EPM Nov/Dec 2014

www.epmmagazine.com

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IN THIS ISSUE: Natoli reveals its latest developments to EPM

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NOVEMBER/DECEMBER 2014

Volume 14 | Issue 08

24/11/2014 10:14

THEY SAID IT COULDN’T BE DONE. running the Four minute mile

6 May 1954

man landing on the moon

20 July 1969

birth of the first test tube baby

25 July 1978

29 august 2013

Irradiation of H2 02

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32

34

Contents

Features 18

November / December 2014 | Volume 14 Issue 8

COVER STORY

Regulars

8

6

21

NEWS

TABLET TOOLING

8

25

Including GCS’ cleanroom and IDT Biologika’s vaccines facility

FREEZE DRYING Lyophal says freeze drying with collapse is not necessarily bad for stability

10

27

REGULATORY AFFAIRS

OPINION From DSP, IAG and this issue’s Good to Talk on Trends & Highlights

34 CHEMICAL REACTION This issue Ecobliss and its Locked4Kids in the spotlight

epm head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE. Tel. +44 (0) 1244 680222 Fax. +44 (0) 1244 671074 Web: www.epmmagazine.com

editorial group editor lu rahman, lu.rahman@rapidnews.com associate editor dave gray, david.g@rapidnews.com

In focus - I Holland

NEWS PROFILE

13

Natoli reveals its latest developments to EPM

www.epmmagazine.com

BIOPHARMA Expertise from Agilent

28 & 29

21

AUTOMATION

30

Fanuc’s Chris Sumner explains the growing appeal of robots in pharma

30 CONTAINMENT

contributing editor aleksandra jones, ola@rapidnews.com publishers mark blezard, duncan wood

production art robert wood

advertising robert anderton tel: +44 (0) 1244 680222, rob@rapidnews.com jacqui priestley tel: +44 (0) 7907 361588, jacqui.priestley@rapidnews.com

subscriptions subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £115 outside qualifying criteria UK - £80, ROW - £115 please subscribe online at www.epmmagazine.com

PSL offers an insight

31 PURIFICATION & FILTRATION

32 SPOTLIGHT This issue we look at the development’s at French firm, Roquette

Address changes should be emailed to subscriptions@rapidnews.com.

European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals.

Volume 14 Issue 8 © November / December 2014.

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. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

BPA Worldwide Membership ISSN No - 2052-4811 EPM 3

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Baxter is a registered trademark of Baxter International Inc. 920917-00 11/14 SAFC is a registered trademark of Sigma-Aldrich Co. LLC EPM 4

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COMMENT

“

Out with the old...

As we draw a close to the end of the year, it’s a good time to take stock and look at the way we work and the methods we use to attract and win new business. We can all be guilty of getting stuck in a rut and failing to recognise new ways of operating. However, a scan over recent industry initiatives and success stories highlights the need for continued re-evaluation.

When Novartis launched an anti-hypertension drug in 1997 – Diovan – sales hit $80 million, a disappointment to the company. Novartis created a longterm brand-building strategy and placed its product in direct competition with the leading rival. The result of this was that by 2007, the product was generating $5 billion-worth of annual sales.

Some sectors are quicker than others to adopt new ways of thinking / working. While the pharma industry is at the forefront of scientific advancement, it would be fair to say that its uptake of all things digital, could be improved.

This is the same for many industries, whatever their specialty and of course, while pharma companies are busy developing groundbreaking drugs, creating partnerships and looking at ways of marketing their businesses, concepts such as social media do understandably, tend to be sidelined.

Of course, there is much more behind these tales than simple anecdotes highlighting the need to ‘think outside the box’. However, we all need to be mindful of the need for reassessment of working practices and be open to new ideas and ways of working. While advances in technology may be daunting, making use of them is beneficial. This was recently discussed in the Frost & Sullivan TechVision programme which indicated that disruption, often seen as a threat, can present financial opportunities and that embracing technological advances, will eventually prove fruitful.

It was interesting therefore, to read that social media is playing a part in clinical research.

Currently described as “an evolving field”, the research team at Indiana University has been using social media a nd A mazon Mechanical Turk and Amazon to conduct indep pen end dent surveyss iinto nto nt o lilive v r independent liver disease. The team m se ssees es p oten ot en ntitial al iin n th this iss way of potential working - in which seven a utoi ut o mmun ne hepatitiss autoimmune social so all m edia ed ia group upss we were re u sed, se d, a long wit long ith media groups used, along with Amaz Am a on nM ec cha h ni nica call Tu ca Turk k, a cr crow owds dsou ou urc rcin ng Amazon Mechanical Turk, crowdsourcing webs bsititite e, ffor o tthe or he h ealtlthy ea yp arrtitici cipa ci p nt pa n e leme le ment nt o website, healthy participant element off the study.

Dr Craig Lammert led the sstudy, t dy tu y, re efe ferr rrin rr i g to in o tthe he e referring use of social media as “a an a an mazzin ma zing ng ttool”. ool” l”. l” “an amazing This positive reaction n tto o th the e wa ay the study was way conducted is encou ou ura ragi g ng gi ga nd hopefully Indiana encouraging and Univ Un iver iv ersity hass h er n so ome mething useful that will University hitit o on something be b e rreplicated eplililica ep cate ca ted te d by o th ther her e rresearch esea es earc rch h ce cent ntre ress in tthe he other centres near ne arr ffuture. utture. ure.

So 2015 might well be the year of disruption and maybe we will all decide to embrace something problem matic and work with it to find we find problematic impr prov ovem ements to the way solutions and improvements w currently currre rent ntly operate? ope erate? we

Lu Rahman Rah hma man man Lu

” EP EPM E PM PM 5

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NEWS Pharma in 3D

Thinking big: Dr Mohamed Albed Alhnan and his team believe 3D printed drugs will be in hospitals within five years.

Y

ou may have heard of 3D printed food (you can print spaghetti and meatballs, if you fancy it), but new research is looking into the 3D printing revolution for use in drug manufacture.

A new study at the University of Central Lancashire may open up new avenues for personalised medicine, with the use of 3D printing.

The technique, which is undergoing a patent application, uses a 3D printer to ‘print’ a tablet of medicine with realistic quantities that can be taken by a patient. The printer can replicate drugs already available in pharmacies and hospitals, and can also tailor medicines directly to an individual patient’s needs.

The researchers behind the study claim that they believe the technology has potential to reduce the cost of manufacturing tablets for individual patients - while also opening the door to new options for doctors and patients that used to be considered impractical or too expensive.

Dr Mohamed Albed Alhnan from the School of Pharmacy and Biomedical Sciences alongside his team developed a drug-polymer filament system that can replace the original filaments in a 3D printer.

The team discovered that the new pharmaceutical “ink” allowed the team to print a challenging tablet design with significant improvement of appearance and high accuracy of tablet weight and dose.

While 3D printers have been used by hobbyists and SMEs for several years, various individuals and organisations have recently been experimenting with medical uses such as prosthetics or dental implants.

The team says it predicts that the technique will be used by pharmaceutical firms and hospitals within five years and by the public within a decade.

Dr Alhnan said: “3D printing has been embraced by lots of different industries but we have shown how this technology can be harnessed to improve medical care, providing low-cost, personally tailored medicines for patients.

“Thanks to this technology, the invented system can provide medical institutions with a new option and maintain dosage form properties while accurately adjusting the dose with simple software order, something that was considered before to be costly and required experienced staff and dedicated facilities. Eventually, we hope to see that units can be kept at home for patients who continuously need to change their daily dose.”

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NEW

Socially savvy

T

he emergence of social media as a tool for the healthcare industry once carried the potential to be very dangerous.

Social networking sites and search engines are unregulated platforms, which at first offered major corporations a chance to interact directly with consumers and patients, without relying on ‘traditional’ channels of communication to relay information.

In effect, this allows marketing claims regarding drugs and devices to assume prominence over unbiased, regulated documentation. But the FDA is catching up. On its blog (its own attempt at a more ‘social’ online portal for both industry and consumers) it outlines its first draft guidelines for the use of social media, aimed at drug and device manufacturers and suppliers.

In the first instance, the agency addresses the issue of character limitation (particularly in the case of Twitter), and its impact on the nature of the information. Highlighting the fact that it’s virtually impossible to provide both benefits and risks of a given product in 140 characters, the FDA gives its recommendations for presenting the information in a balanced way.

The second key set of guidelines is centered around the issue of correcting third-party information. Until now, there was no established protocol for manufacturers and suppliers to correct comments, which make false claims regarding their products. It’s crucial that the industry is allowed to respond to erroneous statements. The new guidelines aim to give detail on the best way to handle this, and suggest that brand owners use forums to their advantage, utilising specific sections for corrections and amendments.

Thomas Abrams, director of FDA’s Office of Prescription Drug Promotion, said: “We developed these new guidances, in part, to respond to requests for best practices from companies and other stakeholders.

We gave careful thought to our draft recommendations, and we understand technology will continue to evolve. So we worked across FDA Centers and Offices to develop best practices that can be applied to existing online Internet sites — and those that have yet to be developed.

Be responsible: The new guidelines support the responsible use of social media by pharma and medtech firms.

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“Prescription drugs and medical devices can provide tremendous benefits to patients, but they can also pose certain risks. As a regulatory agency, we are committed to ensuring that the information about these products that their manufacturers and distributors direct at patients and health care providers is accurate and balanced.”

Despite the efforts to ensure social media is used responsibly however, the FDA has no plans to monitor what companies do online.

Although guidelines are starting to emerge, drug and device suppliers won’t be policed when interacting with potential consumers.

