃcient adherence to controller medication, which even after the first prescription has been filled ranges between 30% and 66%. Connected, external “addon” devices for Asthma and COPD inhalers track patient adherence and connect patients to their physicians and other healthcare providers. In clinical studies, these devices have demonstrated to improve adherence to Asthma and COPD medication and therewith clinical outcomes . Despite the fact, that they also offer advantages for other key stakeholders, like physicians, payers and pharmaceutical companies, their

market adoption has been poor so far. The reasons, we at H&T Presspart believe, are that a stepwise approach to connected respiratory care is needed and that the short-term requirements for mass adoption have not been fully met yet. Long-term connected devices might be “purpose-designed” like a Tesla electric car is around its electric drivetrain, track technique via advanced sensors and might even actively regulate device characteristics, such as the ﬂowrate. For a short-term market success, devices also need to have embedded electronics, but should be simple, intuitive, costeﬃcient and represent limited changes to the status quo. In an effort to realize a broad market adoption in a stepwise manner, H&T Presspart and Cohero Health formed a strategic device development and marketing partnership. As a result, the companies created

H&T PRESSPART'S EMDI CONNECTED INHALER

the first market-ready, fullyembedded, connected metered dose inhaler solution: H&T Presspart’s eMDITM powered by CoheroTM. The eMDI device design is inline with the requirements stated above: It is an evolution of existing metered dose inhaler technology and its connective hardware and software are fully-embedded. The changes to existing MDIs form and function are minimal. As a fully disposable, nonreusable unit, the eMDI secures that users do not need to do anything other than press and breathe, as with their standard MDI. Also, the electronic componentry is separated from the medication delivery pathway and the device incorporates an FDA-approved mechanical dose counter. With our partners, we hope that we can pave the way for a broad market adoption of connected technology in respiratory care. A change is needed, as “drugs don’t work in patients who don’t take them”.

1 Akdis CA et al., “Global Atlas of Asthma”, EAACI, 2013. 2 GARD, “Chronic respiratory diseases”, http://www.who.int/gard/ publications/chronic_ respiratory_diseases.pdf 3 Akdis CA et al., “Global Atlas of Asthma”, EAACI, 2013. 4 WHO, “Burden of COPD”, http://www.who.int/ respiratory/copd/burden/ en/ 5 Ford ES et al., “Total and state-specific medical and absenteeism costs of COPD among adults aged ≥ 18 years in the United States for 2010 and projections through 2020”, Chest, 2015, 147, 1, 31-45. 6 CDC, “Asthma in the US”, https://www.cdc.gov/ vitalsigns/asthma/ 7 Gibson GJ et al., “The European Lung White Book: Respiratory Health and Disease in Europe”, European Respiratory Society, 2013. 8 NICE, “Smartinhaler for asthma – Medtech innovation briefing”, NICE, 2017. 9 NICE, “Smartinhaler for asthma - Medtech innovation briefing”, NICE, 2017. 10 Jung B, Shears D, “Embedded connected metered dose inhalers meeting requirements for mass adoption”, ONdrugDelivery, 2017, 76, 6, 44-48. 11 Jung B, Shears D, “Embedded connected metered dose inhalers meeting requirements for mass adoption”, ONdrugDelivery, 2017, 76, 6, 44-48. 12 C. Everett Koop.

DRUG DELIVERY SUPPLEMENT

Skin in the game European Pharmaceutical Manufacturer editor, Felicity Thomas, sits down with Sally Waterman, COO at Medherant to discuss the benefits of transdermal drug delivery and how industry developments and changes in patient needs are leading to a shift…

n order to keep pace with the changing requirements of patients and the ongoing challenge of adherence to medications, innovative drug delivery methods are a must. Not only are patients expecting more from their medication, but they are also expecting the delivery to be quick, painless, with fewer side effects and easy to implement at home.

REFERENCES:

1. https://www.epmmagazine.com/ technology/medherant-patch-technology-recognised-by-coventry-telegraph-/ 2. https://medlineplus.gov/ druginfo/meds/a682509. html

A distinctive offering from Medherant is the transdermal drug delivery patch (TEPI Patch), which, last year, was awarded with the Excellence in Science & Technology Award at the Coventry Telegraph Business Awards.1 Now, transdermal delivery systems are not necessarily new, with the first — a scopolamine patch2 for motion sickness — launching

nearly 40 years ago. However, the industry has continued to view this segment as niche and with a specific set of limitations, leaving oral solid dosage and injectable solutions as the market mainstays. Yet, further developments in transdermal delivery technology and changing needs of the patient population is perhaps starting to buck the familiar trends…

TRANSDERMAL SOLUTIONS

THE MAIN BARRIERS… The main barriers for transdermal delivery have been limitations in the drugs that can be formulated as a transdermal patch and diﬃculties penetrating the skin barrier. However, thanks to the development of new technologies, such as better adhesives, nanoparticles, chemical permeation enhancers that can improve drug solubility, or other active approaches, like ultrasound or high-voltage electrical pulses, the options available for transdermal delivery are expanding. A DRUG-IN-ADHESIVE PATCH The TEPI Patch is a drugin-adhesive patch that has been formulated with a novel adhesive, which Medherant has exclusively licensed from Bostik. “Through this unique adhesive we are able to provide multiple benefits,” explained Waterman. “The adhesive has a higher loading capacity so more drug, or drug plus excipients, can be incorporated into the patch, which means that a smaller and/or thinner patch can be produced, lower potency drugs can be formulated for transdermal delivery, or the delivery of the drug can be controlled via the inclusion of specific combinations of excipients, including permeation enhancers. “Also, the patch has durable contact with the skin, which ensures comfort and reassures the patient that the correct amount of the drug will be delivered,” she continued. “However, it is still easy to remove and once in place there is no leakage of adhesive around the edges of the patch.” Does this mean that the drug is actually bound into the adhesive? “No,” stressed Waterman, “it is simply dissolved among

