EPM September 2019 by EPM Magazine

YOUR SERIALISATION NEEDS

REDISCOVERING A 25 YEAR OLD CANCER DRUG

THE VALUE OF NEW MEDICINES

September 2019

Natoli Engineering examines the causes and solutions for dark spots in tablet manufacturing.

Contents

September 2019 | Volume 19 Issue 6

REGULARS 5: EDITOR’S DESK Reece Armstrong examines the consequences of faulty data for a well-known pharma company.

6: A SMALL DOSE A brief round-up of some of the latest developments in the industry.

12: OPINION

The complex issues surrounding assigning a value to new drugs.

14: IN THE NEWS A short selection of stories from the world of science.

16: COVER STORY Natoli Engineering examines the causes and solutions for dark spots in tablet manufacturing.

18: ANALYSIS

The impact of AI in pharma and why a cancer drug was lost for 25 years, until now.

FEATURES 26: AN INSIDE LOOK EPM looks at the journey World Courier has taken in becoming a leading pharma logistics company.

28: LOGISTICS & DISTRIBUTION How to keep up with pharma’s changing labelling regulations.

34: FROM THE FACTORY The challenges of developing a new facility with the emergence of new technologies.

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The pharmaceutical industry was in for a shock this month when it was revealed that Novartis included faulty data when it applied for the regulatory approval of its contentious gene therapy, Zolgensma – oh ‘big pharma’ just when I was beginning to trust you.

ovartis was already in the spotlight over the cost of Zolgensma which sells for $2.1 million – and now the FDA has lambasted the company, even mentioning potential ‘civil or criminal penalties.’ The issue stems from Novartis subsidiary Avexis discovering the faulty data before Zolgensma was approved by the FDA. Novartis was notified about the inaccurate data in March, but only notified the FDA at the end of June, one month after the gene therapy’s approval. While Novartis, and indeed the FDA, support Zolgensma’s efficacy and human clinical trials data, the fact that the company hid the truth while waiting for regulatory approval casts suspicion into Novartis’ motives. In the June edition of EPM I argued that people shouldn’t be surprised when drug companies price treatments highly. After all, they’re businesses first and foremost right? But Novartis’ actions indicate a company that is only motivated by profit and one that is unwilling to be transparent about its data -

EDITOR’S DESK actions of which undermine the importance the FDA holds as the body responsible for regulating drugs. This goes against Novartis CEO Vas Narasimhan’s aim of restoring trust with society, which he outlined as one of his five key priorities at the company’s annual press conference in 2018.

So now it stands to the FDA to hold Novartis responsible, with a lack of affirmative action potentially resulting in further misconduct from the industry. But more so Zolgensma represents just another bullet point in pharma’s long list of scandals. Which is a shame as numerous developers work tirelessly to try and improve the world’s health, yet won’t be heard above the uproar of yet another misdemeanour from ‘big pharma’. The question now stands whether pharmaceutical companies will improve the ways they operate when communicating with both regulatory authorities and more importantly the public. After all, you’d think after so many scandals involving price gouging, patent blocking, shortages and more, pharmaceutical companies would be more concerned about protecting their public image. I’m not so certain. After all, investors have failed to penalise Novartis’ stocks, showing that as long as a company is set to be profitable minor public scandals won’t affect their share prices too harshly. As mentioned previously this year, Zolgensma’s approval isn’t without merit. If it offers children with spinal muscular atrophy (SMA) a chance of life, then the drug’s approval can be applauded. But Novartis does need to be held accountable, if only to stop the pharmaceutical industry from getting away with malicious practices that put the rest of the industry in a bad light. I look forward to when we can start promoting the good work life sciences companies are doing instead of relying on scandalous headlines. Hopefully this isn’t too far ahead in the future.

A small dose

TRACK AND TRACE DRUG COMPANY BECOMES INNOVATION CHALLENGE FINALIST

n early stage company has been named as a finalist in the national MSDUK Innovation Challenge awards for developing a service that can monitor drug sources, helping to ensure authentic drugs are delivered through the supply chain. Kapsule was named alongside 12 other finalists and will go on to compete for a £5,000 cash prize, £100,000 worth of mentoring and more. The final of the Innovation Challenge 2019 will take place at the MSDUK 2019 Conference & Awards which is being held in London on 17 September. The 13 finalists will present their products and ideas to potential investors, buyers and industry experts, whereafter three winners will be chosen by a panel of judges. Kapusle has developed a blockchain-powered supply chain tracking service which the

company says enables a clear and solid audit trail with near real-time visibility. David Chen, co-CEO of Kapsule commented on the finalist position saying: “Our vision is for everyone in the world to have access to the medicines they need without having to think twice about its quality. We will do this by stripping out operational costs from inefficient supply chains and use technology to provide price transparency to governments, patients, pharmaceutical companies and local distributors. MSDUK founder, Mayank Shah, said: “MSDUK’s aim is to bring together innovative and high growth Ethnic Minorityowned businesses with global corporations who are committed towards creating an inclusive and diverse supply chain and the Innovation Challenge is just one way we do this."

most inno Switzerla

Switzerland overtakes Germany innovative drug delivery market

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

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

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

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Biopharma partner launches integrated package for mammalian cell bank manufacture

iopharmaceutical partner, Sartorius Stedim Biotech (SSB) has launched a range of new services for mammalian cell bank manufacture. The services are being offered by SSB’s subsidiary, Sartorius Stedim BioOutsource, a contract testing organisation (CTO) with offices in the UK and US.

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

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

SSB will now offer the manufacture of good manufacturing practice (GMP) master and working cell banks (MCB/WCB) for mammalian suspension cells.

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

ovative drug delivery market and overtakes Germany as

as most are now seeing is that this pipeline of new drugs has helped drive increased innovation in packaging and drug delivery devices. In fact, we are witnessing this trend first-hand at Pharmapack with many smaller and nimble companies bringing forward novel delivery systems and advanced packaging solutions, and we now have the data to back it up.”

The facility will use selected equipment that enables closedsystem manufacturing of GMP-compliant cell banks, from vial thaw to automated filling. More so, the entire manufacturing service is being offered as a fully qualified broth technology platform. To help ensure the best possible timelines, SSB cell bank manufacturing is offered in a package along with cell bank characterisation services, the combination of which allows clients to work with SSB as a singlesource provider from vial thaw to released cell

banks. During a manufacturing run, up to 500 cell bank vials will be produced, followed by full characterisation, genetic stability assessment in compliance with EU and FDA guidelines, and release by the respective qualified person. The cell bank vials produced are then shipped to the client or transferred to a long-term storage facility. With all three services combined, SSB is aiming to support clients as a total solutions provider from DNA to released GMP cell bank within a 10-month timeline. Lucia Rieger, product manager for protein expression at SSB said: “We’re really proud that we now offer even more comprehensive services that can be easily combined with those for CHO cell line development and biosafety. As a result, we provide our clients with an integrated package that saves considerable time and minimises risks. Furthermore, they will benefit from client-focused customer service with a single point of contact throughout their entire development and manufacturing projects.”

PHARMA RECRUITMENT FIRM SEES BIG GROWTH IN PLACEMENTS, DESPITE BREXIT

life sciences recruitment firm has seen its interim contracts rise by 250% signalling a demand for roles in the pharmaceutical industry. Concilium Search has now doubled the size of its life sciences recruitment contract team to deal with the influx of applications. The Concilium Search figures were based on the firm experiencing an increase of 250% in life sciences recruitment in the first six months of this year compared to 2018. The international firm has said that despite the uncertainty of Brexit, its business has not experienced any disruption.

A ‘no deal’ Brexit is expected to result in medical shortages with pharmaceutical supplies suffering from extended delays, according to leaked government documents procured by The Sunday Times. Martin Badoo, head of Life Sciences Contracts at Concilium Search, said: “There is naturally some uncertainty within the industry due to Brexit, but we are still placing candidates, and experiencing growth in terms of our life sciences client base. We believe people will still want to work in the UK and UK candidates will still seek work contracts in Europe, even if we leave with a no-deal outcome.”