• Ro Robust and d maiint nten enan ance an ce-ffre ee Hig igh h pr p es essu s re app ppllica licati ation o s,, no se eall rep epla lace la ceme ce m nt

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“

The GCS group is continually improving pharma quality culture throughout its organisation by investing in quality systems and processes

NEWS PROFILE

”

Lite work: The Lite-Loc, lightweight CRC from GCS

W

ith a consolidated revenue of €583 million in 2013 and approximately 3,500 employees, Global Closure Systems (GCS) is one of the world’s largest providers of plastic closure solutions for the global FMCG market. Through its 21 production sites strategically located in 13 countries and 12 active licensees all around the world, the company sells its products in more than 100 countries, for a range of industries including healthcare.

GCS produces almost 1.5 billion closures annually for the European healthcare market and offers child resistant closures (CRC), tamper evident closures, droppers and dosing devices for the pharmaceutical market. In order to reinforce its leading position in the pharmaceutical industry, GCS has built a sustainable growth strategy based on three pillars: highest quality standards, increase of production capacity and new product development.

Recently, the company has invested almost €1 million in its Astra Plastique factory in France

GCS invests in cleanroom facility Global Closure Systems has invested €1 million in new cleanroom facilities which the company says will help it exceed pharmaceutical industry standards

with the construction of a second ISO 7 cleanroom. This, says the company, means it can now exceed pharmaceutical industry standards.

Already known for its expertise and high level of quality and service for 35 years, Astra Plastique is taking the lead by anticipating future increasing demands and market requirements.

The cleanroom has been designed to optimise the flow of people and products and offers an immaculate environment for the pharmaceutical industry. A specific personnel entrance has been built to ensure a total hygienic control. The new clean room includes a dedicated quality laboratory, a bag sealing/welding

machine and specific exit gates for the finished products which keep cartons and pallets away from the clean room.

Furthermore, the GCS group is continually improving pharma quality culture throughout its organisation by investing in quality systems and processes but also by implementing more intensive employee training at all levels. The new cleanroom ISO 7 is based on the integration of existing best practices and improvement where possible – the Astra Plastique teams was involved in obtaining ISO 15378 certification (GMP Pharma) in 2014.

To celebrate the completion of this 12 month project, GCS recently held a ‘Pharma Day’ event to. More than 50 pharmaceutical companies, agents, distributors, bottle suppliers, and also journalists from all over the world participated, which included a presentation and a tour of the factory.

As a market leader and to support the development of its customers in a highly regulated marketplace, innovation is a key pillar of the group strategy. The group employs 72 R&D talented people who have recently designed new product lines, such as CapePharma, a one piece tamper-evident closure and PharmaSafe a last generation twopiece child resistant closure (CRC).

The company is also developing new concepts which it showed at the CPHI show, such as FlipLoc, a single piece CRC for pills, powders or liquids and the Lite-Loc lightweight CRC.

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NEWS PROFILE

Novel idea: IDT Biologika’s vaccine development team is expert in live viral vectors increasingly utilised in the development of novel vaccines

Building success

IDT Biologika, manufacturer of human vaccines designed to address some of the world’s most dangerous infectious diseases has completed and certified the construction of a large-scale production facility dedicated to filling and lyophilisation of biologics and vaccine products. The fully integrated facility in Dessau, Germany, uses a sterile liquid filling line engineered to handle up to 24,000 vials per hour. Certified to biosafety levels (BSL) 1 and 2 for live vaccines, the facility has been designed and commissioned to be used for a range of advanced biomedical technologies required in medium to large clinical stage and commercial stage volumes.

designed for biomedical products manufacture,” said Dr Ralf Pfirmann, chief executive officer. “Completion of this project, announced upon start of construction three years ago, allows us to accommodate production of an ever more diverse range of biomedical technologies with the precision and efficiency that comes with a highly integrated and automated facility.”

“Expanding our capabilities within a further multipurpose facility, IDT Biologika now offers one of the most dynamic facilities

Included among the company’s specialised manufacturing capabilities are drug substance and drug product capabilities for live recombinant

IDT Biologika presents new multipurpose biologics and vaccines facility

and non-recombinant vaccines and, in separate units, fill-and-finish capabilities for other biologics and small molecule drugs including cytotoxics. All biomedical products produced in the new multipurpose facility may be manufactured in the form of liquid or freeze-dried (lyophilised) presentations.

IDT Biologika’s vaccine development team is expert in live viral vectors increasingly utilised in the development of novel vaccines.

The new facility further supports these development capabilities.

The company also boasts a fully automated loading and unloading freeze-dryer system now in place for live recombinant and nonrecombinant products. A freezerdryer shelf capacity of 40m2, equal to at maximum 178,000 vials per batch, compliments its production system.

“With the completion of this facility, we are equipped to manufacture up to 100 million vials per year of freeze-dried and liquid presentations. Our capacity planning and facility designs appear to be on target, as we gear up to accommodate the development, testing and manufacture of vital vaccines and other biological products for our partners in the biopharmaceutical industries,” Pfirmann said.

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abridgement (this is particularly a problem for biosimilars).

However, since the bar was already set, it was not possible for regulators to lower it, without backlash from competitors in Dr Parvinder Punia, industry. One senior regulatory affairs manager, ELC Group, territory did move forward discusses the use of guidelines and applied in drug development minimised development plans in the advice given s costs of development alleviate ambiguities. Advice can but another territory has refused escalate and guidelines be tailored to suit the needs of the grow, the need for scientific other regions without compromising to align. In these cases, either the global plan must become more advice from regulators becomes the requirements of each agency at localised, or the development an essential part of any drug each stage. itself terminated. development timeline. As guidelines are open to interpretation, the basis Another approach would be to use With some regions applying of the scientific reasoning should be precedents set by other companies, strict timetables to how an advice open for debate. In this way, many leveraging decisions made earlier is applied for and finalises the guidelines have gone to turn opinion in your favour. minutes, utilising timings of through evolutions.

However, this is a double-edged committee meetings and experts sword and the opinion previously availability, a company could spend The pharma industry is not given may not be favourable to your years seeking scientific opinion. developing in isolated, single development plan. It can happen, In the EU, for example, the EMA regions. The needs of global where a company has sought development must be accounted for. advice and has developed a product advice is strictly timetabled. In the US, a preliminary meeting request So, which NCA to ask advice from at the high standard that regulators needs to be completed to begin the and how to navigate differences previously thought would be the countdown of days to the allotment of opinion? The logical way is to only route. However, as experience of the audience with the regulators. approach agencies where clear-cut grew, it was noted that maybe some Since there is no way to challenge guidelines do not exist. This can parts of development could enjoy

Guiding light

A

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the timelines, the company must plan in advance – in some cases, years – in order to allot the needed time. In the EU, the problem can be eased by the use of the local NCA for opinion. In any case, a large development of innovation should first be “checked” at the local level.

The regulators sitting on panels at the EMA are primarily made up of personnel at the local authorities and therefore, pinpointing expertise around the EU and approaching those agencies is beneficial.

Ultimately, the EMA opinion should be sought, but the final advice package could be tailored around the general opinion gathered.

The purpose of the meetings is to steer a regulator towards your opinions using scientific facts and regulations/guidelines to assist understanding. Asking a closed question is beneficial. The meeting is the opportunity to create challenges. Ask thought-provoking questions and challenge opinions.

Choosing key personnel within the applicant’s team who can do this is an integral part of planning the scientific advice meeting more efficiently. Ask if the regulator agrees/disagrees with general consensus and guidelines.

However, one can only cite the usual phrase given to any advice: That this document is not legally binding and cannot be taken as indicative of any future agreed position.

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OPINION

Resistance training The legacy of over-use of antibiotics has been well documented. Karl Rotthier, chief operating officer at DSM Sinochem Pharmaceuticals (DSP), speaks to EPM and offers advice on how we can secure the long term health regarding antibiotics

EPM: What do you see as the major issues for pharma sector in the coming years?

KR: The pharma industry is in a critical phase. If you look at our core business – the antibiotics industry – we face a storm of policy and stakeholder pressure developing around its supply chain. At the same time, issues such as antimicrobial resistance (AMR), pollution from production plants, product quality concerns and security of supply are all creating increased business risks.

One of the big threats we see is the issue of non-compliant pharmaceutical producers, which face being closed down by the authorities. This poses a huge risk to the supply chain security of companies sourcing APIs and intermediates from them. Being compliant on environmental requirements also means having Freedom to Operate (FTO). We should not allow companies to pass on their production costs to the environment and society. That is why we see governments shutting down non-compliant producers, banning factories and taking action to enforce environmental laws.

This means customers dependent on non-compliant suppliers could face delays in delivery or be left with no deliveries at all. Sustainability should become one of the key criteria for our suppliers. Reliable supply of high-quality APIs will be essential.

EPM: There has been much talk of antibiotic resistance – what’s your view and what do you feel needs to be done to ensure the situation is handled as safely as possible?

KR: The World Health Organization (WHO) has declared AMR to be one of the top three threats to humanity.

It is a global issue that governments and multinational organisations are working to address.

I believe that as an industry, we also must do our part to tackle AMR.

The illegal and uncontrolled discharge of waste and active pharmaceuticals to the environment also contributes to AMR. However, there are still non-compliant producers polluting the environment, manufacturing poor quality products, and burdening society with the costs. This is avoidable when there are responsible operations and environmental technology throughout the value chain.

EPM: Why does this matter for companies sourcing from such manufacturers?

KR: Because they rely on an unstable and uncertain supply chain, unable to ensure FTO. We see this happening already in China and India where the authorities are cracking down on polluting and non-compliant facilities and recalled poor quality products, with the antibiotics industry being a top target.

Today, our industry is not organised or engaged enough to respond, let alone lead. We need to act and step up to the challenge, by improving our environmental performance, delivering the highest possible product quality and ensuring security of supply.

