EPM September 2016

MATERIAL WORLD: SCHOTT’S HOLISTIC APPROACH TO MATERIAL SELECTION PLUS: • CPhI IN FOCUS • TASTE MASKING • CLINICAL TRIALS

SEPTEMBER 2016

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Contents September 2016 | Volume 16 Issue 6

Regulars 5

7

Features 14

COMMENT

GLOBAL VISION An in-depth look at what this year’s CPhI has in store

6 NEWS FOCUS

23

8

SMOOTH OPERATOR

30

REGULATORY AFFAIRS

13

24

OPINION

A QUESTION OF TASTE

Mettler Toledo is quizzed by EPM

Colorcon discusses how tastemasking can be used as a strategy to improve adherence and Excipact looks at excipient opportunities in Europe

10 COVER STORY Schott describes its holistic approach to material selection

50 PHARMA AT THE FLICKS

How I Holland helped create savings on a sticky ibuprofen formulation

41

29 SMART THINKING ERT and GSK highlight the use of technology in clinical trials

35 PROBLEMS SOLVED Thermo Fisher Scientific discusses the mounting costs of everyday lab problems and how to avoid them

39 SOLVENT BUSINESS Peak Scientific Instruments looks at method implications on lab gas supply for residual solvent analysis using HS-GC-FID

41 KEEPING IT CLEAN Aseptic expertise from Chargepoint

45 DRIVE FOR INNOVATION Telstar outlines how the automotive sector has inspired lean manufacturing in drug manufacture

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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 16 Issue 6 © Septemeber 2016 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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from the editor

Body talk Body talk Like the EPM team I imagine most of you are currently looking forward to CPhI in Barcelona at the beginning of October. As always the event promises to be a hotspot of innovation and ideas as well as providing the perfect opportunity for networking, plus making and establishing fruitful business contacts.

It’s an exciting time in the pharmaceutical sector. In the UK the focus on personalised medicine has become increasingly evident over recent months, highlighted as NHS England recently explained the opportunities this area of life sciences offers for the patient at its recent expo. Using genetic sequencing to offer a more targeted approach to treatment not only makes sense for the patient but the pharma sector too providing potential for the growth and development of new products, tailored to an individual’s needs.

Where opportunities exist for the patient, they also exist for the market. This has been recognised by the organisers of CPhI who will be looking at personalised medicine as part of the Pre-Connect Congress. As we hear patient experiences where it can take years for a successful conventional drug to be found to treat an individual’s condition, the growth of personalised medicine is beyond exciting.

In a recent article in the FT Magazine, Brooke Masters outlined how: “Advocates of personalised medicine say these kinds of narrowly targeted drugs, tied to clear genetic or chemical markers, are the future. They argue that the current state of medicine, in which everyone is given the same drug and it works for some but not others, will soon be seen as barbarous”.

This field of medicine offers a range of benefits – firstly it allows genes at the crux of a disease to be identified leading to more effective and targeted treatment by providing the right drug at the right dose for each person.

Next month’s CPhI promises an extensive array of new products and services from the some of the world’s leading global pharmaceutical companies. It will be interesting to see how personalised medicine is starting to become part of the picture, not just in the UK but on a worldwide scale as well.

Lu Rahman

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5

NEWS FOCUS

Nanobowls deliver drugs with the help of a magnet Imagine a device that could transport drugs to any diseased site in the body with the help of a small magnet…

R

esearchers at the University of California San Diego have taken a step toward that goal by developing nano-sized vessels, called nanobowls, that could be filled with drug molecules and controlled with magnets for guided delivery to specific tissues and organs, including cancer tissue, small organs such as the pancreas and hard to access areas like the brain.

“Our goal is to develop drug carriers that we can direct to any part of the body, hold them there until they release their payload, then direct them away—all done using a small magnet,” said Ratneshwar Lal, professor of bioengineering, mechanical engineering and materials science in the Jacobs School of Engineering at UC San Diego.

“More importantly, we want to direct these drug carriers through places in the body where drugs typically can’t pass, like the blood-brain barrier,” Lal said. This would offer a new way to target and treat brain diseases like Alzheimer’s disease and glioblastoma, the most malignant of brain tumors.

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published in the journal Nanoscale, researchers showed that the nanobowls could be moved around by a small magnet, are capable of going inside normal and cancerous cells and could be used to detect the presence of low abundance molecules.

Researchers created the nanobowls in a multi-step synthesis. They first made templates of spherical silica nanoparticles with partially exposed polystyrene cores. The silica surface was functionalised, then coated with magnetic iron oxide nanoparticles followed by a layer of gold.

The polystyrene cores remained untouched and were washed away with an organic solvent, leaving behind a cavity to create the nanobowl.

Researchers showed they could use a small magnet to move the nanobowls through a hydrogel. “This suggests a potential use of the nanobowls for magnetically controlled delivery through soft tissues,” the researchers reported in the Nanoscale paper.

In a previous study, Lal and his team have shown that they can magnetically guide nanoparticles safely through the blood-brain barrier in mice.

Because of their gold coating, the nanobowls could be used for imaging.

In their experiments, researchers showed that molecules in extremely low concentrations, which are typically impossible to see spectroscopically, were easily detected in the presence of the nanobowls. This feature has applications in detecting disease markers early on, researchers said.

Now, the team has taken its research a step further by making nanobowls that could be used to store and carry drugs, and potentially be used to detect diseased cells and tissue.

Lastly, the nanobowls could be taken in by live cells. Researchers incubated the nanobowls with both normal and cancerous prostate cell lines. Within two hours, the nanobowls were found inside the cells.

The nanobowls, which are at the proof-of-concept stage, are bowlshaped silica nanoparticles—smaller than the width of a human hair—coated in a layer of gold, with magnetic iron oxide nanoparticles sandwiched in between the silica and gold layers. In a recent paper

As a next step, Lal and his team plan on making caps for the nanobowls that can be triggered to open on demand to release drugs.

“This would enable us to control the release of drug payloads in our system,” Lal said.

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NEW FOCUS

Looking to climb the life science ladder?

Head to the UK A new report published by Hobson Prior suggests that life science professionals are more likely to experience faster career progression if they move to the UK

T

he report Global Mobility in Life Sciences is based upon a survey of 1,527 individuals working in the life sciences industry, predominantly within Europe.

According to the report, the UK is one of the top three most popular career destinations for life sciences professionals, alongside Switzerland and Germany.

Yet the UK came out on top for career progression; 71% of Western European respondents who’ve moved here said they experienced faster career progression than in their native country, compared with 58% who’ve moved to Switzerland and 57% who’ve moved to Germany.

This is good news for the UK’s life science industry, which is keen to remain an attractive option for professionals looking to relocate. Following the recent referendum, the Association of the British Pharmaceutical Industry (ABPI) urged the sector to send a ‘strong signal that it is open for business’. Indeed, Brexit has caused some concern within the UK life sciences industry, not least because 7% of its 70,000 workers are EU nationals, whose right to work and reside in the UK will have to be re-negotiated.

However, the report suggests that since the UK’s life sciences industry – which has grown to over £60 billion – is a key contributor to the economy, it’s likely the government will continue facilitate its access to international talent.

On top of good career progression, the report states that 79% of life science workers relocating to the UK gain valuable new business contacts. Indeed, collaboration between life sciences businesses, researchers and academic institutions is facilitated by governmental bodies such as Innovate UK, and four of the world’s top ten universities are located here.

“The UK life sciences sector is experiencing a persistent skills shortage, and as a result employers must often look overseas for the right candidates,” said Jake Thomas, managing director at Hobson Prior. “Many professionals take this opportunity to gain international experience and advance their career, and as our report demonstrates, the UK is an ideal place to do so.”

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7

REGULATORY AFFAIRS

The importance of data integrity in the pharmaceutical sector Dinesh Parsai, ELC Group examines data integrity – the FDA perspective

I

ntegrity in its true sense is applicable in every walk of life and the pharmaceutical industry is no exception. In recent years, health regulators all over the world have come up with guidelines, certifications, rules and regulations for the effective implementation of cGMP practices in pharmaceutical manufacturing.

Essentially, cGMP guidance and regulations allow flexible and riskbased approaches to address product specific needs. In layman terms, cGMP stipulates: “Do what is written and write what is done. If any deviation is observed other than the expected results, then the failure should be investigated, root cause identified and appropriate corrective actions should be taken to get rid of future failures.”

This process of compliance with cGMP requirements entails the generation of a number of policies, protocols, reports, observations and so on, which will be used by the pharmaceutical manufacturer as “data” to assure the quality of products.

However, in recent years, during cGMP inspections, regulators have observed that the majority of cGMP violations involve ‘data integrity’.

Regulators regard data integrity as an important responsibility of the industry to ensure the safety, efficacy and quality of drugs and safeguard the public health at large. The US FDA has identified that most of its warning letters and import alerts are imposed due to data integrityrelated cGMP violations. The FDA, therefore, has proactively taken the initiative to educate the industry in this important aspect and published a draft guideline entitled Data Integrity and compliance with cGMP. As defined in the guideline, ‘Data integrity refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be Attributable, Legible, Contemporaneously recorded, Original or a true copy, and Accurate (ALCOA).’

The FDA also explains the main terminologies used during the cGMP inspections, such as metadata, audit trail, static or dynamic records, back up, systems or computer-related systems.

The guideline recommends that workflows, shared logins or sharing login credentials on computerised systems should be appropriately

8

validated and controlled in order to preserve the integrity of records or data.

Shared logins on the same computer system, or sharing login credentials with other personnel, is discouraged by the FDA because a unique individual cannot be identified and shared data can be compromised.

Another key best practice laid out on the guideline is routine, scheduled audit trail reviews. Audit trails that capture changes to critical data should be reviewed with each record and before final approval of the record. Audit trails review should include, for example, the change history of finished product test results, changes to sample run sequences, changes to sample identification, and changes to critical process parameters.

The FDA suggests that firms using electronic signatures should be able to demonstrate that they are able to identify the specific person who signed the records electronically. If this requirement is met then electronic signatures can be used instead of handwritten signatures.

Similarly, if blank forms like worksheets, laboratory notebooks and so on are used, then they should be controlled and issued by the quality unit and reconciliation should be easy.

Within the guideline, the FDA also encourages saving data instantaneously after completion of tests, to create a record in compliance with cGMP requirements. Use of a Laboratory Information Management System (LIMS) or an Electronic Batch Record (EBR) system – which can be designed to automatically save after each separate entry – is encouraged.

The reprocessing of analytical data is discouraged – the FDA instead feels that analytical methods should be accurate, capable and stable.

Finally, the FDA expects regular training of personnel in all aspects of protecting data integrity while performing their assigned duties, and considers this to be an important aspect in order to comply cGMP requirements. Moreover, firms should be willing to hire a third party auditor to identify data integrity-related problems and ensure continued compliance and adherence to best practices.

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COVER STORY

Material world

Material world: Prefillable syringes are not only manufactured out of glass but increasingly out of polymers

Determining the best material for pre-filled medications is one of the most frequently asked questions in the pharmaceutical industry. Anil Kumar Busimi, Schott, explains how the company takes a holistic approach in selecting its materials that takes the three Ps – the product, process and patient, into account.

Choice words: Anil Kumar Busimi, Schott explains how to determine when to use glass or plastics for pre-filled syringes

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Is glass or polymer the right choice for prefilled syringes?

This is indeed a question we hear more and more. Glass dominates the market, but the use of polymer is expected to grow in the next few years.

Glass’s excellent barrier properties and regulatory ease make it the first choice for drug manufacturers but polymer’s stability and inert properties, as well as its wide design options, make it an attractive choice as well.

So what is Schott’s approach to finding the right solution?

To find out what works best, together with the drug maker we examine the intended use of a drug and the filling process. During this process we consider the three Ps — product, process, and patient — as a best practice: Does the drug require particularly inert packaging materials? How To find out what works best, important are design flexibility, together with the drug maker tighter tolerances, and superior we examine the intended use break resistance? Do we have to of a drug and the filling process consider integration with safety devices or autoinjectors? Does the packaging have to be compatible with different filling machines and ensure easy regulatory pathways for drug approval? And, most importantly, have we considered patient comfort and needs appropriately? To sum it up – each material has its strengths and weaknesses, and drug makers must take a holistic view when deciding on a material for a particular application.

“

”

Can you give us an example of how different drugs have different requirements?

The anticoagulant Heparin, for example, has been stored in glass prefilled syringes for decades without any major recalls or drug contamination cases, making glass an easy choice. Compare that to dermal fillers, typically, highly viscous substances that need to be stored in packaging that allows for consistent gliding force and a robust Luer lock, which is integrated in a polymer syringe. So in this case, polymer has proved to be the material of choice.

The question of whether glass or polymer is the better material cannot be answered generally. It all depends on the respective application. We recommend a holistic evaluation along the three Ps – product, process and patient, to find the best solution.

“

During this process we consider the three Ps — product, process, and patient — as a best practice

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Q

OPINION

Track and trace: What you need to know With serialisation deadlines on the horizon, Reinhold van Ackeren, Mettler-Toledo PCE outlines how contract packagers can best prepare Q: How important is it for contract packaging companies to take notice of the international standards for pharmaceutical track and trace?

Q: Contract packagers often work in multiple industries. Is there a solution that enables them to run serialisation on single lines?

A: Contract packaging companies should take positive action with regard to serialisation and track and trace compliance. Not to do so could lead to contract and revenue losses.

Far reaching requirements for the marking and verification of products are coming into law to protect goods against piracy and counterfeiting.

Contract packaging companies are far from exempt when it comes to compliance.

Manufacturers across a variety of industries are realising the benefits of successful tracking and tracing of products from a quality assurance perspective.