EVENTS

2019 ISPE Europe Pharma 4.0 Conference SHOW SUMMARY:

At a glance: Putting the spotlight on industry 4.0 in pharma Taking place: 20th-21st November Where: Manchester United, Old Trafford Football Stadium Venue

The 2019 International Society for Pharmaceutical Engineering (ISPE) Europe Pharma 4.0 Conference will feature the sector’s brightest minds to discuss how pharma can benefit from the advance of new information technologies. The two-day show will delve on the best strategies and practices for pharmaceutical production operations with information technology being the main focus. The agenda sets to educate industry businesses on becoming more affordable and efficient through the use of ISPE’s Pharma 4.0 operating model. Featured speakers include: • Lawrence Yu, deputy director, Office of Pharmaceutical Quality, FDA/CDER/OPQ • Kevin Bailey, GMP inspector, MHRA • Christian Woelbeling, senior director Global Accounts, Werum IT Solutions • Teresa Minero, founder & CEO, LifeBee • Gareth Alford, lead engineer, GSK

The TCT Show TCT Show returns once again to showcase the latest additive manufacturing technology solutions and innovations from nearly 300 leading exhibitors from across the globe. As a visitor to the event, you’ll be inspired and gain insights from the world-class conference and seminar programmes held across 4 stages: TCT Summit, TCT Tech Stage, TCT Introducing Stage and TCT Insights Stage. Prominent exhibitors including Formlabs, Protolabs, EOS Materialise, Fraunhofer IWU and more are set to lead the show. With around 35 products launching at the show, this year’s TCT Show is set to offer a greater learning experience for current users and those looking to acquire new technology.

SHOW SUMMARY:

At a glance: The place to be for additive manufacturing advances Taking place: 24th-26th September Where: NEC, Birmingham

Lastly, a new partnership between TCT and Create Education will introduce 300 students to the world of additive manufacturing and 3D printing. The Inspired Minds Classroom will provide students in years 9 & 10 with a fascinating introduction to the realm of 3D printing, giving them chances to interact with exhibitors and see the latest innovations up close.

Healthcare Packaging Expo Featuring 250 exhibitors and 5,000 packaging and processing industry professionals from across the top pharma companies, Healthcare Packaging Expo is co-located with Pack Expo Las Vegas 2019 as one the biggest packaging events in the world. Exhibitors across authentication, cleaning, labelling, track and trace, validation and more will be presenting the latest pharmaspecific technologies, giving

SHOW SUMMARY:

At a glance: Showcasing the best solutions for the pharma production supply chain Taking place: 23rd-25th September Where: Las Vegas Convention Centre

visitors a chance to see all of the industry’s upcoming innovations. More so, visitors can stop by at any point for an educational session at the show’s Innovation Stage, The Forum and the Reusable Packaging Learning Centre.

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

Instant Results with FT-NIR Spectroscopy Today, many companies are not only striving to manufacture high quality products, but also to increase production efficiency by installing the analytical systems directly into their production plants. This improves process verifiability and process understanding and gives the company the opportunity to optimize material use, run-time of machines and product quality up to real-time-release. BrukerÂ´s robust and precise spectroscopical technology based on modern FT spectrometers can be implemented in the different process steps and offers a high amount of information to gain better process understanding.

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Innovation with Integrity

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IN PROFILE

Celebration Lola Yomi-Baker is product manager at BioPure Technology - part of Watson-Marlow Fluid Technology Group. Having studied biochemistry and biochemical engineering, she has worked in a number of bioengineering roles, most recently at PALL Life Sciences and Benchmark Vaccines Limited. WHEN WERE YOU FIRST INTERESTED IN ENGINEERING? I think I have always been interested in engineering as I’ve always wanted to understand how things work, but it wasn’t until I had my first pharmaceutical job with Sanofi-Aventis that I decided to pursue a career in engineering. WHAT’S YOUR EXPERIENCE BEEN LIKE WITHIN THE ENGINEERING AND PHARMA INDUSTRIES? That’s such a broad question! I have been lucky enough to work in quite a few different roles within pharma over the years but I have particularly enjoyed the positions which allowed me to utilise my creativity. WHAT DO YOU THINK SOME OF THE BARRIERS ARE FOR WOMEN WANTING TO GET INVOLVED IN ENGINEERING AND LIFE SCIENCES? I have to say I have seen a lot more women working in the life sciences than in engineering so I’m really keen to encourage more women to get into engineering careers. There are obviously still a multitude of barriers for women to overcome and I think one of the main problems is that the public face of the industry tends to be mainly male. There are also so many different types of engineering pathways out there,

but many are not well known. I therefore think the promotion of female role models across the wide-ranging industry is hugely important. Another issue which affects women across multiple industries is that they tend to only apply for a role if they believe they meet 80-90% of the shopping list of skills and experience listed in the job spec. Updating the recruitment process might be one way to help overcome this. Even once you’ve got your foot in the door, men and women work differently. It’s therefore so important that we recognise individuals for their own successes, even if they are not used to shouting about them. OVERALL, HOW INCLUSIVE HAVE YOU FOUND THE CULTURE TO BE IN THE ENGINEERING INDUSTRY? Not very! However, that is definitely changing as people and organisations focus on the numerous opportunities and growth benefits that come from a diverse workforce. I’m excited to see this change continue. HOW WAS WATSON-MARLOW’S RECENT CELEBRATION OF THE INTERNATIONAL WOMEN IN ENGINEERING DAY (INWED) ? I really enjoyed the day, the team did a great job in organising

everyone, especially all the children! Partnering with Goonhilly Earth Station to host the event was a fantastic example of the amazing engineering companies based here in Cornwall and the South West, especially with all the excitement surrounding the recent 50th anniversary of the first moon landing. It would be great to be able to extend the INWED celebrations and open it up to more people in the future, both within the group companies and the wider population. We’re hoping to share future events more widely, possibly by recording the round-table talks for a podcast so it is accessible to all aspiring engineers. As we are still relatively few, the INWED events are a great opportunity to build networks within the female population of Watson-Marlow and Spirax-Sarco as a whole, to help with the recruitment and retention of female engineers. WHAT ARE SOME OF THE MOST EXCITING TRENDS HAPPENING WITHIN ENGINEERING AND PHARMA? I am a biologist/biochemical engineer by training, so I like to keep a close eye on what’s happening in advanced therapy medicinal products (ATMP) manufacturing. These guys aren’t looking to process

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day thousands of litres at a time, like their monoclonal antibody counterparts, so from a supplier point of view we have to think differently in how we cater for their needs. This area is of particular interest to me as there is a lot of space for innovation and creativity, they are forcing us to think outside of the box to satisfy their processing requirements. With all the conversation about artificial intelligence (AI), Iâ&#x20AC;&#x2122;m also interested to see how this will be implemented in companies such as ours in the future. IN FIVE YEARS TIME WHAT WOULD YOU LIKE TO SEE HAPPEN WITHIN YOUR INDUSTRY? Five years is such a short time in the world of pharma and biotech but there are some changes already in progress. Engineering at a professional level is still considered quite elitist so it is great to see the industry actively trying to engage and inspire young people from a wider variety of social backgrounds. Events such as INWED and organisations like the Womenâ&#x20AC;&#x2122;s Engineering Society (WES) are already doing fantastic work in this area, so I look forward to seeing these grow and develop, and working with Watson-Marlow to encourage more people from all backgrounds to pursue careers in engineering.

I therefore think the promotion of female role models across the wide-ranging industry is hugely important.

Opinion

While it is easy to criticise different parties in these pricing debates, these are complex issues for which there are no easy answers.

ASSESSING THE VALUE OF NEW MEDICINES H

ow do you assign a value to saving someone’s life? Then, how do you pay the bill? Those are questions that manufacturers and health authorities are increasingly being asked to answer as pharmaceutical companies attempt to gain regulatory approval and subsequent reimbursement for innovative and, in some cases, curative new therapies; products with limited evidence and small patient populations.

Oliver Leatham – vice president and global head of value and access at Certara

On 24 May, the US Food and Drug Administration (FDA) approved Novartis’ Zolgensma, the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Zolgensma is a one-time treatment, which is designed to be curative, but it will cost more than $2 million, making it the most expensive drug ever brought to market in the US. While unprecedented, Novartis’ price for Zolgensma comes close to what the Institute for Clinical and Economics Review (ICER) estimated. By a measure of cost per life-years gained, ICER judges an appropriate value-based price for Zolgensma to be between $1.2 million and $2.1 million, which seems to favour both the manufacturer and the health system.