A focus on sustainable antibiotics is the only choice for the protection and the future business success of our industry.

EPM: What do you feel the legacy will be on society regarding antibiotics?

EPM: What steps do you feel pharma companies and the wider community need to adopt to ensure long term health regarding the issues we face with antibiotic resistance?

KR: As an industry, is to build the foundation for a strong and respected industry, by immediately focussing on the highest production standards – ensuring they are at the highest level with minimum pollution and waste.

This benefits communities and is directly linked to the battle against AMR; the highest quality standards – making sure our quality is as good as it can possibly be and is highly regarded across the community and valued by customers; security of supply and industry engagement and leadership - we need to apply product stewardship principles and leadership with policy makers and stakeholders.

EPM: What is DSM Sinochem Pharmaceuticals’ role in this?

KR: Sustainability is our core value and a key business driver. This means simultaneously pursuing economic performance, environmental quality and social responsibility. The industry has a responsibility to ensure safe production, product stewardship, and correct use of antibiotics.

Our aim is to lead by example.

Sustainable antibiotics are the only option for our future success – medically, environmentally and ethically.

KR: The discovery of antibiotics fundamentally transformed medicine. Life without antibiotics is unthinkable, they make modern medicine possible. They saved, and continue to save, millions of lives.

It is, without question, one of those rare miracles that has benefitted the entire world. But its legacy and ours are at serious risk. If we don’t step up and act, we run the risk of losing this miracle cure.

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OPINION

Academy award

Alan Dorling, global head of pharmaceuticals and life sciences at IAG Cargo discusses the Good Distribution Practice Academy and how it will benefit the healthcare and life science industry

A

s a leading air cargo company, we pride ourselves on being able to deliver our customers’ shipments on time and in perfect condition.

When it comes to the transportation of pharmaceuticals however, our ability to deliver goods on time and in a usable condition becomes even more important and requires the use of our specialist temperature sensitive product: Constant Climate.

These precious cargos are among the highest in value, both in terms of cost and the use they will be put to. Throughout the delivery of such goods we have to keep in mind what we are carrying – to think inside the box as it were – and work hard to ensure the integrity of these drugs.

Good Distribution Practice (GDP) Vitally important is the safe transportation of medications to the wider healthcare industry and the patients it serves, that it is heavily regulated. In particular, compliance with the Good Distribution Practice (GDP) regulation is essential.

Indeed, revised EU guidance and other international rules make it clear that all those involved in processing and handling these sensitive commodities must be properly trained. The Official Journal of the European Union, Guidelines of 5 November 2013 on Good

Distribution Practice of medicinal products for human use states: “All personnel involved in wholesale distribution activities should be trained on the requirements of GDP. They should have the appropriate competence and experience prior to commencing their tasks. Personnel should receive initial and continuing training relevant to their role, based on written procedures and in accordance with a written training programme.”

The Good Distribution Practice Academy It is for this reason that we have teamed up with Exelsius, the international cold chain management consultancy, to provide the healthcare and life science industry with a certificated training workshop in GDP: The Good Distribution Practice Academy.

The Academy, which began with a two day workshop on the 11 November at the Hilton Hotel at Heathrow Airport, combines theory and practice in a learning environment designed to impart best practice in GDP processes.

In addition to the requisite classroom activities, students will also be taken to the IAG Cargo Constant Climate Centre (our temperature-sensitive pharmaceuticals handling facility at Heathrow).

These ‘live’ visits allow students to put theory into practice and fully embed their training, as well as to interact with our operational experts to hear first-hand the dedication and commitment that goes in to protecting the supply chain.

While the Academy will initially only be available at London Heathrow, we already have plans to expand it to other key pharmaceutical markets such as Singapore, India and North America as we expect demand to be high.

The benefits of this training programme are clear to see.

Supporting a fast growing industry The global pharmaceutical market is booming. Growing at a rate of 5.1% per year, it is expected to exceed an impressive $1 trillion of global spend by 2020 . The trade in pharmaceuticals clearly has real potential for growth, but only if drugs can be delivered in a way that does not compromise the product.

Pharmaceutical manufacturers, logistic service providers, ground handlers and all others involved in the logistics process are therefore tasked with successfully integrating with the wider supply chain; putting in place security and quality assurance protocols to guarantee that these high-value shipments get to market

in an optimum condition; complying with global regulations; and training employees to understand the pharmaceuticals industry in depth.

The Good Distribution Practice Academy delivers on these requirements, providing the healthcare and life science industry a detailed understanding of the world of international healthcare logistics, especially as it applies to the GDP guidelines. At the end of the course participants will be able to better understand good temperature management and the type of cargo solution that best suits various shipments. They will also be able to create Standard Operating Procedures (SOPs) for their working environments, mitigate risk and understand the role of audits in the Quality Management process.

Ensuring excellence Ultimately the aim of the course is to help train those in the pharmaceuticals industry so that all shipments make it to the patients who need them and in a state where they can be used. Concurrently, however, it is also helping to ensure that the industry has a store of trained workers to draw on as demand for pharmaceutical products continues to grow. By being compliant with GDP regulation, every link of the supply chain will be able to carry out their duties to the required levels of excellence.

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IT’S GOOD TO TALK What were your key trends and highlights of 2014?

By the end of October 2014, the FDA had approved 37 new drugs (outpacing 36 approvals throughout 2013). This number confirms the upward trend in drug approvals since 2010, and underpins the large impact that the transition from blockbuster to specialist-care drugs is having on the industry. I am excited to see innovative new drugs serving previously unmet medical needs, and I am convinced that these drugs will continue to trend in popularity and drive the market over the next couple of years.

Dr. Andreas Weiler, head of strategic marketing at SAFC

Counterfeit drugs are a great concern of the UK pharmaceutical industry. Public safety is paramount and product quality cannot be compromised. Molecular Spectroscopy, such as Raman, NIR and FTIR, is a great solution and becoming very well established in the pharmaceutical industry. The latest innovative handheld devices are suitable for verification of many pharmaceutical materials whether finished products, intermediates, excipients or actives in solid or liquid forms.

Ian Laidlaw, managing director, Analytik

Formulation homogeneity is vital during large scale manufacture to ensure the generation of consistent, reliable pharmacology products.

Raman imaging is a powerful technique for investigating and solving issues with tablet dissolution, content uniformity and polymorphism. Systems, such as Renishaw’s inVia Raman microscope, have seen increasing use in this area in 2014.

Many newer biologics in development are increasingly sensitive to certain container materials, and require increased concentrations to enable an effective dose.

This is leading to a trend toward higher-volume injection systems, such as wearable injectors, and an increasing acceptance of polymer-based container systems.

Tim Smith, manager of the Raman Applications group at Renishaw

Graham Reynolds, vice president, marketing & innovation, West Pharmaceutical Services

Developing strategy with my team to serve our customer in laboratories and pharmaceutical processing through expansion of our portfolio (e.g., in antibodies), global footprint (e.g. North America, China) and capabilities (e.g. in e-commerce).

It is rare in one’s career that you have the opportunity to take a big step forward on all three fronts – with the announcement of the pending acquisition of SigmaAldrich we expect to be able to do just that – to serve more customers on 300,000 products globally through state-of-the-art customer interfaces. That’s a highlight!

Continuous manufacturing of tablets is gaining traction with the pharmaceutical industry. Originally, continuous manufacturing was only attractive to manufacturers producing large numbers of tablets.

New technology offers quicker tooling changeovers so that smaller manufacturers or manufacturers of smaller lot sizes utilize the advantages offered by continuous manufacturing.

Dale Natoli, director of Natoli Engineering

Udit Batra, CEO and president Merck Millipore

At Almac we have witnessed a steady growth in the demand for biologics and would predict this trend to rise as the pharmaceutical and biotechnology sectors continue their merger & acquisition activities to pursue their development and commercial activity in this area both in de veloped and emerging markets.

There is a clear trend towards packaging T tthat offers better performance in drug and patient protection, either through a child-resistant solutions, barrier c properties or stable climate conditions. p This is the reason why we have T iintroduced AdCap and AdPack and will even go ahead with climate management next year.

Jonathan Calderwood, marketing development director, Almac’s Clinical Services Business Unit

Holger Frank, CEO at Sanner GmbH

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COVER STORY

T

ooling, tablet compression accessory, and services provider, Natoli Engineering Company has opened an oral solid dosage (OSD) research and development institute to advance the field of industrial pharmacy education and technology. The Natoli Institute for Industrial Pharmacy Research and Development was established in partnership with the Arnold and Marie Schwartz College of Pharmacy and Health Sciences on the Brooklyn campus of Long Island University (LIU).

Supporting one of the remaining industrial pharmacy programmes in North America, the Institute is dedicated to advancing knowledge in the field of pharmaceutical solid oral dosage formulation and engineering. Rutesh Dave, associate professor, a tenured faculty member and director of LIU’s division of pharmaceutical sciences, and Dr Charles Kettler, director of Natoli Scientific, will oversee the institute’s daily activities and projects.

A legacy of technical support Natoli Engineering is a key player in the tablet compression tooling, supporting products and services industry and has been in business for more than 40 years. The company has technical experts on staff who often provide troubleshooting assistance to their clients and travel around the world to present training classes and participate in conferences on various topics affecting the tableting industry.

Pressing issues Natoli, the tablet compression tooling manufacturer outlines the opening of its institute at Long Island University Because of high demand for technical knowledge and the need for resources to investigate customer problems that arise during the production of tablets, Natoli established its Natoli Scientific division. Natoli Scientific can provide or locate resources to help industry professionals find solutions to issues with product formulation, selection of proper tablet design and recommendations for tooling specifications to meet typical as well as specialized tablet needs.

