EPM November 2015

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WHO ARE THE SECTOR’S INFLUENCERS? THE HIGHLIGHTS OF 2015

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Contents

November/December 2015 | Volume 15 Issue 8

Regulars 5

19

Features 22

COMMENT

SELECTION BOX A round-up of some of the key happenings in the pharma sector

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30

NEWS ANALYSIS A look at some of the key developments in pharma

THE IN-CROWD

32

10 OPINION Lu Rahman looks at the North West’s growing role in the industry

Who are the sector’s influencers?

We find out . . .

32 PRESSING ON The latest tablet & tooling from IMA, I Holland and GSK

15 REGULATORY AFFAIRS

40

16

GROUP THERAPY The BIOCAPAN Project outlines its latest research

COVER STORY Expertise from Natoli

50

42

CHEMICAL REACTION

MAP IT OUT

The best of this year’s innovation

Durbin looks at the challenges getting drugs to patients on time

42

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47 ON TRACK Antares Vision explains how Brazil is tackling the challenge of pharmaceutical drug serialisation

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Volume 15 Issue 8 © November/December 2015 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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from the editor A taxing situation It seems we’re never far from a merger or acquisition in the pharmaceutical sector. At the time of wrapping up this issue of the magazine we learned that US-based Pfizer and Irish firm Allergan will join forces under Allergan plc, which will be renamed ‘Pfizer plc’ and will create the biggest drugmaker on the globe.

According to reports the joint company is expected to be based out of Allergan’s Irish legal domicile whilst Pfizer will have its global operational headquarters in New York and its principal executive offices in Ireland.

This will be in biggest transaction done this year in any industry – $160 billion – and beats Pfizer’s previous $116bn purchase of Warner-Lambert in 2000 which was the largest ever deal carried out between drug companies.

Writing in Forbes, Matthew Herper outlines just how M&A activity has been key to this particular deal: “Allergan, the Dublin, Ireland-based company that Pfizer just announced plans to purchase, is not the same company that made the Allergan name famous by turning Botox into a household name. Instead, it’s the descendant of a small, New Jersey-based generic drug maker, Watson Pharmaceuticals, that decided to grow through mergers and acquisitions — and in doing so moved its own tax domicile to Ireland, cutting its tax rate. Last year, the company, re-dubbed Actavis, snatched Allergan from the jaws of Valeant Pharmaceuticals, which had been pursuing the Botox maker. Later on, it changed its name to Allergan.”

According to Herper, this set of deals that “increased Actavis’ market capitalisation, lead to the Allergan deal”.

Unlike previous M&A deals, this one won’t create that much in synergies – a mere $2 billion annually – he says.

Apparently there’s not much to cut because those cuts were announced as part of these other deals.

If this $2 billion a year isn’t much to write home about, what’s the big deal about this big deal? Due to the fact that Pfizer plans redomicile in Ireland, where corporation tax is lower than the US, this is what’s known as an ‘inversion’ deal bringing huge tax savings to the business.

Such moves aren’t popular in any industry. In the US, president Obama has referred to these type of companies as ‘corporate deserters’, calling them ‘unpatriotic’ by upping sticks to lands with lower tax rates - thereby reducing their contribution to the US economy – rather than for any strategic business goal. Only a few days before the deal was announced, the US treasury announced its intention to clamp down on these type of transactions but clearly this did little to stop this particular one from going ahead.

In recent years society has been quick to comment upon the business ethics of companies such as Amazon, Google and Starbucks setting up base in low taxation centres such as Dublin, the Cayman Islands and Luxembourg – should we expect this Pfizer / Allergan deal to receive the same attention? Is there a difference between the selling of coffee and books and life-enhancing drugs? Is profit profit and all companies should endeavour to pay their dues in their home country and contribute to the economic growth of that land whatever the wares they are selling? Or do we feel that where medicine and drugs are concerned, we can overlook big business gains in support of R&D investment, new drug development and cheaper, more widely available medicines? As the details of this deal pan out over the next few weeks only time will tell.

Lu Rahman

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5

NEWS ANALYSIS

UK skills shortage threatens future medicine development The UK life sciences industry is facing a major skills shortage which threatens to undermine the research and development of new medicines in the UK and prevent growth and investment in this vital sector

A

new report from the Association of the British Pharmaceutical Industry (ABPI) has found that pharmaceutical companies are struggling to recruit for high skilled roles in the UK due to low numbers of good quality candidates. The ABPI warns that this could lead to firms increasingly seeking expertise and skills abroad risking the UK’s position as a global leader of research and development.

Launched ahead of this year’s ABPI annual R&D conference, the report – Bridging the skills gap in the biopharmaceutical industry – looks at the skills needed now and in the near future for the biopharmaceutical industry to thrive in the UK. Based on research from 93 industry leaders from 59 organisations the report reveals that the most concerning skills gaps are in the interdisciplinary areas involving mathematics and biology which are essential for the development of the personalised medicines of the future.

Nine out of ten respondents cited concern about quality and quantity of candidates for vacancies in areas including bioinformatics, health informatics, statistics and data mining, where innovation and technology is advancing so quickly that training programs struggle to keep up.

Nine out of ten respondents also cited poor communications and teamworking skills in new recruits, as a particular area of concern.

The report also highlights long-standing issues in the number and quality of applicants in areas such as translational medicine, clinical pharmacology and veterinary and toxicological pathology, which were highlighted in the ABPI’s previous skills report of 2008. However, while action has been taken to address these issues, a lack of ongoing funding or short-term initiatives coming to an end means these skills gaps are now re-emerging as areas of concern.

The increasing number of skills gaps need to be urgently addressed if the UK is to continue to deliver innovative medicines to patients, say the authors. The UK currently has one of the strongest and most productive life sciences industries in the world, generating turnover of

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over £56 billion per annum. The pharmaceuticals sector employs over 70,000 people in the UK; the high productivity of each of these highly skilled people results in more than £149,000 being generated for the UK economy.

Life sciences minister, George Freeman MP, who wrote the foreword for the report, said:“It is essential that the sector continues to have access to a highly skilled R&D, manufacturing and technical workforce in order to achieve its potential, maintain the UK’s position at the forefront of life sciences and help to meet the challenge of addressing the productivity gap. This ABPI report will provide invaluable evidence for industry and policymakers to develop and deliver the right skills initiatives to ensure that the sector continues to thrive in the future.”

The report authors say a multi-sector approach, as well as co-investment from the industry and government, is required in order to tackle what is a complex set of issues. This includes a focus on the education pathway, from the school curriculum to post-graduate studies and more highquality apprenticeships.

Given the findings of the report, the ABPI is very concerned with the decision by government to renege on its decision to support the Science Industry Partnership (SIP), which has already made a significant impact on the skills shortage facing the sector, and which is well-placed to lead on tackling some of the issues raised in this report.

Malcolm Skingle, chair of the ABPI Academic Liaison Expert Network, said: “Securing the appropriate skills and roles across manufacturing, clinical and research and development within life sciences has been a significantly growing concern for our sector in the UK and this report provides the clear evidence of the complexities of the challenge ahead.

We absolutely need to work with government and health and education policy makers to understand how best to address these gaps and challenges, in order to secure the UK’s position in life sciences and ensure it remains able to compete globally for talent and investment.

Only through collaboration and co-investment between all relevant organisations can we ensure that the UK sustains and grows a highly skilled workforce for our sector in the future.”

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NEWS ANALYSIS

Heat-activated ‘grenade’ targets cancer R

esearchers have developed cancer drug-packed ‘grenades’ armed with heat sensitive triggers, allowing for treatment to be targeted directly at tumours, according to two studies due to be presented at the National Cancer Research Institute (NCRI) Cancer Conference in Liverpool.

The team based at The University of Manchester has been developing liposomes – small, bubble-like structures built out of cell membrane that are used as packages to deliver molecules into cells – to carry drugs into cancer cells. The challenge, as with any treatment, is to direct the liposomes and their payload directly to tumours while sparing healthy tissue.

Two new studies show the team has taken a step closer to solving this problem by fitting liposomes with a heat-activated trigger. By slightly heating tumours in the lab and in mouse models, the researchers have been able to control when the pin is pulled so that the cancerkilling ‘grenades’ release the drug and target the cancer.

Kostas Kostarelos, study author and professor of nanomedicine at The University of Manchester, said: “Temperature-sensitive liposomes have the potential to travel safely around the body while carrying your cancer drug of choice.

“Once they reach a ‘hotspot’ of warmed-up cancer cells, the pin is effectively pulled and the drugs are released. This allows us to more effectively transport drugs to tumours, and should reduce collateral damage to healthy cells.

“The thermal trigger is set to 42 degrees celsius, which is just a few degrees warmer than normal body temperature. Although this work has only been done in the lab so far, there are a number of ways we could potentially heat cancer cells in patients – depending on the tumour type – some of which are already in clinical use.”

Professor Charles Swanton, chair of the 2015 NCRI Cancer Conference, said: “Liposomes are small bubbles of cell membrane that act like a cellular postal service, delivering molecules to our cells. Using them to deliver cancer medicines has been a holy grail of nanomedicine. But finding ways to accurately direct the liposomes towards tumours has been a major challenge in targeted drug delivery.

“These studies demonstrate for the first time how they can be built to include a temperature control, which could open up a range of new treatment avenues. This is still early work but these liposomes could be an effective way of targeting treatment towards cancer cells while leaving healthy cells unharmed.”

WWW.EPMMAGAZINE.COM

7

NEWS ANALYSIS

Pharma employees spending too much time online, says software firm

M

ost UK adults are spending almost an entire day a week online.

Business leaders in the pharmaceutical industry need to create more break-out spaces in a bid to keep staff invigorated and boost collaboration, according to Condeco Software.

Figures from the Office of National Statistics (ONS) show that the average adult spends more than 20 hours online a week, which includes time spent on the internet at work. Condeco Software says that breakout spaces are a vital way for businesses across the world to help give staff a rest from the glare of their computer screen. These areas can simply be separate spaces, away from the normal work arena – places where staff eat, relax, brainstorm or hold meetings. Giving people a break from the computer screen also has benefits that some people may overlook, such as helping firms comply with health and safety rules.

Debra Ward, managing director for EMEA at Condeco Software, warns that decision makers must consider the benefits and positive impact on the culture of the office before ruling out creating such an area.

Ward commented: “Forward-thinking pharmaceutical companies were quick to realise the importance of creating break-out spaces in the office. To some businesses however, it may seem like a fad and ‘agility’ and ‘flexible working’ are interpreted as just industry buzz words. That couldn’t be further from the truth. Organisations are increasingly seeing the huge benefit these spaces can yield. It gives their teams a relaxed area to work together, float ideas, collaborate and connect.

It also improves employee engagement by giving a space for staff

8

to discuss the business with one another comfortably, creating better cross-functional relations and partnerships.”