A: Software, such as PCE Line Manager (PLM) Direct, is now available that provides a perfect introduction to serialisation for contract packagers and manufacturers that do not require aggregation and who do not use multiple production lines in parallel. It has been created to network individual stations easily and directly with manufacturers’ IT systems for serialisation purposes. The software supports all of our serialisation stations, with or without tamper-evident modules and checkweighers.

OEM kits also allow the software to be used when extending existing production lines. All systems print folding boxes with text or 2D codes and verify every label with an integrated smart camera. The software connects the systems to customers’ existing MES, ERP and cloud solutions.

Q: What are the regulations specifically?

A: The main regulations are The European Union’s Falsified Medicines Directive (FMD) EU-2011/62 and the US Drug Quality and Security Act (DQSA). Both outline requirements for direct product marking and immediate verification of printed data, as well as the ability to store and submit that data to a central database in order to verify that products are genuine. Other global markets issuing similar regulatory requirements include China, Korea, and Saudi Arabia.

Q: What are the deadlines?

A: For the FMD, the deadline for compliance is 9 February 2019, whereas the DQSA will come into effect in November of 2017. Manufacturers will be required to label products with a unique serial number in both human and machine readable formats. 2D DataMatrix barcodes will include a serial number, expiration date and lot number – and at least in Europe anti-tampering devices will also be required to verify whether the packaging has been interfered with before reaching the end user.

Q: How can contract packagers prepare for serialisation?

A: Contract packagers wanting to continue working within the pharmaceutical industry ideally would have started to work towards compliance already. For those that have not started the process, it is important they work closely with customers to ensure the correct processes can be implemented. Serialisation is the basic requirement but it is important to know whether aggregation is also required. We know that many clients ask their suppliers also to secure product aggregation – even though this isn’t required by law they see the advantages for their supply chain management. Once the requirements have been established, it is then advisable to find a partner who has proven systems and good experience of implementing serialisation solutions.

&A

Q: How do you work with customers to provide serialisation solutions?

A: We work with the producers to determine which coding scenarios are relevant for them.

Experts from Mettler-Toledo visit the production facility to set up and commission the station.

This service is included in the software package as standard, giving manufacturers a ready-touse serialisation solution.

Q: Is the software scalable?

What happens if a contract packager expands its pharmaceutical business?

A: The software package is extremely flexible and scalable. Should requirements change, companies can upgrade the software.

Companies can tailor the software package to fit in with their own unique requirements.

Q: In your opinion, when should contract packaging companies be looking into serialisation solutions?

A: If they are looking to do business in the pharmaceutical sector – or to continue to do so – then it is paramount to look into serialisation at the earliest possible time. Being prepared ahead of deadline will enable contract packagers to avoid relabelling or repackaging old stock in 2017, 2019 and beyond. We have been developing serialisation systems for international customers for years. Tried-andtested hardware and software solutions are already available – and have evolved to be particularly easy to use.

Q: Do you have any advice for contract packagers looking to implement serialisation?

A: It is important to understand customer requirements and work with an expert provider who will make the effort to entirely understand your requirements.

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CPhI

Global vision Forget football – it’s pharma that Barcelona will be famous for over the next few weeks as CPhI Worldwide takes place. As always the show offers in-depth and extensive coverage of the global pharma sector. Lu Rahman takes a pre-show peek into what’s in store

W

e’re heading towards that time of year again when the all eyes of the pharma sector congregate at CPhI Worldwide.

This year the event takes places in Barcelona between 4 and 6 October.

What’s new?

Holding CPhI in Barcelona is a first for this event. Visitors to the event will not only get to spend a few days in one of the world’s most vibrant cities, but they will once again be part of the global pharmaceutical community as it showcases the latest products, services and initiatives hitting the sector this year. The latest research will be revealed and visitors to the show will be able to witness debates on key industry issues while talking to leading decision makers about the latest trends and innovations to hit the sector.

Another first for the event will be the new Finished Dosage Formulation (FDF) area. Billed as the “first co-located event, standing alongside CPhI Worldwide to bring every aspect of the finished dosage supply chain together in one global location,” this new addition aims to unite big pharma, CMO, out-licensing specialists, end product distributors, end-user agents and home markets.

Since its introduction at CPhI Worldwide in 2011, the Finished Formulation zone has grown rapidly to become the third largest segment of the event. Developing this zone into a co-located event is the logical next step. According to the organisers of CPhI, many existing

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visitors and exhibitors have diversified their offerings into finished dosage forms over the last five years. It’s hoped that the FDF area will continue to expand to become a valued ongoing element of the event, reaching new audiences.

Not quite a first but aiming to be – with last year’s event winning the award for the biggest one yet, organisers of this year’s exhibition are anticipating another record-breaking show thanks to an expanded conference venue, more opportunities for content sharing as well as a range of business opportunities.

What to expect?

Organisers of CPhI say that pharma executives from all over the world will gather at Fira de Barcelona Gran Via for three days of collaboration, information dissemination and discussion that will define the future of the industry.

Around 37,000 attendees are expected at this year’s event from over 150 countries. More than 2,500 exhibitors will be on hand to discuss their latest products and services. The event boasts over 20 dedicated zones covering ingredients, APIs, excipients, contract services, packaging, biopharma and machinery.

Running directly alongside the pharmaceutical ingredients halls are four other co-located brands, helping visitors identify the right event for their business’s needs:

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ICSE is an outsourcing event designed to connect the pharmaceutical community with contract providers from clinical trials, CROs, logistics providers, data management firms and CMOs. InnoPack connects buyers and specifiers from the packaging and pharmaceutical industries, showcasing all the newest innovations in pharma packaging.

P-MEC Europe features exhibitors from traditional large-scale capital equipment to companies focussed on instrumental analysis, measuring and testing technologies, materials testing, laboratory and quality control.

As always the CPhI Women in Leadership Forum unites female pharma professionals from across the industry for networking purposes. Offering an opportunity for women to share experiences, exchange expertise and discuss leadership strategies, the initiative also allows participants to communicate about challenges to their careers.

Outside of the exhibition, the CPhI Pharma Insight Briefings provides access to a range of specialised content through 45 minute sessions.

The free briefings cover topics such as ‘Vested Outsourcing,’ ‘Excipients Risk Management,’ and ‘Serialisation Strategies.

Also on offer is the Pharma Forum – a dedicated area that provides thought leadership from media partners and the CPhI Pharma Insight Reports. The most recent Pharma Insight report can be downloaded from the CPhI website. It offers analysis of key trends and innovations forecast by a panel of world class experts.

Topics such as outsourcing trends, orphan drugs, combination products, API sourcing requirements, continuous processing, biosimilars, ADCs, single-use technologies, serialisation, the future of generics and bioavailability enhancement will be among the topics.

Match-making CPhI Worldwide sees the return of the one-to-one matchmaking programme. Helping tailor valuable time at the show, this platform allows attendees to find and connect with exhibitors and companies according to their business needs. The conference will also run its Innovation tours, organised by IMS Health this year, guiding attendees through the show floor to observe the best of what each company has to offer.

And if you get there early?

On 3 October, the day before CPhI Worldwide kicks off properly, the annual CPhI Pre-Connect Congress will take place. This conference offers executives the opportunity to analyse and discuss innovations, trends and market developments through presentations, panel discussions and networking opportunities.

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CPhI

Need to know the latest pharma trends?

Patient centricity, combination products, packaging innovation and biotherapeutics will all be highlighted at CPhI in Barcelona Pharma value chain

Serialisation practices

Providing six tracks across three different theatres, delivered by more than 40 senior level speakers, the Pre-Connect Congress will cover the entire spectrum of the pharma value chain including contract services, drug design and delivery, pharma ingredients, biologics and biosimilars, finished dosages and generics and pharma packaging.

Another important trend this year has been the surge in serialisation practices, and how to secure the supply chain through compliance, adherence and implementation strategies – with the need to meet the upcoming legislation deadlines. A morning track will focus exclusively on pharma packaging and serialisation, including presentations on improving patient care through tamper verification systems, the future of the serialisation process, and accessible packaging – focusing on children and elderly patients. The track will also feature regulatory updates on the falsified medicines directive, patient adherence and compliance in pharma packaging.

Contract services developments Among the most significant contract services developments are ADCs and advanced cell therapies. Sessions will also explore multidimensional CDMO business models, looking specifically at the changes increasingly agile CRO, CDMOs and hybrid providers bring.

The increasing development of contract services globally means pharma executives need knowledge of macro trends, new technologies and M&As to ensure they can react appropriately.

Drug design and delivery A whole afternoon of the congress will be dedicated to drug design and delivery. Experts will look at the latest technologies, approaches and developments for patient centric therapeutics. The panel discussion will analyse special drug designation with small patient populations – looking at orphan drugs, breakthrough therapies and HPAPIs across discovery, development, and commercialisation. Sessions on cutting edge innovations, model based technologies and patient centric design of combination products will complement the agenda.

API manufacturing The changing dynamic of global API manufacturing is forcing manufacturers to innovate and seek new approaches in formulation, sourcing and manufacturing to remain competitive. Key trends include the tightening of GMP regulations, higher costs through user fees, more stringent requirements for API suppliers in Europe, and the changes continuous processing is bringing.

Finished dosage formulation Finally, mirroring the recent addition of the FDF event at CPhI Worldwide, a finished dosage formulation (FDF) track will explore the future of generics, the need for value-added medicines that improve health, and increasing patient access through finished dosage forms. Compulsory licensing as a means to increasing generics access will be discussed, but perhaps more interestingly, this session will consider if big pharma should remove patents for some low-income countries.

Tara Dougal, senior content producer, UBM EMEA: “The Pre-Connect Congress provides a global perspective on the industry, providing attendees with the opportunity to reflect and take on new methods and learnings. It’s an opportunity for visitors to come pre-armed to the global exhibition with the latest trends, and helps them to make better-informed decisions about what type of partnerships and alliances will be needed as the market evolves. The 8th edition of the Pre-Connect Congress covers every aspect of the pharma development and manufacturing supply chain, saving months of costly research, and providing essential insights that will sustain business growth over the next year.”

Innovative products With a large number of biologics and biosimilars being developed, this track will focus on innovative products and technologies addressing complex disease profiles. The global biosimilars sector will be analysed touching upon America, Europe and other emerging markets. Particular emphasis will be placed on the development of Zarxio, one year on, the interchangeability of biosimilars, single-use technologies, personalised medicines and antibody-drug conjugates.

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Depyrogenation (for vials and cartridges)

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Double bagging in Steribag

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Syringes

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Chemical world

CPhI PREVIEW

Schott’s glass act CPhI Barcelona will see Schott officially introduce its new production quality process, Perfexion. When it comes to pharmaceutical primary packaging such as vials, cartridges or syringes, fluctuations in tubing dimensions such as the inner diameter or wall thickness can have a significant impact on the container performance – for instance, the filling or dosing accuracy for high potential drugs The company says that up until now, manufacturers of glass tubing have tended to monitor quality parameters on a random sample base. Perfexion controls and monitors every inch of the glass tubing that becomes a primary packaging container used by pharma companies to store and administer drugs.

“We are taking a major step towards a holistic view of quality in pharma glass production,” says Patrick Markschläger, executive vice president at Schott Tubing. “We could see from our existing control mechanisms, which were already extremely tight, that the quality of our glass tubes meets the highest requirements. Now with Perfexion, we can verify that every inch of the glass tube is accurate.”

Looking for Perfexion: With Perfexion Schott says it’s taking a major step towards a holistic view of quality in pharma glass production

Making it personal August Faller will be presenting products and services for individualised and personalised packaging solutions. The company focuses on small production runs, including the standard folding carton, special designs for clinical trials, and special labels through to packaging services for small to mid-sized amounts.

“There is a clear trend favouring customised individual solutions for medical pharmaceutical packaging, which at the same time means that the pharmaceutical companies will be more inclined toward small lot sizes and well-thought-out packaging services,” Dr Daniel Keesman, managing partner of August Faller.

This trend is further boosted by the increasing number of medications for treating rare illnesses (orphan drugs) and ‘companion diagnostics’ products with which tests are offered together with medications. Studies confirm this development and predict that in the future at least a third of all research projects in the pharmaceutical industry will consider individualisation.

August Faller is offering innovative packaging solutions and services. This includes the manufacture of labels of the highest quality using a digital printing process. With its camera inspection systems, Faller ensures that everything is monitored.

In addition to standard packaging, Faller also makes customised designs for clinical trials or designs for medications for rare illnesses such as packaging with inner partitions to protect against breakage, labels for documentation in the patient records, or wallets for tablets or capsules.

Boxed off: August Faller will be presenting products and services for individualised and personalised packaging solutions

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VISIT GEKA AT

CPhI INNOPACK BARCELONA

BOOTH NO 2P66 04 - 06 OCTOBER 2016

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4-6 October 2016 Barcelona, Spain BOOTH #4L75

Looking for a novel excipient?

Omya, a global producer of calcium carbonate, will showcase Omyapharm, its innovative pharmaceutical excipient.

The newly developed functionalised calcium carbonate can be used in multiple applications, such as orally dispersible granules (ODGs) or tablets (ODTs) that offer high mechanical strength while disintegrating twice as fast as comparable products.

Omyapharm is manufactured from high purity natural calcium carbonate using a surface recrystallisation process.

The external lamellae of the particles provide many interlocking contact points. When compacted during dry granulation or tableting, these contact points ensure greater mechanical strength and higher porosity compared with other currently available excipients – even at increased compression pressures. After drug loading, Omyapharm orally dispersible granules can be directly compressed into ODTs, which keep and preserve the active substances and disintegrate in less than 10 seconds.

Standard market ODTs are manufactured using expensive processes such as freeze drying to achieve fast dispersion rates.

According to Omya, the high porosity of ODTs formulated with Omyapharm, means that disintegration is rapid and even; as such, there’s no need to use cost-intensive production equipment.