Combined with four decades of experience and a network of university, consultant, and resident resources, Natoli Scientific operates from Natoli’s headquarters in St. Charles, USA. It is tasked with the everyday customer requests to help customers determine correct tool selection, tool steel, tool coating, and die configurations that combat common tableting problems such as tablet sticking, picking, capping, lamination, tool binding, and accelerated rates of tool wear due to abrasive formulations.

discussions with LIU began and, in addition to conducting its own research and studies, Natoli Scientific now oversees and partners with the Natoli Institute at LIU to conduct experiments and troubleshoot tableting issues for which customers and other clients have requested a solution.

Supporting the future of tableting science Natoli provided funding to establish the institute in order to not only provide opportunities for manufacturers and external clients to receive solutions for the complex

manufacturing issues they face, but also to strengthen the field of industrial pharmacy. The number of industrial pharmacy programs available to students in the United States has decayed over the last several decades as many schools of pharmacy have focused on satisfying the needs of the market: retail and clinical pharmacists.

Establishing the Natoli Institute expanded LIU’s pharmacy program to provide opportunities for students to study the formulation and manufacture of tablets.

“There are fewer pharmacy programs in the United States that still offer industrial pharmacy opportunities. Many pharmaceutical students will go to work at one of the retail pharmacies or in a hospital formulary. The Natoli Institute supports those who wish to pursue careers at companies that manufacture tablets,” said Dr Kettler.

As Natoli Scientific realised the number and types of customer problems, it became clear that the tableting industry would greatly benefit from the allocation of additional resources to study the issues that are presented to the company every day. Thus EPM 18

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The Natoli Institute features dispensing, granulation/milling, compression and coating suites.

Work will focus on understanding the current problems associated with the development of formulations for new and existing molecules that meet the dissolution and bioavailability for the current clinical requirements. Delivery of the formulation to the tablet press and control of the tablet press will be the focus of some of the research work done as some of the new

formulation techniques provide unique challenges to ensure the resulting dosage form meets the fitness for use criteria. Multiple unit pellet system (MUPS) formulations, multiple layer tablets and multi-tip compression tools all have distinct requirements for powder handling and compression to ensure the resulting tablets consistently meet the quality requirements for the product.

“Many students aren’t familiar with the unit operations that tablet formulation and manufacturing requires. The facility features traditional solid dosage formulation equipment, as well as the technology to measure the physical and chemical properties of tablets. The Natoli Institute will be investigating new technologies for granulation as well as building an understanding of the best way to take a formulation that is currently built through granulation to a direct compression process while maintaining the proper delivery of the API to the patient,” said Dr Kettler.

Students will have the opportunity to receive hands-on training with the proper and most common equipment that is used in tablet manufacture and formulation. They will have the opportunity to learn tablet analysis including principles behind tablet breaking force, dissolution, friability, disintegration, and content uniformity. The

institute will also perform powder rheology measurements, fluid-bed granulation, fluid-bed coating/ drying, high-shear wet granulation, milling, blending, roller compaction, tablet coating (solvent-based and aqueous) and tablet compression with a single-station laboratory press or a rotary tablet press.

“Many pharmacy students haven’t had the opportunity to see tablet manufacturing operations in progress. Watching a high-speed tablet press can be an experience that explains why understanding the underlying science of powder handling and compaction is so important.

Providing students with hands-on experience will help them better understand the actions and attention to detail required to make quality medicine,” said Dr Kettler.

A resource for the tableting industry In addition to furthering pharmaceutical compression science and supporting research into challenges facing the industry, the laboratory will provide realworld research opportunities to undergraduate and graduate students. Tablet manufacturers may submit projects for students to research, which will give them the opportunity to troubleshoot and experiment with real issues that these clients are facing every day.

Together with Natoli Scientific, the Natoli Institute provides resources to the tableting industry, including new product manufacturing studies, tablet tooling sticking and picking evaluations, and new formulation technologies. So not only does the facility provide an environment for students to learn industrial pharmacy unit operations for solid oral dosage forms, it also provides a unique opportunity for Natoli customers to have their tableting problems investigated.

access to capable experimenters,” said Dr Kettler.

Students will work on projects submitted by Natoli customers and other clients with the end result being to provide solutions to complex challenges that customers face during formulation and manufacturing. Students working at the Institute will gain valuable knowledge and learn how formulation adjustments can impact tablet properties and the performance of the medicine. By gaining experience working with troubleshooting equipment and designing appropriate experiments, students will be well prepared for the tablet quality issues they will encounter in the professional world of solid oral dosage forms. This will be true whether they work at a traditional pharmaceutical company, a compounding pharmacy or some other industry in which powders are assembled and compressed into products.

“We are committed to supporting the future of the industry, as well as providing additional resources to our customers to combat their tableting issues,” said Dale Natoli, company president. “By establishing the institute, we are demonstrating our commitment to the support of education in industrial pharmacy operations. We look forward to continuing to provide opportunities to partner with our customers to find solutions to their challenges.”

Any work completed on customer projects will always uphold intellectual property requirements, as well as contracts and nondisclosure agreements as necessary. And no company or product that is researched at the institute will be identified unless permission is explicitly granted.

The institute may prove valuable to generic drug manufacturers as sometimes these companies are on tight timelines and moving from approval to scale up can present many challenges that require additional development work. The institute will work with customers to quickly execute experiments that will provide clients with process and product data which will in turn help them in their discussions with regulatory agencies such as the FDA and EMEA. Graduate students may leverage the resources of the Institute for their thesis or dissertation work with approval from Professor Dave and Dr Kettler. Faculty at the LIU’s school of pharmacy may initiate projects as well. “It’s a resource for them to integrate industrial pharmaceutical science into their classes. We welcome them writing experiments to create new learning opportunities for students,” said Dr Kettler.

“We found that we needed a laboratory setting to explore some of the challenges our customers were facing. With our investment in the Natoli Institute, we were able to help LIU bring back their Industrial Pharmacy program while receiving

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TABLET TOOLING

Make the grade: I Holland’s PharmaGrade range of raw materials has been developed and tested for today’s tooling requirements

Wear and deterioration of tooling is unavoidable in tablet manufacture, but it can be reduced significantly by using the correct tooling materials and coatings. Global tablet tooling manufacturer, I Holland, has researched the science behind this complex issue and offers a number of solutions to extend the life of punches and dies.

I Holland’s R & D manager, Rob Blanchard, says: “Deterioration of tablet tooling is inevitable and is a problem that leads to other tablet-making problems, including adherence of the granules because of the pitted and worn surfaces of the punches and also capping or lamination of the tablets. I Holland has studied these issues and have a comprehensive offering of materials and coating solutions to eliminate this common problem.”

High quality tooling should be able to offer a long life and be anti-abrasive and wear resistant.

To achieve this there are several options. The company has introduced the PharmaGrade range of raw materials, that has been developed and tested for today’s tooling requirements. The range incorporates several wear-resistant

Wear it well I Holland offers an answer to tablet tooling degradation with a combination of solutions

materials including HPG-P high quality ESR grade punch and die material, HPG-MP and HPG-MD specialised powder metallurgy grade steels, as well as HPG-TC, a sintered micro-grained tungsten carbide cemented with cobalt.

its PharmaGrade range of steels has been tested to achieve the following necessary characteristics: • Strength: ability to withstand an applied stress without failure.

Blanchard comments: “Tungsten carbide is often used for the dies to prevent wear and deformation of the die bores. It features a high compressive strength with an extremely high wear resistance.

This helps to reduce die bore wear and ringing and lasts longer than conventional die steels.

I Holland’s understanding of steel metallurgy, allows the company to further improve the properties of its PharmaGrade steel types for tablet tooling. The right steel is key to the successful performance of punches and dies and the company says that

• Fatigue resistance: aggressive and localised structural damage that occurs when a material is subject to cyclic loading.

• Toughness: resistance to chipping, cracking and punch tip breakage.

• Abrasive wear resistance: resistance to abrasive wear of punch tips and die bores.

• Adhesive wear resistance: resistance to adhesive wear, galling and welding.

• Hardness: resistance to impregnation from hard, sharp granules.

• Compressive strength: resistance to die bore ringing and plastic deformation of punch tip edges.

• Corrosion resistance: resistance to oxidising, staining and discolouration.

Chemical composition of the steel is only one part of the overall equation, material selection must also be considered together with good tablet design for strong punch cups and punch tip edges.

All PharmaGrade materials can be applied to a range of tool types for pharmaceutical, nutraceutical and industrial applications, including multi-tips, and designer shapes, as well as standard designs.

“Another option for improved wear resistance is to use enhanced coatings and treatments. The I Holland range includes several coating options to increase tooling life. PharmaCote RS is one of the products that has been specifically developed to combat abrasion and one customer reported increasing tablet output by 900% from one set of tools due to the application of this coating.”