In order to address the concerns of many business leaders about whether they have sufficient space to create such zones, Condeco Software created Condeco Sense, a market first in sensory technology that enables business leaders to access accurate, real-time data on how their workspaces, meeting rooms and breakout spaces are used.

Ward added: “By embracing technology, decision makers can now simply use data to re-arrange their workspace. Having tangible data means that firms can make full use of their office space, which is vital when real estate is so costly. But having data goes further, it gives businesses the power and information to drive change in their workplace, efficiently and effectively.

“Many organisations currently employ walk-through surveys to assess the usage of their office and these can add real value, but this does not paint a full picture. These methods should be combined with technology to give decision makers a holistic view which empowers them with to make business defining decisions.

“Creating well-planned and well-thought out breakout spaces can make it easier for staff to work together, which in turn drives collaboration.

The connectivity which these areas create also means that that a more engaged workforce is created, helping them pull together as a team towards business goals.”

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OPINION

Is the North West UK leading the way in drug development?

Over recent years the UK, in particular the North West, has been leading the life sciences charge.

Lu Rahman highlights how the region is looking to become a global leader for the sector

T

he North West of England has a history of groundbreaking enterprise. From its cotton mills to playing an integral role in the development of the computer and aerospace sectors, the region has a solid track record of industry and innovation.

More recently the pharmaceutical sector has been benefitting from the area’s scientific expertise. Add to this its excellent road, rail and air links as well as the proliferation of academia, and the North West could become a life science hub to rival the Oxford, Cambridge, London triangle. Some estimates say the sector is worth £50 billion to the UK economy. Within this the pharmaceutical sector is showing significant world-class capabilities.

The region’s potential was recently highlighted by PwC which claimed that the “rejuvenation in the North of England demonstrates how the coming together of the right pieces of the puzzle is having a positive impact on UK life sciences”.

“

“By identifying the city region’s assets in precision medicine, we will be able to build on our strengths in this area, tapping into our regional expertise that will not only bring national and local benefits, but act as a magnet for inward investment. This initiative therefore, creates significant follow-through momentum.”

Some estimates say the life science sector is worth £50 billion to the UK economy.

Within this the pharmaceutical sector is showing significant world-class capabilities.

Within the region Liverpool is showing particular promise for precision medicine and a proposal has been put forward by Liverpool Local Enterprise Partnership (LEP), the North West Coast Academic Health Science Network (NWC AHSN) and Liverpool Health Partners (LHP) to make the city the fastest place in the UK to develop and commercialise research in this field.

The report, Precision in Medicine (PRiME), outlines aims to build on the government’s Health North initiative, partnership with life sciences minister, George Freeman and maximise on the potential of the region in this field.

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Speaking to the Liverpool Echo, LEP chair Robert Hough, stated: “The PRiME report is a further example of how Liverpool city region is putting science and innovation right at the heart of the Northern Powerhouse and establishing itself as a global leader in the life science and health sector.

”

As sponsor of the report, the NWC AHSN has a keen interest in the Liverpool’s status in this sector. Dr Liz Mear, chief executive NWC AHSN, said: “The AHSN has sponsored this report because our role is to drive forward improvements in health care; precision medicine is the key to predicting and preventing disease and targeting treatments so they are bespoke to individual patients.”

Visiting the University of Liverpool last year, the life sciences minister said: “The North of England represents a real powerhouse of life sciences, driving forward growth for the country. With more than 1,000 businesses, supporting around 38,000 skilled jobs and being supported by our world leading universities, the region is contributing significantly to our growing economy.

“We want to be the best place in the world for life sciences and Liverpool is a fantastic example of how the region is attracting investment and developing new 21st century medicines.”

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And more recently Freeman was quoted on the Politics Home website as highlighting the wealth of talent in the UK: “The truth is we are retaining huge talent and skills in the UK and in fact one of our great strengths around the world is in pharmaceuticals, in biotechnology, in digital health, in diagnostic devices. There is a huge UK diaspora of UK leaders in very influential positions in the sector.”

A supporter of the digital health movement, Freeman recognises the role the North West has to play in the overall growth of the life sciences sector.

“In my first nine months as a minister I’ve been to see extraordinary inward investment into clusters of excellence in Northern Ireland, in Wales, in the North East, in the North West and in the South West.

Innovation Manchester, asked how we can make, “Greater Manchester the best place in the world for clinical trials?” highlighting the potential the region has to become a hotspot for life science innovation.

The University of Manchester is also at the forefront of life science enterprise. Researchers there have recently developed heat-activated ‘grenades’ to target cancer. These drug-packed structures are armed with heat sensitive triggers which mean that treatment can be aimed directly at tumours.

While the North West of England has always been a hotspot for innovation and scientific advances, it seems the time has come for it to become a world leader in the pharmaceutical field. Not only does the region have the expertise, the academia and the investment, it also has government support – key factors to help boost its progress on a global scale.

“So while it’s sometimes characterised as being very Oxford, Cambridge, London focused, in fact in these new emerging fields of digital health, clinical informatics, advanced manufacturing, there are huge growth opportunities in all parts of the UK.

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“I think there is a huge opportunity for us, as part of our broader hard and soft infrastructure programme, for connecting our northern and regional life science clusters, as part of making this a key area of growth for the UK in the 21st century,” he added.

Aside from the expertise coming out of Merseyside, the North West boasts the Alderley Park BioHub and Sci-Tech Daresbury Science and Innovation Centre which has been praised by prime minister David Cameron as being “a great collaboration between scientists and businesses”.

Since its launch two years ago, the BioHub now has 30 physical customers as well as 92 virtual customers. It offers entrepreneurial schemes, a mentoring network and has attracted over £10 million in funding during that time.

In October of this year it was also announced that both Leeds and Manchester would be part of the initial locations for the Precision Medicine Catapult, the UK’s innovation centre for precision medicine.

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13:4

OPINION

Invested interest Chris Wilkinson, Siemens Financial Services, looks how to drive growth in an innovative industry such as pharmaceutical manufacturer

T

he UK is home to some of the world’s most renowned pharmaceutical companies.

On a worldwide scale, British companies are responsible for developing one-seventh of the medicines currently in use across the globe1, commandeering the second largest share of the market behind US pharmaceutical organisations. According to the Association of the British Pharmaceutical Industry (ABPI), after Japan and the US, the UK is also the third greatest investor in pharmaceutical and biotechnological research worldwide2. Latest figures from the Office for National Statistics indicate that pharmaceuticals’ investments on research and development (R&D) account for 22% of total expenditure on R&D performed in UK businesses, twice that of the second largest contributor.

Aside from the home-grown global players, small and medium-sized pharmaceutical companies also play a significant part in maintaining the UK’s crucial position as a frontrunner in the pharmaceutical market. In fact, it is estimated that activities from small- and medium-sized enterprises (SME) generate around 80% of the pharmaceutical innovations in the UK, with these companies supplying 40% of the branded products used by the NHS3. Because of the sector’s specialist expertise and emphasis on innovation, the development and manufacture of pharmaceuticals needs to be underpinned by cutting-edge research and sophisticated production facilities. With the growing requirements to comply with increasingly restrictive industry regulations and best-practice policies, it is imperative that pharmaceutical companies enhance efficiency and productivity, through, amongst other things, the use of state-of-the-art laboratory equipment and up-to-date technology.

Harnessing technological innovations can help realise costs savings while ensuring high-quality outputs and waste reduction. Nevertheless, keeping pace with technological advancements requires considerable capital expenditure. More often than not, businesses have to preserve their cash flow and lines of credit to support other working capital requirements; moreover access to affordable bank credit has become more restricted following the financial crisis. For smaller-sized pharmaceutical companies where funds can be scarcer and restrictions on capital tighter, realising technology investment can prove particularly challenging. With downward pressure on drug prices across the world and, specifically, changes to the 2014 Pharmaceutical Price Regulation Scheme, smaller businesses are likely to feel the squeeze further.

This explains why asset finance techniques such as leasing and renting are gaining popularity as a cost-effective investment-enabler. Such financing solutions spread the cost of the equipment over an agreed financing period, with monthly finance payments arranged to align with the expected benefit of its use, such as efficiency gains.. This removes the need for a

large initial outlay, thereby increasing the funds available for operating expenditure. Asset finance thereby allows pharmaceutical companies access to the latest technologies, without having to commit scarce capital or use traditional lines of credit. Fixed finance payments also eliminate the volatility of interest rates, inflation and credit conditions while assisting with long-term budgeting. In addition, financing arrangements can incorporate other costs such as installation, maintenance, service and sometimes consumables, as well as introduce the possibility of technology upgrade in broad line with technology developments.

Such tailored, all-encompassing financing packages tend to be offered by specialist financiers who have an in-depth understanding of production technology and its applications. They are therefore more inclined and more able to create customised financing packages that fit the specific requirements of a business – for instance, flexing the financing period to suit the customer’s cash flow. This contrasts with the standard financing terms usually available from generalist financiers.

As changing regulations and a growing demand for innovative research and ground-breaking medicines have placed greater pressure on the sector, the use of outdated equipment could hamper industry progress and slow future development. In order to remain at the forefront of the industry, UK pharmaceutical companies should exploit the enhanced potential offered by advanced equipment and modern technology.

Capital investment, however, must be undertaken under the premise of sustainable and affordable financing. Instead of tying up precious capital in equipment acquisition, pharmaceutical companies can utilise flexible asset financing techniques through which they can more effectively deploy available financial resources in research and development – a crucial area that underpins the sector’s ability to make a vital contribution to raising healthcare service quality.

1) The Pharmaceutical Journal, 5 July 2014, Vol 293, No 7817, online 2) Ibid. 3) Ibid.

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PHARMINTECH 2016.

N E V E R S T O P I N N O VAT I O N .

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With the patronage of: UCIMA

Italian Packaging Machinery Manufacturers Association

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REGULATORY AFFAIRS

Access all areas Kushal Vyas, ELC Group, looks at barriers to generic entry in Europe

A

ccess to medicine and return on investment have always been key public policy considerations for governments to balance increasing healthcare cost and promote innovation. Lifecycle management strategies by brand companies have been successfully challenged and generic companies have subsequently launched products. However, pharmaceutical research on new actives involves relatively less certainty and substantial investment. To promote further research and secure return on investment, various monopolies with specific scope have been awarded to the originator companies.

Exclusivity Exclusivities are the incentive given for the specific period of time to the innovator companies upon the submission of clinical and other research data for specific types of products. Recent rules now provide protection of eight years data exclusivity plus two years marketing exclusivity plus other additional exclusivities, wherever applicable.

Data exclusivity is the period during which companies cannot rely on innovator’s data to obtain a marketing authorisation for generic application unless licensed by the innovator. Market exclusivity refers to the period during which generics can submit an application referencing the innovator’s products but cannot receive the approval of its product till its expiry. New indication exclusivity (plus-one year) may be received if registered during the initial eight year period and demonstrates significant clinical benefit over existing therapies. It may also be obtained for a new therapeutic indication for a well-established substance based on significant clinical data. Change in class exclusivity (plus-one year) may also be added, for example, OTC switch. Orphan drug exclusivity and Pediatric use marketing authorisation are given separate exclusivity for 10 years.