Current market formulations also require special packaging because of the inherent friability of ODTs. With their high mechanical strength, tablets formulated with Omyapharm as an excipient can be filled in regular bottles and blisters, which significantly reduces the cost of packaging.

Novel idea: Omya will be showcasing Omyapharm, its innovative novel pharmaceutical excipient at CPhI

How to spot a fake

3C technology on show

Schreiner MediPharm will be presenting an improved Flexi-Cap, an innovative security solution that indicates the opening of primary pharmaceutical containers and prevents illegal filling and reuse of empty containers with counterfeit substances. FlexiCap Plus features a tear strip running through the label as a new integrated element. This offers enhanced tampering protection because the label is destroyed upon initial opening, and can no longer be reused as an alleged original label.

DSM Nutritional Products will be showing its next generation 3C technology for omega-3 EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) at this year’s CPhI. DSM says the 3C technology delivers highly-concentrated (up to 85%) and customisable combinations of EPA and DHA for pharmaceutical applications, while also providing peace of mind through a consistent supply chain. With this new launch, DSM says it is continuing to innovate in providing manufacturers with the versatility to create tailor-made, targeted EPA / DHA products that connect with consumers and patients throughout life.

To counteract illegal practices, Flexi-Cap is based on the combination of a film cap with a label for clear and irreversible first-opening indication. “The specialty of the new Flexi-Cap Plus variant is that the tear strip does not run through the film cap, but rather is integrated directly in the label. When the tear strip is opened, it automatically destroys the label and makes it impossible to illegally reuse the container with the original label,” explains Ann Merchant, president, Schreiner MediPharm.

Real deal: Flexi-Cap contains a security solution that indicates the opening of pharmaeceutical containers while also preventing illegal filling

DSM says it is the only company with CEPs for all vitamins and is continuously expanding its global reach, now offering Drug Master Files also for the US. With a range of API-certified products for the pharmaceutical industry, DSM helps its customers gain a competitive edge by accelerating the registration process to get products to market faster. It brings full regulatory, scientific and quality expertise, to provide customised support on projects from a very early stage in the development pipeline.

Real deal: Flexi-Cap contains a security solution that indicates the opening of pharmaeceutical containers while also preventing illegal filling

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LENGTH

WIDTH

TABLETTING

Smooth operator How I Holland helped create time and costs savings with a sticky ibuprofen formulation

A

UK-based global supplier of health, hygiene and home products has built relationships for over 150 years by coupling scientific developments and social responsibility to provide consumers with cutting-edge solutions.

By placing a strong emphasis on R&D and tapping into a variety of innovations, the supplier has driven consumer health forward and holds a stream of household names as happy, loyal and long-standing customers.

CT Macro: PharmaCote CT generates an antistick tip face for tablet production

The challenge

The solution

I Holland helped this company make time and cost savings

I Holland ran the parameters of the company’s formulation through its computer model, TSAR Predict. This model accurately forecasts the correct anti-stick PharmaCote solution for any formulation. As every granule is different, the best way to ensure that the correct anti-stick coating is selected accurately and efficiently is to run the parameters through the TSAR Predict model. This showed the CT coating as having the lowest particle adhesion force to their granule.

in the manufacture of ibuprofen 400mg. Previously the business had experienced a history of difficulties with this drug, a notoriously sticky formulation.

As ibuprofen 400mg runs at four batches per campaign, the supplier’s cost of waste granule was placed at approximately £1,800 per campaign and its tablet press overall equipment effectiveness (OEE - the time taken per batch through the number of tablets per hour) was running at only 58%. With a minimum standard of 92%, it was clear that the current system was under-performing and swift action was needed.

Hearing about the benefits of I Holland’s PharmaGrade steel, the ibuprofen manufacturer made the switch to I Holland several years ago and saw an improvement in sticking, just by moving to a better quality of tooling steel. However, the issue had not been eradicated completely and I Holland sought to help further. In order to overcome the sticking problem completely I Holland deployed its TSAR Predict Service.

PharmaCote CT is a patented coating. According to I Holland it generates a superb anti-stick tip face for tablet production. It also has good corrosion resistant and wear resistant properties.

Equipped with this information, the global supplier ordered a full set of PharmaCote CT coated tools, for its Fette P2100 press. As a result, significant and positive changes have been seen. The waste cost per campaign has decreased to just over £38, creating a significant saving.

In addition, the tablet press’ OEE is now running at a productivity level of 94%, halving the number of working days it takes to complete the batch.

“What used to take a week now takes roughly only 3.5 days. We are obviously delighted with this as it has enabled us to double the capacity available on that press,” says the company’s process technician.

PharmaCote CT Description: I Holland’s patented surface treatment in combination with its PharmaCote CN coating is design to generate superb anti-stick tip face for tablet production.

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Superior anti-stick properties, good corrosion resistance, good wear resistance more than two times the hardness of PharmaCote HC. Easy to clean and maintain using an ultrasonic bath and light automated polishing

Textured surface treatment applied to punch tip faces only.

Remainder of the punch is CN coated as standard (tip & barrel option available to optimise wear characteristics of HPG-P steel on the compression rollers)

Application: Applied to HPG-P steel only

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23

TASTE-MASKING

A question of taste Elizabeth Shen, Colorcon, discusses how taste-masking can be used as a strategy to improve adherence

E

ven Mary Poppins sought out a method to mask the bitter taste of medicines. Making medication palatable is not just about masking bitterness and tasting good; it is about improving medication adherence and ensuring that patients are getting the treatment they need.

Child’s play: Children are more sensitive to tastes compared with adults, as they don’t have the ability to rationalise ingestion of unpalatable medicine

In 2003, the World Health Organization linked medication non-adherence to nearly US$300 billion in potentially avoidable annual medical costs as well as increased patient morbidity and mortality (1). Pharmaceutical regulators and manufacturers have focused considerable effort on improving adherence with many approaches, including taste-masking.

In a study in the USA, 20% of adults complained of bad after taste or struggling to swallow when trying to take medication. Of these, 48% reported having a bad after taste in their mouth (2). Those surveyed admitted to delaying a dose, skipping a dose, or even discontinuing the medication because of these difficulties. Poor taste, for example, may lead to prematurely ending an anti-malarial regimen increasing the risk of getting the infection.

Children are far more sensitive to tastes compared with adults, as they don’t have the ability to rationalise ingestion of unpalatable medicine. As such, the European Paediatric Formulation Initiative (EuPFI), founded in 2007 to promote and facilitate development of better medicines for children includes a specific division dedicated to Taste Assessment & Taste Masking (TATM). In 2013, the European Medicines Agency (EMA) published guidelines on pharmaceutical development of medicines for paediatric use, acknowledging the importance of palatability of medicines (3).

Aligned with these regulatory initiatives, Colorcon has seen an appreciable rise in taste-masking developments, most commonly targeting paediatrics. There is now a paradigm shift in pharmaceutical development practices; whereas paediatric dosage was previously an afterthought, infant and child dosages are now considered earlier in the product development timeline.

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“

The World Health Organization linked medication nonadherence to nearly US$300 billion in potentially avoidable annual medical costs

”

medication. The various pH conditions of these foods can complicate the

Put your coat on For most solid oral dosage forms (SODs) or tablets, the active substance is blended with a number of excipients and an immediate release film coating, such as Opadry complete film coating system, provides sufficient barrier for the brief residence time in the mouth prior to swallowing.

However, for alternatives such as sachets, ODTs, and chewable dosage

release of pH-dependent coatings and cause premature dissolution of the coating, completely nullifying any taste-masking effects. Additionally, pH conditions of the stomach may vary from patient to patient, and elevated pH levels from medication or other physiological conditions may interfere with release of the drug.

forms, increased surface areas and oral residence times pose additional

When medicines are likely to be in a mixture with low pH foods or juices,

challenges in taste-masking. For these systems, there are a number of

a pH-independent taste-mask can be more effective. An insoluble

taste-masking technologies available for formulators to choose from,

polymer, such as ethylcellulose, provides an effective pH-independent

including sweeteners, flavouring agents, taste barrier coating systems,

taste barrier. Typically, the ethylcellulose coating in combination with

and ion-exchange resins. Simple blending of the drug with flavours

a soluble pore-former, ensures rapid drug release once the dosage

and

sweeteners

would

is past the mouth, post-

be ideal in terms of cost

swallowing and in the

and

stomach.

technical

difficulty.

Because

the

However, for many actives,

pore-former

flavours and sweeteners

soluble, there may be a

alone do not provide

small amount of drug

sufficient

taste-masking.

released prior to reaching

It is commonplace to

the stomach. However,

use

the

multiple

strategies,

is

pore-former

water

ratio

with taste barrier film

and coating thickness are

coating being the most

tailored to achieve the

popular approach, often

desired taste-mask profile

in

combination

with

sweeteners and flavours.

and still meet drug release Cover story: There are two main coating approaches for taste masking — pH-dependent and pH-independent taste barrier coating

requirements.

At Colorcon, we support

The use of pH-independent

our

taste-masking coatings

customers

with

a

variety of coating technologies to create a barrier around bitter drugs,

also holds regulatory benefits. Colorcon’s primary recommendation

which present as drug particles, granules, drug-layered beads, or

for a pH-independent taste-mask coating consists of Surelease

mini-tablets. These coated substrates in combination with flavours,

aqueous ethylcellulose dispersion and Opadry as the soluble pore-

sweeteners and other fillers result in a variety of dosage forms including

former. These coating materials are GRAS (generally recognised as

suspensions, sprinkles and chewable tablets.

safe) by the US Food and Drug Administration and have been used for decades in both immediate and modified release products for

There are two main coating approaches for taste masking —pH-

adults and paediatrics. Recently, Merck, Sharpe, and Dohme (MSD)

dependent and pH-independent taste barrier coating. The former,

employed the combination of Surelease and Opadry in a taste-masked

referred to as reverse enteric systems, are insoluble in the neutral pH

version of ISENTRESS (raltegravir), which is designed for the treatment

of saliva, then dissolve rapidly in the acidic pH of the gastric fluid.

of HIV in paediatrics. With this product, a precedence of use is set and

With these types of coatings, drug release is retarded or prevented,

usage limits are generous, allowing formulation flexibility to meet a

providing very good taste-masking in a neutral pH environment.

range of taste-mask goals.

However, the challenges of reverse enteric pH-dependent systems can become apparent if pH conditions of the stomach is elevated, affecting

Colorcon supports taste-mask applications across market segments

dissolution of the drug and its bioavailability.

spanning from pharmaceuticals and over-the-counter products, through to dietary supplements. The right taste-mask coating can help

Parents or caregivers of paediatric patients frequently sprinkle the dosage

the medicine go down in a most delightful way, without a spoonful

onto yogurt, desserts, or other baby foods as a way to administer the

of sugar.

REFERENCES 1. Sabaté E, editor. , ed. Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization; 2003.

2. “Pill-Swallowing Problems in America: A National Survey of Adults”. Harris Interactive, Inc, for Schwarz Pharma, 2003.

3. “Guideline on pharmaceutical development of medicines for paediatric use,” European Medicines Agency, EMA/CHMP/QWP/805880/2012 Rev. 2, 2013.

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Success in the making D

COMMENT

rug delivery is far from simply taking a pill or swallowing a medicine. New ways of developing drugs are leading to sophisticated products that require a range of delivery methods. Not only does this have implications for the patient but it also requires pharmaceutical manufacturers to consider the way in which drugs are made, how they could be made better and faster and of course, more cost-effectively.

As the push for innovative drug formulations continues, the importance of the drug delivery sector is evident. Manufacturing methods and costs plus R&D have a key role to play in the way new products are developed and brought to market. As the industry continues to explore issues with the way medication is taken and why it’s sometimes not taken, problems with adherence as well as staying on top of innovative delivery technology, challenges and opportunities arise for pharmaceutical businesses.

This dedicated drug delivery guide offers insight into the market via market-leading expertise.

Where are the growth areas? What do we need to think about in terms of patient experience and medication adherence? Where do the opportunities lie both short and long term? And importantly, what considerations do we need to be aware of now to ensure a successful pipeline of products and a profitable future?

Contents 5

14

IT’S ALL IN THE DELIVERY

FLEXIBLE WORKING

Lu Rahman looks at some of the trends in the drug delivery sector

Flexible manufacturing can be a key asset, says Patheon

6

16

SATISFIED CUSTOMERS

SAFETY FIRST

Catalent outlines how to develop a successful oral dosage form

Schreiner Medipharm looks at ways to enhance the patient experience

9

18

THE DRIVING FORCE

DOUBLE DOSE

West explains the importance of biologics

Dave Gray explains how pharma and medtech are putting the patient at the heart of healthcare

13

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 deputy group editor dave gray david.g@rapidnews.com reporter: reece armstrong reece.armstrong@rapidnews.com publishers mark blezard, duncan wood

production

STRATEGIC THINKING

art robert wood

Phillips-Medisize reveals one of drug delivery’s key strategies

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

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3

Maximum protection, from the bottom up Effective defense against contamination, breakage and tampering In addition to offering all the benefits of the original Flexi-Cap’s label + cap combination – namely, premium defense against counterfeiting – Flexi-Cap Protect adds an entirely new form of integrated label protection: A second cap on the bottom of glass bottles or vials. This unique concept for highly toxic drugs such as oncology products means that the container’s surface is carefully protected against surface contamination, breakage and lateral impact. Plus, Flexi-Cap Protect’s label can be applied without heat. Schreiner MediPharm: We’ve got you covered from top to bottom.

To learn more, scan the QR code below, go to www.flexi-cap.com/protect or call (845) 848-9000.

Specialty peel-off labels Combination hanger labels Functional syringe labels

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Brand protection solutions

Innovative labels. Smart solutions.