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>ĂďŽƌĂƚŽƌLJ ĂŶĚ ƉŝůŽƚ ƉƌŽĚƵĐƟŽŶ ŵĂĐŚŝŶĞ ĨŽƌ ƚŚĞ ĐŽŶƚĂŝŶŵĞŶƚ ĂƌĞĂ | WP 120 Pharma Isolator ͻ ƚŚƌŽƵŐŚƚƉƵƚ ŽĨ ϴ ƚŽ ϰϬ ŬŐͬŚ ŝŶ Ă ĐŽŶƟŶƵŽƵƐ ŽƉĞƌĂƟŽŶ ͻ ƚǁŽͲƐƚĂŐĞ ŐƌĂŶƵůĂƟŽŶ ŝŶ ŝĂŐŽŶĂůͲ ĞƐŝŐŶΠ ͻ ĐŽŶƐŝƐƚĞŶƚ ƐĞƉĂƌĂƟŽŶ ďĞƚǁĞĞŶ ƉƌŽĐĞƐƐ ŵĂƚĞƌŝĂů ĂŶĚ ƚĞĐŚŶŝĐĂů ĞƋƵŝƉŵĞŶƚ ͻ ƌŽůůĞƌƐ ŝŶ ĐĂŶƟůĞǀĞƌ ĚĞƐŝŐŶ ͻ ƚŽŽůͲĨƌĞĞ ĚŝƐĂƐƐĞŵďůLJ ͻ ŵĂĚĞ ĐŽŵƉůĞƚĞůLJ ŽĨ ŚŝŐŚͲƋƵĂůŝƚLJ ƐƚĂŝŶůĞƐƐ ƐƚĞĞů ͻ ĐƵƐƚŽŵĞƌͲƐƉĞĐŝĮĐ ĐŽŶƚĂŝŶŵĞŶƚ ƐŽůƵƟŽŶƐ ͻ ůĞdžĂŶĚĞƌǁĞƌŬ ŝƐŽůĂƚŽƌ ƚĞĐŚŶŽůŽŐLJ ĨƵůĮůƐ K > ϰ ĂŶĚ ϱ ͻ ŶŽŶͲŵĞƚĂůůŝĐ ƉĂƌƚƐ & ͲĂƉƉƌŽǀĞĚ ͻ ĞĂƐLJ ĂŶĚ ĂĐĐƵƌĂƚĞ ƐĐĂůĞͲƵƉ /ŶƚĞƌŶĂƟŽŶĂů ƌĞĨĞƌĞŶĐĞƐ ĐŽŶĮƌŵ ŽƵƌ ƐƵĐĐĞƐƐĨƵů ŝŵƉůĞŵĞŶƚĂƟŽŶ͘ www.alexanderwerk.com | +49 (0)2191 795 0

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REGULATORY COMPLIANCE

Success story: The success of manufacturers depends highly on their ability to comply with new pharma rules and regulations.

T

he success of manufacturers depends highly on their ability to comply with new pharma rules and regulations. The regulatory compliance burden on pharmaceutical manufacturers has become more stringent over the last years. This makes achieving regulatory compliance with REACH, cGMP, EMA and FDA regulations easier said than done. It is not only the quantity of regulations, but also the complexity that causes problems.

It all started with the electronisation, from a paper-based pharmaceutical industry and the implementation of best-of-breed solutions. As of today, these non-integrated solutions continue to prove to be costly, resource intensive and oppose a high risk of error. What’s more is that the pharmaceutical manufacturers working with these separate nonintegrated solutions need to mitigate the high risk of human error and the incorrect handling of information (for example the duplication or wrong versioning of critical documentation).

Following the electronisation of the pharmaceutical industry, the United States Food and Drug Administration (FDA) introduced 21 CFR Part 11, a regulatory standard considering that electronic records and signatures are trustworthy, reliable and equivalent to paper records and handwritten signatures. FDA 21 CFR Part 11 applies only to the United States; however, similar international standards have been introduced in several countries.

Rules of engagament Ben van den Bosch, AX for Pharma, looks at regulatory compliance – FDA 21 CFR Part 11

The European Commission has adopted Annex 11 (Computerised Systems) to Volume 4 (Good Manufacturing Practice (GMP) - Medicinal Products for Human and Veterinary Use) of the Rules Governing Medicinal Products in the European Union (EudraLex).

Annex 11 is patterned after 21 CFR Part 11 and applies to all forms of computerised systems used as part of GMP-regulated activities.

FDA 21 CFR Part 11 provides control objectives for establishing trustworthiness and reliability of electronic records and electronic signatures. These control objectives can be technical or procedural: • Technical controls relate to the status of, and specific functionality built into, computerised systems used to support regulated activities; each applicable computerised system must evidence compliance to these controls. Technical controls include the following: 1) the computerised system performs as intended; 2) only authorised access to and use of the computerised system is permitted; 3) all regulated data is maintained,

can be reconstructed and can be readily retrieved; 4) the uniqueness of credentials using the computerised system and applying electronic signatures can be guaranteed, etc.

• Procedural controls are those policies and procedures which define processes that support compliance to 21 CFR Part 11, including: 1) computerised systems are developed, deployed and maintained in a formal and appropriate manner; 2) all documentation for computerised systems is current and reflective of the operation of the respective system; 3) all electronic records are backed up and recoverable; 4) all electronic records are protected against unauthorised logical and physical access; 5) all staff who develop, maintain and use the respective computerised system is appropriately trained.

All policies and procedures should be developed, approved and maintained as “controlled documents” which are versioned documents, populated with specific information, and are generated and maintained to support a regulated activity.

The majority of the business areas covered by an enterprise resource planning (ERP) system that are relevant to FDA GxP must comply with 21 CFR Part 11.The functional areas that are exempt from the FDA are finance, administration, sales and marketing, planning and forecasting.

AX for Pharma is a fully integrated ERP solution for the pharmaceutical industry, based on Microsoft Dynamics AX. The solution provides integrated modules to ensure global regulatory compliance and specifically FDA validation by controlling critical actions with electronic signatures, audit trails and the use of extensible, dynamic record-level security and permissions to define access rights and functions by user group, document status and other parameters.

The following AX for Pharma modules comply with 21 CFR Part 11: -

Advanced Quality Management (quality control, quality management);

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Basic Pharma (supply chain, manufacturing, inventory);

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Dispensing;

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GMP Plant Maintenance.

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3 370 international suppliers in packaging and advanced drug delivery technologies 3 3,300 senior level managers from pharma companies expected

EXHIBITION & CONFERENCE 11&12 FEBRUARY 2015 PARIS EXPO, PORTE DE VERSAILLES, HALL 5

Innovation, Networking & Education in Pharmaceutical Packaging and Drug Delivery Technologies

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ED th FEA ITION TUR ING :

3 2 day conference to hear about the latest market trends for packaging developments and new drug delivery systems 3 1 day Technical Symposium dedicated to Serialisation, Track & Trace 3 Workshops allowing an in-depth discussion in ÎÈäc ëiV wV ÌiV V> ÃÃÕià 3 NEW! A learning lab to enable visitors to learn how to apply new concepts or tools to their projects 3 NEW! 2 networking breakfasts on the North American and Chinese markets 3 Innovation Gallery showcasing recently launched products, organised by product category 3 The Pharmapack Awards ceremony rewarding the most innovative solutions

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FREEZE DRYING Stable mates Freeze drying with collapse is not necessarily bad for stability and can reduce cost

Concerning the process, the cycle is usually running below collapse temperature to avoid a loss of physical structure, an incomplete drying (high moisture content), a decrease of solubility (or increase of aggregation), or a decrease of activity and/or stability. In addition, the best freeze drying cycles are those that have been optimised to be as short as possible: run at high temperature to run fast. In that case, formulation should have a high glass transition temperature to facilitate freeze drying. Some disaccharides like sucrose are often good stabilisers for proteins but unfortunately they have a low collapse temperature.

esters at alkaline pH, the method for the measurement of alkaline phosphatase specific activity was based on the conversion of paranitrophenylphosphate (p-NPP) to para-nitrophenol and the colorimetric determination of the resulting coloured product.

A formulation by combining alkaline phosphatase, Tris HCL buffer and sucrose was defined. The collapse temperature (Tcoll) was measured using freeze drying microscopy (figure 1).

The formulation was poured into a vial and loaded in a freeze dryer. Two cycles were running: one with a “conservative” freeze drying protocol which maintains the product temperature below collapse temperature (time of cycle : 72 hours, cf. figure 2) and an “aggressive” freeze drying protocol carried out at higher temperature and higher pressure which does not maintain the product temperature below collapse temperature (time of cycle : 48 hours, cf. figure 3). In the first case the appearance of the freeze dried products were good, in the second case they showed signs of collapse but the cycle was shorter (figure 4).

+20°C

Specific activity recovery of alkaline phosphatase during storage

-15°C Tc = -38.5°C

Collapse sucrose Shelf Temperature

Product Temperature

Chamber Pressure

Figure 2: Conservative cycle.

F

Fi Figure 1 1:: Mi Microsco Microscopic pic i observ observation b atition off fformulation ormullatition by combining alkaline phosphatase, Tris HCL buffer and sucrose.

Figure 4: macroscopic view of freeze dried formulation by combining alkaline phosphatase, Tris HCL buffer and sucrose, on the left collapse structure, on the right no collapse structure.

Conservative Cycle : 72 h

-40°C -50°C

Collapse area C

This presentation is for informational purposes only and it is not about new guidelines for stabilisation of proteins by freeze drying but it suggests that in some cases, not generally speaking, we can freeze dry above the collapse temperature to have a short cycle which implies lower costs without causing damages to the product if we do not care to have a not elegant product, if the product aspect is not that important.

Specific activity recovery %

L

yophilization is often used to increase the stability and shelf life of proteins which are physically and/or chemically unstable in aqueous solution. Freeze drying removes water protein solutions, including water from the protein surface which plays a major role within the protein structure, and this frequently causes damage. An appropriate choice of stabilising additives is necessary to protect the protein from the denaturing during both the freezing and the dehydration. The components of the excipients displace water by replacement, which makes the drying possible without causing damages to the proteins. In addition the solidification of the excipients forms a matrix around the particles which keeps the protein in their native structures.

T These measurements are performed in a accordance with a TO and after storage at a 2 25°C temperature conditions. The results of s storage stability in dried state (figure 5) confirm th sucrose stabilises the protein conformation that a against denaturing but more particularly the re results suggest that the freeze dried product with s signs of collapse did not damage the alkaline p phosphatase quality. The specific activity recovery o alkaline phosphatase is quite the same with a of collapse macroscopic structure than with none.