Supplementary protection certificate (SPCs) SPC is the ‘Sui generis’ system which provides additional monopoly to compensate time lost for granting MA. Patents are filed in the initial stage of research and its expiry is calculated based on its filing date.

However for pharmaceutical inventions, multiple years are lost in gaining regulatory approvals. To compensate, additional monopoly is awarded as an extension to the basic patent, with a maximum of five years. SPCs take effectafter the expiry of patent to which it is attached.

The term of SPC is calculated as (date of first MA in the EEA − date of

filing of corresponding patent) − five years. The SPC may be extended for 6 months after compliance of an agreed Pediatric Investigation Plan (PIP).

Patents Patents are territorial rights to exclude othersfrom making, using, selling or importing the claimed invention. In the case of pharmaceuticals, drug substance related patents may be granted with claims covering markush/ genus structure, species/specific substance, for example, compound per se, derivatives like salts, esters etc, polymorphs, process for preparation of drug substance, intermediateand so on. Method of treatments patent may be granted to indications and other treatmentrelated patent eligible inventions. Formulation patents are also granted with the product claims or process for its preparation. Patents are applied for invention identified during various stages of product development. There can be multiple patents covering a single product.

Barriers/Strategies Exclusivities are the primary form of monopoly which restricts the filing or marketing of generic applications. Grant of exclusivity is rejected by the regulatory authorities in few cases, and in very few instances, generic applicants have also tried to challenge such grants. SPC are usually applied for the basic drug patent, however, originators do apply for other types of patents. SPCs are challenged by generics in multiple cases for eligibility, scope, term of protection etc and there are positive outcomes in many instances. Alternatively, depending on the scope of protection, generic companies may also file MA having freedom to operate over the granted SPC.Patents form a third set of barriers for the generic companies. However, each granted patent has specific scope and generics may design specific freedom to operate or challenge strategies.

In summary, generic companies may come up with early launch products by well-designed strategies withcombined input of scientific, regulatory andlegalexperts’inputs against various forms of monopolies. Originator companies usually try to protect all feasible options likely to be explored by generics. By involving early stage research, generics may also come up with inventive feasible strategies with patent protection which gives right to exclude others.

Views provided herein are general. Kindly seek necessary diligence from relevant experts.

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COVER STORY

Pressing points Robert Sedlock, Natoli Engineering Company, discusses compaction dwell time and the impact of punch head designs

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ransitioning product from one tablet press to another during scale-up has been an ongoing challenge in the industry for many decades. There are many different approaches and aspects that must be considered including the tablet press design, punch design and powder characteristics.

When developing a new formulation scientists are equipped with a small-scale tablet press to study and understand their product’s tabletability. These systems are useful at the research level but do not always transfer successfully to larger scale manufacturing machines. Ideally, developing the product on a manufacturing press would eliminate the transfer challenges but the amount of powder required to operate such a machine is very high and not cost-effective.

There are many stages that occur during tablet production on the rotary tablet press and a full understanding of their functions is crucial in the success of producing a quality tablet. Stages include: • Powder filling from the hopper to the feed system • Powder filling from the feed system to the die cavity • Proper fill cam and dosing cam settings • Centrifugal acceleration and the need for a pull down cam • Pre compression – is it needed and how much force?

• Main compression consolidation time and rate • Main compression dwell time • Main compression decompression event • Ejection force and rate • Tablet take off – sticking and picking adherence removal Every step in the tablet press process merits a full discussion but this article will focus on the compression dwell time and how the tablet press and punch head designs impact this process.

At a particular turret RPM the TV is dependent on the PCD which varies depending on the number of stations on a turret. Figure 2 depicts examples of different size machines and the relationship between turret RPM and TV.

Discussion Dwell time expressed in milliseconds is the time in which the punches achieve maximum penetration in the die under the main compression rollers and the punches are no longer moving vertically. In other words dwell time occurs when the compression rollers are in contact with the punch head flat. This time is a contributing factor to the tablet strength and a means for product transfer from one tablet press to another.

Although turret RPM or tablets per minute are a common language for the turret speed, it doesn’t allow a true comparison for tablet presses with different turret sizes but the turret velocity is a normalisation of turret size and the dwell time is a normalisation of the turret size and punch head flat. It is important to understand the turret velocity before we can discuss dwell time.

Figure 1Turret Pitch Circle Diameter

As the turret PCD increases the required turret RPM is reduced to match a particular TV. A representable manufacturing velocity is above 1,000mm/sec. At 1,000mm/sec the larger scale NP500 press will operate at a turret speed of 34RPM where the medium scale NP400 operates at 65RPM and the smaller scale BLP16 at 84RPM. Running at 84RPM turret speed can pose some challenges with powder flow into the die cavity inhibiting the ability to evaluate tablet attributes. In fact some industry smallscale tablet presses are not able to generate manufacturing velocities due to their smaller PCD or limited turret RPM. This is where the punch head flat can be designed to provide this gap for scale up matching.

Turret velocity: When comparing press speed the tangential velocity or TV expressed in mm/sec allows for a true comparison.

The TV is a function of the turret RPM and pitch circle diameter or PCD which is the measurement of the turret from center of the die to the opposite die center. (See Figure 1) The PCD is critical as this is where the compression event occurs.

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Figure 2 - Tangential Velocity for Different Size Presses

Examples of Different Pitch Circle Diameters

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Head flat and dwell time Compression tooling heads are designed with a flat providing a constant strain to the powder bed while under the compression rollers. The longer the head flat the longer the dwell time and depending on your powder deformation characteristics and strain rate sensitivity a longer dwell time may be needed to produce a robust tablet. Slowing the turret speed can also increase the dwell time but slowing the turret speed will decrease production rates.

There a many different types of tools used in the industry that have different head configurations. Some are designed specifically to increase dwell time while others are designed to reduce premature wear. The two most recognized tool configurations are the European ISO standard and the American TSM. These standards are provided to allow tablet press tool interchangeability, consistent quality between tooling vendors, simplified inspection processes and inventory. Within both configurations the ‘B’ and ‘D’ type tools are the most common. ‘B’ tooling is designed with a smaller body allowing a higher population of punches in a turret which is favourable for high tablet output where the ‘D’ tooling is designed with a larger body allowing for larger tablets approaching up to 1 inch. As a ‘D’ tool is larger the head profile and flat for a standard configuration is also larger providing a longer dwell time. Figures 3 and 4 provide a chart of different head designs and their respective dwell times for a given TV. Notice that the TSM Domed Std. and EU19 Std. are almost identical as their head profiles are very similar. Also notice that the dwell time is less sensitive at the higher turret rates.

or closely match dwell times. The flexibility you have on your flat dimension is dependent on the punch neck diameter. To ensure the robustness and integrity of the punch, the neck diameter should be larger than the head flat and with some safety margin.

Figure 5 is an example of comparing dwell time of a production press (NP500) and an R&D tablet press (BLP16-D). The NP500 is a high speed 45 station double sided production tablet press with extended head flat tooling and the BLP16-D is a 16 station D tooled development press. The NP-500 running at 80% of its maximum speed reaches 50RPM and 17m of dwell time. With standard TSM domed heads the BLP16-D must reach 80RPM turret speed to match 17ms. It can be challenging to maintain consistent tablet weights at such a high speed. When using the reduced head flat of 7.95mm on the BLP16-D the required turret speed is now only 40RPM which is a more manageable speed for tablet weight consistency and helps reduce powder wastes.

to ensure proper installation, alignment and tablet consistency. The punch head flat also specifies an acceptable tolerance of +/- 0.2mm for the Euro standard and +0.00 / -0.76mm for the TSM standard.

At common production rates the extreme difference is less than 1ms and as low as 0.2ms at higher production rates. Figure 8 depicts the small dwell time differences for the European tolerances. To accurately measure your punch head dimension a Horizontal Optical Comparator can be used. (Figure 9)

Figure 8 - European Punch Head Tolerances & Impact to Dwell Time

Figure 5 - Production Press vs. R&D "D" Tablet Presses

Another challenge that can be resolved with head flat designs is transferring product from a B tooled machine to a D tooled machine or vice versa.

Figure 6 is an example of matching dwell time from an NP-500 to a BLP16 utilizing B tooling. The standard B tooling matches dwell time of the NP-500 at similar turret speeds. When using the 50% of standard B head, the turret speed is reduced to 25RPM which again, at slower speeds helps reduce powder wastes.

Figure 9 - Horizontal Comparator

Figure 3 - B Type Tooling Dwell Time Comparison

Conclusion

Figure 6 - Production Press vs. R&D "B" Tablet Presses

Tooling designs and dwell time are one of many important parameters that play a role in tablet quality. Tooling head flats can be designed to achieve your desired dwell to assist in product transfer scalability processes or tablet robustness issues. Normalizing for turret size, speeds and tooling allows for a clearer understanding and comparison of different size tablet presses.

Figure 4 - D Type Tooling Dwell Time Comparison

Dwell time can be calculated by taking the punch head flat dimension divided by the turret tangential velocity. This simple calculation is helpful when transferring product to a different size press. And in the case of the large gap between TV as discussed previously with smaller R&D machines and larger scale machines, the tooling head flat can be designed by your tool manufacturer to match

Figure 7 - NP500, Standard D and B Head Flats

As previously discussed the European ISO standard and American TSM are the references for the tooling specifications. They provide the acceptable tolerances

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17

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HEAT TRANSFER

Just the medicine Clive Jones, Global Heat Transfer, discusses best practice for keeping heat transfer systems running efficiently in pharmaceutical manufacturing

W

e really have come a long way since Alexander Fleming famously discovered what he affectionately referred to as 'mould juice', but which we've come to know as penicillin.

The current global pharmaceuticals market is estimated to be worth $300 billion a year and is growing rapidly. Pharmaceutical manufacturing is not only big business, but also pivotal in keeping the population healthy.

Pharmaceutical processing requires the use of specialised heat transfer fluids designed to work at optimal operating temperature for prolonged periods of time. However, fluids must also be flexible: manufacturing pharmaceuticals requires broad operating temperatures because chemical reactions take place at high temperatures, whereas the crystallisation process takes place at lower temperatures.

Furthermore, thermal fluid used in pharmaceutical processing should be food grade in case of incidental contact with the product.

Food grade thermal fluids are highly refined mineral or synthetic oils designed specifically to be used in the processing of products for human consumption - food, beverages and pharmaceuticals. They are nontoxic, non-irritating and have no odour to ensure consumer safety in the event of a leak or spillage. As you can imagine, this is an essential health and safety measure in the pharmaceutical industry.