the polymers in the adhesive and seepage of the drug from the patch whilst it is stored is prevented via a transparent liner. The liner is removed prior to the patch being placed onto the skin; once applied the drug can then permeate from the adhesive into the skin.” She went onto explain that the free base or acid of a drug is used in the adhesive rather than a salt, which facilitates its passage through the skin. BENEFICIAL FOR A RANGE OF PATIENT GROUPS Are there specific patients that would truly reap the benefits of a transdermal delivery option? “Yes, transdermal delivery is of particular benefit for patients who struggle to swallow oral medications, those who do not like injections and those experiencing nausea or vomiting, for example,” Waterman stated. So, transdermal delivery using a patch is of particular benefit to patient groups, such as geriatrics and paediatrics, that have the potential for poor adherence rates if their treatment requires them to swallow their medication or be injected. By using a transdermal route of administration, the drug can bypass the stomach, which could improve treatment eﬃcacy and reduce side effects. “This is particularly helpful for drugs that have a significant impact on the gastrointestinal mucosa or for those that are poorly or variably absorbed by the but after oral administration or are subject to extensive metabolism in the liver,” she added. “Furthermore, multiple drug administrations can be avoided as the drug can be delivered from a patch over an extended period of time — this also offers potential cost benefits,” said Waterman. “Compliance can also be improved

transdermal delivery is of particular benefit for patients who struggle to swallow oral medications, those who do not like injections and those experiencing nausea or vomiting

by administering a drug as a transdermal patch. A health worker/carer could apply the patch easily to a patient who is unable to swallow or might forget to take their medication, such as those suffering with Alzheimer’s disease or other forms of dementia.” COMMERCIAL AVAILABILITY What is the current position of the product in terms of market readiness? “Our first product, an Ibuprofen TEPI Patch, will be tested in Phase I clinical studies over the summer of 2018. A Phase III safety and eﬃcacy study in patients with acute sports injuries is planned for 2019. The product is expected to be available to patients in 2021,” Waterman revealed. “Subsequent products will also be patch formulations of currently approved drugs and will include treatments for chemotherapy-induced nausea and vomiting and pain associated with a surgical procedure as well as products for chronic CNS diseases. “We expect to have at least three of our own products in clinical development in 2019/2020.”

DRUG DELIVERY SUPPLEMENT | AMR

THE TIME IS NOW In this article, Adrian Fellows, head of R&D at AGA Nanotech, looks at the current state of play in the global antimicrobial resistance crisis, revealing that we need solutions — like delivering high-energy oxidative molecules in a controlled manner — now, not later!

I While highly reactive chemicals could not normally be used therapeutically, because of collateral damage to the patient, by modifying the approach it is possible to deliver micro biodegradable particles to the infection and prevent patient harm.

t was no surprise when the World Health Organisation (WHO) named antimicrobial resistance (AMR) as one of the biggest threats to global health. We’ve known for some time, that the widespread misuse of antibiotics has created a substantial increase in the number of antibiotic resistant bacteria. The question isn’t why but how do we overcome the problem of antibiotic resistant bacteria? Irreparable damage has been done through the over-prescribing of antibiotics in human healthcare. The growth of antibiotic resistant organisms has accelerated, resulting in bacteria which are resistant to all types of antibiotics — a pharmacist’s worst fear. One thing is for certain, multidrug resistant organisms (MDROs) is the most major healthcare threat humanity faces and we need solutions.

If nothing is done to replenish the pipeline of antimicrobial treatments, it is estimated that by 2050, more than 10 million deaths per annum would be due to resistant bacterial infections.

infection without harming the patient.

But, as you’ll be glad to hear, there is some good news. There are some potentially lifesaving solutions already in the works.

While highly reactive chemicals could not normally be used therapeutically, because of collateral damage to the patient, by modifying the approach it is possible to deliver micro biodegradable particles to the infection and prevent patient harm.

COLLABORATIVE WORK In efforts to develop a potentially lifesaving solution to global antimicrobial resistance, AGA Nanotech have collaborated with researchers from University College London, led by Dr Richard Day.

The primary aims for developing a solution to the global AMR crisis that affects us all, are simple: the anti-infective must be delivered safely, eﬃciently and with minimal patient side-effects. Patient care should be at the forefront of all of our minds.

This collaborative work has seen the creation of poly lactic-co-glycolic acid (PLGA) nanoparticles and microparticles that use Thermally Induced Phase Separation. This can deliver safe and inert precursor molecules which in turn produce highly oxidative biocides at the site of infection.

AGA Nanotech explored numerous technologies that could deliver high energy oxidative molecules in a controlled manner to the infection without harming the patient, to find the perfect fit.

The long and short of the scientific language is this: these processes produce oxidative antimicrobials, which are capable of killing all antibiotic-resistant bacteria. This is the cheerful bit — where we marvel at the transformative and miraculous work scientists are capable of… AND THE REALLY IMPORTANT PART? DELIVERY… AGA Nanotech, with the help of expert researchers, has discovered a way of delivering these highenergy, potentially lifesaving and oxidative molecules to the

After screening several technologies, Thermally Induced Phase Separation (TIPS) became the obvious choice for an eﬃcient, reliable and patient-centred drug delivery platform. A HUMAN ANSWER The global scale of the AMR crisis demands more than simply a global solution, but a human answer. We need a drug that combats antibiotic resistant bacteria and prevents patient pain. We need preventative research to stop this kind of medical catastrophe happening again. We need to thank and invest in our scientists and engineers who work tirelessly to put us, our health and our well-being first.