Schreiner MediPharm, a business unit of Schreiner Group Schreiner Group GmbH & Co. KG · Bruckmannring 22 · 85764 Oberschleissheim · Germany · Phone +49 89 31584-5400 Schreiner Group LP · 300 Corporate Drive, Suite 10 · Blauvelt, NY 10913 · USA · Phone +1 845 848-9000 Additional products and further info at www.schreiner-medipharm.com

DRUG DELIVERY OVERVIEW

It’s all in the delivery Lu Rahman looks at the drug delivery market and where present and future opportunities may lie

D

eveloping a new drug that receives market approval can cost $2.6 billion, according to the Tufts Center for the Study of Drug Development.

“Drug development remains a costly undertaking despite ongoing efforts across the full spectrum of pharmaceutical and biotech companies to rein in growing R&D costs,” said Joseph DiMasi, director of economic analysis at Tufts CSDD and principal investigator for the study.

The most obvious dosage form is oral – largely tablets, capsules or orally disintegrating granules (ODGs). A recent survey using 1000 individuals from the US and Germany commissioned by Hermes Pharma found that over half of them reported difficulties swallowing tablets or capsules, with a third of them rating the problem as serious.

According to Hermes: “The most frequent reasons cited were the tablets / capsules being too big, becoming stuck in the throat and having an unpleasant taste / odour. People did not report similar problems with foodstuffs or liquids.”

Go large The biologics market has opened up opportunities for drug manufacturers. According to a report by BCC Research, the total global market value for biologics is expected to reach $252 billion in 2017. These substances, manufactured from living organisms – animal or plant cells – are much larger than the small molecule compounds traditionally used to create synthesised drugs. Often produced using recombinant DNA technology, they are more expensive to produce – manufacturing biologics presents different challenges to conventional drugs as the slightest alteration can change the make-up of the end protein. The proteins in biologics are highly sensitive meaning that ultra careful culturing and purification is required to ensure a consistently high standard of active ingredient. Well known biologic drugs include AbbVie’s Humira – a global best-selling anti-inflammatory; Avastin which at one point was one of the most expensive drugs on the market and Herceptin used to treat breast cancer.

Small wonders

Hermes’ research found that 32% of people tried breaking tablets, 17% tried dissolving them in water and 9% tried chewing them. It highlights, “these approaches can negatively affect API release profile, bioavailability and medical efficacy.”

The nanotechnology market – including nanocrystals, nanoparticles, liposomes, micelles, nanotubes – has experienced market growth over recent years. The development of nanomedicines has increased with conditions such as cancer, cardiovascular disease and obesity benefitting from the development of this form of drug delivery.

Addressing these issues offers potential for the pharmaceutical sector. Given the costs involved in the drug development process, formulating products that improve delivery has clear cost implications for the industry as well the patient experience. Certain factors play a part – bioavailability, drug release profile and effectiveness. Is the product for self-administration, likely to be for emergency use? Is it for a child or someone with swallowing issues such as the elderly? Does it need to be a slow release formula or take the form of suppositories?

Addressing patient requirements can make the difference between a drug being taken correctly and not being taken at all, which may have adverse effects on the health of the patient.

According to Transparency Market Research, Eurostat data says that: “The nano-medicine industry in the EU includes 97 start-ups, 64 SMEs, and 38 large pharmaceutical or medical device companies. Furthermore, technological advancements and rising interest of key companies to invest in nanotechnology boost market growth. For instance, in 2011– 2012, Pfizer, Amgen and AstraZeneca signed agreements to collaborate with BIND Therapeutics to develop nano-medicines… The global nanotechnology drug delivery market was valued at US$ 41,062.5 million in 2014 and is projected to reach US$ 118,527.2 million by 2023, expanding at a CAGR of 12.5% from 2015 to 2023.”

The drug delivery marketplace is exciting and innovative. As research informs the way we tackle illnesses, drug formulations are advancing paving the way for new products. With on-going development into the way medicines are taken, there is admittedly still work to be done but hopefully many opportunities to be explored.

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5

ORAL SOLID DOSAGE

Satisfied customers Chris Halling and Ronak Savla, Catalent Pharma Solutions explain how to develop a drug design concept into a final oral dosage form that marries manufacturer requirements with best medical treatment. The key is to produce a drug with a specified therapeutic profile that guarantees best performance

P

harmaceutical companies see the development of oral dosage drug forms as an especially attractive objective, and particularly the inexpensive development of a simple, once-daily small white tablet that gives the best possible therapeutic performance. The pathway from a drug design concept to a final delivered oral dosage form can be complex and recognising and meeting the needs of pharmaceutical companies, medical practitioners and patients is an essential part of the process.

Drug development is costly, and the faster development studies are completed and the drug is launched onto the market, the quicker the return on investment. It is also desirable that the drug remains on the market for as long a period as possible without generic competition. It is possible to begin preclinical and even clinical trials without having a finished formulation by using bridging studies to show the bioequivalence of tablet, liquid, or capsule oral dosage forms. The speed of developing an oral drug may be accelerated by performing development steps in parallel. This approach begins with an assessment of molecule properties and molecule classification and is followed by a parallel formulation screening phase.

The drug developer first needs to specify the target therapeutic profile (TTP) to work towards, and then examine how the physicochemical properties of the candidate molecule affect therapeutic performance.

Preclinical and clinical testing of the drug substance ideally results in achieving proof-of-concept for the proposed drug. The creation of stable and robust formulations – including effective delivery methods for poorly-soluble molecules – ensures the development of a product with the desired profile.

Target therapeutic profile determination The TTP summarises all the required properties of a new drug in its final dosage form, and creating the profile is the first step in the drug development process. Early planning will improve outcomes and ensure a smoother and more cost-efficient process. The TTP can also assist with decision making in dose and formulation development, and with satisfying the regulatory process. It should be created before Phase I trials commence so it can act as part of the go/no-go decision process.

Factors that need to be considered2 at this stage can be broadly divided as medical aspects and drug molecule/ product characteristics.

The medical aspects encompass the condition to be treated, patient population profile, clinical efficacy and safety, dosing size and frequency, length of treatment, and pharmacologic target. Then, from a drug molecule and product perspective, formulators need to assess the chemical properties and physical form of the drug, enhance absorption, permeability, and bioavailability by screening formulations, understand the relationship between pharmacokinetics and pharmacodynamics (the dose profile), and monitor stability

6

under different climatic conditions. It is also necessary to look at the economics and cost of goods sold when beginning to develop a drug product to ensure viability within the marketplace.

The importance of assessing drug physicochemical properties It is absolutely essential to assess the physicochemical properties of the drug substance molecule in order to develop an ideal oral formulation. Ideally, there will be no need to enhance the drug or change its properties to produce the dose form, but many promising compounds have physicochemical liabilities. The two key factors to consider are the permeability and solubility of the active ingredient: these affect extent and rate at which the drug is absorbed, and therefore its bioavailability.3,4,5,6 These factors need to be recognised in preclinical or early clinical trials so that the right bioavailability enhancement technologies can be screened and evaluated.

Good solubility ensures that drugs are in solution to be absorbed through the gut wall. Poor solubility may be the result of slow dissolution or low inherent solubility. These causes are not mutually exclusive and a molecule may present poor solubility due to a combination of mechanisms. Solubility can be improved by various technologies such as reducing particle size to increase the surface area, creating a lipid formulation, or forming solid amorphous dispersions (hot melt extrusion and spray drying).

Enhancement of drug molecule solubility and permeability Particle size reduction is a proven technology for improving the oral bioavailability of poorly soluble small molecules, whose absorption is limited by dissolution rate (DCS Class IIa). The decrease in particle size results in a corresponding increase in the surface area and hence the dissolution rate of the compound. Lipid-based formulations and solid amorphous dispersions may improve absorption for DCS Class IIb compounds by improving their solubility. Lipid-based formulations are produced by dissolving drugs in lipids with or without surfactants.

A drug emulsion is formed when this combination comes in contact with an aqueous environment in the case of self-emulsifying systems.

Some lipid systems will require digestion by lipases in order to form emulsions. In the case of hot melt extrusion and spray drying, drugs are mixed with a polymer and may be heated to create a solid solution of the amorphous drug in the polymer matrix. These technologies can also result in greater dose uniformity and minimise variability between patients.

Early pre-clinical formulation screening can yield drug formulation candidates that can be tested in animal pharmacokinetic and toxicology studies. The enhanced bioavailability of these candidates can be a more accurate representation of the final dosage form in humans and help to get into the clinic faster.

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Optimising delivery to obtain the TTP

Stable and robust formulations

The delivery technology and dosage forms of a drug have to be optimised in order to meet the requirements of the TTP. Oral dosage form options include the development of solutions, suspensions, powders for reconstitution as a suspension, dispersible or effervescent tablets, chewable tablets, disintegrating tablets, sprinkles, oral powders and granules, and capsules among many others.

Finished oral formulations have to be sufficiently physically robust to withstand packaging, transport and storage processes, and have to be stable to ensure consistent drug performance after its manufacture. The International Conference on Harmonisation (ICH) stability guideline will require long term storage stability data for a minimum 12 months through the proposed shelf life of the drug product.8 The proposed shelf life for a commercially viable should be around 18 to 24 months and ideally up to five years. A short term storage stability study during the pre-clinical formulation screening stage can be beneficial as well.

Softgel technologies, for example those developed by Catalent RP Scherer, are ideal dosage forms for the administration of lipid based formulations. Most lipid formulations are liquids and the softgel technology is a robust method for encapsulating them into a soft capsule shell. The solvent-free solids produced by hot melt extrusion can be milled and formulated into different dosage forms. Particle size reduction techniques result in powders that can similarly be formulated in dosage forms such as tablets, suspensions, and hard shell capsules.

The lowest-cost and preferred options The preferred dosage form for manufacturers is the simplest and least expensive option, which is the plain white pill at singledose strength. However, these may not be very patient-centric, especially for patients taking a number of different medications at different times during the day. Too many similar small white pills could make tablet-taking complex and confusing.

Different shapes and colours can also improve acceptability and brand recognition. For example, Nexium (esomeprazole magnesium) is recognised as ‘the purple pill’. Images of shapes, colours, and designs of pills can be submitted to the FDA as part of the approval process. Printing or embossing on the surface of pills may also help to differentiate products.

In addition to physical and chemical properties, the cost of drug manufacturing is a contributory factor in deciding on the target therapeutic profile. For higher-value drugs with an expensive API and little competition in the marketplace, cost considerations in oral dose development are not as significant. For generics, however, costs must be controlled to preserve profits and any increase in manufacturing expense is significant. The FDA encourages generic manufacturers to produce generic versions of drugs that are similar to the brand product in terms of size and/or shape.7 In addition, well-designed drugs improve patient adherence and the effects of this need to be considered as part of the overall health economics assessment for the product.

The manufacturing process itself also needs to be reproducible and robust, with simpler processes resulting in better quality and reliability. Coatings can help increase the physical stability and robustness of oral tablets and capsules, especially for particularly fragile products, and can also control drug release by protecting against degradation as the drug passes through the gut.

Practical and pragmatic dosage form development Creating a convenient, easy-to-take, cost-effective, safe, and efficacious patient-centred drug with broad-based applications that improves patient adherence and outcomes. It is most important to focus on the science while being both practical and pragmatic to ensure the best possible therapeutic approach. A risk assessment can help rank formulation options based on physical and chemical properties, processing, and stability.

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BIOLOGICS

The driving factor Graham Reynolds, Global Biologics West Pharmaceutical Services, explains why biologics are a key driver behind the future of drug delivery

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s more biologics and biosimilars come onto the market— including those used for the treatment of cancer and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn’s disease and psoriasis — patients around the world are offered new hope in the management of their chronic conditions.

However, despite the promise for patients, maintaining the safety and efficacy of these cutting-edge therapies can present unique challenges around packaging, containment and delivery for pharmaceutical manufacturers.

To begin, many biologic drugs are sensitive, creating potential for interaction with containers and packaging components. Areas of concern include potential delamination of glass vials, interaction with silicone oil and tungsten from glass syringes, and extractables and leachables from elastomeric closures. All these issues may compromise a drug’s quality and potentially put patients at risk.

Additionally, some biopharmaceuticals require storage at extremely cold temperatures. Such nuances inherent to these advanced therapies are leading drug manufacturers and their packaging and delivery system providers to think differently about containment and delivery to better ensure drug efficacy and patient safety throughout a drug product’s lifecycle.

To that end, pharmaceutical manufacturers are now making packaging and delivery systems an integral component of drug development and research, as opposed to an afterthought to address right before bringing a therapy to market. Increasingly, pharmaceutical and biopharmaceutical companies are moving toward polymers, not glass, for containment. Additionally, they are adopting innovative approaches to drug delivery that strike the needed balance between high-quality drug containment and user-friendly design.

It starts with containment Still widely used, glass became a standard for containment of injectable drugs decades ago. However, glass containment – while suitable for many drug products – can present compatibility challenges with the newest biologics. Some biologic drug products do not react well with glass vials, prefilled syringes or cartridges; sometimes interactions between a drug and its glass package arise, requiring new approaches to containment and delivery. For example, modern biologic formulations sensitive to silicone oil or tungsten may require alternative packaging. Other undesirable interactions include breakage, delamination, particulates in the suspension, and design limitations that don’t allow for higher doses.

Smart th injecto inking: We st Sma r has been rtDose the de de livery electr o of inn signed for ovativ patien nic wearab e drug t com fort an le produ d cts

Enter cyclic olefin polymers, which can be moulded into a variety of shapes and designs. These systems can be designed to enable larger fill volumes, and tighter dimensional tolerances, meaning that functionality and performance can be optimised. This is particularly critical when the container interacts with a device in a combination system. Throughout the development, however, it is important to ensure that containers can be filled using conventional filling equipment. These high-quality polymer systems, when combined with high-quality coated elastomer components, add value to sensitive biologics through enhanced cleanliness and decreased interaction with the drug product.