No collapse sucrose

120,00 100,00 80,00 60,00 40,00 20,00 0,00 0

5

10

15

20

25

30

Days

Figure 5: Specific activity recovery of alkaline phosphatise as a function of the storage with or without collapse structure.

Aggressive Cycle : 48 h

Recent studies seem to indicate that drying above the collapse temperature is not necessarily bad; the protein stability is not always damaged. Our objective was to study the activity and stability of a freeze dried protein in vials which shows signs of collapse. The protein selected was the alkaline phosphatase (from Sigma Aldrich) which is used to help detecting liver disease. The enzyme may catalyse the hydrolysis of various monophosphate

+20°C

freeze drying above the collapse temperature

-15°C Tc = -38.5°C

-40°C -50°C

Shelf Temperature

Product Temperature

Chamber Pressure

Figure 3: Aggressive cycle.

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PARTNERSHIPS Team effort: Following discussions between Debiopharm and Frewitt, meetings were held to discuss the possibility of changing the HammerWitt mill to meet customer needs

A few points are presented about the new challenges faced by pharmaceutical companies at the conclusion of Ernst & Young's study: "Product demand has historically been determined by the physician.

Patient product forums have an increasing influence on competition.

This increases transparency leads to... increasing price pressure."

The comment by Dr Hartmut Klocker, the head of VSS Pharma Siemens, may provide a direction to suppliers to the pharmaceutical industry on how they can respond to increasing price pressure: "The demand for so-called multipurpose systems to manufacture several substances in one system will increase."

The benefits of a flexible system in the production of very small and small volumes should be shown in a project which has been codeveloped by Debiopharm and Frewitt in a collaborative partnership.

Flexible thinking The change in the pharmaceutical industry has led to a change in perspective for all participants: In the past, the majority of people at Frewitt discussed machines; today, processes and the customer's products are the key areas of focus.

There is no longer a question of finding the right machine, but rather adapting the machine to the process and the product to the customer. That does not make things easier, but does make the issue more exciting. The process is designed during development to be able to avoid quality deviations.

Understanding critical quality attributes and process parameters can lead to better control of

Results driven According to a study by Ernst & Young in 2012, the world’s 19 largest pharmaceutical companies invest nearly 70 billion in R&D; there are about 200 projects in clinical development at the pharmaceutical giant in Switzerland production processes. Design of experiments (DoE) has become an indispensable tool in determining the relevant process parameters in many cases.

Debiopharm, a developer and manufacturer of medicines in the areas of oncology, immunology, metabolic and infectious diseases, contacted several Frewitt managers during 2012. Following the first few discussions, meetings were held to discuss the possibility of changing the HammerWitt mill to meet customer needs.

The machines should be operated under stable process conditions, and small quantity (50g) manufacturing should be reproducible. A further requirement was a modular design for easy assembly and disassembly.

Stable process conditions The term 'stable process conditions' is used often in chemistry where reactions must be run at a controlled, stable temperature, and in metallurgy, where the temperature must be raised in a stable manner. A stable temperature increases the precision of the workpiece, decreasing rejects.

In Debiopharm's case, the product temperature needed to be stabilised

below -0 deg. C in order to ensure stable flow characteristics and product moisture contents.

The HammerWitt-3 was best suited to fulfill these requirements. At first, the feed hopper of the hammer mill was modified in order to be able to cool the product load with liquid nitrogen to the target temperature.

C. An inlet plug for a 1 litre container was used for gassing with nitrogen.

The grinding chamber was executed with ATEX II 1G/D (zone 0/20) conformity, and mounted under the Conidur perforated plate with two temperature probes, in order to measure the screen temperature and control and hold it stable by the PLC. A time measurement instrument was built into the drive unit in order to ensure that the run time remained the same. An important factor for temperature control is a fan with a pressure sensor to control air volumes. A filter and de-dusting ProFi-Clean 90 system was mounted at the connection to the air supply of the building.

A cylindrical 3-litre product container was installed at the outlet as a further customer-specific product.

Debiopharm did not want to mount the electronic switchbox on the hammer mill housing, but rather to connect it by cable to the machine in order to be able to use this with a wall-mounted system.

Process display It is important to the user to be able to intervene in the process, if needed. Several means are available to achieve this: A mill speed display (measured on the shaft), the actual current value of the motor and the motor starting time. RPM can be set using a potentiometer. The mill is automatically stopped if there is a fault.

Filter system The ProFi-Clean 90 filter system is a module that ensures that there is no overpressure in the discharge hopper, and the product always flows out of the mill chamber at the same rate. The suction system valve is activated (using a venturi effect) as soon as the mill motor runs and remains in this state, until it stops. The filter is cleaned with a one-second impulse at least every three minutes.

The future and a look back It's important to keep our heads when discussing the development of a mill with an integrated cryogenic system and a continuous dosing system that fulfills quality requirements. At this point, we should look back to the project which allowed Debiopharm to realise considerable savings; the customer commented: "We hope in the future for Frewitt's continued support in carrying out such mill projects."

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BIOPHARMACEUTICALS

Growth chart Stephen Luke, Agilent Technologies, discusses driving innovation in the biopharmaceutical industry with new technologies for mAb characterisation

I

n recent years there has been a dramatic shift within the pharmaceutical industry towards the development of biopharmaceuticals.

The global pharmaceutical/biopharmaceutical industry is expected to grow in value from $830 billion in 2012 to $980 billion in 2017 and the biopharmaceutical market share is set to almost double from 18% to 31%.

The increasing focus on the development of biopharmaceuticals has meant that both large and small pharmaceutical and biopharmaceutical companies as well as contract research organisations (CROs) have had to consider the techniques and technologies they use to achieve reliable, accurate, reproducible results.

Trends and technologies While biopharmaceuticals is not a new market one area receiving increased attention is monoclonal antibodies (mAbs). Growing at a rate of 18% and representing 32% of the biologics market, there has been a significant shift in emphasis and spend on the development of mAbs for the biologics pipeline. mAbs are designed to attach to binding sites with high specificity but any changes in primary structure can have a negative impact on efficacy and immunogenicity. The full characterisation of mAbs is therefore essential but it is a complex and multi-step process that requires multiple techniques.

Due to the complexity of biological materials, regulatory bodies require the absolute and accurate characterisation of biologics and new technologies have been developed in order to provide the accurate, high-throughput and robust analysis required. The key challenges for those involved in biopharmaceutical analysis are achieving excellent accuracy quickly, complete characterisation to meet regulatory requirements and reliable results to ensure product consistency.

Liquid chromatography (LC) methods that enable the effective characterisation of mAbs

are required to support the development of mAb biotherapeutics during late drug discovery, early drug development and QA/QC. In addition, the need for faster analysis methods has led to a move towards UHPLC and smaller particle size columns. Protein biopharmaceuticals are heterogeneous a number of chromatographic techniques may be required for full characterisation. Methods include size exclusion chromatography (SEC) for the quantitation of dimers and aggregates, and ion-exchange (IEX) chromatography for the identification of charge variants. Reversed-phase (RP) liquid chromatography and hydrophilic interaction chromatography (HILIC) are also key techniques used in biochromatography.

Removing the puzzle There are four key considerations to achieve full mAb characterisation including; establishing the primary structure of a mAb, identifying glycosylation patterns, analysing charge variants and monitoring aggregation levels. Each of these steps is essential to establishing the efficacy and toxicity of a biopharmaceutical early on in the development process to avoid major, and expensive, setbacks downstream.

Column selection, column quality, mobile phase selection and detection requirements are all crucial to achieving high quality, reproducible and robust separations. Two of the most significant developments have been in improvements in the technologies available for peptide mapping, which is part of the process involved in establishing the primary structure of a protein, and glycan mapping.

Despite the fact that run-to-run reproducibility and stability are essential for maintaining robust peptide mapping separations, the quality of the column used is often overlooked. Smaller diameter fully porous column materials using slower flow rates are the popular choice for the separation of peptides which has led to an increase in sub-2Âľm

packings, achieving more efficient peptide maps.

However, superficially porous columns, such as the Agilent AdvanceBio Peptide Mapping column, have recently become the column of choice for biological separations in biopharmaceutical applications because they address the limitations of protein and peptide mass diffusion. Peptide maps rely on repeatable operation of the column for delivering precise mapping fingerprints and repeated validation protocols so when choosing a column for peptide mapping, column quality should be at the forefront of the decision making process.

The glycosylation patterns of mAbs have a significant impact on the efficacy of a biotherapeutic drug. Glycan mapping is therefore an essential part of the mAb characterization process but it is a complicated and multi-step process. Glycans are hydrophilic structures so hydrophilic interaction chromatography (HILIC) using fluorescence detection, is a robust separation method for glycan analysis. One of the biggest challenges in HILIC/LC is achieving high-resolution with fast analysis times without compromising performance. Rapid, reproducible and high resolution glycan mapping is now achievable thanks to developments in column technology.

The future In the drive to reduce the time and costs associated with the development of biopharmaceuticals, researchers cannot compromise on analytical accuracy. Patient safety is paramount which makes the complete and accurate characterisation of mAbs essential to the delivery of the next groundbreaking biotherapeutic. New technologies for the characterisation of mAbs provide the selectivity, resolution and reproducibility required to enable researchers to meet regulatory requirements, avoid costly re-work and continue to innovate in the field of biopharmaceuticals.

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AUTOMATION Auto route Chris Sumner, managing director of Fanuc discusses the use of robotic applications within pharma. The sector has been slow to adopt the technology but industry figures suggest that the tide is turning and the sector is starting to realise the potential of robots in a range of applications

T

he future certainly looks bright for robots in the pharmaceutical sector. They have found their way into the packaging process and, as the sector becomes more comfortable with robot technology and begins to integrate it into legacy systems, new applications are now starting to be found throughout the pharmaceutical manufacturing process.