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DRUG DELIVERY SUPPLEMENT | INNOVATIVE TECHNOLOGY

Bubbling up In this article, Dr Malcolm Haddrick (Medicines Discovery Catapult) and Professor Steve Evans (University of Leeds) highlight the exciting and innovative new method of drug delivery — microbubbles.

REFERENCES: 1.

Waring, M., et al., Nature Reviews Drug Discovery, 2015;14:475–486. Foster, A., et al., Cancer Metastasis Rev., 2000;19(1– 2):131–138. Peyman, S.A., et al., Lab Chip 2012;12:4544– 4552 Ibsen, S., et al., Drug Design, Development and Therapy, 2013;7:375–388. Liu, H.L., et al., Theranostics, 2014;4(4):432–444.

current challenge across the pharmaceutical industry is how to improve the rate of attrition in the delivery of new medicines to patients.1 Innovative drug delivery technologies have the potential to address this challenge by overcoming the cell permeability limitations of promising novel therapeutics (e.g., PROTACs) or by ‘rescuing’ existing drugs with poor solubility or those with a low therapeutic index. Investment in therapeutic delivery platforms has the potential to be broadly impactful across multiple drug modalities that can be applied to a wide range of disease areas. The Medicines Discovery Catapult, a not-for-profit research company established to support UK drug discovery, is collaborating with the University of Leeds to evaluate microbubble technology as a new drug delivery system. Microbubbles are safe and well tolerated, they are currently in use in the clinic as a contrastenhancing reagent for ultrasound imaging scans2 and have useful properties to exploit as vectors for therapeutic agents.

Microbubbles are micron-sized gas filled phospholipid bubbles which can be manipulated or destroyed by ultrasound energy. They are generated on-chip in a microﬂuidic production platform3 and form the core that enables the assembly of therapeutic microbubble drug complexes. Drugs, or other modalities, are encapsulated into nanoparticles, such as liposomes, which are attached to the microbubble, achieving high drug loading levels while stabilising the bubbles. Targeting to specific cell surface molecules can also be achieved by the incorporation of antibodies to the bubble and liposome lipids. Post injection into the body, the microbubble complex travels through the circulation and accumulates at the target site, for example a tumour. The drug cargo is then delivered in a controlled way by ultrasound-triggered microbubble destruction which simultaneously generates transient micropores in the cell membrane, enabling drug penetration and activity in cells.

The aim of the Medicines Discovery Catapult and Leeds collaboration is to develop the Horizon microbubble production platform to be suitable for firstin-human trials to treat colorectal cancer within two years. This will include validation of production technology, optimisation of microbubble/drug carrier assembly, pre-clinical assessment of the eﬃcacy of ultrasound enhanced drug delivery and establish safety profiles in multiple drug and disease combinations. Therefore, microbubble technology can deliver multiple modalities in a targeted way, drug payloads may be ‘masked’ into nanoparticles and activity controlled by ultrasound. This technology is ideally placed to minimise the issues associated with chemotherapy treatments for cancer.4 The ability to enhance local concentration and the non-invasive nature of the delivery may enable treatment into pharmacological sanctuaries like the blood brain barrier.5 This is an innovative and exciting new technology option for drug delivery.

microbubble technology can deliver multiple modalities in a targeted way, drug payloads may be ‘masked’ into nanoparticles and activity controlled by ultrasound.

Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

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LEGAL — IP

AT RISK? With intellectual property arguably one of the most valuable assets a life science business possesses, Kathryn Moon, Life Science Risk & Insurance specialist at UK broker Gallagher, looks at why it can be essential for businesses in the industry to have a robust insurance policy in place to protect it. REFERENCE:

1. KPMG – Life sciences innovation and cyber security: Inseparable http:// www.kpmg-institutes.com/content/ dam/kpmg/healthcarelifesciencesinstitute/pdf/2017/ cyber-report-life-sciences.pdf

any companies in the life science industry typically stop short of taking out insurance for intellectual property (IP), despite its value as a business asset. This is because, historically, the insurance market made the application process unnecessarily complicated and drawn out. If and when quotations were provided, these were often expensive and restrictive in terms of cover. The good news is that things have changed. New insurance companies have entered the market to bring much-needed competition and redefine the underwriting approach, offering enhanced policy coverage and lower prices that are more proportionate with the level of risk. But in order to determine the value of investing in IP cover, a life science company first needs to consider the facts. So, what exactly does IP insurance protect and provide? This type of policy is designed to enable a company to defend infringement allegations eﬃciently, whilst also protecting innovation by allowing the opportunity to pursue infringers of their own rights. An IP policy can provide protection for defence costs and for damages awarded where an action has been brought against a company for infringing or alleged infringement of third party’s IP. It can also provide cover for

professional fees and expenses for pursuing infringement or theft of a company’s IP. Furthermore, the policy can cover costs incurred to avert or mitigate potential litigation, which may entail product recall expenses, pre-emptive and assertive actions or counter-claims. Life science companies also face the threat of their own IP being stolen as a result of a cyberattack or data breach and, with an increasing dependence on technology, the likelihood of this risk has increased. IP has been found to be one of the most vulnerable assets of a life science company1 and breaches can include a complex ransomware attack denying access to vital data or even a disgruntled employee stealing and passing on information to competitors. Losing such data can obviously have reputational and commercially damaging consequences and whilst strengthened security procedures, good digital housekeeping and high user awareness will reduce the likelihood of a cyber-security breach, it does not guarantee a business will not be hit. That’s where a tailored cyber insurance policy can help protect a business against the multiple impacts of a cyber-attack. Especially as a standard IP policy may not cover the theft of information from such methods.