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There is no question that considering reimbursement options for these new, potentially curative therapies requires a different way of thinking. “A therapy that can cure disease in a single treatment isn’t a unit of drug. It’s a public health solution,” stated former FDA commissioner Scott Gottlieb. While it is easy to criticise different parties in these pricing debates, these are complex issues for which there are no easy answers. They require thoughtful discussion and creative solutions, which meet the needs of an evolving revolution in healthcare. It can cost $2-3bn to discover and develop a new drug and submit it for review by the appropriate global regulatory agencies, payers and health authorities. If a new medication can be curative with a single treatment, its market is limited, so the sponsor has only one opportunity to recoup costs. On the other hand, health authorities and state-run programmes, like Medicaid, have finite resources and must manage their healthcare budgets and costs to provide equitable access to therapies for all their members/participants. How can they pay for these extremely expensive, lifechanging therapies without blowing their budgets? This problem is compounded by the fact that the assessment criteria in all countries were established long ago, to manage chronic conditions, which tend to have lower, predictable, measurable costs. Several approaches, such as risk sharing (refunding patient failures, versus rewarding success), co-creation (developing real-world evidence studies in collaboration with health technology assessment (HTA) bodies), outcomes-based agreements, and try-beforeyou-buy schemes have been tested by sponsors and payers with varying degrees of success. They have often been seen as a ‘nice to have’ that can aid a corporation’s public perception, but are often only tested at a local level and not expanded to wider markets. Despite this, there is much to be learnt from best practices: what solutions are most accepted by payers and regulators? How does a solution in one market or patient population transfer to another? How do we build, package, and communicate the offering to relevant stakeholders to generate awareness and create the appetite for change? Takeda Pharmaceutical Company has taken a valuebased pricing approach with Alofisel, its stem cell therapy that is used to treat complex perianal fistulas in adults with Crohn’s disease. It has agreed to reimburse part or all of the $67,000 drug cost for patients that do not see an improvement. Other drugs that are sold under a value-based arrangement include Novartis’ CAR T-cell therapy Kymriah, which costs $475,000

per treatment for children with acute lymphoblastic leukemia, and Spark Therapeutics’ Luxturna gene therapy product, which costs $850,000 to treat both eyes of a patient with inherited retinal disease. The UK’s National Health Service (NHS), which does not cover many very expensive drugs due to its focus on cost-effectiveness, has taken a different approach. It has reached ‘first of its kind’ agreements with Gilead, AbbVie and Merck to provide their hepatitis C therapies at ‘best prices’ in a quest to eradicate the disease. This is considered a mortgage or “Netflix” approach, where a significant cost is paid in installments over several years. In this case, the outcomes are being tracked over five years. The NHS is simultaneously conducting hepatitis C testing to gather real-world data to improve disease prevention. It is calling these agreements a “smart deal.” They offer a relatively cost-effective alternative to treating patients with hepatitis C for a lifetime or conducting liver transplants. A mortgage-based system can also work for products such as anti-infectives where demand for the product varies according to disease outbreaks. This type of agreement both guarantees the manufacturer a set level of income and ensures the healthcare system an ongoing supply of product that could be needed at any time. How did they arrive at these agreements? Reimbursement discussions are increasingly focusing on a drug’s actual, measurable real-world impact and not just clinical trial results. Extensive evidence gathering and quantitative, science-based modelling and simulation with real-world data are being employed to differentiate the new product from on-market competitors, show its anticipated impact on disease progression, and make economic projections based on current costs and potential payment plans. If a sponsor is going to sign a sales contract based on a new drug’s performance, it needs to understand it intimately. Once compiled, all of these data can be uploaded into value communication tools to help sponsors and payers agree on the most appropriate price for a new drug, and then determine the best price, approval, and reimbursement strategy. Regardless of approach, sponsors and payers need to work closely together to identify what constitutes good practice and then determine how best to predict, measure and evaluate performance. Moving from large, late-phase clinical trials to resourceful, real-world reimbursement approaches will help to ensure that payer and health authority budgets are used wisely, reward innovation, and deliver the most positive impact possible on patients’ quality of life.

IN THE NEWS

down to discuss the current thinking around diabetes and how healthtech can help.

THE MEDTALK PODCAST NUDGES ITS WAY INTO HEALTHCARE

he latest episode of The MedTalk Podcast has the team sitting

The editors discuss what nudge theory is and why everyone with a Fitbit is inadvertently being influenced by it; how healthtech is helping diabetes patients’; and why the FDA had to issue a particularly risqué product warning.

CANNABIDIOL PRODUCTS MISLEADING MILLIONS Millions of consumers are being misled by cannabidiol (CBD) products, according to a new report by the Centre for Medicinal Cannabis (CMS). The report highlights how millions of consumers are being misled by marketing surrounding CBD products, signifying stark contrasts in the quality of products currently available. The research analysed 30 products in the UK in a bid to verify the quality of CBD products being sold and to define any areas of concern. The findings showed that almost two-thirds (62%) contained less than 90% of the declared CBD ingredient; that 45% had measurable levels of THC, making them

technically illegal in the UK; and that 11 contained levels of solvents exceeding food safety regulations. One product which retails for £90 was also found to contain no trace of CBD and another product classes as an alcoholic beverage due to it containing 3.8% of ethanol. With an estimated six million people having tried CBD in the UK, the report calls on the industry as a whole to use these results to identify areas of weakness and to secure the supply chain.

UK prime minister urges uptake in vaccinations Boris Johnson has called on health leaders to renew their efforts to increase vaccination rates for measles, mumps and rubella (MMR). Visiting a hospital in the South West, the prime minister laid out new measures to improve the UK’s efforts into fighting measles. These include having GPs promote ‘catch up’ vaccination programmes; having healthcare professionals promote vaccinations in low uptake areas; and addressing any concerns by parents through a new website that will offer evidence-based vaccination information. Johnson also called for a summit to speak to social media companies to discuss what they can do to promote accurate

information around vaccination. The UK’s vaccination rates remain high but hundreds of cases of measles mean that the country has lost its ‘measle-free’ status. Head of Immunisation at Public Health England Dr Mary Ramsay said: “Losing our ‘measlesfree’ status is a stark reminder of how important it is that every eligible person gets vaccinated. Elimination can only be sustained by maintaining and improving coverage of the MMR vaccine.” “Making it as easy as possible for parents to access vaccines so that they can offer their

children the best possible start in life is a priority for us, DHSC and for NHS England. Through our Value of Vaccines campaign we’ll be using all opportunities to remind people to get two doses of MMR vaccine – whether that’s new parents, school children or younger adults. This will be crucial to the UK achieving elimination status again in future.”

Did you know?

Measles vaccination prevented around 21.1 million deaths between 2000 and 2017.

A high fever is usually the first sign of measles.

Unvaccinated young children are at the highest risk of measles.

AT50 —

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COVER STORY

Natoli Engineering examines the causes and solutions for dark spots in tablet manufacturing.

H John Norman — mechanical drafter and designer for technical service support at Natoli Engineering

Image 1: Punch lubrication has fallen onto the die table and mixed with the formulation during filling. The result is a dark spot on the tablet.

Image 2: Upper and lower punch diagram with excessive tip wear which results in dark spots around the outer edge of the tablet.

as production ever been halted due to dark spots on your tablets? If you answered yes, you’re not alone. Dark spots are a common defect that arise during the tablet manufacturing process and determining their primary cause can be difficult. In this article, we’ll discuss how to determine if the dark spots in your tablets are a result of one of these common causes: - Punch lubrication in the powder - Scorched material - Improper tablet press set-up The first step in troubleshooting the cause of dark spots is to evaluate where the spots are located on the tablets. If the dark spots are only seen on the upper tablet face, it is likely the defect is a result contaminated material, e.g. punch lubricant or scraped material from the bottom of the feeder. When spots are present on the lower face of the tablet or around the tablet band, it is often scorched material from within the die bore or from the punch tips. Additionally, a tablet should be split to verify if the spots are throughout the tablet. If there are dark spots present in the interior of the tablet, it is likely the result of an upstream process issue during powder preparation, such as blending. If the dark specks are only observed on the tablet faces (upper or lower), one of the following troubleshooting methods can mitigate the problem. 1: PUNCH LUBRICATION IN THE POWDER? One of the most common causes of dark spots are the result of a contaminant, typically tooling lubricant such as oil or grease, being transferred to the powder (see image 1). It is critical to have lubrication on the punch heads and barrels to maintain satisfactory operating conditions. Adhering to the recommendations for

lubricant as supplied by the tablet press manufacturer is strongly advised. If the lubricant is of an inadequate viscosity or is used in excess, the chances of spots within the tablets increase. Guide seals in the turret should be in optimal condition to restrict punch barrel lubricants from entering the compression zone. If guide seals are not supplied in your turret or if the problem persists, dust cups must be utilised to capture and contain excess lubricant. The cups also deflect dust from within the compression zone away from the punches. 2: SCORCHED MATERIAL? Another common cause of dark spots on tablets is a result of scorched material that flakes off during manufacturing and finds its way into the powder fill. Scorching occurs when small particles migrate in-between the punch tip and the die bore thus generating additional friction and heat resulting in product buildup. The material flakes off during punch movement and can then be seen around the perimeter of the tablet (see image 2). Tooling vendors offer lower punch options to mitigate this issue. Double-deep reliefs and narrow tip widths, as depicted in image 3, are designed to clean out the die bore during the downstroke of the lower punch following tablet ejection. Although more common on worn tooling, new tools also run the risk of forming dark spots if the formulation contains excessive fines. Utilising special tip sizes and tolerances on the tooling allows for greater control over the amount of clearance between these critical components. 3: IMPROPER TABLET PRESS SET-UP? Dark spots may also occur due to the improper set-up or adjustment of the feeder. All rotary tablet

presses operate on the overfill principle where the dies are initially overfilled. During the weight adjustment phase, the extra fill is ejected from the die, swept away by a scraper, and recirculated back into the feeder. When the product is recirculated,