To keep heat transfer systems in tip top shape, regular monitoring needs to be undertaken to establish the condition of the fluid. The best way to get the most out of thermal fluid is to test thoroughly and regularly. Regular representative fluid analysis and top-ups ensure a healthy system, while reducing downtime and decreasing the amount of costly thermal fluid changes.

Problems in heat transfer systems occur when fluids are left for prolonged periods of time without correct supervision and preventative maintenance. Due to their chemical structure, thermal fluids degrade with age. Thermal cracking and oxidation cause molecules in the oil or fluid to break down, which produces solid carbon. If left, this carbon builds up and clogs pipes, making the entire system inefficient and more expensive to heat.

Food grade fluids carry a HT-1 certificate issued by governing bodies such as NSF International and the US Food and Drug Association (FDA).

Maintenance Heat transfer fluid maintenance and analysis are essential operations that need to be conducted on a regular basis. Unfortunately, some plant managers don’t realise there is a problem until it’s too late.

A heat transfer fluid’s thermodynamic attributes vary according to operating conditions. At high temperatures, a thermal fluid will experience chemical degradation. The freezing point of thermal fluid must be lower than ambient conditions. Alternatively, the temperature of the thermal fluid needs to be kept above ambient temperature to stop the heat transfer fluid from freezing. For example, some products freeze at 12 degrees Celsius, which is higher than you might expect.

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At this stage, maintenance activities are relatively easy to conduct, as the carbon is still soft and can be flushed by using thermal cleaning products.

because light ends have lower boiling and ignition temperatures.

Flash temperature represents the proportion of flammable decomposition products in a thermal oil.

However, if the fluid is left to degrade further, pharmaceutical manufacturing companies run the risk of solid carbon becoming baked onto the inside of the heat transfer system - causing dangerous hot spots. Carbon is an excellent insulator and if hot spots form near the heating element of a system, there is a severe fire risk.

The development of light ends needs to be monitored by routine laboratory testing of open and closed flash temperatures, because poorly maintained heat transfer systems pose a danger to staff and infrastructure.

Blocked pipes and hot spots eventually lead to breakdowns and costly repairs or replacements, not to mention the added expenses associated with flushing the system and refilling.

“

Pharmaceutical manufacturing is not only big business, but also pivotal in keeping the population healthy

In addition, disposal of old fluids has to be carried out by qualified professionals in accordance with environmental regulations. This can be extremely expensive if unplanned, hence the need to have a comprehensive maintenance contract in place.

Light ends are another aspect of heat transfer fluid degradation that pharmaceutical manufacturers need to be aware of. The formation of short-chained hydrocarbons, or light ends, are denoted by a decrease in flash temperature, which represents a potential fire risk. This is

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By monitoring heat transfer fluids on a regular basis, it is possible to detect problems and to take preventative actions that minimise degradation and oxidation, keeping pharmaceutical heat transfer applications efficient and cost-effective.

Ideally, any plant using heat transfer fluids should create a robust maintenance plan that contains regular system analysis, fluid top-up and careful flashpoint and fouling management.

Maintaining a healthy heat transfer system is key for keeping a pharmaceutical manufacturing line rolling. Plant managers have to contend with severe costs associated with downtime should thermal fluids be left to degrade to an extreme level. Well-maintained and healthy fluids facilitate a harmonious heat transfer system, which in turn keeps producing the medicines for a healthy world.

By monitoring heat transfer fluids on a regular basis, it is possible to detect problems and take preventative actions that minimise degradation and oxidation, keeping pharmaceutical heat transfer applications efficient and cost-effective

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EPM HIGHLIGHTS

Selection box As always innovation has been a key element in this year’s pharmaceutical sector. Lu Rahman handpicks her favourite stories showing the breakthroughs that have taken place over the last 12 months

Delivery service Drug delivery is a key aspect of pharmaceutical manufacture.

The list of breakthroughs in this field is immense. At the start of the year we heard that researchers from the Wyss Institute had created 3D structures using a minimally invasive technique to enrich and activate a host’s immune cells, attacking harmful one in vivo.

Owen Mumford discussed the growth in biologics and how this will be a key driver for the emergence of large volume injectors, with around 50% of the top 100 selling drugs expected to be biologics by 2016. Biologics are estimated to contribute 27% of the total drugs market by 2020, causing pharmaceutical companies to focus on developing drug delivery devices that allow self-administration of high viscosity, large volume drugs and/or biologics.

Craig Thompson, Owen Mumford commented: “There are multiple ways in which you can add value to the end user; alterations can be made to the injection devices to change the method of administration, making it more of a comfortable experience when injecting. Involving human factors experts during the design and development stages can help steer the design to make the process of injecting less intimidating for the user and can provide insights to improve adherence.”

Meanwhile 3M’s Hollow Microstructured Transdermal System (hMTS) was designed to be patient-friendly and easy to use while opening up opportunities for pharmaceutical companies. The device became available for clinical trials comes after 3M conducted a number of studies and design verification tests. Based on 3M microreplication technology, pharmaceutical and biotech companies were able to take advantage of this patient-friendly hollow microneedle device for difficultto-deliver biologics.

22

All sys 3M’s te Hollow ms go: Micro Transd stru e was d rmal System ctured esigne (hMTS d ) to friend ly and be patien teasy to use

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ods: , the go Deliver wen Mumford l O w to ing nies il Accord utical compa elivery d e c a drug pharm loping on of n deve inistrati m d focus o s -a lf e s lo r io fo b gic devices osity and/or c high vis

Other breakthroughs included the team of researchers at Washington University School of Medicine in St. Louis and the University of Illinois which developed a wireless device the width of a human hair that can be implanted in the brain and activated by remote control to deliver drugs.

Meanwhile Novo Nordisk announced a research collaboration with the Langer Laboratory at the Massachusetts Institute of Technology (MIT) for the next generation of drug delivery devices for the administration of peptides.

The aim of the research collaboration, conducted at both MIT in Boston, US and at Novo Nordisk’s research facilities in Måløv and Hillerød, Denmark, is to develop the next generation of drug delivery devices as an alternative to parenteral or injection-based delivery of peptides.

We also had US researchers at the Purdue University,, who had reportedly developed an electronic smart capsule that could deliver medication directly to the colon. This would be ideal for conditions such as Crohn’s disease and Irritable Bowel Syndrome which need medication to reach the large colon in order to work. As well as being more effective, this development could also prove to be more cost-effective.

Go West: vices’ West Pharmaceutical Ser rable wea nic ctro ele ose SmartD se, le-u sing a is injector system r that cto inje le rab wea nic electro body adheres to the patient’s

And the drug delivery innovation didn’t stop there.

According to Graham Reynolds, West Pharmaceutical Services, one of the most promising options in drug delivery is wearable drug delivery technology. West Pharmaceutical Services’ SmartDose electronic wearable injector system is a single-use, electronic wearable injector that adheres to the patient’s body, usually on the abdomen and is pre-programmed to deliver high volumes of viscous or complex drug products. The system incorporates a polymer-based drug container system with a drug delivery device that controls the delivery of large doses over time, making it easier for patients to self-administer medication outside of the clinical setting.

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Finding solutions Mike Straw, Achieve Breakthrough highlighted some of the challenges that the industry faced such as the influx of generics onto the market. In his opinion middle managers are reluctant to take risks are are adapting to change rather than capitalising on it. On top of this, pharmaceuticals are finding it hard to attract the new talent needed. Straw believed that senior management within pharma companies are missing a trick. The talent they need is there all around them – but they need to unlock it from what he calls the ‘frozen’ middle. The task for senior leadership is to find ways to enable the layers of middle management to work to its full potential and reach new heights of productivity.

Let’s Get Digital Digital health was a key feature of the year. It would have been difficult to miss plethora of digital health devices and wearables to hit the sector in the last twelve months. The EPM team launched a sister website dedicated to this important and growing market – www.digitalhealthage.com – as well as the #Let’s Get digital campaign to support the work being done in this field by medtech companies.

Let’s Get Digital was launched in August this year and part of its aims is to look at the way digital health is playing an increasingly major role in the pharma sector – moving ‘beyond the pill’ to revolutionise clinical trials. Making use of social media, surveys and other online forums, the project’s founders are busy compiling a list of the most important things for the pharma sector to consider in this market.

The project also hopes to work with government and policymakers to help improve digital switchovers and transition processes within hospitals.

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Novartis launched the ‘Trials of the Future’ initiative to digitally connect and aggregate medical device data during clinical trials. Teaming up with Qualcomm Life, the pharma group said it aims to “leverage health care technology to improve the experience of clinical trial participants and patients using Novartis products, and provide connectivity with future products marketed by Novartis”.

Graham Reynolds, West Pharmaceutical Services looked at wearable technology and the concept of taking it one step further by connecting injectable drug delivery systems with tools that can improve the user experience and drive adherence. The connected health movement has helped the pharmaceutical industry realise the potential of using consumer technology and electronic devices to further engage patients in their care and address the issue of non-compliance.

Rick Valencia, Qualcomm Life, explained how wearable technologies would be able to enhance the effectiveness of clinical trials. He described the way that wearables have grown in popularity in the last two years and are primarily known for smartwatches and fitness bands.

But this new technology could save the US health care industry hundreds of billions of dollars.

One emerging area in which connected wearable devices may have the biggest potential impact is in the clinical trial space, he said. Valencia cited Kevin Patrick, a professor of family and preventive medicine at the UC San Diego School of Medicine, who discussed in an Xconomy piece, how clinical trials are growing into a multi-billion dollar global market for wearable health trackers and other related technologies – pharmaceutical companies are the primary customers.

Currently, trials are costly, time-consuming, demanding and come with an extremely high rate of failure. Because data during these trials is typically collected in paper form, much of it is lost; the remainder that isn’t lost is susceptible to concerns with accuracy and analysis. The industry needs an easier, more efficient and more reliable method of collecting data from clinical trials. Connected wearable devices could be the solution.

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27

Meanwhile Klaus Wassermann an that without competent researchers medicines development would not way in which during the past deca research and development had u Core structures have shifted from big between industry, academia and sm scientific discoveries have been ma molecular basis of disease for stratifi the overall focus of the business is patients and society.

Within all these dynamics the pharm a lack of new product emerging fro departments. Licences for blockbus there are currently not enough new To provide patients and society wit equally sustain prosperity for the bus to be done, they commented.

According to Patheon’s Mike Me essential to the pharmaceutical indu focus on innovative solutions that i for vaccines, but also for new drug he said.

Natoli’s Dale Natoli believed that industry, where manufacturing is con the need to improve efficiency – to pr “We’ve seen it with inquiries ab facilities, and with the advent of electronic components on tablet pr to improve efficiency during tablet m tip punches and dies.”

nd Christa Janko, EMTRAIN, said s innovation processes in European be sustainable. They looked at the ade, the environment for medicines undergone unprecedented change. g pharma to extensive collaborations mall and medium enterprises. Novel ade, with greater emphasis on the fied and personalised medicine. And s shifting to needs and priorities of

Meanwhile Klaus Wassermann and Christa Janko, EMTRAIN, said that without competent researchers innovation processes in European medicines development would not be sustainable. They looked at the way in which during the past decade, the environment for medicines research and development had undergone unprecedented change.