Nevertheless, there are a number of legitimate reasons for why life science companies should be considering IP insurance as a key protection for the business, regardless of their size. These include: BUSINESS ENABLER: Investors would rather deal with companies that can meet their indemnification obligations and which will not spend its research budget on expensive litigation. In addition, the policy will help to meet indemnities in third party contracts and will provide protection for licences and customers in terms of litigation associated with the IP. PROCESSES: Cover is no longer limited to just products. Policy wordings can be tailored to cover claims arising from process patents, business method patents and trade secret misappropriation, to ensure protection across the entire business activities of the company. SINGLE CONTRACT PROTECTION: Cover can be tailored to apply to a single contract, a specific division of a company or a specific product as insurers now offer the ﬂexibility to meet a company’s specific requirements rather than a one size fits all approach.

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80/20 RULE: Patent attorneys perform freedom to operate opinions to minimise the risk that products infringe third party patents. However, non-infringement can never be guaranteed and even if a search reveals 80% of the risk, there will be some outstanding. Real freedom to operate can be achieved by having the financial means to defend a claim, provided by an IP Insurance policy. PATENT COVER WHERE EXCLUDED ELSEWHERE: Claims arising out of IP, and specifically patents, are often excluded from many policies including Directorsâ&#x20AC;&#x2122; & OďŹ&#x192;cersâ&#x20AC;&#x2122; Liability and Professional Indemnity Insurance. This can be a key risk for the business yet remains uninsured relative to both the company and its individual directors where named as a joint defendant. In the event that a company is forced to stop selling a product due to an alleged IP breach, such as a patent infringement, the policy can also cover potential loss of profit the company has suffered during the period it has been unable to sell its product. The reality is that intellectual property is undeniably one of the most valuable assets a life science company owns. So, can any business really afford to ignore the protection that both IP and tailored cyber insurances could provide? Essentially, developing a robust strategy and ensuring you have suitable protection in place can be critical for safeguarding the future of your business.

Life science companies also face the threat of their own IP being stolen as a result of a cyber-attack or data breach and, with an increasing dependence on technology, the likelihood of this risk has increased.

LEGAL — IP

A decent proposal? Earlier this year, the European Commission proposed the introduction of a manufacturing exemption for SPCs. Here, Alexander Kritharidis, associate in the Life Sciences sector group at Taylor Wessing, London, who is specialising in patents law, goes into more detail…

n May, the European Commission published its proposal to introduce a manufacturing waiver for supplementary protection certificates (SPCs). The commission’s proposal comes out of its public consultation on SPCs and patent research exemptions. The EU has a strong intellectual property rights framework in place that sustains a multitude of industries’ innovative capabilities. To improve the current system further and remove a competitive disadvantage faced by EU manufacturers, the commission has tabled a targeted amendment, a so-called ‘export manufacturing waiver’ to SPCs. INTRODUCTION OF AN EXEMPTION Currently, EU manufacturers of generics and biosimilars cannot, during the SPC term of a product in the EU, manufacture these products for any purpose, whilst manufacturers based in those non-EU countries are free to do so. The commission considers that this competitive disadvantage creates a risk of delocalisation of manufacturing outside the EU and loss of investment opportunities.

The commission’s proposal would see the introduction of a manufacturing exemption to Article 4 of Regulation (EC) No. 469/2009 (the ‘SPC Regulation’), whereby EU-based manufacturers of generics and biosimilars may manufacture a product protected by an SPC, in the territory of a member state during the SPC term, for the exclusive purpose of exporting their products to non-EU markets where patent or SPC protection has expired or never existed. The exemption would only apply to SPCs that have not yet been granted and only after a transitional period to accommodate pending SPC applications. SAFEGUARDS TO PREVENT CIRCUMVENTION OF THE EXEMPTION The proposal would also see a series of safeguards introduced to ensure transparency and avoid the possible diversion onto the EU market of generics and biosimilars manufactured for export purposes during the SPC term. The safeguards include: • An obligation for businesses to provide a notification to public authorities of their intention to commence manufacturing and the information contained in that notification would be made public.

• An obligation on the manufacturer to inform its supply chain that the products in question are for export only, and that placing on the market, import or reimport of the products to the EU might infringe an SPC. • Specific labelling requirements for the export of products outside the EU that are protected by an SPC. The commission considers that the combined effect of these safeguards will make it easier for both SPC holders and public authorities to detect and address infringements by existing means through the national courts or other control mechanisms including market surveillance and customs control. The European parliament has set a target implementation date of before 2019. Once adopted by the European parliament and council, it will be directly applicable in all EU member states. The commission considers that the manufacturing exemption will create investment and job opportunities in the manufacturing of generics and biosimilars in the EU. The waiver will also contribute to a more timely onset of competition in EU markets for medicines upon expiry of SPCs.

The commission considers that the manufacturing exemption will create investment and job opportunities in the manufacturing of generics and biosimilars in the EU…

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STERILISATION

DOWN TO THE WIRE In this article, Chris Maughan — managing director and Autoclave Validation SME at Thermal Compliance — investigates the use of wireless dataloggers for autoclave validation, looking into the how they can help and issues with their use.

f you have ever been involved in the process of autoclave validation you’re probably aware of how frustrating and time consuming it can be. Working validation slots into production schedules, failures in test equipment, machine failures and test failures all lead to a challenging project. But is there anything we can do to streamline the validation process? Wireless dataloggers have been around for several years now and are regularly used for temperature mapping of controlled temperature units (CTUs), where they offer substantial time savings in the validation process. So, can they be used for autoclave validation and if so what benefits and pitfalls do they offer?