Primary containers made from materials such as the Daikyo Crystal Zenith cyclic olefin polymer can also offer drug manufacturers the flexibility to create new delivery systems around customised primary containers that are designed to provide higher dose volumes, as is common with biologic therapies, and effectively deliver more viscous drug products.

Such options enable pharmaceutical companies to offer their product in combinations that clinicians and even patients may notice. As such, the containment system can become a differentiator influencing patient and provider choices.

Using delivery as a differentiator Treatments for some chronic conditions require multiple and repeated dosing at frequent intervals. Combine that with the new healthcare trend of enabling self-administration in the home care setting, and that gives patients an even greater role in deciding which delivery system works best for them. As healthcare systems shift treatment into the home care setting, self-injection systems must not only be designed with a patient-centric focus to improve adherence and outcomes, but also give the pharmaceutical manufacturer an edge in product differentiation.

Biologics are gaining traction thanks in part to attributes that allow for self-administration, but their next-generation formulation and delivery options present multiple challenges when determining containment and delivery requirements that can accommodate dose volume, frequency of dosing, a variety of patient groups, and multiple delivery mechanisms. continued overleaf >

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At Phillips-Medisize We’re All About Process

We know process is the absolute key to assuring that we deliver upon our customers’ expectations, the first time and every time.

That’s why our people are all about process. In fact, our process requirements apply not only to manufacturing and quality SOPs, but also to our customer facing operations such as Program Management and Design and Development engagements, ensuring our customers benefit from a repeatable and scalable model.

So, when you work with Phillips-Medisize, you can be certain we’ll exceed your highest expectations the first time and every time.

Contact Phillips-Medisize: phillipsmedisize.com / eu_sales@phillipsmedisize.com

BIOLOGICS

Many of these medications require subcutaneous delivery, however, when higher dose volumes are needed (>1ml), there may be a benefit in considering a wearable injection system, which can deliver a higher volume over a prolonged time. Some electronic wearable systems also offer an option to pre-program the dosing time.

An example of addressing these challenges lies in West’s SmartDose electronic wearable injector system, which incorporates a Daikyo Crystal Zenith cyclic olefin polymer container combined with FluroTec coated elastomeric components, and is designed to enhance the experience of patients required to self-inject a larger volume biologic drug at home. The SmartDose system has been designed for simplicity and patient comfort, while facilitating the delivery of innovative drug products. West has completed the development and validation of the SmartDose electronic injector to support our customers’ human clinical trials and filing activities. We have also completed our own first-in-human study, which has demonstrated the performance of the system.

While patient preferences will be as varied as much as patients differ from one another, they will likely share some preferences. For instance, most will likely rank convenience and portability high on their list of attributes that may help them follow treatment plans more closely.

Choosing the correct packaging and delivery system can not only make medication adherence easier on the patients, but it can also encourage brand preference among patients and practitioners. By making the right choices early on in the development process, packaging and pharmaceutical manufacturing companies can mitigate risk, deliver a high-quality product and foster patient affinity in the process.

Collaboratively addressing regulatory and quality demands A sharpened focus on safety – now that chronic disease patients are treating themselves more frequently at home – drives pharmaceutical companies’ demand for increased quality from drug containment and delivery system manufacturers. While glass remains the standard for injectable drug containment for the prefilled syringe market, the material’s higher dimensional variability in manufacturing can be a concern when evaluating the functionality of the syringe or cartridge in conjunction with the delivery system.

Problems with primary containment materials can result in delayed regulatory approvals, packaging variability and shortages of needed drug product on the market. All three problems can significantly damage a company’s bottom line as well as its reputation. But higher quality can come with higher investment, so the challenge for drug containment manufacturers becomes achieving the balance between managing the costs of provide higher-quality products while staying mindful of the customer’s total cost and profitability. Polymers can help companies to address this intersection of higher quality and improved overall cost.

Additionally, by partnering early in the drug development process, pharmaceutical and biotech companies can design and develop an integrated system that addresses both potential quality challenges of primary containment, as well as components facilitating delivery.

It’s particularly effective when these partners implement Quality by Design (QbD) concepts, which continue to gain momentum within the pharmaceutical industry.

This data-driven component of container development helps ensure the biologic reaches the market in a delivery system that not only helps to protect the drug product’s efficacy, but will also help maintain reliable drug delivery throughout the therapeutic lifecycle. It is the convergence of the drug product itself, the drug manufacturing process and its container closure and delivery system that establishes the quality attributes necessary for control of specifications such as sub-visible particulate, extractables and other quality issues.

An example of QbDdesigned components i n c l u d e s t h e We s t N ova P u re b ra n d of elastomeric components.

NovaPure components for vials and prefillable syringe systems – such as stoppers and plungers – were created through QbD processes that have been shown to optimise breakloose and extrusion performance, provide low partto-part variability and particulate specification while ensuring high cosmetic quality. When combined with West FluroTec barrier film, the components have helped to improve auto-injector performance through dimensional consistency.

d cal an aceuti ving m o r a m h P t ies are n ange: h a c inmen p e m th r conta cal co o f ti Make u , s e s c arma not gla bioph mers, d poly r a w to

Looking to the future From early stage development, through manufacturing, to patient use, modern biologics require innovative solutions for containment and delivery. In addition, regulatory agencies and pharmaceutical companies have increased quality expectations in an effort to enhance patient safety.

As the next generation of drugs become available, the limitations of past approaches to containment and delivery are more pronounced, and greater scrutiny should be paid to the interaction between the drug product and its container closure system. Additionally, stability during shelf life, particulate burden and the ease of delivery to patients are important factors to consider.

In order to ensure that biologic drug products are used to their full potential, biologics and biosimilars manufacturers along with their containment and delivery system partners need to collaborate early in the drug development process to gain a thorough understanding of the needs of both the patient and the drug product. With this close collaboration, novel primary containment materials and innovative delivery systems can come together to drive product differentiation, patient compliance and caregiver safety for the cutting-edge therapies of the future.

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TWIST‘N‘BRUSH™ The Twist‘n‘brush™ tube expertly combines Neopac‘s proven Twist‘n‘use™ system for single application with the extremely fine micro bristle applicator (MBA™) from GEKA Healthcare.

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Available tube content: from 1 ml to 13 ml

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18/07/2016 16:16:45

PATIENT OUTCOMES

Strategic thinking Bill Welch Phillips-Medisize, explains how an outcome-based approach is becoming an increasingly important strategy in drug delivery

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he delivery of healthcare globally, is increasingly focused on medical outcomes: delivering results for patients and tying industry profits to those results. As with any fundamental change in industry structure this is happening slowly and at different rates globally. The case for change however, is strong and compelling: population growth and rising incomes globally create increased demand for access to healthcare; incidences of lifestyle-related health conditions (eg diabetes) continue to grow and technological innovation continues to support increasing targeted disease and associated therapy identification – whether it is through genetic analysis or the discovery and commercialisation of large-molecule therapies (ie biologics).

The biopharmaceutical industry has seen a significant increase in the production of large-molecule drugs, like biologics…in ten years this market will be as large as the self-administered insulin market is today.

The value of the ensuing biologics market is forecast to grow 60% rising to a value of $291 billion annually between 2014 and 2020.

The path to outcome-based care (rather than simply providing a prescription) requires a strong device strategy, creating a delivery system suitable for the intended patient population and drug formulation. Device strategy considers therapeutic requirements from multiple angles to uncover risks and opportunities in delivery innovation, establishes a development path, and creates a device roadmap from clinicals to market approval, and even post-approval enhancements. A comprehensive device strategy balances the biopharmaceutical company’s need for innovation and costeffective drug delivery systems with the total disease management requirements associated with outcome-based healthcare. From a development standpoint, presence of a strategy drives direction from concept feasibility through production, and addresses the fact that ‘me-too’ devices do not create differentiation nor add value.

With large-molecule biologics, there are new challenges that face the biopharma industry. One concern includes new delivery challenges for patients which often take the form of self-administered injections. The viscous solution often requires special care to ensure proper dosing. A more challenging dose administration leads to lower dosing adherence rates and ultimately reduced patient outcomes. In an effort to improve dosing adherence and ultimately therapeutic outcomes, biopharma companies are placing more focus on drug delivery devices, including connected systems to facilitate information sharing between patients and caregivers. For injection systems this information may take the form of injection speed, dose volume, and date/time of delivery.

Ultimately, connected drug delivery systems enable the patient and caregivers to have a 360 degree view of both the patient and the disease, to not only manage adherence but improve outcomes by understanding effect of the regimen.

in the device strategy. In this sense, the device strategy drives a cohesive development plan and manufacturing strategy spanning from early clinical trials, validation, supply chain establishment, and volume manufacturing.

Recognising the increasingly integrated nature of drug delivery development, Phillips-Medisize recently acquired Medicom, headed up

by Morten Nielsen. It is expanding its device strategy and connected health capabilities while growing its European development footprint.

According to Nielsen: “We partner with our clients – large and small – helping them uncover innovative approaches and develop a solid device strategy for the molecule, focused on the patient and improved management of the disease. The device – or connected system – strategy is followed by the next phases of the development process.

When beginning at pre-concept device strategy, it establishes an early partnership, such that by the time the drug is brought to market, we have been working with our clients for several years and are well positioned to provide a rapid, low-risk manufacturing launch.”

Partnerships that facilitate a smooth transition through each stage have distinct advantages: reduced time and cost and reduced regulatory and market risk. On the contrary, a disjointed approach marginalises development, introduces lurking risk, isolates strategic design decisions and negatively impacts downstream activities. Further, if manufacturing development (DFM/DFA) is abruptly introduced at the end of the design phase, manufacturing strategy is not aligned with the device strategy, and it is likely late-stage changes could be introduced that threaten stakeholder requirements or programme feasibility. It is important that biopharma partnerships mutually understand the value of device strategy and are committed to connecting the early strategic effort to the intended solution. Design development and user considerations – while important aspects to consider – are all but a few facets of the greater value proposition provided through committed implementation of device strategy. During years of growth to come, the biopharma industry will benefit from forming partnerships built on innovation that consider the entire opportunity lifecycle.

Connecting strategy to partnerships and development 80% of a product’s cost and quality is often determined during the first 20% of the product development timeline. Development programmes that reach market acceptance frequently implement a device strategy that drives development of connected systems and devices that are useful, usable, desirable, and manufacturable. As an example, integrating Design for Manufacture (DFM) and Design for Assembly (DFA) activities early in the process ensures the device concept will achieve the quality, cost, and risk targets established

Focal po int: To im p compan ies are p rove dosing ad herence la includin and outc g conne cing more focu o s on dru cted sys g delive mes biopharma tems ry devic es,

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SUCCESSFUL PRODUCT LAUNCHES

Flexible working Joe Principe, Patheon discusses how flexible manufacturing can be the ideal solution for inaccurate demand forecasts

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ressure from regulators, legislators, payers and patients to reduce the cost of drugs, coupled with the emergence of specialty and niche companies that rely on contract manufacturing organisations for drug development and production is forcing pharmaceutical company leaders to look closely at every aspect of their business to identify areas where they can save money.

However, while marketing executives have become fairly accurate in positioning their new product in the marketplace, profiling prescribers and understanding and responding to the reimbursement landscape, predicting the actual demand for products, and the timing of that demand still remains a challenge for most pharmaceutical companies, particularly when they are planning for the launch of a new product.

Demand forecasts provide critical input that ultimately affects pharmaceutical companies’ decision-making processes. Companies utilise drug forecasts to design clinical programs, position sales force resources, allocate geographic resource distribution and obtain company or licensing assets. Incorrect forecasting proves difficult for pharmaceutical companies and can lead to sales losses and reputation damage.

A recent survey by ORC International of 50 pharmaceutical industry senior managers across the US and Europe found that a majority of companies either overestimated or underestimated demand for new drugs by as much as 25%, with some reporting instances of their forecasts being off target by a staggering 50%.

In the production lifecycle, certain hard costs, like manufacturing expenses and raw material prices, are fairly easy to predict. Survey respondents felt confident in their understanding of the unique products, from the formulation processes to pricing structure. These areas represent costs with little expected variation. In contrast, predicting the exact levels of active pharmaceutical ingredients (API), general manufacturing capacity needed and lead times are increasingly difficult variables to address.

Nearly all survey respondents noted the absolute, most unpredictable variable in a forecast is the estimate of market demand. Without knowing the overall market need for the product or the rate of growth it will experience, it can be very difficult to appropriately budget time and resources for manufacturing of the product.

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Cost centr e: In the productio manufact n lifecycle uring exp , certain enses an easy to p cost d raw ma redict. terial price s, like s, are fair ly

Inaccurate demand forecasts can have expensive and serious consequences for operational efficiency and the bottom line.

Adverse effects of over- or underestimation often center on reputational damage.

Underestimating demand generally results from not having enough background data to support forecasting information, can lead to a production shortfall, and can cause a company to face a fair amount of backlash both internally and externally. Investors and overworked employees often lose trust in management, while suppliers and customers face disappointment by not having a new therapeutic option, which leads to a loss in sales and damaged reputations.

Research shows that a blockbuster drug can lose $1 billion in revenue annually until capacity is developed to meet demand.

On the other hand, overestimating demand forces manufacturers to overproduce and as a result, mark down the price of the product, which can lead to plant closures, employee layoffs and destruction of inventory. Pharmaceutical companies also risk losing the roughly $500 million investment made to build and equip their manufacturing facility. Survey respondents said they often overestimated demand during times of greater market volatility or when they were overly optimistic in their forecasting.

Inaccuracies in demand forecasting, combined with increases in complex manufacturing processes, are driving the need for more choices in manufacturing solutions. A large majority of survey respondents noted that they plan to improve their forecasting tools, and almost all say they will be honing their inputs and assumptions over the next few years. In order to avoid these demand forecasting challenges and mitigate risks, many pharmaceutical companies are choosing to outsource drug production and take advantage of more flexible manufacturing options, which can help the industry avoid the costly results of inaccurate demand forecasts. Several survey respondents noted that the less certainty they have about demand, the more likely they are to outsource, even if they do have the capacity to produce the item in-house.