Core structures have shifted from big pharma to extensive collaborations between industry, academia and small and medium enterprises. Novel scientific discoveries have been made, with greater emphasis on the molecular basis of disease for stratified and personalised medicine. And the overall focus of the business is shifting to needs and priorities of patients and society.

maceutical industry continues to see om their research and development ster medicines are phasing out and w product lines to fully compensate. ith novel innovative medicines and siness in the future, something needs

Within all these dynamics the pharmaceutical industry continues to see a lack of new products emerging from their research and development departments. Licences for blockbuster medicines are phasing out and there are currently not enough new product lines to fully compensate.

To provide patients and society with novel innovative medicines and equally sustain prosperity for the business in the future, something needs to be done, they commented.

encer, innovation would continue ustry. “There needs to be consistent improve speed to market, not only gs and drug-device combinations,”

According to Patheon’s Mike Mencer, innovation would continue essential to the pharmaceutical industry. “There needs to be consistent focus on innovative solutions that improve speed to market, not only for vaccines, but also for new drugs and drug-device combinations,” he said.

innovation in the pharmaceutical ncerned, is almost always driven by roduce more, faster. He commented: bout continuous manufacturing in functionality being added to the resses. However, a very simple way manufacturing is to consider multiple

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en ly. Wh rt supp o h me s a c r in ses is neve respon ed e ld r th o fi , e w 15 al ed n s in 20 inners will b aceutic ic m lso p r a a to h e the p y ’s w e key ies. H tr it th s in n u e tu d r b ip rsh e in ppo uld le will that th new o t leade ght wo nd sca f h r u a o g a o u d le e o th e c g e s ta ey ays, th ct, wa advan te at sp what th As alw Genpa rces to take innova aders , to e d r r e a r d p u e tu ep so ec we ask eter Sh e-allocate re s archit ee the r usines g in. P b in ly d ir id e o p ould s o th a fl r w e r lv to o to y sec a and t ev abilit pharm ies tha e, the n by an e id a g s r p la m O “In CR hip, or at co ented: rest. n the artners said th o p e m t th m O a o M te th c is right He mpe O/C said e time dustry. out-co ent CR ntific, th r in r s ie u e c p c S a th f ategic no nyx Perh ross new str se, O aluatio ars ac ctively. ir v u e e e e o y p h th s e r r w e o h r s it fe s rd Mo e past ation w e towa tnership Adam hibern on of th ere is a mov O par ti to M a in d C li / p o u th RO sy cons techs, de on of C efore they co ger bio A deca anisati b g r r e o y the lar said: “ ic la g p e ed te H d ig a . n b tr s inte 015 new a more me un uring 2 o d oach a s p eet ic d p m e to m yield d to big to e g il a . in s fa e r for the y b a tu ts s c c uld rs,” he manufa f their produ lity wo partne t and o el, qua n g e ty u li m s a p p u q elo , Ca al dev as the emann aceutic 2014, n Steg m e r in v a S s h r p Fo panie g in y com t-cuttin r man of cos fo s e uenc ” conseq d standards. he s li b ta s e WWW.EPMMAGAZINE.COM

Natoli’s Dale Natoli believed that innovation in the pharmaceutical industry, where manufacturing is concerned, is almost always driven by the need to improve efficiency – to produce more, faster. He commented: “We’ve seen it with inquiries about continuous manufacturing in facilities, and with the advent of functionality being added to the electronic components on tablet presses.

However, a very simple way to improve efficiency during tablet manufacturing is to consider multiple tip punches and dies.”

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SOCIAL INFLUENCERS

The in crowd In the last five years the pharma sector has finally become socially connected – but there’s more to be done to get the most out of the tools available We’ve hand-picked 10 of the most important social media accounts and groups to connect with, no matter whether you’re just starting out, or you’re a regular tweeter.

These brands and users have been collated based on a typical month’s social activity and influence. We looked at popular hashtags, users who engage with industry, Klout score, audience sizes and a host of other analytics data to find these accounts and groups.

1) FDA Drug Information The FDA has several Twitter accounts for its various department, but this one has evolved into a surprisingly light digest of the latest approvals, breakthroughs and thought leadership. They don’t engage with any other accounts (except for other FDA departments) so don’t expect a re-tweet – but then, it is the FDA.

3) Professionals in the Pharmaceutical and Biotech Industry This is one of the biggest groups on LinkedIn for our sector.

If you’re not a member, you should be. With over 200,000 members, anything you share will be seen by a lot of people.

Discussion is wide-ranging, from the potential impact of big data (yes, people are still talking about that), right through considerations for tablet coating – it’s a broad church.

2) Michelle Petersen Petersen is the founder of health-innovations.org, an online community dedicated to supporting innovation in health. Her feed is worth following for general interest, but she’s also a great person to interact with if you’re connected to a new launch or development product.

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4) Euro Pharma Mag This is EPM’s very own Twitter account – we couldn’t leave it out of the list. We love connecting with our readers, and share our daily news roundups – follow us and stay in touch.

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5) WHO Arguably, everyone working in the life science sector should connect with the World Health Organisation.

As the chief authority on guidance for stakeholders, this is really a must-follow account – as is evidenced by its 2.7 million followers. WHO on Twitter is concerned with highlighting global health issues and urging life science communities to act.

6) Ben Hirschler

7) Matthew Herper

Hirschler is a top scorer in terms of ‘Twitter Klout’. He’s one of the most respected voices, writing on healthcare and pharma for news agency Reuters. Join his 15,800 followers for a mix of witticisms, insight and other, broad interest news.

Another leading name from the world of journalism, Herper’s account is a must for political commentary around the pharma sector. Herper writes for Forbes and always has something to say about big pharma.

8) EFPIA “EFPIA is the voice of the research-based pharmaceutical industry in Europe”. That’s the description underneath the Twitter handle, and it sums the account up nicely.

The European Federation of Pharmaceutical Industries and Associations represents the research side of the sector, and its Twitter account engages with the global community on a regular basis.

9) Pharmaceutical Discussion Group This group is great for manufacturers. Many people use it to post technical queries and conundrums regarding their in-house process. Group members are all invited to collaborate and share intelligence. Join this group to learn a lot and stay in touch with your fellow experts.

10) NICE Another one of those accounts that everyone (at least those working in the UK market) should follow. Stay upto-date with the latest guidance and updates from NICE.

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TABLETS AND TOOLING

Pressing on

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taly’s IMA, a global brand in processing markets, opened its doors at the end of October for an exclusive look at its base operation in Bologna – as well as its latest offering to a competitive market

For this rare glimpse into the company’s many activities, IMA invited over 300 customers from around the world to a special launch event held at the Palazzo di Varignana near its headquarters in Bologna. Surrounded by classic architecture and landscapes dating back to Ancient Rome, the Palazzo provided an impressive and contrasting backdrop for this contemporary launch.

Big reveal Unveiling Prexima 300 – the culmination of two years of development work – IMA put on a grand display. The message was clear: this machine has been designed to capture market share.

On first glance there’s no questioning the Italian design credentials of the machine (the aesthetics draw inspiration from crystal structures); but IMA says it has backed up style with plenty of substance.

Prexima is equipped with the new Xima human-machine interface, recently awarded the 2015 A' Design Award for its strategic role in improving operator efficiency.

Drawing on IMA’s previous Comprima concept, Prexima offers complete separation between the processing and mechanical areas with the use of carefully designed seals and protectors.

Accessibility was a key consideration in the development of Prexima, according to IMA, and as such operators can reach the whole processing area via the main doors.

The compression support is based on three columns linked together by two strong cast iron structures.

The compression rollers are incorporated within the two cast iron structures and supported on both sides.

IMA believes that the secret to high quality tabletting is a sturdy machine structure. Andrea Semprini Cesari, IMA Active vice president, welcomed IMA cus The Prexima offers precompression and main compression forces up to 100 kN. The removal of the turret is made possible by a rotating arm, which is housed in the upper compartment.

The Xima software guides the operator through each step of turret removal.

Crowds gathered at the Palazzo di Varignana in anticipation of the grand unveiling

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Walking the floor Customers were given a complete tour of the company’s Active (solid dose solutions) Safe (packaging) and Life (aseptic processing and freeze drying) divisions in Bologna, with engineers on hand to discuss projects and processes. From solid dose right through to coating and washing, the company displayed its complete offering for the pharma sector – with a quick stop to look in on the teabag-making operation, one of IMA’s earliest activities.

An impressive visual display accompanied the big launch

The event was attended by Alberto Vacchi, IMA’s chairman and CEO, who later said: "We were delighted to be hosting numerous customers from all over the world in the elegant Palazzo di Varignana and at the Group's plants, emphasising the importance of our local territory. It was an opportunity to enhance the innovative capacity of our Group. IMA has grown thanks to acquisitions, but it has always remained deeply rooted to its territory. IMA looks out to the world with its brain, but its heart remains in Bologna - and this is a key value”.

The company invests approximately 5% of its consolidated revenues in R&D. The IMA Group owns 1,300 patents and applications for patent in the world. It also employs more than 500 designers involved in product innovation.

Andrea Semprini Cesari, IMA Active vice president, said: “We have invested a lot in this new range of tablet press machines, by creating a department inside the IMA Active division specifically dedicated to this sector of solid dose processing. The so-called “tablet academy” has been created to consolidate the important investments made in the tableting sector and to better serve the needs of our customers all over the world. We are happy to announce that ten Prexima have already been sold in different countries. Everything that we have gained over years of experience and expertise in this field has been carefully

Prexima 300 on display

channelled into this new range of tablet presses, confirming our ability to anticipate all future challenges and our firm commitment to developing new solutions that incorporate the most advanced technology.”

When asked about the future, Cesari added: “Our aim for the next three years is to increase our market share in tablet press machines, while consolidating our wide range of products aimed at driving our customers’ productivity to a higher level of efficiency.”

stomers to the event

“

IMA looks out to the world with its brain, but its heart remains in Bologna”

”

Operators can reach the whole processing area

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TABLETS AND TOOLING

Born in the USA: GEA ConsiGma 25 installation at Pfizer labs in Connecticut, USA

Team talk GSK has become the latest addition to a consortium developing a solution for on-demand tablet production

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partnership of pharmaceutical manufacturers and suppliers, including Pfizer, GEA and G-CON Manufacturing, welcomes GSK to a consortium dedicated to the development of a continuous technology solution for on-demand tablet production.