TABLE 1: Validation timelines for thermocouplebased system and wireless dataloggers.

BENEFITS The most significant benefit of using wireless dataloggers as opposed to a wired system is time saving. Table 1 shows a time line of a typical validation exercise for both a thermocouple-based

system and a wireless datalogger. The main time saving benefits arise due to the following reasons: 1. Setting up a thermocouplebased system requires leak rate tests. Using wireless dataloggers does not break the integrity of the autoclave chamber so leak rate tests are not required. 2. Thermocouple-based systems require pre- and post-test calibrations (typically every three to six cycles). This is due to the short-term drift of thermocouples. Wireless dataloggers often use PT sensors with minimal drift which require annual calibration. Calibration verifications can be performed as well, however, this would not impact autoclave downtime. 3. When using wireless dataloggers, thermocouple and biological indicator setup and removal can be performed oﬄine whilst the autoclave is in production use.

Wired system Wireless system Single run Triplicate runs Single run Triplicate runs 4 hours 4 hours N/A N/A

Equipment setup and calibration Run 1 load probe up 1 hour 1 hour 1 hour 1 hour Run 1 cycle time 2 hours 2 hours 2 hours 2 hours Run 2 load probe up 1 hour 1 hour Run 2 cycle time 2 hours 2 hours N/A N/A Run 3 load probe up 1 hour 1 hour Run 3 cycle time 2 hours 2 hours Equipment removal and 3 hours 3 hours N/A N/A calibration Total time 10 hours 16 hours 3 hours 9 Hours Table 1: Validation timelines for thermocouple-based system and wireless dataloggers.

Wireless dataloggers also provide ﬂexibility to work around production requirements. The autoclave can remain in use until the load is fully prepared with thermocouples and biological indicators. It can then be returned immediately to production use after the validation cycle. This works very well during requalification of loads, although for performance qualification triplicate runs should be performed consecutively. Wireless sensors are available in many different shapes and sizes. Manufacturers are keen to provide solutions for all applications from ultra-low freezers to depyrogenation tunnels. With autoclave validation, ﬂexible sensors can be used in long tubing, bendable sensors for repeatable placement in filters or smaller sensors to be placed in sealed items or packaging well before the validation takes place. Wireless sensors also mean pressure can be monitored within load items, for example in terminally sterilised bottles or within vessels. Manufacturers are also increasingly assisting with sensor placement not only by developing sensors suitable for specific applications but also by offering the accessories to repeatedly place sensors. Solutions are available for repeatable sensor location in vials, bottles, IV Bags, syringes and so on.

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Software improvements also allow for significant time savings with validated software processing complex calculations in a repeatable and robust manner. Data analysis and processing times can therefore be significantly reduced, and the subjectivity of individual engineers can be removed. Reports can be generated within minutes of test completion providing clear pass/ fail 21 CFR compliant data that is easy to review from a technical and quality perspective. Software packages therefore have the ability to produce fast, accurate and detailed test results. LIMITATIONS Whilst using wireless dataloggers brings some benefits to the table it also brings particular issues which are certainly worth some consideration. The main issues we have found when using wireless dataloggers or discussing projects with our clients are live data, sensor cost, sensor failure, battery life and specifications. During the validation process engineers who are used to seeing live temperature and pressure data within the autoclave may find using dataloggers a challenge. There are options available to allow for live data, with transmitting loggers, for example. However, receiving a signal from outside a jacketed stainless-steel vessel can be a challenge. We have been able to receive a signal from dataloggers for autoclave validation, but it is not always possible without the addition of an aerial. Live data can therefore be an issue, however with suitable software a wireless datalogging system can produce clear pass/fail reports very soon after completion of the validation cycle. Suitable wireless dataloggers are expensive and for a good system

this is significantly more expensive than a standard wired system. Switching from thermocouples to PT sensors is going to be an expensive option and replacing damaged sensors can also be costly. Although a damaged thermocouple can be frustrating they are simple and fast to replace. Wireless dataloggers are more robust than thermocouples but sensor failures do happen. It is worth considering the return on investment of wireless dataloggers and the benefits they bring to validation, production and quality departments. An important question to ask is how many days production can you save and what is that worth to the business? Thermocouple based systems are typically powered by mains power and battery life is not a significant problem. Battery management is however an important concern for wireless dataloggers and should be considered as part of the system use. If the battery life is managed correctly then the only consideration regarding batteries in the ongoing cost. Equipment specification is possibly the most important and under considered issue with wireless dataloggers. There are now a significant number of manufacturers producing dataloggers that are marketed as suitable for autoclave validation. Not all loggers meet the required standards, however, and it is important to ensure the accuracy

and the sensor are compliant to the relevant standards such as EN285:2015 and HTM 0101 Part B. CONCLUSION In conclusion, wireless loggers are highly likely to become the standard approach for autoclave validation. The time-saving and ďŹ&#x201A;exible nature of the systems work well with the increasing demands of production and validation departments. A robust URS for the specifications of the system should be in place to ensure they meet regulatory standards for response time and accuracy. Consideration should also be given to the ďŹ&#x201A;exibility of the software.

wireless loggers are highly likely to become the standard approach for autoclave validation.