Proper press setup plays a vital role in preventing dark specks from occurring in tablets

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the formulation is â&#x20AC;&#x2DC;damagedâ&#x20AC;&#x2122;, and results in additional fines within the material. Minimising the amount of product that gets recirculated is crucial. Proper press set-up plays a vital role in preventing dark specks

from occurring in tablets. Confirm that the feed frame is positioned at the correct distance above the highest point on the die table. If not properly set, particles can become lodged in-between the feeder and die table, leading to scorched material on the

tablets. Also, setting the feeder clearance at the correct location prevents contact between the feeder and the die table during press operation. Small amounts of ferrous metal from these components could scrape off when contact is made and end up on your tablets as dark spots. Metal detectors should be utilised to detect foreign material. 4: LESS COMMON FACTORS There are instances where dark spots are a result of

something far less common, but should be considered during the troubleshooting process. Poorly maintained or worn processing equipment can result in contamination. For example, sieves utilise mesh screens to control particle size distribution. The screens may deteriorate leading to contamination of the formulation, and must be inspected regularly. Blenders, used for processing powder, require bearings for general mechanical operation. If a bearing or seal is damaged, its lubricant may leak into the formulation, thus resulting in a contaminant that may be seen throughout the tablet. Ensure that all processing equipment is in good mechanical order prior to use to significantly reduce the likelihood of dark spots. If youâ&#x20AC;&#x2122;re unable to ascertain the source of the problem, contact your tooling vendor for further assistance. In some cases, sending sample tablets and/or tooling for further analysis is an option as well. Dark spots are a tabletting defect that no manufacturer wants to encounter. Understanding the primary causes of dark spots, whether as a result of lubrication in the powder, scorched material, or improper set-up, can help you to implement proactive solutions to produce high quality tablets and reduce production downtime.

Image 3: Depicts the differences between a standard tip vs. a narrow tip width with a double-deep relief. It is required that all lower punches have a sharp relief for consistent, quality operation.

Image 4: Damaged feed frame.

ANALYSIS

AI’S IMPACT ON THE FUTU AND DRUG DISCOVERY The rise of artificial intelligence (AI) has been popular within the life sciences industry and in particular pharma. Find out why and what it means for the future of drug development.

T Charlotte WalkerOsborn, partner and international head of technology - Eversheds Sutherland Nabil Asaad - senior associate – Eversheds Sutherland

he recent surge in activity in deploying AI capabilities in pharmaceutical R&D shows no sign of abating, with ‘big pharma’ investing significant capital in streamlining or accelerating the drug discovery process and applying AI methods to identifying new targets and medicines. If AI delivers on its promise, then there will be a material increase in the rate of new medicines coming to market. This could lead to a corresponding up-tick in the demands on manufacturing. Running in parallel is the question of how the same technologies can be applied to increase efficiency and improve outcomes in manufacturing as well as how AI technology might help improve efficiencies within these businesses. AI MEETS ‘BIG PHARMA’ Major pharmaceutical companies are data-rich and experts at developing new medicines starting from an implicated gene, protein, process or pathogen. They have powerful computational tools at their disposal and are early adopters of new technology. The leading AI companies have developed tools capable of analysing vast data sets, including natural language documents. The convergence of the two means that the deployment of leadingedge AI to pharmaceutical R&D is accelerating. Pharma-AI collaborations are being structured in different ways.

For example, the AI partner may simply offer consultancy, and a technology platform for use with the pharma partner’s data, or the AI partner may wish to conduct its own pharmaceutical R&D and hence may wish to take learnings from and reserve usage rights in the collaboration outputs. INTELLECTUAL PROPERTY AI technologies evolve through use. Training an existing model on new data gives rise to a new model whose properties and behaviour are modified by that training data. Where the AI platform and data belong to different parties, the question arises as to which party should own the new intellectual property in the trained model and any derived data. There is no set rule. As with the fee and any royalty structure, this is ultimately a commercial discussion between the parties. Where AI technologies are used, for example, to prioritise follow-up research efforts, the downstream creative and technical input may generate IP which is distinct from the output of the AI system. The ownership and exploitation rights attaching to each should be dealt with clearly and separately. DATA USAGE, PRIVACY AND ETHICS Usage rights for the confidential/ proprietary information need to be considered. Are there any restrictions on the data being used? Is the data personal

data or personally identifiable information (PII)? AI is particularly suited to the analysis of genetic data. Analysis and application of privacy laws, including around whether data can be anonymised, is essential. The UK Information Commissioner’s Office has set out an auditing framework for artificial intelligence. The European Commission’s High-Level Expert Group on AI, Ethics Guidelines for Trustworthy AI (April 2019) – seven essentials has a strong focus on privacy and data governance as well as transparency and ethical application of AI. There will be more law and guidance emanating from regulators across the globe in these areas. TECHNOLOGY AND CYBERSECURITY AI technologies reside on servers, whether on-premise or in the cloud. It is critical that a detailed analysis takes place, early on, as to the technology set-up, data flows, and security arrangements. The analysis is broadly the same as for other technology projects, but is a critical step given the large amounts of data and the potential sensitivity of the data and the results, especially if any personal data being used is voluminous and not anonymised. FUTURE PROSPECTS AI technologies are now used at every stage in pharmaceutical R&D, as is evidenced by the

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URE OF PHARMA If AI delivers on its promise, then there will be a material increase in the rate of new medicines. coming to market.

numerous high-value deals between ‘big pharma’ and providers of AI technologies. As a recent example, Eversheds Sutherland advised global biopharmaceutical company AstraZeneca on its long-term collaboration with BenevolentAI to use AI and machine learning for the discovery and development of potential new treatments for chronic kidney disease (CKD) and idiopathic pulmonary fibrosis (IPF). Further to this, even if the prospect of machines inventing medicines is some way off, the use of AI to improve efficiency

and speed up drug discovery is a realistic prospect today. AI technologies may also be utilised in areas of manufacturing which are amenable to predictive modelling and predictive support, such as process optimisation. The use of such AI tools within smart factories and smart manufacturing is enabling less down-time in the manufacturing process and driving stronger results. And AI tools are also beginning to be deployed on a more wide-spread basis within the ‘back office’ such as within accounting technology. As AI tools and computing power become more accessible and affordable, as with any technology, it will become very much part of the process within pharma and manufacturing – the future will be ‘AI-enabled’.

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ANALYSIS

LOST AND FOUND At the end of July, a team of clinicians at the Sheba Medical Centre in Israel treated a patient with a drug that had been lost for over 25 years.

Bisantrene’s history then is one of promise but in the early 1990s, the drug was lost due to a series of pharmaceutical mergers.

he patient, diagnosed with relapsed/refractory Acute Myeloid Leukaemia (AML), is one of 12 to be recruited as part of a clinical trial designed to help return this lost drug to clinical use after such a long time. Bisantrene, as the drug is known, was rediscovered by specialty pharmaceutical company Race Oncology after its founder’s interest was piqued by the promising data Bisantrene showed. “There’s so much clinical history on this drug, it’s been in 1,800 patients and 46 phase II trials in various cancers,” Race Oncology CEO Peter Molloy told European Pharmaceutical Manufacturer. Bisantrene’s history then is one of promise but in the early 1990s, the drug was lost due to a series of pharmaceutical mergers. “[Bisantrene] got left behind despite the fact it showed quite remarkable effectiveness in treating acute myeloid leukaemia (AML) when everything else had failed,” Molloy says.