GEA has announced a next-generation collaboration with GlaxoSmithKline (GSK) to further develop self-contained, pod-based mini-factories to develop and manufacture pharmaceutical oral solid dosage (OSD) forms. This partnership expands on GEA’s existing alliance with Pfizer and G-CON Manufacturing to design a portable, continuous, miniature and modular (PCMM) prototype unit, which is currently being implemented at Pfizer’s labs in Groton, Connecticut, USA. Conceived in conjunction with Pfizer and G-CON, the three companies formed a consortium to design and build an autonomous manufacturing environment for continuous OSD production using GEA’s ConsiGma 25 equipment and G-CON’s modular pod system.

This manufacturing system aims to accelerate the speed at which tablets are produced. By miniaturising the equipment, the continuous process can be enclosed in a portable, modular facility, which can be shipped by truck to any location in the world and quickly assembled. Once up and running, the system will deliver the capability to transform powders into uncoated tablets in minutes, which can take days or weeks with current technology.

H Knight, vice president, APC Pharma, commented: “GEA is delighted to welcome GSK to the consortium. The involvement of another significant player from the global pharmaceutical manufacturing environment increasingly demonstrates the industry’s commitment to continuous processing and the acknowledgement that PCMM truly represents the future of on-demand drug production. We look forward to working with GSK and pushing the boundaries of our autonomous manufacturing environment for continuous OSD production even further.”

Highlights of PCMM’s potential for smaller, more flexible, continuous processing technologies include a 60–70% smaller footprint than a conventional production facility, the ability to use the same equipment for development, clinical trials and commercial manufacturing, and significantly reduced timelines: a PCMM facility takes about one year to set up and start running compared with two to three years for standard processes.

With PCMM, the consortium of partners is leading the way toward smaller, more flexible, continuous processing technologies with the potential to transform the future of pharmaceutical development and manufacturing, and deliver customized quantities of drugs to patients in need in a quick and efficient way.

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TABLET TOOLING

Success story: Dwell time plays a significant part in determining if a tablet can be produced successfully

Dwell on it Rob Blanchard, I Holland, talks through the effect of dwell time on tablet production

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well time can have a huge impact on tablet manufacture, with many formulations sensitive to how this key element of compression is performed. The importance of this process is even more apparent in today’s need for tablet production to be fast, efficient and fault free. But the question is how do you ensure the dwell time in your manufacturing process is optimised to form quality tablets at maximum productivity?

What is dwell time?

In order to produce tablets from granule/powder it is necessary to use compression force; however, it is vitally important that the correct amount of force is used for just the right amount of time. Too much, or too little of either, can result in tableting issues. Excessive force or over pressuring of the punch can cause catastrophic failure of the tool and damage to the press. Not only can this be very expensive but it carries significant health and safety risks to press operators and the patient, therefore it is vital to understand how to optimise dwell time correctly.

Dwell time in the context of tablet compression is the amount of time each individual punch head flat is in contact with the compression roller(s) of a rotary tablet press; and that the compression force applied when forming the tablet is above 90% of its peak value. Key factors affecting dwell time are punch head flat size and shape, use of precompression and RPM used during production.

Dwell time plays a significant part in determining if a tablet can be produced successfully, especially those incorporating formulations that are challenging to compress. Not all formulations are dwell sensitive as some will compress effectively at any speed, however the majority are very susceptible to even the slightest change. Sometimes the punch head flat diameter is a major factor that is overlooked or misunderstood, and it is this area that tooling manufacturers like I Holland are investigating and producing innovative technologies in order to offer productivity enhancing solutions.

Formulation characteristics The characteristics of ingredients in a formulation can severely affect tablet manufacture leading to common tabletting problems which we will discuss below.

Plastic or elastic properties Many issues can be traced to the characteristics of certain ingredients in a formulation which display differing plastic or elastic properties.

‘Punch displacement velocity (ie. strain rate) and dwell time are two factors that can significantly affect the compression behaviour of powders. As a general rule of thumb, slower compression and decompression speeds and longer dwell times will improve the mechanical properties of a tablet. When particles are subjected to a compression force for a longer period of time, further plastic yielding can occur and the degree of elastic recovery is reduced.’

Pharmaceutical Dosage Forms - Tablets, Third Edition - Edited by Larry L. Augsburger, Stephen W. Hoag Essentially, where the behaviour of a particle under compression can either stay deformed or ‘spring back’ to its original shape, the dwell time applied can be critical. In cases of formulations with more time dependant consolidation behaviour, a long dwell time is important to create strong bonds between the particles. When particles are subjected to a compression force for a longer period of time, further plastic behaviour is demonstrated, less ‘spring back’ happens and this results in a more stable compacted tablet.

Sticking Tablet sticking is perhaps the most common problem in tablet manufacture. This build-up of granule on the punch tip face causes tablet press downtime and reduced tablet output. It has a negative effect on tablet appearance and often results in the removal of tablet tooling from production for regular cleaning and maintenance.

The first resort for tablet manufacturers is often to apply more compression force or to slow the press down to solve this problem.

Either or both of these can often solve sticking, but carry with them trade-offs in productivity and tooling/press lifetime. What if you could extend dwell time without slowing the press down?

The eXtended Dwell Flat from I Holland tooling does exactly that.

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Conclusion The pharmaceutical industry’s need for technology and push for operational efficiency that allows them to produce quality tablets quickly and efficiently without major cost implications involved with the purchase of new equipment or through solutions that can reduce productivity are a major influence upon manufacturing decisions. This trend in cost reduction without consequence to tablet quality is a key factor for tablet tooling development.

Air waves: Trapped air pockets in the forming tablet can cause severe problems during manufacture

Capping Trapped air pockets in the forming tablet can cause severe problems during manufacture. If the air is insufficiently squeezed out and/or density variations occur in the tablet volume, the tablet tensile strength is negatively affected and the risk of tablet capping or de-lamination increases. There are several solutions available such as employing tapered dies or using a press with a pre-compression stage, but one of the most effective solutions employed by tablet manufacturers is the method of slowing the press down and extending dwell time in order to allow air to escape. Once again, today’s requirement for faster and more efficient tablet production makes this an undesirable option and so increasing dwell time through tooling is highly desirable.

The crucial importance of extended dwell time can be illustrated by the frequent application of a number of techniques to increase the time that the punch is in contact with the compression roller, for example: • Reduction of the tablet press speed in case of sticking, capping or insufficient hardness • Installation of larger compression rollers to increase the total compression time • Use of up-sized punches with a larger head to increase the size of the dwell flat.

These solutions are not always viable due to strict time constraints and budgeting so other solutions are sought. Making small changes to the size of the compression roll does not extend dwell time, so another method is required. The most feasible answer is through the use of specific tooling that can be used without slowing the press so production runs sufficiently.

Specifically designed tooling for increased dwell can do the following; • Improve productivity • Run on standard cams

Friability Friability, or the tendency to crack, chip or break during compression is in part due to the formulation. If the formulation is not cohesive and does not bind together sufficiently then friability will occur. There are several ways to compensate for friability including looking at dwell time, weight control, expansion and of course tooling condition. All of these should be examined to produce a quality tablet. In selected trials I Holland has found that eXtended Dwell Flat tooling has completely eradicated friability issues.

Moisture All formulations have very different characteristics, and compressing a tablet containing a variety of differing powders can be difficult. Each powder contains a different moisture content, which is often needed to help the binding, or compaction effect but too much water within the tablet can be one of the causes of a rise in adhesive forces and therefore sticking. Moisture can enter into the process either in wet granulation or due to excess humidity in the compression chamber, formulation preparation and storage areas if they are not temperature and humidity controlled.

• Solve dwell time problems without upsizing punches • Allows faster press operation • Enhanced tablet compaction • A better quality tablet The requirement for quality tablets to be produced quickly and cheaply will always lead to innovation and the introduction of newly developed elliptical tooling like I Holland’s patented XDF is helping to make the tablet production process one which is faster and more efficient with tablet manufacturers able to achieve higher press speeds with challenging products and formulations.

The purchase of a modern tablet press with dwell enhancing features will probably improve productivity but obviously involves significant capital expenditure. It should also be noted that the use of elliptical eXtended Dwell Flat tools, (which are currently the only way to achieve more dwell time without slowing down your existing press or upsizing punches both of which are inefficient,) will add cumulative associated benefits in dwell time to a modern press.

Michael D. Tousey explained the effect of formulation moisture in his paper ‘The Granulation Process 101’.

Put a cap on it: In tablet manufacture if air is insufficiently squeezed out in the tablet volume, the tablet tensile strength is negatively affected and the risk of tablet capping increases

‘Think about the example of making a snowball: If the snowflakes are rather large and wet, then they compact very easily into a snowball.

However, if the snowflakes are very light, fluffy, and dry, then compaction is more difficult. Every kid knows that to make a snowball with light, fluffy, and dry snowflakes, they must hold the snowball together for a longer period of time (dwell time) and be careful not to over compress. If the snowball is over compressed, then the flakes no longer lock together but instead laminate (flatten out) and fall apart. The same is true of powders used in pharmaceutical tablets. If the formula has some of both characteristics—large particles with high moisture content and small, dry particles—then the tablet may or may not compress well and probably will have difficulty holding together.’

In these instances, the importance of using the correct dwell time can have an impact on the end product. The dwell time needs to be optimised to allow for the formulations moisture content.

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RESEARCH

Group therapy The BIOCAPAN Project has been funded for four years by the European Commission. It was started to develop an innovative GMP-grade cell-therapy product to treat diabetes without insulin injections, says Florence Rivera

Point taken: According to Florence Rivera, the BIOCAN project began to develop an innovative GMPgrade cell-therapy product to treat diabetes without insulin injections

In 2011, the World Health Organisation estimated that 356 million people suffered from diabetes, and the number is expected to reach 438 million before 2030. In 2014, 9% of the adult population (18 or older) were diabetics. The key therapeutic issue in diabetes mellitus types 1 and 2 is glycaemic control. For these patients, the disease is ever-present in day-to-day life requiring glycaemic measurements, calculations of carbohydrate intake, and insulin injections. Reducing continuous selfmonitoring and insulin injections would tremendously improve the quality of diabetics’ lives. Indeed, incorrect levels of insulin often lead to serious co-morbidities such as hypoglycaemia, stroke, heart disease, or diabetic foot (amputation). The World Health Organisation estimated that diabetes directly caused 1.5 million deaths in 2012.

The best option for such therapy is the transplantation of allogeneic islet cells, but the current state of the art limits the applicability of this approach. Implanting unmodified islet grafts requires lifelong administration of immunosuppressants, which is frequently associated with adverse effects such as higher blood pressure, higher susceptibility

to infections, and higher risks of cancer. One alternative to such immunosuppressant treatments is allogeneic islet cells encapsulation to make the donor cells furtive with regard to the host immune system.

In response to these facts, the BIOCAPAN Project, which stands for BIOactive implantable Capsule for PANcreatic islet immunosuppressionfree therapy, has been funded for four years by the European Commission under the Horizon 2020 program (Grant number: 646272). The project has started to develop an innovative GMP-grade cell-therapy product to treat diabetes without insulin injections.