ACHEMA REVIEW

In review After catching our breath post-ACHEMA, we discuss* some of the innovations that were showcased during the massive German event and major industry trends both now and in the future with five key manufacturing companies who were all in attendance.

A CONTRIBUTORS Christian Treitel — head of strategy & business development, Bosch Andrea Semprini Cesari — managing director, IMA Active Division Sushaant Bakhru — head of sales, South East Asia, Zeta Biopharma Javier Raposo — sales & marketing director, I Holland Sven Poulson — senior director segment manager, Getinge

CHEMA — the huge trade show specifically geared for the process industry — closed its doors in June after a massively successful year. Featuring more than 3,700 exhibitors from 55 countries there was plenty to see, including the latest equipment and innovative processes for the chemical, pharma and food industries. So, from the experience of those in attendance what were the major trends and topics that were clear from the 2018 edition of the vast exhibition halls? DOING DIGITAL… There was a digital craze happening everywhere during the show, which was something that some of our contributors agreed upon as one of the major trends for the event. “This year there has been a lot of Industry 4.0 solutions, either in the form of virtual reality or augmented reality, being showcased,” explained Treitel. “What we have witnessed at Bosch is that there has already been a lot of development of these solutions from the ideas to actually commercial products available now on the shelf!” Semprini Cesari conferred with Treitel on this matter. “Digital is the main development that all companies seem to be interested in that we have witnessed at this year’s ACHEMA,” he said. “As a company,

we presented our solutions in automated manufacturing as well as our idea and solution for the automated factory. This is an issue that will continue to increase in importance in the future.” Further breakthroughs in Industry 4.0 were one of the predictions for what we can expect in the future from Treitel. He added: “We have seen a number of solutions already, but I believe we have solutions out there that we don’t yet know about today. So, there will be new things in the next three years and, personally, I’m looking forward to seeing them.” SMALLER BATCHES AND MORE COMPLEX PRODUCTS This event, there was a trend towards customer request around smaller batch sizes and solutions to help with this. “This trend has accelerated due to orphan drugs,” revealed Treitel. “So, small patient populations have led to a need for smaller batch sizes and we are catering for it with various solutions.” “These smaller batches lead to more patient batches required,” continued Poulson. “This, in turn is putting a lot of requirements on our customers to be able to run their production in perhaps a more ﬂexible manner than what they used to in the past.” Additionally, Treitel highlighted that in the face of an increase in biologics and complex products machinery and manufacturing

processes need to keep pace and also become more complex. “Containment has accelerated a lot, the requirement to protect not only the operators but also the product has risen in demand a lot and a lot of countries and companies have set standards that we must fulfil to cater for this trend,” he stated. “We have witnessed a lot of talk around customised solutions,” added Bakhru. “Particularly in the area of biologics, we are seeing customers put forward very specific requirements, And, when looking at scaling up from R&D to commercial scale there is a lot of talk about how customised engineering solutions can help. CONTINUOUS MANUFACTURING Continuous manufacturing was another theme being heavily talked about at the show. “This makes a lot of sense,” said Bakhru. “It has already been adopted in other industries, so, it will surely be an area for considerable attention over the next three years.” Semprini Cesari completely agreed that the concept of continuous manufacturing would be a key topic for the next ACHEMA in 2021. “At IMA, we are working on an ambitious project in this field to develop a complete ‘endto-end’ solution in continuous manufacturing. It should start with the synthesis of the active ingredient and go all the way through to the final drug delivery stage.”

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SPEED-TO-MARKET Time-to-market is always a factor for companies looking to develop a product for commercialisation and of course if this is achievable at a lower cost while maintaining quality then all the better. “Anything that has to do with the speed of response in that timeto-market is becoming a critical request for all of our customers,” revealed Raposo. “In situations where it is imperative that our customers are the first to launch a new product in a short period of time then anything that will help them in this endeavour, in terms of reducing waste and cutting lead times will very much be in trend.” SINGLE-USE According to Poulson, there was a very clear trend of customers moving away from the cleanable stainless steel components for single-use items. “Our contribution to this trend has been the DPTE bag,” he said. “Over the next three years, I think we will see more solutions developed for single-use , particularly manifesting in the areas of biopharma production.” At Zeta, there was a promotion of the hybrid solution. “We have worked with a single-use bioreactor supplier to create a custom solution that integrates key components of the singleuse bioreactor with a stainlesssteel framework,” added Bakhru. “We believe that through this collaborative approach, we can build best practice solutions that bring out both single-use and stainless-steel ﬂexibilities.

Bosch show highlights � Flexible formulation system — SVP250 LF � New freeze dryer: Closing the gap in the process line � Extension of continuous manufacturing — Xelum R&D � Flexible capsule filler — GKF 720 � Industry 4.0 solutions IMA show highlights � Croma — continuous coating machine � Containment solutions that offer ﬂexibility to the customer � Pilot projects for Industry 4.0 Zeta show highlights � Focus on kLa — measuring method for optimised processes � Hybrid solutions — single-use/ stainless-steel systems I Holland show highlights � Three concepts for the show: o Clinical design support o Working together to solve problems o Speed of response � New coating launched — Wear Indicator Layer Getinge show highlights � New solutions to respond to customer requirements � DPTE-XO eXternal Opening docks � GSS Steam Sterilizer *Full interviews will be available on our website after publication.

Featuring more than 3,700 exhibitors from 55 countries there was plenty to see…

EVOLVING PHARMA. BY YOUR SIDE. ACHEMA 2018 | HALL 3.0 - STAND F49 www.ima.it

EXCIPIENTS

Here, Jim Morris from NSF International, summarises the benefits of an excipient GMP certification programme (ECP) both from the point of view of the excipient manufacturer and the excipient customer.