This is key to the drug’s clinical use. While AML is a difficult disease to treat, a number of therapies do exist “that are targeted treatments for specific mutations in AML cells and they can target more effectively than the broad spectrum drugs,” Molloy says. But Bisantrene is intended as a salvage therapy, or in other words, for patients who have exhausted all other means of treatment. One of the drug’s particularly attractive attributes is its reduced risk of cardiotoxicity when treating children with AML.

The company has recently secured a new patent for the drug in the United States, enabling Bisantrene to be used in combination with other drugs to treat AML and breast cancer. And while Race Oncology’s efforts could bring back Bisantrene from the annals of history, the fact it was lost isn’t something that surprises Molloy. “Frankly, when I worked in big pharma, I would have deprioritised [Bisantrene] as well because from big pharma’s perspective it was never going to be a billion-dollar drug,” Molloy states.

“When it comes to children it’s a major issue because you could end up curing the child – and often it’s infants who have this disease – but giving them congestive heart failure; it’s lifelong cardiac damage that current drugs can cause and Bisantrene doesn’t have that attribute,” Molloy explains.

But that hasn’t stopped Race Oncology and the conclusion of the trial taking place at the Sheba Medical Centre should give the company more insight into the efficacy of Bisantrene. Hopefully, the drug’s resurrection will prove successful.

That’s why Race Oncology is now looking for a partner to help fund and run a paediatric clinical trial in the US.

“I sincerely hope it leads to new remissions in patients who wouldn’t otherwise have much hope of survival,” Molloy adds.

CHROMATOGRAPHY & SPECTROSCOPY

Dagmar Behmer marketing manager Bruker

Examining the online monitoring of fermentation processes using FT-NIR spectroscopy

ermentation, ‘the anaerobic conversion of sugar to carbon dioxide and alcohol’ is commonly associated with producing beer or wine. In the pharmaceutical environment, cell fermentation is used to manufacture a large number of active pharmaceutical ingredients (APIs), targeting a wide range of medical indications from anti-cancer drugs to vaccines and many other medications. It is always used, when the synthetic route is very complex and requires significant and time-consuming development stages.

Figure 1: Principle of transmission, transflection and reflection measurements

Basis for the synthesis of an API, like biopharmaceuticals or biologics are genetically modified organisms (GMOs). Under optimal conditions, they are cultivated in a nutrient solution to maximise the cell growth and thus the productivity of the organisms. For an optimal result − and to apply to the strict regulatory requirements in the pharmaceutical industry − it is necessary to measure, control and adjust the parameters, like

glucose, lactate, protein content and more during the fermentation process from the startup media to the final product. HOW TO SOLVE CHALLENGING MEASUREMENT CONDITIONS Fermentations are initially transparent but become increasingly opaque as the cultivation progresses. The challenging measuring conditions of fermentation processes require smart technical solutions. Neither transmission nor reflection probes are suitable for monitoring the entire process. To provide reproducible measurements even for opaque slurries and emulsions, transflection probes are advised, which combine the benefits of transmission and reflection measurements. This is becoming clear when looking at the measurement principles of probes (Figure 1). Transmission probes (left) guide the light once through the medium at a given path length - ideal for clear liquids. Reflection probes (right) illuminate the sample and collect the scattered light – ideal for solid samples. Since the fermentation starts as a clear broth and changes over time to a very turbid liquid, neither of these probes will perform well through the complete process of fermentation. A transflection probe (Figure 1, middle) solves this

by combining these two options. At the beginning, it behaves like a transmission probe when the light is reflected by the built-in mirror. The more turbid the solution becomes, the more the light is being reflected by the cells. These probes can usually be adapted to different process conditions, flange types, immersion depths and steel types. Also, FDA-compliant sealings as well as fully autoclavable versions are available. In combination with the advanced measuring modes of modern fourier transform nearinfrared (FT-NIR) spectrometers, which can suppress the influence of gas bubbles on the spectra, reliable results can be obtained. SUMMARY Cell fermentation processes are today a reliable production method for small molecules and protein-based APIs, allowing pharmaceutical companies to optimise the production process and time to market. FT-NIR spectroscopy can help to tightly control e.g. fed-batch fermentations by monitoring parameters such as: • Concentration of Glucose, Ammonia and Lactate • Protein and Carbohydrate Content • Cell Number / Cell Density • Recombinant Protein Concentration

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ASEPTIC PROCESSING – CASE STUDY

Who: Andrew Barrow, Cherwell Laboratories What: Investigates media fill simulation failures

Case study

How: By identifying the root cause

Cherwell Laboratories outlines an investigation undertaken to identify the root cause of a series of media fill simulation failures not attributable to operator competency, while also identifying the appropriate corrective and preventative action (CAPA) measures to reduce risk to the aseptic compounding process.

alidation of compounding is essential to demonstrate that appropriate controls are in place to ensure asepsis of the process and the sterility of filled products, and ultimately, guarantee patient safety. To monitor the aseptic liquid transfer technique of compounder operators, Great Ormond Street Hospital (GOSH) routinely undertakes aseptic process simulation validation (media fill simulations) using tryptic soy broth (TSB). STATUTORY REGULATIONS AND DISINFECTION MEASURES TO KILL SPORES Patient health can be seriously compromised by microbiological contamination of compounded medicines, particularly in the most vulnerable patients. Good Manufacturing Practice (GMP) regulation in the UK has been applied for many years following the introduction of the Medicines Act 1968, then the Human Medicines Regulations 2012.2,3 Compounding pharmacies have no exemption. Despite stringent disinfection procedures, Bacillus cereus contamination of intravenous total parenteral nutrition (TPN) caused 19 cases of septicaemia and three deaths on Bacillus subtilis endospores | Magnification: x7000

a neonatal unit in England 2014.6 An investigation by the Medicines and Healthcare products Regulatory Agency (MHRA) concluded that the contamination was introduced during manufacture and did not originate from any raw materials. This 2014 outbreak was considered an isolated incident, however, it highlighted the risk of contamination by resilient spores from the environment. Subsequent guidance from the MHRA included use of sporicides in a two-stage spray and wipe disinfection process during compounding.7 This guidance has been incorporated into a report by the NHS Pharmaceutical Micro Protocols Group which recommends a two-minute dwell time with sporicide.8 ASSESSMENT OF OPERATOR ASEPTIC TECHNIQUES DURING COMPOUNDING One of the standard procedures to maintain sterility during compounding is by assessing operators’ ability to transfer liquids aseptically in a simulation. Bacteriological medium, such as Tryptic Soy Broth (TSB), replaces compounding medicines and the flow through the compounder is examined for microbial growth. Any contamination events result in immediate cessation of compounding by the operator concerned, followed by retraining in aseptic liquid transfer. This is essential to uphold standards, provided the validation results are an accurate portrayal of competency. After a series of aseptic process simulation validation failures from multiple operators at GOSH, it was deemed unrelated to operator competence. This is because all operatives involved displayed excellent cleanroom techniques and practices. However, Bacillus species had been transferred to the Grade A environment in which compounding of parenteral nutrition is executed, despite adherence to new NHS guidelines regarding addressing sporicidal issues.8 This necessitated the investigation. IDENTIFYING ORIGIN OF MEDIA FILL SIMULATION FAILURES The study first confirmed GOSH’s media fill

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transfer procedure to be extremely rigorous; following all NHS guidelines comparable to best practice in the pharmaceutical industry. Yet, despite this thorough process, media fill simulation samples were found to be contaminated with a number of different species of Bacillus (Figure 1). To identify the source of contamination, microbiological samples were obtained from different surfaces within GOSH’s controlled compounding environments and from the surfaces of items subjected to sporicidal transfer disinfection. No bacteria were recovered from the surface of large volume licensed medicinal products, confirming that risk of spore contamination was during media fill validation and not actual medicine compounding. Contamination was ultimately identified to solely originate from the TSB media bottle surfaces following storage in an uncontrolled environment. HOW DID THE CONTAMINATION OCCUR? Despite the use of sporicides, it is feasible that Bacillus spores on the TSB bottle surface and bung survived disinfection steps during transfer to the compounder. Spray and wipe steps reduce the risk of contamination as bottles are transferred to the compounder, but increased handling at each stage is also a risk. The contents of large volume TSB bottles are aseptically transferred during filling via the insertion of a sterile large bore spike pushed through the rubber septum in the cap of the bottle. This has a relatively large surface area compared to a needle used for transfer of smaller volumes. Therefore, any contaminants that have evaded disinfection, such as those under the edge of crimped bottle collars, may be disturbed and introduced into the bottle at this stage. COULD SPORE CONTAMINATION OCCUR IN ACTUAL COMPOUNDING? The recovery of Bacillus isolated on the surface of the TSB bottles and the lack of recovery from the outer surfaces of starting materials was linked to the different manufacturing controls of TSB versus licensed medicinal products. Large volume products used in aseptic compounding are licensed sterile pharmaceutical products. The bungs are sterilised prior to use, added and crimped in a Grade A environment reducing risk of spore contamination (Table 1). As contamination was only ever found during media fill simulations, rather than during actual drug compounding, this highlighted a potential risk to the sterile

REFERENCES:

Sterile / Aseptically Prepared Licensed Drugs products

Autoclaved TSB

Bungs / rubber septa sterilised via validated sterilisation before transfer to Grade A filling line

Bungs / rubber septa not processed prior to use

Bungs applied In Grade A environment

Bungs applied in uncontrolled environment (but usually Grade C)

Caps crimped in Grade A

Caps crimped in uncontrolled environment

TSB Bottles stored in a cardboard box in an uncontrolled environment.