Mirroring many other industry sector requirements today, the pharmaceutical industry needs to be able to ensure that its packaging solutions are reliable and effective and that the valuable product is protected throughout the packaging process.

The particularly innovative nature of pharmaceutical products needs to be matched by equally ingenious packaging variations and this can make the packaging process increasingly more complex and difficult to achieve using manual labour.

Having the flexibility to quickly adapt a packaging line to accommodate these developments could prove to be a key differentiator for success in the sector. End-users are becoming more receptive to the use of robotic solutions. In the UK, for example, the use of robots in the pharmaceutical, healthcare and medical sectors is increasing.

According to figures from the British Automation & Robotics Association (BARA) no robots were sold into these sectors in 2000. In 2012, however, there were a total of 43 recorded sales.

This figure represents an increase of 115% since 2011, and makes it the biggest growth sector for robots between 2011/12, after the automotive sector. In 2009 Fanuc reached a total of 295 robot installations in the pharmaceutical sector, 150 of these are being used in major international pharmaceutical companies.

Figures from the International Federation of Robotics (IFR) also demonstrate a noticeable increase. Global robot deliveries into the chemical, pharmaceutical and cosmetics sectors in 2010 totalled 1,468, with Europe accounting for 512 of these. European figures include a mix

of articulated, cartesian, articulated parallel (also known as delta robots) and SCARA style robots.

The main type of robots used in these sectors are said to be articulated arm robots (mostly 6-axes) for picking, packaging, handling and palletising. A large number of SCARA robots are used for picking and packaging. A new and growing area highlighted by the IFR for the sector is that of delta type robots, for high speed picking and packaging.

Fanus has identified some typical application areas, which include palletising, packaging and pick & place, as well as machine tending.

Although not currently well used in the sector, there is also a growing trend towards the use of delta robots too, which are able to offer a very high-speed picking solution for small parts.

Merck, for example, has successfully employed a Fanuc M-1iA delta robot on a bottling line, to place dispenser caps onto bottled allergy medications. The M-1iA is capable of operating at 120 cycles per second. Ten variants of the bottle can be run on the system and the only robot line change requirement is to select the appropriate programme on the robot controller.

Although uptake of robotics in the pharmaceutical sector is increasing, it is still slow and this can be attributed to companies continuing to rely on specialised manual labour for picking and packaging operations. Many, wrongly believe that a robotic solution would be too costly and would require too much system integration work and expensive personnel training. A good solution to overcome this reticence could be to start to introduce robots initially into areas where working conditions are toughest for human operators – where noise and dust can pose problems, for example, allowing operators to be redeployed to more pleasing working environments.

Areas that could gain the most benefits from the introduction of robots are in pick & place applications, where product needs to be removed from a machine or conveyor and packed into blister packs or boxes. Robots can also offer consistently gentle packaging solutions including

palletising boxes at the end of the line. In such applications robots are already well-proven and evidence has shown that they can offer a fast, clean, efficient and cost-effective alternative to manual labour.

A vision solution is vital in many pharmaceutical applications to enable inspection, position and orientation capabilities. Where products are picked from conveyors by a robot, the addition of robot vision is essential to ensure fast and precise handling and packaging. Additionally, barcode reading and visual quality control can be incorporated to further streamline and accelerate production capabilities.

The pharmaceutical sector in particular depends on automated process-control and qualityassurance systems to ensure that every batch is identical to the previous one. In addition, the requirement for pharmaceutical packaging to carry identical labels can be streamlined through the use of robot vision and barcode scanners which help speed up throughput, automating the task of comparing the labels on incoming products with an original, master copy.

There is also a growing requirement to monitor and record every step of the production process.

These traceability requirements – combined with the need for labelling and traceability right down to the individual product – will almost certainly benefit from an automated solution which can ensure accuracy, continuity and reliability.

Meeting demands Today’s robots are able to meet demanding pharmaceutical requirements. For example, grippers are available that can gently handle the wide range of product formats, such as bags, bottles and tubes. Cleanroom robots are also available to help automate laboratory processes.

Robot models, such as the as Fanuc M-430iA, have been developed with clean surfaces – for regular disinfection, for example.

In the laboratory environment robots can now replace human operators undertaking sterile

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Seeing is believing: iRVision from FANUC. Adding ‘sight’ to a robot is vital in many pharmaceutical applications to enable inspection, position and orientation capabilities

Point of interest: A six axis Fanuc LR Mate 200iB handling syringes

manufacturing processes, where there may be a contamination risk. In one laboratory application a Fanuc M16iB was chosen for its reliability and speed to create a single point handling solution for vial processing.

A bright future?

Justification for the use of robots in the pharmaceutical industry is wide-ranging – from better worker safety to improved overall product quality. Speeding up the drug discovery process could be yet another benefit, helping industry to meet the ever-increasing call for new drugs to treat the world’s growing ageing population. Robots have already shown that they can improve productivity and efficiency in many industries and the pharmaceutical industry is now starting to make use of these abilities too.

SOURCES: *FEC FANUC Europe Corporation *BARA – British Automation and Robot Association Statistics *IFR – International Federation of Robotics - World Robotics Industrial Robots 2011 Report

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Containment: Case study Who:

Powder Systems Limited (PSL)

What:

A European contract manufacturer, needed to safely manufacture clinical trial batches of ADC for antibiotic production

How:

By using high containment full synthesis facilities from PSL

Boxed off

T

he API manufacturing site was awarded a contract for the production of advanced antibiotics using ADC drugs.

Antibody-drug conjugates (ADCs) are a new class of highly potent biopharmaceutical drugs. These complex molecules are composed of an antibody (a whole mAb or an antibody) linked, via a stable, chemical, linker with labile bonds, to a biological active cytotoxic payload or drug.

The end user was contracted for the clinical trial production of this drug by a blue chip pharmaceutical group. To fulfil the contract, the API plant required the installation of new process equipment and facilities for the synthesis of small scale ADC for injectable antibiotics.

The new production line consists of the following process steps: reaction, filtration and drying. The synthesis steps requires the use of isolation technology to protect both the product and the environment from the potent ADC. A full high containment suite was designed and built by PSL to integrate efficiently and safely the synthesis process equipment necessary to the production of ADC.

High containment synthesis facilities PSL’s scope of supply was a full process solution from engineering and feasibility studies to Installation and Qualification. The isolation suite consists of 10 gloveboxes combined together including clinical trial production process equipment.

First the preparative chamber made of two gloveboxes, one for the safe entry of the raw material with airlock system and one integrating the dissolution vessel supplied by another manufacturer. In this chamber the raw material is dissolved under controlled parameters prior to transfer to the reactors.

Plus points: Compared with a cleanroom, the solution provided is more compact, ergonomic, flexible, safe and economical This is the second step, the reaction chamber. However, the isolator suite separated here into two mirrored production lines: one for the crude production and one for the finishing. Each of the chambers is identical and contain process glassware and filter used for the reaction operation.

The third synthesis step is within the drying chamber. Again, the process is duplicated in two chambers, one for the Crude and one for the Finishing. Each cell contains a tray dryer for efficient vacuum drying. The tray dryers supplied by PSL are designed in accordance with sound engineering practice and manufactured in accordance with ASME VIII. The ovens work under full vacuum up to 0.5 bar, and 6 bar for the heating element. The temperature of the dryer is up to 130°C to efficiently dry the product contained into bottles at this stage.

Finally, two airlock chambers finish the two production lines for a safe transfer of the crude and finishing product at the end of the synthesis operations.

The high containment facilities guarantee an Occupation Exposure Level (OEL) of less than 20 nanogram per m3 on eight hours time weighted average (TWA). Such level of containment was required to ensure the protection of the operators and the environment from the potent ADC. After installation, OEL tests were performed on site by a third party industrial hygienist and the results exceeded the levels requested by the end user, with a 15ng/m3 8h TWA exposure in the finishing drying chamber and less than 2.7ng/m3 8h TWA to nondetectable exposure in the crude drying chamber.

Extreme containment is achieved by considering the following key elements:

Installing a full new process suite is a lengthy process requiring the expertise of all the entities involved (buyer, project manager, suppliers, OEMs, third parties…)

The new clinical trial facilities were a successful project in term of integration between the various suppliers, and the installation is now ready to produce ADC drugs.

Compared with a cleanroom, the solution provided is more compact, ergonomic, flexible, safe and economical. The end user benefits from the process and engineering expertise from experienced manufacturer in their field providing equipment renowned for their longevity and performance.

• Quality of main fabrication and welding • Product transfer • Extraction and air filtration • Cleaning method • Ergonomics review • Control and full automation • Factory Acceptance Test (FAT) • Installation and Operation Qualifications

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PURIFICATION AND FILTRATION Automated call A rise in automated processes has seen life scientists free their time, increase productivity and lower costs within their research. How can scalable lab automation work for you?

BioPharma Dynamics explains If you’re considering whether to automate your lab processes, the first thing to determine is what you are trying to achieve. Life scientists have seen the benefits of lowering costs, reducing time and introducing an element of repeatability to their processes. Once you are clear on this, you can begin to look at the options available.

When automating a system, a variety of control parameters – including pressure, temperatures, flow and conductivity – must be considered along with the level of accuracy you are looking to work to. With these considerations in place, scientists can set up, run and analyse the results of experiments with maximum efficiency.

The growing emergence of laboratory automation eliminates the time operators spend on repetitive and tedious tasks, allowing them instead to carry

out more productive projects as the system stops, starts and logs readings based on the criteria.

Automation is also the best way to minimise, or even eradicate, operator error, giving a repeatable process every time through accurate monitoring and control. Regardless of an operator’s level of experience, any mistakes made can have a profound impact on data; removing the dependency on the operator’s interpretation will deliver consistent quality to the results.