Everyone wins M

aking a case for GMP certification of an excipient manufacturer should be a straightforward exercise since the benefits appear so clear cut and regulatory guidance in the EU underscores the value of certification.

confirmation of the maturity of their quality programme. Other manufacturers needed to make significant improvements to their quality systems and, in some cases, their facilities in order to meet the requirements of the NSF/ IPEC/ANSI 363 standard.

Specifically, Chapter 3 of the EMA Guidance on formalised risk assessments to determine the appropriate GMP for a pharmaceutical excipient states that ‘certification of quality systems and/or GMP by the excipient manufacturer and the standards against which these have been granted should be considered as such certification may fulfil the requirements’.

Yet, both groups of companies have realised the benefit of increased operator risk awareness, more effective internal audits, greater process understanding, increased crossfunctional communication, and clear evidence of management’s commitment to quality management principles. These benefits are often diﬃcult to monetise, however, a single problem avoided through increased operator GMP awareness can result in significant cost avoidance.

Furthermore, FDA participation in the development of a consensus standard, NSF/IPEC/ANSI 363 Good Manufacturing Practices (GMP) for pharmaceutical excipients, reinforces agency interest in ensuring pharmaceutical excipients are manufactured to an appropriate GMP standard. BENEFITS FOR THE MANUFACTURER As an excipient certification body, one of the primary benefits is significantly improved quality systems and quality compliance at the excipient manufacturer. We have seen these improvements in the months leading up to GMP certification and continuing during the years immediately following GMP certification. Some excipient manufacturers were already at a high level of GMP compliance, and GMP certification provided

BENEFITS FOR THE CUSTOMER Excipient customers will typically modify their oversight of excipient manufacturers that have been GMP certified. They may move the excipient manufacturer further down on their supplier risk profile and choose to audit less frequently, if at all. Excipient customers are aware that in order to be certified, the excipient manufacturer must have systems in place and provide evidence that nonconformances and changes that require customer notification are handled appropriately. This assurance is typically not obtained through a one-day supplier audit that pharma companies carry out;

rather, it is obtained as a result of thorough, multiple day audits of an excipient manufacturer as part of a certification audit program. The benefit of an ECP for the excipient customer should be close to zero surprises and very low regulatory risk. Furthermore, excipients received from GMP certified manufacturers are excellent candidates for a reduced QC testing programme. Pharmaceutical excipient customers, particularly biopharmaceutical customers, are increasingly requesting more technical information to justify their selection of excipients. Therefore, it would be of far more value for the excipient customer to focus on the technical aspects of the excipient it is purchasing and worry less about GMP compliance once the excipient manufacturer is GMP certified. That is where the true value lies for both parties and ultimately for the end user or patient. Consider the above benefits and select a certification scheme — such as NSF’s ECP — which will deliver long-term GMP improvement at your company, embed a culture of quality, and help your company establish a high level of confidence and trust with your excipient customers. If you are an excipient customer, select a GMP certified excipient manufacturer and reduce supply chain risk while freeing up resources to devote to other areas of the business.

PERSONALISED MEDICINE

Automatic for the people Here, Trevor Marshall, director of global engineering at Zenith Technologies, goes into detail about how integrating and automating cell therapy production with manufacturing execution systems (MES) will help grow the personalised medicine sector and ultimately benefit patients worldwide.

he growth in the clinical adoption of advanced cell therapies is one of many indicators showing an increased focus on personalised medicines. As anticipation builds around cell therapy and the promise it holds, more attention is being paid to the manufacturing strategies that will allow it to benefit more patients.

High costs, logistical challenges and antiquated approaches to documentation associated with the current processes present a formidable roadblock to the industrialisation of cell therapies. This is creating a need for cost effective, reliable and eďŹ&#x192;cient ways of working which will be imperative to its success. The answer, in my opinion, is

integrating and automating the cell therapy process through manufacturing execution systems (MES). CELL THERAPY AS IT STANDS Cell therapy involves genetically modifying a patientâ&#x20AC;&#x2122;s immune cells. White blood cells (T-cells) are taken from a patient and transported to a dedicated lab,

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these T-cells are then programmed to attack the disease in the person at a cellular level. Once modified the T-cells are grown and multiplied before being returned to the patient for injection. This therapy is typically performed at designated hospitals with specialised labs available to execute the cell therapy process. The cold chain transportation of the patient’s blood cells in vials between the hospital and lab is a very important aspect logistically. Currently, the patient’s blood cells are frozen in vials before being sent to the lab and patient data is coded and anonymised before entering the lab. Once the cell therapy process is performed the patient’s blood cells are re-frozen and sent back to the hospital. While cold chain logistics isn’t new to the pharma sector, we are seeing an emergence in the outsourcing of the cell therapy process to dedicated lab facilities, which can service multiple hospitals in a region with the ability to cater for different treatments. The upshot is an increased demand for specialist logistics contractors which will need to be met to ensure the cell therapy market is adequately serviced. ROLE OF AUTOMATION AND MES Cell therapy is now moving from a manual oriented lab environment to identifying production scale principles from the larger scale bioprocess industry and applying some of these best practises with a goal of making the process as robust as possible, error free with reduced costs. The cell therapy process by its nature requires the tracking of a patient’s blood cells through multiple, sophisticated pieces of lab equipment.