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When you’re trying to project market behaviour three years in advance, even the most sophisticated forecasting models will suffer some level of variability. To help with forecasting predictions, pharmaceutical companies can look to alternative formulation processes or consider insourcing or outsourcing their manufacturing.

The challenges around forecasting present an opportunity to evolve contract development and manufacturing organisation (CDMO) and sponsor relationships for capacity planning. Flexible manufacturing services, like those provided by Patheon, complement the traditional outsourcing service model through adaptable and scalable capacity, and allow clients to increase and decrease capacity as needed. In the face of uncertain forecasts, CDMOs like Patheon can offer the facilities, equipment and process technology expertise needed for operations and risk management.

As an example, allocating space for sponsors (ie. the condo model) allows a sponsor to provide the equipment and the CDMO to provide a dedicated space. The sponsor contributes certain capital costs relating to the suite, including dedicated equipment, and pays a periodic fee to cover a share of the ongoing expense of operating the facility in which the suite is located. However, the sponsor gets the benefits of a dedicated manufacturing operation that it can operate as needed to meet its supply requirements while sharing high-cost capital and operating expense functions such as water and air handling systems, warehousing, shipping and receiving, security, quality assurance (QA) and quality control (QC). This option is also ideal for niche technologies not readily available in the CDMO space.

Patheon offers a range of flexible manufacturing options, all designed to allow the sponsor outsourced manufacturing options that can ebb and flow with actual demand in real time.

Larger service providers are able to better handle these sorts of agreements as they can be more flexible, leveraging their large footprint to fulfill various needs. The departure from the ‘build or buy’ paradigm represents a superior value for clients, as these flexible capacity solutions require a strategic and collaborative approach – different from the traditional ‘price per batch’ concept.

CDMO experience and knowledge in process development, facility engineering and equipment procurement can be leveraged to develop solutions specific to the product and sponsor – a far more cost effective approach than building a dedicated full-function facility for all of them. CDMOs have to understand that the current industry environment, marked by new products that are more technically challenging, produced in smaller volumes and subject to greater market uncertainty, requires new solutions to supply chain management.

CDMOs can bring a lot of assets to bear on the challenges of new product supply in the face of uncertain forecasts. Those assets are not just their physical facilities and equipment; they include their expertise and experience in process technologies, engineering, procurement, operations and risk management. By using those assets in creative ways, sponsors and CDMOs can work together to develop the innovative manufacturing solutions that will ensure successful product launches.

In addition to seeking more-certain forecasts, it’s also important to think about how to utilise flexible, scalable capacity that can accommodate the uncertainty. This is just what Patheon is trying to do for its clients. In the traditional outsourcing model, CDMOs provide an agreed amount of capacity to alleviate internal manufacturing constraints. Patheon complements this service with “adaptable capacity” solutions that allow customers to increase and decrease capacity as they need. We know that our solutions can’t eliminate risk, but we do know that they will help mitigate it.

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Point in case: A labelintegrated needle trap ensures needlestick prevention after the injection.

SAFETY

Safety first Ann Merchant, president Schreiner MediPharm examines innovative and smart label solutions for injectables to enhance patient safety and user experience

Smart thinking: Smart, multi-functional labels for injection devices allow interactive applications via integrated NFC chips.

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ithin a complex regulatory landscape as well as diversified markets and medications, the pharmaceutical industry is facing many challenges. While some of the key objectives remain product and patient safety and the reliable dispensing of drugs by healthcare provid-ers, the well-informed patient becomes increasingly important and requires convenient tools for self-administration of drugs. Sophisticated label solutions can play an important role in product and patient safety by providing additional functionalities beyond mere product iden-tification. In addition, they add value to the product by enhancing user convenience and supporting the trend towards patient-centricity.

Supply chain security End-to-end supply chain integrity plays a major role for the pharmaceutical industry to en-sure product safety. Injectables are often delivered in glass containers, such as vials or bot-tles and container integrity is crucial to avoid drug contamination. Also pharmaceutical manufacturers are exposed to a growing threat posed by counterfeit medicines, particularly in developing countries and emerging markets. In addition, there is a risk of re-imports and illegal reuse of original containers. Regulatory demands in various countries require special packaging and labelling solutions for product and brand protection, as well as for tracking the entire supply chain.

When it comes to injectables in vials and bottles, intelligent labelling solutions ensure product integrity at unit level and can avoid illegal re-use of original containers An innovative security concept, combining a label and a film cap, clearly and irreversibly shows first-opening of primary containers.

The film cap is first put over the closed container, then the label is applied without covering the peel-open tab on the opening strip.

Once the strip is opened, the bottom part of the cap, together with the label, remains attached to the container. Attempting to remove the rest of the cap destroys the label. This eliminates the possibility of illegal, unnoticed reuse. The flexible solution can be adapted to different container types, forms and sizes. Unlike shrinkwrap solutions, the label construction can be applied without using heat, making it suitable for temperature-sensitive medicines. The top of the film cap allows space for bar code printing or NFC chip integration for electronic tracking. Adding extra security features to the label such as holographs, colour-shifting inks, guilloches or hidden features such as a void effects or covert colour pigments gives suppliers, pharmacists, healthcare personnel and patients additional certainty that the product is genuine.

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Packaging and labelling are critical to product authentication and should provide a reliable hurdle against tampering and counterfeiting.

Ideally, integrated security concepts should combine several security technologies in a multi-layered approach including overt and cov-ert features. Ultimately, the objective should be to work closely with the pharmaceutical manufacturer in a consultative approach to identify the optimal solution that suits his spe-cific security requirements, while integrating easily into the existing brand appearance.

The label and cap security concept can be developed by adding an additional cap to protect the bottom of bottles or vials against glass breakage and surface contamination. In addition to the cap which covers the closure and upper part of the container, a second cap is added to protect the bottom and lower part. Both caps are fixed to the container using a label, which can optionally be provided with an integrated foam layer to provide further protection against lateral impact. Consequently, the container’s surface is completely protected.

In addition, the upper cap offers space for imprinting warning notices or codes for track & trace systems. This concept is especially suited for highly toxic drugs, such as oncology products, since glass breakage of primary containers with cytostatics can have serious consequences.

Healthcare personnel and patient safety A growing number of injectables are administered in pre-filled syringes, which are ready to use and easy to handle. However, needlestick injuries harbour a high risk for healthcare personnel to be infected by contaminated blood after the injection. Roughly three and a half million work-related needlestick injuries occur globally every year. Regulatory requirements by the US FDA and NIOSH demand that sharps instruments have to be equipped with safety devices. In the European Union member states had to implement directive 2010/32/ EU on the prevention of sharps injuries into national legislation in May 2013 to im-prove occupational health and safety.

By integrating the safety mechanism into the syringe label, regulatory demands can be met in a smart and user-friendly manner. The compact design of the needle trap label allows the blood-contaminated needle to be simply and safely secured after the injection and can be easily operated by healthcare personnel in a controlled, single-handed fashion. After the needle is locked into the plastic trap, it is irreversibly protected. Additional features to cover patient safety aspects may be integrated into the label, like peel-off parts for documentation of the administered injection, graduation lines for delivery of the right dose or anti-counterfeiting features for product security and brand protection.

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For the pharmaceutical manufacturer, equipping a syringe with a needle protection system frequently involves the need to change the complete packaging design for the product. This is not required with a label-integrated solution: The blister pack remains the same, and the user is able to immediately recognise the product. Consistency in the brand presentation of pharmaceutical products avoids confusion when using the products. Due to its compact de-sign the label-integrated needle trap system, like conventional labels, can be easily proc-essed on commonly used labelling equipment at the same speeds. Only minor modifica-tions to existing labelling equipment and processes are required. Unlike more complex, so-called passive injection devices, a needle trap label needs minimal storage space and de-creases transport costs, while reducing the environmental footprint.

Self-medication and enhanced user experience User safety and comfort is the primary concern in the development of pens and auto-injectors for self-injection. Multi-functional label solutions can be individually customised to further enhance reliability and ease of use of these injection devices. The range of function-alities that can be realised includes a temperature indicator producing a reversible colour shift that shows when a defined room or cooling temperature has been reached. A special varnish coating improves the grip and feel of the surface and helps patients to safely use the pen. In addition, integrated tactile elements make it easier to identify similar systems containing different active ingredients through touch. If the pen has a transparent window to check the medication, sensitive contents can be protected against UV rays by a double-layered label which can be easily opened and closed again. Alternatively, the transparent window included in the label can be equipped with UV protection. Integrated peel-off parts serve to remind the patient to regularly check the contents. First opening indication as well as anti-counterfeiting features can be integrated as well to ensure product safety.

injection device by simply tapping the label with an NFC-enabled phone. Due to their thin and flexible construction, NFC or RFID labels inconspicuously blend into the existing design and can simply be applied to the primary containers during the production process.

The wide-spread use of NFC-capable smartphones enables easy and convenient use by the patient.

In addition, patient compliance plays an important role, especially with regards to an ageing population and a growing homecare market.

Non-compliance to prescribed drugs can har-bour severe risks for patients, particularly in case of chronic diseases. Also, in clinical trials medication adherence is crucial to prove effectiveness of tested ingredients. More ad-vanced NFC or RFID labels in combination with printed electronics solutions can support patient compliance by app downloads that allow recording and tracking of patient compli-ance behaviour, or enable reminder options for regular medicine use.

Additionally, the at-tending physician, based on the data gathered, can adjust the therapeutic regimen and op-timize compliance together with the patient. Thus, patients can be treated effectively, while saving healthcare costs that might arise from additional health problems in case of non-compliance.

Conclusion Innovative and sophisticated label solutions for injectables address current market trends in the pharmaceutical industry and can further enhance the end product. They integrate multi-ple functions that are optimally tailored to the specific product and its application, helping to ensure product security and patient safety while enhancing user experience. Last but not least, the customised labels have to be easily and efficiently integrated into the production processes at the pharmaceutical manufacturer.

Smart ‘e-labeling’ solutions with integrated RFID (Radio Frequency Identification) and NFC (Near Field Communication) technology provide an innovative approach to equip injection systems with interactive functionalities that enhance patient safety and user experience. This meets digitisation trends and allows, for instance, to easily check product authenticity, expiry date or relevant recalls via a smartphone. In addition, the patient may access import-ant additional information or explanatory videos on the medicine or the use of the

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DRUG DEVICE COMBOS

Double dose A perfect pairing of pharma and medtech takes us closer than ever to truly patient-centric healthcare. EPM’s David Gray writes

T

he market for drug device combination products was valued at $66 billion back in 2012. By 2019, it’s expected to be worth $115 billion. Why are analysts predicting such growth? There are many things to consider.

For a start, global healthcare systems are feeling the strain of ageing populations, and so are crying out for innovations that enable minimally invasive procedures.

Interventional cardiologists in particular see drug device combinations as a viable means of delaying or avoiding surgery – that most costly and time-consuming last resort.

It’s true that in the majority of examples, combination products are typically used as treatments, and rarely constitute a cure. They’re commonly used for pain management, and reducing healing times.

Increasingly, since the rise of digital health, drug device combinations are also being used in diagnosis. Wearable devices that simultaneously administer and monitor drug efficacy could be the future of general practice.

One of the most exciting drug device combinations is Civo, a futuristic tool for cancer treatment. Civo consists of an arrayed microinjection drug delivery device and quantitative analysis methodology.

The device is able to simultaneously compare the patient’s response to multiple cancer drugs or combinations while a tumour is still present in the body.

According to researchers at Fred Hutchinson Cancer Research Center, the device has been shown to accurately predict systemic response to the drugs.

Jim Olson, a member of the Clinical Research Division at Fred Hutch, a paediatric oncologist at Seattle Children’s Hospital and founder of Presage – the firm behind Civo, said: “Currently, only seven percent of new oncology drug candidates that demonstrated anti-cancer activity in preclinical studies subsequently demonstrate sufficient efficacy in clinical trials to warrant FDA approvals.

“I deal every day with the limitations of current cancer therapies, and I’ve made it my life’s work to help find solutions to this challenge.

“We developed Civo because patients desperately need better approaches to identify treatments that will provide benefit and improve patient survival.”

A handheld device, CIVO can be used to deliver up to eight different cancer drugs (alone or in combination) into tumours close to the skin.

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Along with traceable fluorescent dye, the drugs are deposited in the centre and the edges of the tumour, enabling the analysis of drug reaction in different tumour microenvironments. Following drug delivery, portions of the tumour can be excised and studied.

“The system is internally controlled – allowing direct comparisons of drug responses in the same tumour,” Olson told The Scientist. “What we are looking for here is whether the cancer is inherently resistant to the drugs administered.”

Who’s the real winner?

Sometimes it’s easy to make the mistake that the drug itself is the chief beneficiary of the device innovation. Whilst this may very often be the case, new developments in medication could improve the way patients use their devices.

For example, JDRF, a specialist in type 1 diabetes research, recently partnered with Arecor, a UK-based formulation technology company, to undertake pre-clinical trials of ultra-concentrated insulin. This could be a massive step towards the advancement of the miniaturisation of delivery devices, such as next-generation artificial pancreas systems for people with type 1 diabetes. Using better drug formulations to minimise the burden of the device itself should be high on the agenda for both industries.

There’s money in this wearables business In one of the most lucrative drug device combination deals to date, device maker Unilife partnered with Sanofi to supply wearable injectors to the big pharma giant for 15 years.

Sanofi, sensing the shift towards wearables for medicine, gained nonexclusive access to Unilife’s technology. Unilife CEO Alan Shortall told investors: “This supply agreement with Sanofi is unprecedented. It is arguably the largest and longest supply agreement ever done in our industry. We will supply our wearable injectors to Sanofi for use with all of their applicable pipeline drug needs, excluding insulins, for the next 15 years at a minimum.”