More precisely, this project is based on the implantation of smartly microencapsulated allogeneic islet cells, which will allow an effective long-lasting blood glucose normalisation and stabilisation, without the need for immunosuppressants. This treatment would be appropriate for all type 1 and about one-in-six type 2 diabetes mellitus patients – about 80 million people worldwide.

To reach this goal, the BIOCAPAN Project has three objectives: 1) Designing a complex GMP-grade bioactive microcapsule that will enhance biocompatibility, functionality and survival of transplanted allogeneic islets, in order to provide a two-year injection-free supply of insulin, without the need for immunosuppressants.

2) Establishing a method to encapsulate freshly harvested islets quickly, using a GMP-grade platform, to provide standardized and reproducible bioactive microcapsules.

Team spirit: The initial meeting in Brussels

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3) Establishing a full preclinical validation, a complete Investigational Medicinal Product Dossier (IMPD) in accordance with the provisions of the Advanced Therapy Medicinal Products (ATMP) Regulation, and a whole clinical protocol for the submission of the Clinical Trial Authorisation (CTA) dossier to the relevant regulatory agency in order to start clinical trials within one year of completing the project.

To complete this research successfully, the BIOCAPAN Project, coordinated by CEA-Leti (FR) brings together a multi-disciplinary international team of experts comprised of Charité - Universitätsmedizin Berlin (DE), Etablissement Français du Sang (FR), European Research Services GmbH (DE), NanoImmunotech (ES), NovaMatrix (NO), Université Catholique de Louvain (BE), Université Joseph Fourier (FR), Wake Forest University Health Sciences (US).

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DISTRIBUTION

Although it is possible to organise MAPs in-house, navigating the varying regulations in the most effective manner can be challenging, says Donnell

MAP it out Robert Donnell, Durbin, specialist distributor of pharmaceuticals, medical and relief supplies, examines the increasing prevalence of Managed Access Programs, and the challenges faced in getting the most appropriate drug to the patient in time

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aking a product through clinical trials is a costly process. A report from the Tufts Centre estimated the cost of developing a new prescription medicine and gaining market approval at $2,558 million – a process that could take more than a decade to complete1. Recently there has been an increase in clinical trials involving orphan drugs, designed to meet the need of a rare medical disease. Studies suggest there are 6,000 – 8,000 orphan diseases, of which only 500 have treatment options2.

Orphan drug clinical trials are usually smaller, shorter and successful treatments receive regulatory approval much quicker than medicines for more common diseases. As a result, orphan drug development and regulatory approval is usually a smaller burden on financial and time resources, and has picked up considerable pace.

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Access point: According to Robert Donnell a MAP can offer a patient access to a drug at various stages of the product lifecycle

Product lifecycle Patients with orphan diseases, and their physicians, tend to be highly active in finding potential treatments, and often investigational drugs are a viable option. Managed Access Programmes (MAPs) are a blanket term to cover the supply and distribution of these preregistration and unavailable drugs, and take into account the patient’s needs, local regulations and importation protocols, which vary from country to country.

A MAP can offer a patient access to a drug at various stages of the product lifecycle, including: • Drugs in clinical development, which have typically completed phase 3 clinical trials, but have not been commercially launched yet • Drugs that will never be approved, because they treat such a small subset of patients and are therefore not financially viable to develop, but do treat a condition with no other treatment options • Drugs that have had authorisation in one country but not another. This is common when a company works to achieve approval where the majority of patients reside, but excludes patients living in other areas • Drugs that have been discontinued, but still retain medical value in a small subset of the population

Finding the right patient Unlike common diseases, orphan diseases have a much smaller population size, making it challenging to find the number of patients required for a clinical trial. Often specialist physicians are able to identify patient populations quickly and efficiently. However this can dictate the location of the clinical trial, and can result in a need to distribute the orphan drug internationally. This usually warrants the support of a specialist supply and distribution partner, to fulfil the requirement.

If a specialist physician is not available, vast databases of heath insurance and public health databases must be investigated to identify patient hotspots. While there have been many advances in the management of big data, the reality is orphan diseases patient populations are sparse, many are undiagnosed, and identification can be extremely difficult.

Even once identified, there are, and rightly so, stringent criteria in place to ensure the patient is appropriate for the clinical trial. This can be frustrating for patients, particularly when no other treatment option is available.

When to give access There is an important ethical debate about the supply of unregistered medications to patients whose needs are not met by registered pharmaceuticals. This dilemma is particularly prevalent in considering the situations of the terminally ill or children affected by rare orphan diseases. Emotions can run high and patients, or their physicians can become impatient with regulations, designed to protect their safety. In general, phase 2 data must be present to prove the safety of a drug, before it can be made available through a MAP. The normal practice is not to supply any medication before full market authorisation and commercialisation. However this should be carefully considered. In the ‘digital age’ patients are connected on an unprecedented level. Forums, patient networks, dedicated disease websites etc. all track and monitor the progress of orphan drugs. As a result, withholding access could be harmful to a company’s reputation and not save lives.

There are many positives to MAPs, a service which can allow pharmaceutical companies to fulfil their mission to help patients, as well as gaining greater market understanding and real patient experience.

Although it is possible to organise MAPs in-house, navigating the varying regulations in the most effective manner can be challenging, and a distraction from core activities. Many companies look to seek the support of a specialist, such as Durbin, to help ensure that the orphan drug reaches commercialisation, whilst most importantly, using MAPs to put the needs of the patient first.

References 1. Tufts Center for the Study of Drug Development. Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion. [Internet]. Tufts University. 2014 [cited 2015 Oct 16].

2. Ehinger C. Can rare diseases be a viable option for the pharma industry? [Internet]. PMLIVE. 2015 [cited 2015 Sep 18].

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CONTAINMENT

Designs on you Chloé Guilmet and Jean-Luc Schneider, Getinge–La Calhène, describe airflow simulation in virtual reality to optimise isolator design

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he ‘Virtual Isolator’ was created as a result of a close partnership between Getinge-La Calhène and CEA LIST, part of the French Commissariat à l’Energie Atomique et aux Energies Alternatives.

This virtual reality tool is mainly used to study issues related to the ergonomics of the isolator and accessibility inside its working area. It is employed in project design before any physical construction (mockup or prototype) is produced [1]. Getinge-La Calhène wanted to go a step further by enhancing the Virtual Isolator with a new functionality - to perform numerical simulation of a bio-decontamination cycle with H2O2 inside a virtual isolator.

The bio-decontamination process is a complex, critical technique which creates and maintains the necessary aseptic conditions inside an isolator.

The process is commonly based on the use of sporicidal gassing agent, such as H2O2 vapour which is injected inside the isolator during the bio-decontamination cycles.

A typical H2O2 bio-decontamination cycle consists of a series of phases: 1. Conditioning: injection of hot air to achieve the required conditions of humidity for bio-decontamination of the isolator chamber, 2. Injection: initial injection of H2O2 to reach the appropriate concentration in the chamber for the decontamination 3. Stabilisation: injection of small amounts of H2O2 at intervals to maintain the appropriate concentration 4. Aeration: a fresh airflow is injected in the chamber in order to reduce the concentration of H2O2 to the desired residual level.

A typical cycle may last for some tens of minutes during which time the isolator is not in production. The periodicity of these cycles varies from once a month to several times a day, depending on the applications for which the isolator is used.

The efficacy of the cycles and their optimization depend on a combination of interactions between several factors. One particularly critical factor is the airflow patterns. They are in fact caused by the ventilation system, the geometry of the isolator, the locations of pieces of equipment etc., which are defined during the Design Phase by designers, engineers and isolation experts, mainly according to their experience. The design of the isolator may be validated for flow behavior by smoke tests. As for the bio-decontamination process, the cycles are validated with tests using biological indicators [2]. Both of these tests are realised when the isolator is built and once its design is frozen. The tests cost time and money and are limited in terms of tested configurations / hypotheses.

The work conducted together with the Virtual Reality Team at CEA-LIST resulted in the creation of a simulator combining numerical modelling of the isolator and computational fluid dynamics.

This simulator is based on two modules/units: the first one is able to define the mesh of the enclosed volume of the isolator by subdividing the numerical mock-up of the isolator into hundreds of thousands of cells. The role of the second module is to define input parameters of the bio-decontamination cycle (ambient temperature, duration of the 4 phases, injected and extracted airflow rates, etc.).

The simulator is configured to determine, from the numerical mock-up of the isolator and from input parameters, the temperature changes in each cell of the mesh during a bio-decontamination cycle. As the air injected during the bio-decontamination cycle is warmer than the initial air inside the isolator, the temperature changes indirectly indicate the airflow inside the isolator during the cycle. Then it is possible to look for any potential “dead areas” where air circulates less easily; these zones are likely to have an impact on the effectiveness of the bio-decontamination cycle.

The simulator can also be configured to indicate the evolution of H2O2 concentration in every cell of the mesh during the bio-decontamination cycle in order to assess its effectiveness. And by defining the temperature and the H2O2 concentration in every cell, the simulator is also able to check that there is no condensation of H2O2 which may affect the efficacy of the cycle and extend the duration of the Aeration phase.

This leading-edge airflow simulation tool gives a better understanding and visualization of flow behavior during bio-decontamination cycles inside an isolator as early as the Design Phase. With this new feature, Getinge-La Calhène’s Virtual Isolator contributes to identifying and testing opportunities for improving and optimizing products very early in the Design Process in a timely and economical manner.

Hence Getinge-La Calhène looked for a way to investigate the issues of airflow for bio-decontamination earlier in the project, during the Design Phase.

Principle of the simulator: input & output data.

[1] « The Virtual Isolator : imagination, interaction and immersion improve product development », W. Daniel , T. Girard, C. Guilmet, J-L. Schneider, Pharmaceutical Technology Europe, May 2015 [2] « Maîtrise des paramètres et des aléas d’une biodécontamination au H2O2 », C. Mounier, Salles Propres N°69, 2010

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SERIALISATION

Antares Vision explains how Brazil, the first large country to adopt Track & Trace Regulation, is tackling the challenge of pharmaceutical drug serialisation The pharmaceutical industries working in Brazil must comply with the upcoming Track & Trace Regulation. The objective is to increase patient safety thanks to reliable traceability and anti-counterfeiting. With a local branch, Antares Vision is close to its customers who are in the process of implementing serialisation and aggregation systems. Here we present three cases, with very diverse needs, where it has been applied.

Brazil will be the first large country to adopt the Track & Trace Regulation for the pharmaceutical sector. Following the regulation's coming into effect in Turkey in 2011, the South American country represents the first true testing bench, on a large scale, of the implementation of tracking systems intended to radically change the drug supply chain. The objective is to constantly increase patient safety, thanks to the complete traceability of each individual medicine packet and protection against tampering and counterfeiting, throughout every phase of packaging and distribution.