The blood cells pass through the equipment using disposable single-use bags. With more than one patient’s blood cells ﬂowing through the lab it is critical that the manual steps are tracked, and all critical activities are verified by more than one person. Currently, many of the steps in the lab are manual with records stored on paper. This is where the introduction of MES to the lab and automating the tracking of the patient’s blood cells through the system can offer significant value. Electronically verifying the process negates human error and can also improve throughput for a lab. More importantly, MES offers a means of reducing risk by alerting operators to problems that could have catastrophic consequences. Once the patient’s blood cells are manipulated they are multiplied for many days with the use of a wave bioreactor. Most labs are unmanned at night and integration to the MES system to cater for equipment alarming and alerting is imperative. These alerts are then used to trigger a call out to the lab to investigate any problems. Cell therapy is often a last resort for patients, a delay or failure to return their modified blood may lead to the worst possible outcome. SINGLE-USE TECHNOLOGIES Single-use technologies are imperative to the cell therapy process. Currently, there are many manual aseptic connections required, which increases the risk of connection failure in the process. Manufacturers are working to create pre-made disposable bags already interconnected specific to individual processes, this reduces the need to tube weld separate aseptic bags together, thus

Automation and MES are two vehicles that will play an important role in making labs more eﬃcient and lower-risk which will lead to increased adoption, to the benefit of patients around the world. reducing manual activities involved in the process. These bags are also identifiable via printed barcodes, which can be scanned by the MES for traceability purposes through the process before disposal. FINAL THOUGHT Cell therapy treatments are truly personal, with the process being carried out for a specific person on their blood cells. This is unlike traditional drug treatments where the manufacturing process is very much removed from the dispensing of the drug to a future unknown patient by a chemist. The success in cell therapy treatments will lead to an increased number of hospitals that will offer these treatments and to the outsourcing of cell therapy process to dedicated lab facilities servicing multiple hospitals in a geographical region catering for many different cell therapy treatments. However, the rate and scale of this growth will depend on the pharma industry’s ability to make cell therapy more affordable. Automation and MES are two vehicles that will play an important role in making labs more eﬃcient and lower-risk which will lead to increased adoption, to the benefit of patients around the world.

TECH TALK

Keeping pace in mHealth In the latest instalment of Tech Talk, Dr Neil Polwart, Novarum founder and BBI Group head of mobile compares pharma and digital start-ups coming to the conclusion that to keep pace in mHealth companies should be ‘thinking pharma, but acting start-up’

harmaceutical companies are increasingly engaging in or competing with the mHealth sector (mobile health), but an interesting dichotomy is developing. Pharmaceutical firms, by their nature, are meticulous and consequently classically slow to make decisions, develop new products and adopt novel approaches. On the contrary, digital technology businesses are more often fast, dynamic and agile both in their development process. When pharmaceutical companies only had to worry about competing with other businesses on a similar scale, and with similar process restrictions, there was a level playing field. Increasingly however, threats come from disruptive technologies. With the typical development time for a new drug being 12 years and costing over £1 billion1 — it is easy to see why pharmaceutical companies take their time to make slow, carefully considered decisions and conduct extensive market research before engaging on new projects.

However, contrast that with typical Silicon Valley start-ups, who might launch a Minimum Viable Product (MVP) inside 12 months having invested under a million dollars and see their company grow into a multibillion dollar business in the same timescale it takes to develop and launch a drug candidate. Pharmaceutical companies might therefore turn their attention towards mHealth thinking that there is a route to accelerated growth. Indeed, on paper they would seem to be at a huge advantage over the typical tech start-up. However, to realise that potential they’ll need to think much more like a start-up. The start-up world often talks about an MVP — the minimum set of features necessary to engage users and start understanding which other features will be helpful. It’s an approach largely alien to the drug development world. It’s also an approach, which if applied incorrectly, has the potential for harm. Johnathan Friedman, a partner at LionBird Ventures, coins the term2 Minimum Viable Claims

(MVC) to better describe what a digital health product should be aiming to do in the early stages. With a carefully designed development programme, led by people who not only really understand the regulatory landscape but also the commercial realities it’s quite possible to incrementally improve the MVC product learning from user feedback. Once a company gets into the habit of thinking in highly regimented ways it can be particularly diﬃcult to break down the cultural barriers that make high impact, accelerated growth possible. When the event horizon for pharmaceutical companies is measured in years, and the start-up is working in months or even weeks, it quickly becomes clear why pharma may be at a massive disadvantage unless it can learn to control its corporate structures.

Alternatively, simple acquisition of start-ups beginning to look promising in a particular space is another approach — however once integrated into the new parent there is a risk that their previous agility is strangled out of them. An effective strategy might be for the leaders of pharmaceutical companies to take the time to understand how the emerging digital health world differs from their own and understand how to bring in some of the key benefits — including radically changing the thinking on product launch timelines. Even planning mHealth products within a two to three-year timeframe means companies will be building platforms on outdated technology and probably numerous product versions behind their agile, lean, start-up competition. REFERENCES:

One approach that can prove successful is to put the innovation in a separate entity with much greater agility and ﬂexibility, but it must have a shared understanding, vision and control or disaster looms.

1. https://www.pharmaceuticaljournal.com/publications/ tomorrows-pharmacist/drugdevelopment-the-journeyof-a-medicine-from-lab-toshelf/20068196.article 2. https://vcpov.com/can-lean-startupwork-for-mhealth-db705ef061f3

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Simple tablet retrieval

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Ensure tablet compression reproducibility

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Evaluate porosity and robustness curves

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Save time by generating projected data results from slight formulation changes

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Store tableting data points in a SQL database architecture for later use

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Export fill depth, main compression force, ejection force, and tablet sequence data received from the press