Table 1: Manufacturing controls of licensed drugs for compounding compared to bacteriological medium used for validation

environment rather than an immediate risk to patients. CORRECTING AND PREVENTING CONTAMINATION - CAPA Measures to minimise any risk of contamination of TSB media bottles because of the tabulated differences (Table 1) were identified: 1. Increase sporicidal dwell time to 20 minutes 2. Identify product that has been triple wrapped and irradiated, which we discuss below. The Royal Pharmaceutical Society and NHS Pharmaceutical Quality Assurance Committee has issued guidance recommending multiple layers of sterile packaging, thus reducing the need to disinfect items at each stage of transfer.9 As part of its CAPA measures GOSH sought an alternative microbiological media supplier to develop a way of ensuring the TSB units for aseptic process simulation validation were sterile, and Cherwell Laboratories were invited to collaborate with GOSH on this project. To remedy the situation, Cherwell developed a sterile, triple packaged Redipor media TSB product in line with the Royal Pharmaceutical Society recommendations. Following further studies, including stability, post-media fill and post-incubation growth promotion (fertility) testing, GOSH pharmacists found this product was easyto-use. Also, in line with CAPA it removed all risk of spore contamination of the medium prior to compounder validation, thereby eliminating false results and ultimately increasing workflow efficiency in the pharmacy unit.

1. Drug Topics. 2017. How the NECC Case Changed Compounding Pharmacy. 2. http://www.legislation.gov. uk/. 1968. Medicines Act 1968. 3. http://www.legislation.gov. uk/. 2012. The Human Medicines Regulations 2012. 4. Tara Culp-Ressler. 2012. Massachusetts Approves Tighter Regulations To Help Prevent Future Meningitis Outbreaks. 5. Congress.gov. 2014. H.R.3204 - Drug Quality and Security Act. 6. Public Health England. 2014. Bacillus cereus infections: 1 July 2014. Publication of the main findings from the PHE and MHRA investigation into the Bacillus cereus outbreak. 7. MHRA. 2015. MHRA Guidance for Specials manufacturers. 8. NHS Pharmaceutical Micro Protocols Group. 2015. Guidance for Aseptic Transfer Processes in the NHS: Addressing Sporicidal Issues. 9. Royal Pharmaceutical Society and the NHS Pharmaceutical Quality Assurance Committee. 2015. Quality assurance of aseptic preparation services (QAAPS).

LOGISTICS & DISTRIBUTION

AN INSIDE LOOK

at World Courier Sam Herbert President, World Courier

The complexity of drug development is not to be contested. From discovering a molecule; moving from pre-clinical to clinical testing; gaining regulatory approval, pharma companies invest so much resources and time into developing cures and therapies which are ultimately unlikely to make it to market.

ut while we may all have an idea of the scale of the pharma market, the area of logistics often goes unsung for the role it plays in delivering much needed medicines around the world. On the back of sector leader World Courier’s 50th anniversary, European Pharmaceutical Manufacturer editor Reece Armstrong sat down with president Sam Herbert to discuss the complexity of the pharma supply

chain and the role the company has played on the industry’s world stage. Founded in New York in 1969 by Jim Berger, World Courier soon developed a global network that helped it move products quickly and efficiently around the world. In the 1980s, the company was approached by pharma companies working on infectious disease trials.

“It was at a time when clinical trials were looking more globally and looking to do more of the testing in central laboratories,” Herbert explains. At that point, no one was moving infectious samples around the globe, so it came down to World Courier to learn. The company moved most of its products on commercial airlines, petitioning them to move infectious samples largely destined for HIV and AIDS-based trials. Since then, the company has moved into investigational products, set up in-country clinical trial depots and established offices in over 50 countries. For Herbert, who joined in 2013 one year after the company was acquired by AmerisourceBergen, it makes sense that World Courier’s ‘value proposition is that flexibility and that adaptability’, he tells me. Herbert gives the example of the emergence of cell and gene therapies, treatments which bring about a whole new set of challenges in how they’re transported. “People talk about these as the third wave of innovation, from small molecules to big molecules, to now these personalised

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therapies which are someone’s engineered cells that are being moved,” Herbert says. “The complexities of those logistics are just much, much more challenging. The patient is actually in the supply chain.” The pressure on the company to deliver these therapies in a time-sensitive manner is immense, Herbert explains. “The tolerance for anything not to go right is very small so the contingency planning that you need to go through, and the active monitoring and issue resolution is extremely high for these therapies. But at the same time they’re incredibly exciting if you look at some of the outcomes we’re seeing from these therapies.” It’s not just treatments that are evolving but the ways in which pharmaceutical companies conduct clinical trials, all of which bleed into how World Courier operates as a company. Herbert tells me about how certain pharma companies are targeting therapies for smaller populations, such as rare and orphan diseases, and how clinical trials now need to recruit patient populations from further afield. Traditional clinical trials, which are usually based at one site and might require daily infusions, can place a huge burden on families having to choose to move closer to the site’s location or decide not to participate in the trial. Clinical trials targeting patient populations which may be more dispersed require an approach which Herbert calls personalised supply chains or a direct-topatient model. The ability for World Courier to deliver infusions to a patient’s house, or school

at which a nurse can administer the therapy, removes the burden of families having to suddenly move and brings benefits to the pharmaceutical company conducting the trial such an increased retention rates and faster recruitment times. Our conversation delves on the innovations occurring in the supply chain sector, the importance of industry integration and standardisation, and how the company’s global reach has enabled it to help its clients deal with emerging regulatory challenges. But one area Herbert identifies as needing improvement is in unlicensed medicines. While unlicensed medicines can be prescribed by a healthcare professional, Herbert alludes to more nefarious parties making certain drugs available on an unlicensed basis into other countries. Hebert mentions how he sees the practice occurring particularly around drugs for rare and orphan diseases and also in the paediatrics market as well. For children with a certain type of cancer or genetic disease, there’s little parents wouldn’t do to obtain a therapy they think will help, Herbert says. “I feel for pharma companies cause they’re trying to control

this through different distribution set ups, but these drugs are getting out. Personally, in terms of counterfeiting and profiteering I see large opportunities for improvement,” Herbert adds. Talking of improvement, World Courier has recently expanded its distribution capabilities in a move which Herbert believes comes back to operating at scale. With over 150 offices, World Courier’s scale means it can respond to client needs much more quickly. “If you have a patient in a specific city, where something has changed in terms of the day, we can respond much more quickly, because we can have the right packaging on hand with the right capabilities to then move that sample rather than needing to have a one-to-two day lead time.” “There are a lot of cost pressures on pharmaceutical companies and we’re seeing more and more pharmaceutical companies want to work with global companies rather than have different partners in every country,” Herbert says. World Courier certainly now seems to be that global company Herbert alludes to. From small beginnings in New York, the company has played an unsung role in helping to deliver life-saving medicines all across the world. Here’s to another 50 years.

The tolerance for anything not to go right is very small so the contingency planning that you need to go through, and the active monitoring and issue resolution is extremely high for these therapies.