The pharmaceutical industries that work in Brazil have in a short time to comply with the new regulation and will provide the international market with a very interesting test, considering the great volumes involved, in view of the coming into effect of the second milestone of the US Drug Supply Chain Security Act (DSCSA).

Antares Vision, who for number of installations and technological level, is the international standard setter for drug tracking systems, has been active in Brazil for some years through its local branch, built around a designated group coordinated by Rafael Latorre, an expert manager in primary and secondary drug packaging safety.

The branch has already acquired numerous projects for the implementation of serialisation and aggregation systems. Below are three cases, which exemplify different challenges that can arise in this phase of great evolution: a large multinational, an important producer concentrated on the domestic market and an industry that may have smaller dimensions but a greater percentage of foreign sales.

Local regulation to worldwide management The first case looks at a large multinational with the largest of its 40 facilities, spread out worldwide, right in Brazil.

With the pilot system already running, Antares Vision has started to install its systems on the first half of the more than 40 packaging lines involved, with the aim of completing this first phase by the end of 2015.

The entire project will be completed by the end of 2016.

One of the main challenges of this installation concerns the management of all of the events relative to Track & Trace. With a two-fold requirement: in fact, the multinational needs to manage facility data locally, sending it to Brazilian authorities, and at the same time, the data needs to go into the global repository, which collects the information coming from all the systems around the world, and keeps it for at least 10 years.

"This large group chose Antares Vision as its global supplier for serialisation in all its facilities", said Rafael Latorre, country manager for Antares Vision do Brasil.

“Thanks to the experience that we have gained with the implementation of over 600 serialisation lines and the use of plug-in modules, we are able to offer quick installation and reduce line downtime to a minimum", continued Latorre. Adopting such modules is beneficial and helps minimise the impact on the customer’s production lines.”

"We are used to working alongside factory managers, jointly planning intervention times in synch with the production requirements", added Latorre. "Accordingly, as with other projects, we have put together a multi-disciplinary team that brings together ours and the customer's technical managers, for periodic updates on progress.”

The number of lines to be deployed in the two plants is impressive and by 2016 over 35 lines will have to be equipped. In view of this size, the project has been split into two phase – by the end of 2015, the target is to have a total of 15 lines operational. By September 2016, the

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remaining lines will be completed. All the lines include full aggregation.

From the automation point of view we have here the complete range of situations: most of them are fully automated. The includes machines from leading manufacturers such IMA, with their renewed CP28 and CP18, Pester, Marchesini with a fully robotised line, and the Brazilian manufacturer, Tecnor.

“100% reading success is fundamental in maintaining a high OEE. Putting a camera inside a case packer and reading sometimes over 100 codes for each layer can be very challenging”, said Simone Orsi, technical manager at Antares Vision do Brazil.

“A case can contain 400 cartons in four layers, and the packaging can have different layouts and colours according to the drug we pack. T light reflectivity and contrast can, therefore, interfere with the reading performance of the camera.”

Missing even one of the 400 readings, will reject the whole case and rework all the cartons, with a dramatic loss of OEE. For this reason, the mechanical position of the camera and lighting must be perfectly designed to ensure all the codes are perfectly lit and focused.

When the geometry of the case packer doesn’t allow for a full image of the layer to be taken, the Antares Vision engineers have designed an intermediate solution, consisting of reading all the cartons as they enter the case packer (last code reader).

Support for a national big player The second application example, for which a pilot system has been built, also concerns a large facility, with considerable production volumes and a variety of lines. This case, however, is dedicated to domestic consumption. There is an evident difference in approach to tracking.

In the previous example, the pharmaceutical multinational was already familiar with the new production concept in countries where it is in force, such as Turkey. The Brazilian experience was triggered based on those competencies. In this case, however, the local producer faced the Track & Trace issue almost from scratch.

"Basically three factors led them to choose Antares Vision: for the availability of modules with integrated functions, for the experience that Antares Vision was able to concretely demonstrate, by organising a visit to a system installed in Turkey, which is becoming an international standard-setting model for pharmaceutical serialisation, but most of all for the incredible pre-sales service provided by our branch", explained Adriano Fusco, global marketing director for Antares Vision.

Also, this plant has some very interesting aspects: some lines for example, don’t have enough space to fit the new serialisation modules, so the customer decided to introduce the P&C-CW. This solution, which is only 1.7 m long allows the old checkweigher to be removed and integrates both functions virtually in the same space.

The checkweigher control is completely integrated in the T&T software, so the unit configuration is done automatically and remotely, minimising set-up times for a new lot.

Even in this case, due to the size of the project, the deployment was split into two phases, with 23 lines to be deployed by the end of 2015, with three pilot lines already fully operational.

Machine manufacturers present here include, in addition to IMA and Marchesini, German manufacturers such as Uhlmann, Skinetta, Romaco, besides the Brazilian Tecnor. From the automation point of view, the lines can be viewed as: fully automatic, semi-automatic, completely manual.

The greater the human intervention, the higher the risk of mistakes in the aggregation process. To avoid these potential problems, the Antares Vision solution has a number of redundant controls that alert the operator in the case of error and prohibits certain operations that can jeopardise the integrity of the process.

As serialisation involves completely new operating procedures and an additional number of devices on the lines, operator training is a crucial aspect of this project.

Flexible systems for a small industry Another different, third case of concerns a smaller producer, mainly involved in exports, as much as 80% of production. "The first production line was installed over a year ago to comply with Korean regulations, while we are now complying with Chinese regulations, and then completing the entire system for Brazilian serialised production.

"The great variety of drugs that are produced and the markets that are served require smaller batches, therefore manual lines are still the most efficient", explained Latorre.

"The know-how and the flexibility of the software that we offer make it possible to comply completely and effectively with the various regulations in the different countries they export to. When new regulations are introduced, re-validating the entire software is not necessary. Only the new modules, know as domains, need to be tested and validated. The individual packets, once they are serialised, are placed inside the box by hand. As the operation is completely manual, the machines must not have any downtime, to avoid slowing productivity. The hardware defined for this task is the new ‘Packing station top view’.

This is a second generation machine, developed and improved after the Turkish experience.

The decoding system is even more powerful and can decode hundreds of datamatrix codes in just fractions of a second, immediately providing the operator with confirmation of the reading, so that he/she can then proceed to fill the next layer without losing time. When the box is full, the system automatically prints out the label to apply to it.

"This is one of our best sellers", explained Adriano Fusco. "This station has just been announced and we have already installed almost 100 of them”.

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CHEMICAL REACTION It’s important to keep on top of the latest services, companies and innovations.

EPM’s Chemical Reaction highlights a technology, service or business we think would be worth keeping an eye on...

Star performers In the last issue of the year we look back at some of our favourite Chemical Reactions and what made them the best of the best

D

rug delivery is always a hot topic in the pharmaceutical sector. Cecilia Mendy, Owen Mumford, revealed the current and future initiatives at this drug delivery device business.

The company was recently awarded the Red Dot award for Product Design for its new diabetes pen needle with built-in remover, Unifine Pentips Plus.

Unifine Pentips Plus is said to be the world’s first pen needle with built-in remover, developed for end-users with diabetes who are self-injecting insulin or glucagonlike peptide-1 analogues. Unifine Pentips Plus is designed to encourage adherence to a good injection routine and is proven to increase the rate of pen needle change among end-users.

According to Mendy, a study observing the impact of Unifine Pentips Plus on pen needle changing behaviour amongst people with diabetes, showed that when using Unifine Pentips Plus, the rate of pen needle change increased by 61% compared with their current pen needle.

Mendy believes this product has the potential to bring about change. In addition to end-users needs and adherence issues, the company says it understands the complexities of creating medical devices for partners with complex requirements and international markets.

What’s the alternative?

There was a lot of interest when Alastair Smith, Avacta Life Sciences, outlined his company’s work developing engineered alternatives to antibodies. He explained how the company is focussing on creating tools to support research into ubiquitin and the ubiquitin proteasome system. The covalent addition of ubiquitin to a target protein is now known to modulate most key processes in a cell. This is a relatively new area of biology and the tools, specifically antibodies, are not yet available to allow researchers to do the fundamental biology research that is required. There are several classes of proteins involved in this system: Ligases that add the ubiquitin to a target protein, DUBs which remove ubiquitin chains and then the ubiquitin chains themselves.

Avacta provides Affimer binders that recognise specific di-ubiquitin chains and offers Affimers that it says are unique as no equivalent antibody exists. Customer feedback has been strong with K33 and K6 ubiquitin

50

binders, for example, having proved very popular.

Smith is excited about the potential applications of Affimers as therapeutics.

Having already signed an exciting licensing partnership with Moderna Therapeutics to provide exclusive access to Affimers against certain targets, the potential of Affimers is now being recognised by the industry, he says.

Q & A Cecilia Mendy

One example of where Affimers are being used in an exciting application is around the modulation of blood clotting. Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in the developed world. Fibrin clot structure and fibrinolysis can determine predisposition to CVD and manipulating the prothrombotic environment can reduce the risk of vascular events.

One 4 pharma Meanwhile other exciting developments came from N4 Pharma. Nigel Theobald explained how the company’s initial focus has been on developing Cocrys which can be used to improve a drug’s solubility either to improve onset of action or increase bioavailability and can also be used to control the solubility to enable a sustained release effect. Crucially the process uses standard twin screw extruders and is therefore capable of large volume efficient commercial production of the co-crystals.

N4 Pharma has also developed Nuvac a nano-carrier delivery system for antigens that improves both humoral and cell mediation effects for vaccines. It can be used to reduce vaccine dose or improve vaccine or antibody drug conjugate performance and our first program with Nuvac is a single dose version of the hepatitis B vaccine using the antigen HBsAg.

Supply and demand Further innovation came from AMCo. CEO John Beighton, CEO explained how the company supplies medicines that the big pharma companies no longer want to supply. AMCo continues to produce them for groups of

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Smith Alastair

Past and present: Cecilia Mendy, Owen Mumford, revealed the current and future initiatives at this drug delivery device business

Nigel Theobald

Alternative scene: Alastair Smith, Avacta Life Sciences, outlined his company’s work developing engineered alternatives to antibodies

In focus: Nigel Theobald explained how N4Pharma’s initial focus has been on developing Cocrys which can be used to improve a drug’s solubility

patients who are unable to get them anywhere else.

These medicines, says Beighton, are often hard to make from a technical point of view and are often only required by small groups of patients. By ensuring they continue to be produced the company provides a vital service for those who need them most.

The ongoing thread of AMCo’s strategy is to acquire and develop niche medicines which are vital to patients who would be unable to get them elsewhere.

The company is working on streamlining and reversioning these medicines so they absolutely suit patients’ needs.

This involves changing formulations or even strengths of medicines that were often developed decades ago to make them much more suited to the modern patient. This often leads to reducing the pill-burden on patients and therefore to greater compliance and improved efficacy.

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