Solutions solutions: There are off-theshelf automation solutions available for some of the more common processes in the lab

There are off-the-shelf automation solutions available for some of the more common processes in the lab, such as bioreactor harvesting, filter integrity testing, normal flow filtration (NFF), tangential flow filtration (TFF), dispensing, sampling, and cell culture filtration.

Clean act Bosch introduces the CIP system specifically for use with human vaccines The development of human vaccines comprises three successive process steps: preparation, purification, and formulation.

During the first phase, eggs are inoculated with virus-containing material for selective replication of viruses in the laboratory.

To separate the viruses, the egg-based preparation is purified in several steps by means of filtration and addition of buffer solutions.

The CIP system from Bosch is used for cleaning the pharmaceutical purification equipment, which ranges from the harvesting system to a variety of filtration and separation systems to the process tank with finished active substance concentrate, and at the same time thermally inactivates the wastewater.

Operator safety Handling of live viruses poses a threat to the staff and requires high equipment security measures. Consequently, the CIP system and all system modules are designed according to biosafety level 3 (BSL 3).

To keep viruses from escaping to the outside, Bosch has designed a completely closed system with fixed piping and a hermetic CIP pressure vessel. The pumps for supply and return of rinsing media are equipped with double mechanical seals and sealing liquid (pure steam condensate) in the space between the seals, ensuring that no contaminated cleaning media escapes into the environment.

Clean and clear: The CIP system from Bosch is used for cleaning the pharmaceutical purification equipment

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SPOTLIGHT Centre piece Roquette, a global supplier of raw materials for the health sector, describes the benefits of its new pharmaceutical application development centre at its Lestrem site

l quette’s pharmaceutica Centre of attention: Ro the le ab en l wil e ntr ce nt application developme l s for the pharmaceutica creation of new solution industry at global level

R

oquette, one of the world’s largest starch producers, now has a new pharmaceutical application development centre at its site at Lestrem, Pas de Calais, France.

For the Roquette Group, a global player in the transformation of plant-based raw materials, the new centre will help consolidate its position as a leading supplier of excipients and active ingredients to the pharmaceutical industry. The dedicated laboratory of 800 m2 benefits from the latest technologies and a team of experts and should help reinforce the company’s relationships with its customers.

A place to share expertise Designed as a place to share expertise, the pharmaceutical application development centre will enable the creation of new solutions for the pharmaceutical industry at global level. The technologies in this laboratory, such as compression, film coating or granulation, will ensure the development of new galenic forms. They will also

provide expertise and know-how in the science of pharmaceutical formulation.

The centre offers the highest standards of safety, hygiene and quality in this sector. By working with the group’s laboratories for research, control and analysis, the new pharmaceutical development centre will reinforce existing collaborative relationships and help develop new partnerships. It will also provide technical support and act as a training centre both for Roquette’s internal teams and its customers.

Listening to market needs For more than 40 years, Roquette has carefully listened to the needs and expectations of its pharmaceutical customers.

The group has become a key supplier of excipients and active ingredients, the two main components of medicinal drugs.

The company generates value from its plant-based raw materials to develop and offer numerous galenic forms to patients: syrups, drinkable solutions, tablets, capsules,

powders, etc. The excipients produced by Roquette are designed to facilitate industrial production and cover a broad range of pharmaceutical applications. They allow medications to be taken in ways that are appreciated by patients (from infants to seniors, from young children to adults, or patients in hospitals).

compression simulator, as well as the expertise of the dedicated team allow us to pursue our innovations and respond to the expectations of this highly demanding sector in terms of quality, safety and performance.

Thanks to this centre, Roquette again demonstrates its ambition to establish privileged long-term partnerships with its customers.”

One of the latest innovations of the group applies to a galenic form that is currently generating a lot of excitement. Roquette has developed an excipient for orodispersible tablets. This new form melts directly in the mouth without the need to drink any water, providing immediate action for the patient.

Guillaume Fichet, director of the Roquette Lestrem site, added: “The creation of this new application development centre on the group’s largest site at Lestrem enables synergies with all of the group’s research laboratories and production units at the site. Its ambition however is global. Located at the heart of Europe, this application development centre is in direct contact with the three other major regions of the group (North America, Asia and India) and will serve our pharmaceuticals customers throughout the entire world.”

Isabelle Routier, vice-president, application development centres for food nutrition health, said: “With an annual global growth rate of nearly 5%, the market for excipients offers excellent opportunities as well as numerous challenges in terms of formulation. This new pharmaceutical application development centre is proof of Roquette’s commitment in the health sector. The technologies acquired, such as this latest generation of

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Go ahead, save the day.

You can when you have unparalleled ultrafiltration.

At the last crucial step before your product goes out the door, you don’t want to take chances with a less than perfect solution. At Merck Millipore, we know the entire purification process, allowing us to provide you with the insight and products, including Pellicon® ultrafiltration cassettes, that provide you with confidence in the purity of your final product. So go ahead and save the day.

Your cape is waiting at:

www.merckmillipore.com /ultrafiltration

Merck Millipore, the M logo and Pellicon are registered trademarks of Merck KGaA, Darmstadt, Germany.

PS-14-10454 11/2014 © 2014 EMD Millipore Corporation, Billerica, MA USA. All rights reserved.

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CHEMICAL REACTION It’s important to keep on top of the latest services, companies and individuals. EPM’s Chemical Reaction highlights a technology or business we think would be worth your while keeping in the mix...

Leading the way Creating what’s thought to be the world’s first child-resistant recloseable packaging and scooping an innovation in packaging award, are no mean feats. Ron Linssen, Ecobliss explains what’s behind the company’s success and its Locked4Kids packaging innovation

EPM: Who are you and what do you do?

RL: Ecobliss expertly and successfully guides and executes the packaging processes of companies of all sizes throughout the world.

With comprehensive supporting services, we provide an integrated approach to both traditional and innovative packaging projects. We do this using our three-step business model of development, realisation and implementation.

From the development of packaging designs, the production of the packaging components, the supply and configuration of the right equipment, Ecobliss will make sure that everything falls into place.

Ecobliss has a strong position within the blister and high visibility packaging industry. Large companies in the electronics, DIY, automotive, pharmaceutical, cosmetics sectors use Ecobliss as their starting point when pursuing a packaging solution.

EPM: What have you focussed on recently?

RL: Our focus has been on the protection of young children against poisoning through the development of mass producible child resistant packaging.

80% of solid drugs in Europe are packed in blisters, compared with less than 20% of those in the United States. The vast majority of all drugs in Europe are put on the market in cartons containing blister strips.

There is a substantial chance that, in an unguarded moment, small children might open such a carton and swallow its contents. In Europe alone, 3,000 young children die each year from the consequences of drug poisoning or poisoning due to the ingestion of household chemicals.

EPM: What is your latest service / innovation?

RL: Our latest innovation is Locked4Kids, the world’s first child resistant carton that complies with the stringent European (ISO 8317) and US 16 CFR 1700.20) standard for child resistant packaging.

EPM: How can you benefit the pharmaceutical sector?

In October 2014 Locked4Kids has won the CPHI Pharma Award for innovation in packaging, and silver in the most competitive packaging contest in the World “De Gouden Noot” Locked4Kids consists of a carton and a tray in which products such as blisterstrips are positioned. The carton has openings at two sides in which the tray automatically locks when fully inserted. The tray has hooks at two sides which have to be pushed simultaneously to unlock. While keeping the hooks pressed the tray should be pulled out of the carton.

RL: Locked4Kids cartons can accommodate as many blisterstrips as required per carton (equal to non CR cartons with blisterstrips). It’s a regular carton construction which is simple to produce on existing production equipment.

Locked4Kids is very competitive against any other mass producible CR solution in the market. Automation is possible at the same speed and efficiency as non CR cartons with blisters. The cartons can be processed on existing production equipment, from companies such as Romaco.

EPM: Future plans?

The push points are placed diagonally across each other at a distance that adults can physically cover. This distance however is too much for young children.

RL: Locked4Kids will be made available to the pharmaceutical industry by licensing pharmaceutical carton manufacturers for the production and marketing.

To prevent children from tearing the carton box, a tear resistant laminate has been applied to the cardboard. Locked4Kids is patent pending.

Furthermore, Ecobliss will continue to develop new packaging solutions, and improve existing packaging concepts.

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Our Commitment To Deliver an Exceptional Customer Experience.

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We believe our customers deserve nothing less than exceptional service, at every stage of their product’s development, from each phase of clinical development to successful commercialization. Our experienced team offers expertise in all aspects of clinical packaging, storage, and distribution services. We are with our clients every step of the way, providing scalable solutions to support the earliest Phase I studies to the largest global Phase III/IV studies.

The ultimate measure of success is commercialization of your product, and PCI helps navigate the clinical phases in launching over 50 new products a year. Our expertise helps clients bring products to market efficiently and effectively, with keen insights to enable launch and commercial success. With an expert team focused on your investigational product, PCI is uniquely positioned to support your product throughout its life cycle.

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Exceptional customer support for the success of your clinical trial.

PCI - One Partner for all your development needs.

Global Reach with 14 packaging facilities in North America and Europe

www.pciservices.com Š Copyright 2013 Packaging Coordinators, Inc. All Rights Reserved.

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For 60 years Elizabeth has excelled in offering total tableting solutions to the pharmaceutical, nutritional, confectionary, battery, chemical catalysts, energy and automotive industries. Our products include Hata & Eliza-Press rotary tablet presses, Elizabeth compression tooling (punches and dies), Elizabeth Scheu & Kniss replacement press parts, turrets and Your Global Source for Tableting Solutions services, and Elizabeth blister packaging format tooling and feeders. www.eliz.com 412-751-3000

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