27 AN INSIDE

Graham Francis – product marketing manager Kallik

LOGISTICS & DISTRIBUTION

Balancing act How the pharma industry is keeping up with changing labelling regulations and compliance ‘Labelling’ is a broad term that covers a number of elements, such as control and package labels, directions for use, and maintenance manuals. It’s also not limited to print and encompasses electronic media presented via a mix of user devices. With the evolving pharmaceutical market, the industry has had to shift and adapt to the changing times. There’s a need, now more than ever, to balance complex regulations, rising consumer demand and shifting market realities. And due to the uncertainty surrounding Brexit, potential changes in regulations will increase organisations' need to stay agile to achieve compliance. Regulation is of paramount importance and a challenge to manufacturers every day. Therefore, processes need to be adapted to meet changing production demands of speed, safety and flexibility while still continuing to comply with regulations. So, how can the

industry overcome some of the biggest challenges it faces, embracing new technologies in order to empower workforces and allow the industry to move forward? RELATIONSHIPS In line with this, the relationship between document-centric regulatory environments, content centric labelling and artwork processes will be of paramount importance. Small but problematic details can lead to significant inaccuracies in both packaging and labelling. This therefore requires content alignment, where approval and review processes need to be visible and auditable to check accuracy of spelling, artwork, graphics, regulatory content and barcodes at every stage of production. In building more collaborative processes, labelling executives should seek to: • Bring all assets under control in one place where they can be reviewed, approved and version controlled

• Surface and share regulatory and product information buried within documents and spreadsheets to better substantiate claims • Store all labelling content, translations and artwork as digital re-usable assets, whether printed or published electronically • Take steps to simplify collaboration across all areas of content collation, artwork authoring review and approval REMAINING FLEXIBLE AND AGILE Maintaining compliance will comprise of a connected and agile process between print and electronic labelling. Fundamental to success here is getting labelling compliance right for printed labels first as opposed to implementing new technology to deliver eLabelling. Many organisations often start out thinking they need to find new ways to present content electronically, but quickly go on to discover that the problem they really have is around levels

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of consistency across printed labelling content. Once this challenge is addressed, repurposing structured approved content to be able to present this electronically becomes much simpler. To bridge the gap between consumer packaging groups and converters, the pharma industry will require an evolution of traditional manufacturing infrastructures. The obvious and ultimate solution is electronic packaging and smart labels to enhance the consumer experience and strengthen brand loyalty. New smart devices will inevitably become the new normal and manufacturers will then search for new functionalities to continuously achieve the best possible packaging and labelling. SIMPLIFY CONTENT COLLATION Making it easier to capture multilingual labelling and embracing linguistic minorities will better position manufacturers to exploit growth in emerging markets. Tailoring content collation to meet localised regulatory and product labelling requirements through expanded use of business logic will lead to less errors and lower the risk of non-compliance. Graham Francis, product marketing manager, Kallik sees labelling and supply chain executives achieving measurable benefits delivered by embedding business logic into labelling content collation processes as they begin to eliminate reliance on tribal knowledge. “They will also be better positioned to satisfy market-specific labelling variants and quickly adapt to ever-changing market and regulatory needs. Organisational decision making will also improve.”

It goes without saying, that all internal and external stakeholders need to be connected to eliminate dependency on uncontrolled processes (e.g. email). This makes it easier for labelling execs to capture and report on performance against key performance indicators (KPIs) and to target and implement process improvements that will have a measurable impact on performance. DIGITAL LABELLING Digital labels can also help solve the issue of adapting and are quicker and easier to update compared to print, as well as making it easier to present content in a coherent and attractive format. This will aid patient transparency and see manufacturers more easily adapting to localised language needs, leading to better informed patients and improved outcomes. “Organisations must also move from processes that are impossible to measure, to ones that are fully transparent as part of the migration towards digital labelling,” adds Francis. “This will sharpen focus on inefficiencies in areas of the business that are true bottlenecks, rather than risk assigning valuable resources to projects that might have limited impact on productivity.” SMART PACKAGING Smart packaging will empower manufacturers to rapidly make changes to label content without enduring the costs associated with reprinting and

repackaging. Smart packaging will enable manufacturers to be more responsive and adaptable, without facing the normal constraints imposed by physical printed labels. With this more dynamic approach, patients could have instant access to all information in the language of their choice, and as we move closer to patient-centric treatments we could envisage tailored personalised labelling becoming more prevalent. LOGISTICS AND DISTRIBUTION The move towards a more agile, connected community through embracing digital supply chain concepts is never going to be an easy transition, but the benefits are clear to see. Despite all the challenges of migrating from a vertical to a horizontally integrated business, increased use of manufacturing and distribution partners spanning a global market means that industry has to change if it is to remain competitive. But it’s not just external partners that need better integration, each internal function right from R&D to customer fulfilment needs an end to end transparency to support real-time collaboration and informed decision making. The only way to do this is to have all stakeholders fully connected and empowered at all times.

With the evolving pharmaceutical market, the industry has had to shift and adapt to the changing times.

SERIALISATION

BOXING CLEVER Smart labels with integrated RFID/NFC chips support digitalisation trends in the pharmaceutical industry. Arne Rehm - product manager RFID/NFC Solutions at Schreiner MediPharm

he current trend towards selfmedication puts a stronger focus on the patient. On the one hand, easy and comfortable dispensing of a medicine is becoming more and more important. On the other hand, increasing digitalisation changes usage behaviour and strengthens the well-informed patient. Innovative labels with integrated NFC/RFID technology enable new, interactive applications and thus make an important contribution to assisting the patient. In addition, wireless communication is able to optimise processes, for instance to secure the supply chain or for intralogistics workflows. Radio Frequency Identification (RFID) allows for quick, contactless reading and storage of digitised data for a wide range of applications. Due to their thin and flexible construction, RFID/NFC inlays are easy to integrate into labels for medicine containers or medical devices and inconspicuously blend in with the existing design. The smart labels can simply be applied to the primary containers during the production process and offer attractive fields of application, such as counterfeiting protection, interaction with the patient and process optimisation. In the case of Near Field Communication (NFC), reading is possible within a range of just a few centimetres using an NFCcapable smartphone. Suitable readers are integrated in many mobile phones, thus contributing

to high availability and ease of using the NFC functionality. The technology is commonly known primarily due to the wide-spread use of contactless smartphonebased payment. However, it offers new, attractive applications for the pharmaceutical industry and medical device technology as well. PRODUCT AND BRAND PROTECTION VIA DIGITAL AUTHENTICATION Smart labels with integrated NFC technology open up diverse and scalable opportunities to pharmaceutical manufacturers for product and brand protection because easy digital authentication of the respective medicines is possible anytime, anywhere by means of smartphones. Readouts via smartphone provide the user with a clear, readily understandable result that can be complemented by other content such as descriptions of security features or additional information for the patient or physician. For instance, the technology – by means of password protection, signatures or encryption techniques – provides reliable protection against counterfeiting attempts, depending on the respective threat scenario. Pharmaceutical manufacturers benefit from the wide-spread use of NFC-capable smartphones with integrated readers in this context. Whereas reading of NFC labels used to be largely limited to Android devices, it is now also easily possible with current Apple devices using the iOS operating system.

During an online verification, information stored on the chip, the serial number or – in compliance with data protection regulations – even user data, may be sent to a database. This additionally provides the pharmaceutical manufacturer with an option to obtain important information for monitoring the supply chain and avoiding potential grey-market activities. FAST AND INTERACTIVE ACCESS TO INFORMATION Labels with NFC inlays make it possible to exchange information with the user. While reading the label-integrated chips with an NFC-capable smartphone, users receive easy access to important information about their medication, which the manufacturer can update and adjust anytime as needed. For this purpose, data stored on the NFC chip or additional information can be accessed via the internet. Thus, patients or healthcare staff receive extensive background information about the product – from clear identification of the medicine to easy query of the expiry date through to important product details or warnings. Moreover, a respective NFC label can assist with challenging applications. The pharmaceutical manufacturer can store explanatory videos or audio files on the chip in order to support proper handling and thus therapy success. For instance, video tutorials or interactive step-bystep instructions are particularly

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helpful in the case of pens and autoinjectors because using them properly often requires several steps in the correct sequence and the handling of such injection aids is not always intuitive.

or wrong medicines and helps to avoid dosing errors. Via the programming of the labelintegrated RFID chip, the reuse and thus abuse of an original container is prevented.

Label-integrated NFC technology also supports the current trending topic of Patient Compliance Monitoring: taking medications correctly as prescribed by a therapy plan is crucial to the successful outcome of a treatment. By means of mobile apps, patients are reminded to regularly take their medicines and are able to monitor their own usage behaviour. In addition, the attending physician can use the data obtained to adjust the therapeutic regimen together with the patient and/or optimise compliance.