The deal, some have speculated, could result in $1 billion per year in additional sales for Unilife during the lifetime of the agreement.

So the race is on: pharma firms are heavy bidders, but the devices market is quickly getting crowded. Luckily, the net result of heavy competition and strong demand is usually innovation.

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EXCIPIENTS

Pure potential

Wise words: According to Kevin McGlue excipient assurances are required which don’t generate unsustainable workloads on manufacturers and users

According to Kevin McGlue, Excipact, the European excipients market offers a new era of challenges and opportunities

E

xcipients are a diverse range of materials from many origins. Some are produced especially for pharmaceutical product use but in many cases the main market for the materials is not pharmaceutical and only a small proportion of the global production is actually used as excipient. This can obviously provide many challenges in the assurance of suitability for use in pharmaceutical applications.

In past years, specification was often the main (and sometimes only) attribute considered when assessing suitability. More recently regulation has decreed that excipients must be of ‘suitable GMP’ and from known supply chains.

In Europe, the requirements of Eudralex Volume 4 Chapter 5 (Production) relating to starting materials state that ‘excipients and excipient suppliers should be controlled appropriately based on the results of a formalised quality risk assessment in accordance with the European Commission Guidelines on the formalised risk assessment for ascertaining the appropriate Good Manufacturing Practice for excipients of medicinal products for human use’. The requirements for compliance with this guideline came in to force on 21 March 2016 and this has therefore now forced manufacturers of pharmaceutical finished products to undertake formal risk assessment to determine the required GMP for each and every excipient they use.

With such regulation and risk assessment decreeing that excipients must be of ‘suitable GMP’, this obviously presents many challenges to both regulators and pharmaceutical users of how to reliably assure suitability for use without undertaking audit of every supplier. Past practices for such assurance have varied across the entire spectrum, from simple acceptance of ‘pharmaceutical grade’ or ‘certified to pharmacopeia monograph’ materials, through to elaborate audit and approval systems operated by the major multinational pharmaceutical companies. In many cases it was the middle ground approach of a supplier and/or material questionnaire that has been used to qualify ‘suitability’.

In this new environment, it is unlikely that simple acceptance of materials based on the supplier’s grade will be adequate as there would be no real knowledge whatsoever of the ‘suitability of GMP’ required to satisfy the outcome of the formalised risk assessment.

Supplier questionnaires potentially provide more detail and hence opportunity to align with the user’s assessed requirements, however these are still reliant only on the supplier’s own answers and hence do not really provide evidence of compliance.

So for many, the only real answer remains physical audit, however if everybody took this approach the outcome would be overwhelming.

Even for a supplier with just 250 customers auditing on a five year cycle that would be 50 audits a year ….one every week! If that were the case, it’s likely that many chemical / food ingredient suppliers, whose interest for their products is not primarily pharmaceutical excipient usage, will simply decide to exit the pharmaceutical market.

Even for the pharmaceutical manufacturer the burden would be unrealistically high, and although many major multi-nationals have dedicated auditors and audit programmes, smaller manufacturers do not have such resources. It is therefore clear that an alternative approach is needed that will give the assurances required whilst at the same time not generating unsustainable workloads on both manufacturers and users of excipients.

One solution is the use of certification schemes, though these must be independent and of demonstrable credibility. Regulators have already indicated that such approaches would be acceptable, provided the scheme met the requirements of such demonstrable credibility. For a certification scheme to meet these requirements there are three basic premises: (i) Assessment must be to a suitable recognised and published standard. All too often in the past, many third party audits have been undertaken either based on the auditor’s own ‘judgement’, or against standards that are not suitable for excipient manufacture. (ii) The auditor must be demonstrably competent to undertake the assessment of an excipient manufacture against the standard. (iii) The certification body must have quality management systems suitable for providing such services; conformity to ISO 17021 is the basic tenant here.

The Excipact initiative, launched in 2014 was designed to fulfil these objectives. Excipact is a ‘not for profit’ organisation comprised of a number of industry associations with members from both the excipient manufacturer and user communities; as such it is an ‘association of associations’ and independence is assured. Excipact is the owner of the standard and has oversight of registered auditors and certifying bodies.

The scheme is already finding great favour in the industry with all parties, including regulators and has taken the place of many potential individual customer audits.

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CLINICAL TRIALS

Smart thinking Laura Khurana and Karin Beckstrom, ERT explain how wearables can enhance patient data collected during clinical trials

T

here is increasing interest in incorporating data from wearable devices (activity and sleep trackers, heart rate monitors, smart watches) into clinical trials.

This is mainly due to the advantages sponsors, sites, and patients can recognise from their use. Sponsors can gain additional data to better understand a treatment’s effect on the participant. Investigative sites can use the data to monitor the patients’ health and to gain insight into the patients’ engagement. And, patients can potentially see metrics about their life and health they wouldn’t otherwise have access to.

Accurate and validated. Data from wearables that were originally created for commercial use may not be subject to the same standards of accuracy as medical devices vetted by the FDA. Some efforts are underway to validate wearable or smartphone data with existing COAs, including an app developed by Roche that uses smartphone sensor data to measure symptoms of Parkinson’s Disease and attempts to predict patient scores on the Unified Parkinson’s Disease Rating Scale (UPDRS).1

As existing wearables mature and as new products enter the market, the possibilities for their use in pharmaceutical research may be endless. By integrating varied data streams captured from wearables with electronic Clinical Outcomes Assessment (eCOA) data (symptom frequency and occurrence, quality of life, etc.) captured by the patient on handheld and/or web interfaces, sponsors may soon be able to gain complete insight into the patient experience during clinical development.

Operational considerations Beyond the scientific considerations of wearable devices, there are several operational aspects a trial team needs to consider when adding a wearable into the protocol, including:

Wearable goals

Scientific considerations

Prior to looking at any devices, sponsors need to determine what data is needed. There are hundreds of wearables on the market but you can quickly narrow the scope by knowing exactly what data you want to collect and for how long you want to collect it. An important consideration is if the data will be submitted to regulatory agencies and if any regulatory precedent has been established for their use in clinical research.

Data from wearable devices can best serve the scientific objectives of a trial when they are:

Wearable selection

However, there are many factors trial sponsors must consider before including wearables in their clinical trials.

Here we present some of the scientific and operational considerations.

Fit for purpose. Trial sponsors should let the decision to use wearable data be driven by their ability to support the trial’s endpoints (or serve as independent endpoints themselves), rather than letting the choice of data collection technology drive the scientific questions of the trial.

In context. Data about sleep patterns, activity level, and physiological measures such as heart rate are only meaningful if you know the context in which this data was collected.

Integration of wearable technology with eCOA enables the real-time capture of context surrounding a clinical event.

When people refer to wearables they often mean activity meters but the wave of innovation in wearables means there are options beyond just activity, including many that have multiple sensors. For example, Vital Connect has a wearable patch that collects single-lead ECG, heart rate, RR interval, respiratory rate, temperature, body posture, fall detection and activity including steps.

Similarly, you can select the form that best meets your trial population’s needs. Maybe a wrist worn device works fine but perhaps a shirt like Hexoskin offers would

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be a better fit for your trial participants. Researchers are also working on minimal, tattoo-like health monitors that could be used in the future.2

Patient experience Part of the patient centric movement in clinical trials is to understand the impact that trial requirements have on a participant’s life. This is especially important for wearables, as an uncomfortable device or one that requires extensive set up can lead to loss of data and non-compliance.

Data retrieval Data from some wearables can be quite extensive, so it’s important to have a plan about what is a useful collection interval. Collecting a data point for every step may be more than you need, an alternative might be steps per minute or per day.

Conclusion The possibilities for wearables in clinical research are endless, but not all will meet the objectives of a given clinical development program. Having plan that addresses the scientific and operational considerations of wearables and optimizes the integration of data sources such as eCOA will lead to a smoother roll out, a higher likelihood of success, and potentially significant improvements in efficiency and accuracy during new drug research and development.

1

http://www.roche.com/media/store/roche_stories/rochestories-2015-08-10.htm

2

ihttp://ucsdnews.ucsd.edu/pressrelease/temporary_tattoo_offers_needle_ free_way_to_monitor_glucose_levels

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CLINICAL TRIALS

Leading the way: GSK announced it would become the first major pharma company to use Apple’s ResearchKit as part of clinical research

A mission to modernise: a digital future in clinical research Rob DiCicco, head of clinical innovation and clinical platforms at GSK, talks about the future of digital in clinical research and the industry’s progress in embracing these developments

C

linical trial design poses a number of key challenges, including participant recruitment and ensuring the studies deliver scientifically useful data. Here at GSK we are committed to modernising our clinical trials process in an effort to overcome these challenges.

Digital innovation will play an increasingly important role in this journey.

either using closed databases or giving patients greater access to clinical trials through technology, such as supporting them through telemedicine or promoting clinical trials through social media.

Putting patients at the centre of research

Earlier this year GSK announced headline results Expert opinion: According to Rob from the Salford Lung DiCicco, GSK, clinical trials pose several challenges including participant Study, which took a ground- recruitment and delivery of scientifically breaking approach to not only useful data widen participation beyond traditional parameters but also to work with local health providers and use electronic health records to monitor patients on the study in real-time, with minimal intrusion into their everyday lives.

In July, GSK also announced it would become the first major pharma company to use Apple’s ResearchKit as part of clinical research; in this case, a study into mobility of rheumatology patients. Patients who agree to take part in the study can use an app on their iPhone to input both physical and emotional symptoms, such as pain and mood, while the phone’s sensor can record motion during a guided wrist exercise.

These are just two examples where studies can be made more valuable and scientifically useful by data analytics from larger patient datasets,

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Healthcare is becoming more and more consumerised, in terms of how people think about it and make decisions, as illustrated by the growing interest in wearable technology. GSK is responding to this trend and one aspect of this is where people can choose to share their data to support research, through their phone or other devices. Beyond the data itself, the practical benefit is that you might see better participation in trials if people can participate at home, as well as greater retention over the length of the study.

From a scientific perspective, one question we are now looking to answer is around the potential benefits of more regularly monitoring trial participants. This could be through a device or monitor, or perhaps even a small sensor sown into someone’s clothing. We’re asking questions on the role of multimedia including video and audio, and how can we make use of that information. How can a wider range of ‘experience snapshots’ provide a different way measure of someone’s activity, mobility or wellness, for example, which can all enhance our understanding?

This is all part of the feedback loop of drug development and may also help us better understand issues relating to adherence and medicines management. At the same time, if we’re using a mobile app as part of a study, can we also learn and make it better for patients to engage with?

In that regard, medical apps are not that different from any other. Every time we pilot something in this space, not only do we need to collect the medical insight, we also need to understand the user experience.

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Reshaping the future

The road ahead

While pharma companies rely on innovation, overcoming individual mind-sets is often a vital first step in pushing boundaries and driving the conversation forward within our industry. Getting to a place where teams are prepared to try something new is progress in itself, but putting patients at the centre of decision-making to participate in research may totally reshape the future of interventional clinical trials.

Eventually, the key differentiator will be in how each company uses the data it gathers through new, innovative means. We may see more emerging on issues relating to patient behaviour or social interaction with mobile technology, which especially has an impact on how GSK can better recruit for its studies.

As we continue these efforts, patient responses will become clearer over time, but what is certain even now is that in future, pharma companies will need an end-to-end patient engagement strategy for clinical trial participation. This goes beyond recruiting through social media, to the enablement of real-time engagement and data feedback. Clear communication on how data will be used can boost participation and is vital to ensuring compliance with data privacy laws. Our team at GSK is working to develop new technologies that stand up to scrutiny and comply with regulations and transparency will play an important role here.

Despite the potential benefits, there are still challenges which need to be overcome. Within our industry there is a sentiment of risk-aversion around new technologies, but there are also more practical barriers. We need to think about how to work with investigators under this different model and there is also a question for companies in terms of interpreting the data. At the same time, the return on innovation like this relies not only on the device reliability, but showing the analytics and evidence in a way that patients, physicians and payers would recognise and act on.

GSK invests a significant amount of time and effort surveying the technology space and spotting emergent trends, but it also participates in a number of different consortia through which we share and exchange information. A collaborative approach will be key as the sector moves forward with digital adoption as a whole.

The entire ecosystem inclusive of health care professionals and patients might well benefit ,from greater collaboration between companies on device performance and data-sharing, but at the moment this remains one of the biggest obstacles to progress in this space. However, programmes such as the Clinical Trials Transformation Initiative and TransCelerate are great examples of where different pharma companies are already working together in partnership with health authorities, tech companies and academics.

There is still more to be done to fully realise the potential of digital technology in research, but at GSK we have overcome the activation energy and are on our way. Exciting times lie ahead.

The Salford Lung Study: A world-first in randomised controlled trials The Salford Lung Study (SLS), a Phase IIIb multi-centre openlabel randomised controlled trial, is a new way to explore the effectiveness of treatment for respiratory disease in everyday clinical practice.

But what really sets SLS apart from other real-world studies is how it utilises Salford’s electronic health records system, a clinical information system providing a single, integrated electronic patient record across A pioneering GP surgeries and collaboration between hospitals that enables GSK, the NHS and data to be collected Breathe easy: The Salford Lung Study explores the effectiveness of treatment The University of for respiratory disease in everyday clinical practice continuously and Manchester, the study remotely. This ensures is designed to meet patients are closely the needs of the healthcare community by providing data in patients monitored in real-time but with minimal intrusion into their everyday who more closely reflect the population healthcare professionals lives, removing the need for enforced interventions and controls treat and see in everyday clinical practice. required in traditional clinical trials which may also affect the way a patient behaves – for example, how they take their medication.