OPTIMUM PROCESSES IN INTRALOGISTICS Consumables or equipment provided with RFID labels are able to optimise processes in the operations of pharmaceutical manufacturers, hospitals, laboratories or in other professional fields of application. Automated inventory management is an example of a possible scenario: due to automatic reading of the removed and stored products, the current inventory is always stored in a database. In addition, modern sensor chips are able to simultaneously monitor the integrity of the label and thus events of first-opening or tampering with a container, among other things. The use of RFID also makes it possible to monitor and control logistics material and product flows in real time: the labels are automatically read at various stations for maximum transparency and concurrent documentation. The processes optimised and automated in this way help to enhance efficiency and process reliability. Manufacturers can directly use automatic and clear identification of their products via RFID technology in their internal processes and, in addition, provide major benefits to their customers and enhance workflows in hospitals, laboratories or blood banks.

COMMUNICATION BETWEEN PRODUCT AND DEVICE However, label-integrated RFID/ NFC technology not only enables the interaction between the user and the physician or the user and the manufacturer but also between the product and the corresponding medical device: according to the lock-and-key principle, a product marked with an RFID label and the corresponding medical or laboratory device are able to exchange information in real time. When administering medicines this enhances patient safety and ease of use. The chip assumes control: the lock-and-key principle stands for two parts that have to be precisely matched in order to perform a specific function. In the case of medication, the medical device, for instance a blood pump, reads the data stored on the chip. In the first step, authenticity and shelf life are checked. Afterwards, the information transmitted by the chip assumes control of the device. This principle prevents the administration of falsified

SERIALISATION

5 steps to compliance

Bart Vansteenkiste - global life sciences sector manager, Domino Printing Sciences

• Showcase your expertise and industry knowledge • Raise brand awareness • Transform the way you engage with We are now six months passed the EU Falsified Medicines Directive (FMD) deadline customers • Run a cost-effective and convenient alternative to conventional seminars and various organisations like have begun to ask the authorities to take out • Gain more insights your target audience • Attainwith clearly and qualifiedWith salesaleads sanctions againstinto companies that don’t comply thedefined FMD regulations.

recent European report claiming that up to 30% of the 2D codes containing the Drug Supply Chain Security Act (DSCSA) serial number failed to scan, late adopters must understand the business risk they are taking by not complying.

ith some form of serialisation expected to cover 80% of the global drug supply by 2022, having a system that can meet stringent requirements outlined in the EU directive will certainly make any subsequent compliance procedure a simpler progression. Bart Vansteenkiste, global life sciences sector manager for Domino Printing Sciences, highlights five steps that companies need to take to ensure accurate coding and marking. QUALITY CODE Key to the EU’s FMD regulation is the quality of a 2D data matrix code, incorporating all the important information. It must be machine-readable and durable, in some cases, beyond five years. Both laser or thermal inkjet printbased solutions have the capacity to deliver on the eight code quality parameters. A METICULOUS VERIFICATION SYSTEM Integrating a vision inspection system into a serialisation solution can make readiness happen within two to three months. It’s true that operating your production lines prior to full automation will be labour intensive, but you will have a system or process that allows you to sell your products in EU member states. Additionally, It is a system which it will be possible to add to in the future.

UNDERSTAND WHAT IS REQUIRED The first thing is to establish how the regulation will impact your business, its processes and assets. Generate a clear and comprehensive statement of what you need to do. This will provide the basis for your vendor selection and form the foundation document for your validation approach. Look beyond your own internal organisation. Consider your extended supply chain and what the requirements are defining for them. Will they be ready on time? VENDOR SELECTION AND IMPLEMENTATION It’s important to select a vendor with a mature, proven track record of product implementation experience with a number of early adopters. Producers need to think about the technology stack. Can the selected vendors meet the required expectations from the printers and cameras at level 1? Can they also deliver on those expectations right through to the enterprise level 4/5 EPCIS (Electronic Product Code Information Services) solution needed to manage their data and report to external authorities? These are complex programmes and you require the best programme and project management capability you can find to execute effectively all the way through to testing

and validation in the short time available. It’s too close to the deadline to fail, it’s even too little time for a fast fail, so experienced practitioners are essential. TRANSITION TO SUSTAINABILITY So, you’re finally FMD compliant – it’s now time to focus on achieving manufacturing effectiveness. It is vital to ensure serialisation becomes a conduit to boost business performance, then you need to make serialisation business as usual – integrating the processes and procedures throughout the wider organisation.

IS THE SPOTLIGHT ON YOU AT CHPI? With CPhI Worldwide just around the corner, EPM wants to make sure your business gets the most out of the world’s largest pharmaceutical exhibition. That’s why as a media partner to the show, EPM is offering a bespoke advertising package to help you maximise coverage and bring customers to your stand. Featured within our October issue will be a special CPhI Worldwide preview, highlighting the best of what the show has to offer. What’s more, our handy sponsored Hall Plan will help encourage attendees to visit the stands of featured businesses. THE PACKAGE INCLUDES: • Full Page advert • Client e-blast • E-newsletter banner • CPhI exhibitor showcase (product or service spotlight) • Logo on Hall Plan • Social media support There will also be bonus distribution for on-site visitors to the show, perfect for attracting visitors to your stand and enhancing brand awareness.

CLOSING DATE 30TH SEPTEMBER If you would like to book a package or find out more details, please contact. Rob Anderton t: +44 (0)1244 952 359 e: robert.anderton@rapidnews.com

FROM THE FACTORY

BREAKING GROUND On the back of opening a new facility in Dundalk, Vincent Dunne, CEO of The Wasdell Group explains some of the challenges of developing a facility in the midst of Brexit and new technologies. What are some of the biggest challenges when opening a new production site? A new facility build is always a complex process, but we faced different challenges with our site in Dundalk, Ireland when it came to the scale and speed of delivery. From breaking the soil in September 2018, to achieving GMP approval and commencing operations by early July 2019, we were ambitious with our timeline. Ensuring we kept to our plan, we adopted an accelerated programme management approach running several aspects of the build in parallel. We also adopted a process to enable rapid decision-making while maintaining effective communications between all contractors and stakeholders; while these were challenging in practice, I also believe they became our biggest strengths for the project.

How does the site support preparations for Brexit? Prior to opening the new site in Ireland, we were offering fully outsourced supply chain and EU launch capabilities across our group from our UK bases, so the new facility has future-proofed our operations in the event of a hard Brexit. By creating a foothold in Ireland, we can continue to carry out EU release testing for the drug products we manufacture, package and distribute and ensure continuous supply for our customers regardless of the outcome of Brexit negotiations. What advice would you give to other companies starting this type of project? Collaboration was at the core of overcoming any difficulties we faced during the build. At times we would have up to 75 contractor companies

all working cohesively around each other, which required careful planning and communication. Breaking down the silos between contractors from the outset is something we’d strongly advise. If you can facilitate an environment that drives all involved towards a common goal, you’ll enable a collaborative team that can navigate issues together effectively. Is Wasdell ready for the emergence of industry 4.0 or digital technologies within manufacturing? We have always been known to explore new technologies and innovative solutions ahead of the industry, and even our new facility has been built with industry 4.0 in mind. In addition to integrating our systems with our key customers to allow full visibility, our latest packing lines have various advanced capabilities including full diagnostic functionality that can be accessed remotely. We are also looking at emerging technologies such as blockchain more closely to determine how it can aid

the sharing of data across the supply chain, particularly for clinical trials. What benefits does the site’s location in Dundalk, Ireland bring? Being so close to the international airports of Dublin and Belfast, we are able to supply key hubs in mainland Europe within hours. We are also in the heart of the incredible talent pool Ireland has to offer and we are really proud of the team we have built at the facility - they boast hundreds of years’ experience between them and come from a diverse range of backgrounds, from the Health Products Regulatory Agency (HPRA) to large pharma companies. Dundalk and the M1 corridor has become a new pharma hub as many more well-established companies from across the globe are beginning to create a foothold in the region. It’s fantastic to be neighbours with such companies and we are really excited about what the future holds for the Irish pharmaceutical industry.

GEODIS FLUENT IN PHARMA

GEODIS have a proud pharma heritage of over 15 years, with a dedicated GDP trained team spanning warehousing and operations, to sales and supply chain management. We offer a true understanding on the complexities faced by the pharmaceutical industry particularly with GDP compliance. Our teams are vastly experienced and diligent in ensuring the integrity of the product and ultimately patient safety. We can offer unique solutions and provide guidance and support in getting your product to market using our extensive network and strong carrier partnerships.

LICENCE HOLDER WDA (H) 43825 www.geodis.com

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