Traditionally the efficacy and safety of a medicine is tested through double-blind RCTs which typically involve a specifically defined group of patients with a particular diagnosis in a highly-controlled The study team was able to monitor all hospital admissions, outpatient and emergency department visits, as well as data from setting. It’s an approach that is scientific and robust. primary care (including all healthcare contacts, out-of-hours activity But to take part in an RCT, patients have to meet strict recruitment and prescriptions of antibiotics or oral steroids) via the electronic criteria. For respiratory conditions, this is particularly problematic, health-records. where often just a small percentage of patients would be eligible because their age, the severity of their disease or the presence of other illnesses.

By contrast, SLS began recruitment in 2012 on the basis that enrolment would be open to a much broader population. All suitable patients at 80 primary care sites in and around Salford and South Manchester were identified from practice databases and invited to participate in the study by their own general practitioner.

The study is intended to enable healthcare professionals and decision makers to assess more fully the potential value of treatments by providing data collected in a more representative clinical practice setting. It adds to the existing data set from RCTs for a medicine which, while critical to establish the safety and efficacy of a medicine, are conducted in a highly controlled environment and enrol a more highly selected patient population than would be expected in everyday clinical care.

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DATA AND DRUGS

Record collection Christian Martin, Medisoft, outlines how advanced Electronic Medical Records (EMR) can help in the development and monitoring of ground-breaking drugs

W

ith an ageing population millions more people will suffer from degenerative eye conditions, particularly age-related macular degeneration.

Drugs such as vascular endothelial growth factor inhibitors (anti-VEGF) have transformed patient outcomes in recent years, and new molecules to treat a wide range of ophthalmic conditions will be increasingly important in the battle against sight loss. Efficient systematic recording of medication use and outcomes is now becoming more commonplace. As well as improving patient care and safety, these data enable research and development teams to better understand eye diseases and the real-world use and effectiveness of ophthalmic medications.

It is estimated that 196 million people worldwide will suffer from age-related macular degeneration by 2020 and this will rise to 288 million by 2040, according to a study in the Lancet Global Health. Increasing disease prevalence and an aging population mean that many more people are predicted to suffer from a variety eye conditions such as glaucoma and diabetic retinopathy in the coming years.

Such an escalation in patients diagnosed with degenerative eye conditions is a concern for many ophthalmology departments, with the clinical workload expected to surge rapidly.

However, it also presents a unique opportunity for pharmaceutical companies aiming to enhance treatment for previously untreatable conditions such as the â&#x20AC;&#x2DC;dryâ&#x20AC;&#x2122; form of agerelated macular degeneration.

More patients inevitably means more clinical appointments, but thanks to advanced EMR systems which are increasingly coming to the fore, accurate data on disease progression, treatment and outcome is much more readily available. As a result, the case for efficient electronic data collection is strengthening â&#x20AC;&#x201C; with pharmaceutical companies willing to invest in such records, both to support eye departments in treating the right patients in the most appropriate way, and to learn from pooled databases of huge populations of patients with a particular condition or treatment.

Traditionally, pharmaceutical companies would be reliant on expensive clinical trials or postmarketing surveillance studies to gain insights into the need for and use of medications.

The information compiled using EMR systems provides a short-cut, allowing such research to be conducted in a fraction of the time and at a much lower cost.

Wide-ranging benefits Forward-thinking pharmaceutical companies are becoming increasingly reliant on the data gathered by specialised EMR systems, using it to understand the natural history of potentially treatable conditions, to support marketing initiatives, and to compare realworld treatment patterns and effectiveness with the results of clinical trials.

Data collection in ophthalmology has now reached the required level of sophistication that clinical teams should no longer depend

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on data that is distributed across paper notes and a range of diagnostic and imaging devices. EMR records can be drilled down to give information not only on how effective a treatment has been, but also variations across specific cohorts of patients, such as those with complicating comorbidities.

The accessibility of pooled data on hundreds of thousands of patients is an important breakthrough for pharmaceutical research teams which have always faced the challenge of accessing information which is consistent, reliable and well linked. EMR systems are now automatically collecting that data at all stages of the value chain, from trials to real-world use after regulatory approval.

By embracing the latest EMR innovations and collaborating with clinicians and hospitals that make best use of electronic records, pharmaceutical companies can better understand many aspects of their market and product development. This could lead to identifying areas of unmet clinical need, market potential and rapid recruitment into trials which have the potential to give more years of patent protection after regulatory approval.

The tools to identify the best applicants for trials and to measure the effectiveness of new drugs on large numbers of patients or particular groups of patients are all embraced within a modern EMR. Information is already being used beyond clinical trials, with leading pharmaceutical companies investing in data networks to gather, analyse, share and respond to real-world outcomes and claims records.

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LAB ISSUES

Problems solved Trish Meek and Darren Barrington-Light, Thermo Fisher Scientific discuss the mounting costs of everyday lab problems and how to avoid them

I

f you’ve worked in a lab, you know firsthand that it can be frenetic, fast-paced and at times overwhelming. And this is especially true today, as shrinking budgets force many lab managers and analysts to do more with less. But there’s a path forward, and it starts by looking at the lab holistically, solving the obvious, everyday problems first.

Problem one: Inventory mismanagement

Problem two: Missing analytical trends

Inventory varies from lab to lab, but is often fairly predictable within a single lab running specific tests and using consistent workflows. Let’s take a high-dollar consumable such as a disposable well tray. Suppose your lab routinely analyses samples for E. coli: you know what’s required for each analysis, you know how many tests are run each year, so you should know how many trays to keep in inventory. That’s the first step in the process: budgeting in advance based on historic patterns.

Identifying errors is hard. What’s more, the way many labs go about it is also error-prone, starting with the fact that they focus on solving errors after they occur. For example, during data generation, decisions and actions should ideally be taken in real time based on in-run results and the method requirements. However, these are usually made manually by users after the analysis and can therefore be subjective or error prone and cause delays. Having a software system in place, such as a chromatography data system (CDS) that can take automated, inrun pass and/or fail actions based on the real time chromatographic results can minimize analytical errors and improve efficiency in the laboratory. Thermo Scientific Chromeleon CDS, for example, provides this capability with its built-in Intelligent Run Control (IRC) allowing users to define the pass/fail criteria and the actions that should be taken to try to rectify the issue.

Tracking what has been used, when and by whom is yet another critical but often-ignored step. Gas chromatography (GC) vials are a great example. Since these are in such high demand, lab technicians often hoard them, which disrupts the lab in costly ways. First, if inventory is depleted, it can have downstream impacts on other tests, affecting productivity. Second, the technician suddenly short of vials will likely hotshot them to minimise disruption. This could mean paying double the price for expedited shipping. If this happened infrequently the impact would be trivial but it happens too often.

The obvious answer is better budgeting and tracking and this is where a laboratory information management system (LIMS) is highly effective. While it’s not easy to manage inventory – even with software – spreadsheets are simply not dynamic enough to establish an inventory management system that supports proactive planning/budgeting and up-to-the-minute accuracy. With Thermo Scientific SampleManager LIMS for example, labs can carefully track inventory as part of a comprehensive lab management programme.

But it’s also predicting and preventing errors – small, seemingly inconsequential ones – that should similarly be a focus for labs. Errors that mask small QA/QC problems, for example, can mushroom into much larger and systemic quality issues or create productivity gaps that eventually require costly reconfiguration.

Understanding whether an experiment is out of spec – or more importantly trending that way – is especially challenging. Even the most experienced, high-achieving lab analyst is unlikely to discern subtle patterns and trends in data, especially at the scale most labs operate.

And for those that can – or do – the analysis is retrospective, perhaps weeks after an experiment.

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Co-located with:

4 - 6 October 2016 Fira de Barcelona, Gran Via, Barcelona, Spain

InnoPack: Bringing together buyers and sellers from the pharmaceutical packaging network Leading European show for pharmaceutical packaging and drug delivery systems

InnoPack Worldwide is the leading European show for pharmaceutical packaging and drug delivery systems, born out of the success of ICSE’s Packaging Zone. It brings together the packaging and pharmaceutical industries, creating business opportunities through a dedicated worldwide forum.

“A chance to network with professionals from around the globe.”

“80-90% of our key customers show up in the 3 days. Extremely efficient. It was great.”

Helge Tippmann Novo Nordisk A/S

WHAT VISITORS SAID ABOUT 2015 SHOW

87% 85% 80%

rate CPhI Worldwide as the leading global gathering of the pharmaceutical industry

agree that CPhI Worldwide is the most important show in the pharmaceutical industry’s calendar

agree that CPhI Worldwide is the best place to find new suppliers and products

“I’ve been in the industry for over 30 years. You learn something new every day, CPhI is a great place to do just that.”

Marc van Gerwen Global Business Director, DOW

Sharon Johnson SVP Quality, Product Development & Regulatory Affairs, Catalent

WHY ATTEND InnoPack  Join 36,000 pharma professionals from 150+ countries; network, source suppliers, develop new and existing relationships and do business in pharma.

 

Find companies across key sectors A separate zone within InnoPack show is dedicated to labelling and introduces the latest labelling solutions in the packaging industry

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Talk to people from the pharma packaging industry about latest innovations in: API packaging bio packaging, fine chemicals packaging, FDF packaging and sustainable packaging

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Meet companies from around the world: this is the most efficient and effective way to meet suppliers from major and emerging markets including the US, China, India, Turkey and Russia

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Free access to all co-located events: your registration will also be valid for CPhI, ICSE, P-MEC, and FDF

Register now: gotocphi.com/innopack

SOME OF OUR EXHIBITORS

Organised by:

LAB ISSUES

Statistical quality control (SQC) absolutely must be built into whatever technology the lab uses each day.

SampleManager LIMS, for example, built that capability into its LIMS. What this does is detect nonconformance trending before it reaches predefined thresholds, and this is the key for labs: real-time monitoring using statistical algorithms is critical for decision-making.

Problem three: Uncontrolled SOPs It takes time to develop and document standard operating procedures (SOPs), but failure to do so is a recipe for disaster. Laboratories cannot tolerate inconsistent application of procedures.

“

Calling SOPs one of the top problems to address in a lab is certainly not breaking news. Recommending how those SOPs are created, distributed and tracked for productivity and compliance purpose is a different story. Many labs still use paper, and that puts them at a distinct disadvantage. The good news, however, is that technology has evolved to a point where managing SOPs is easier and more efficient than ever. time to develop

It takes and document standard operating procedures (SOPs), but failure to do so is a recipe for disaster.

Electronic SOPs (eSOPs) are the modern lab’s defence against techs ‘going rogue’.

If they don’t exist or if paper copies aren’t handy, clear or widely understood, it’s too easy for an analyst to err, even unwittingly.

With SOPs defined in SampleManager LIMS, for example, there’s a rigid workflow with clearly defined technical corrective actions to ensure consistency and adherence to protocol. Furthermore, if the lab CDS can help enforce the eSOPs of the LIMS system then it is possible to ensure they are adhered to during each analysis.

”

Problem four: Measurement traceability A single laboratory may be responsible for hundreds of tests each week, if not more. And a test is not simply a test; it’s the sum of many parts.

Defending data involves painstakingly retracing steps, many of which are so embedded in the fabric of the lab and its workflows that it may be impossible to isolate them. Imagine sorting through handwritten notes from fellow analysts and still not finding what could have gone wrong – it’s frustrating. But it’s also costly: analysts routinely spend a quarter of their productive time simply collecting data to defend a result.

Thankfully, technology can do work in the background that can dramatically reduce the time, expense and aggravation associated

with defensibility.

A lab CDS should be the first tool in this battle, providing traceability of all tasks, recording who did what, when and why. The ability to quickly find data related to an analysis and the associated audit trails enables measureable productivity gains, cutting into that 25% of time many must devote to defending their data.

With the advancements in LIMS from the days where labs relied on them for basic sample management and data reporting, the modern LIMS reaches across an enterprise: it integrates with data in the CDS, MRP, ERP and other enterprise systems in ways that directly impact defensibility. No more searching in multiple places; everything you need to defend your result is neatly organised for rapid analysis and reporting.

Problem five: Misunderstood maintenance When many labs think of trend analysis, they don’t often associate it with instrument maintenance, but that’s a mistake. Data such as area counts, baseline conductivity and retention time provide valuable evidence that if trended and analysed can reveal much about the health of an instrument. Both CDS and LIMS offer capabilities that allow users to monitor instrument health so that work can be assigned more effectively on a regular Analysts will tell you maintenance schedule. Users are notified that they “get to know” of upcoming maintenance – even of wear- their instruments, but part failure, so that maintenance can be sometimes signs are too scheduled before failure becomes an issue.

“

subtle to sense the failure

Analysts will tell you that they “get to know” before it occurs and the their instruments, but sometimes signs are instrument goes down. too subtle to sense the failure before it occurs and the instrument goes down. And with many labs cycling through new grads, transfers and others unfamiliar with an instrument type (or even a specific instrument), reliance on feeling or gut is risky. To understand what an instrument is telling you, you’re better off relying on data: if you set a sample point and watch for deviation, you’ve effectively given yourself an early warning system.

”

Conclusion: Small steps create big changes The pace in today’s labs is more frenetic than ever before, and the demands on an analyst’s or lab manager’s time are even greater. So now, more than ever, it’s time to return to basics. Labs should embrace available technology to take a much more strategic, proactive and intelligent approach to what many consider routine.

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37

Performance.

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Quality.

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NovaPure plungers are designed to reduce particulate, ensure consistency of delivery and fit the changing needs of higher volume injectable drug delivery systems. By choosing NovaPure syringe plungers, you can help ensure drug product compatibility with components designed specifically for optimized performance and consistency in delivery systems.

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www.westpharma.com West Pharmaceutical Services, Inc. I 530 Herman O. West Drive, Exton, PA 19341 West and the diamond logo, By your side for a healthier world™ and NovaPure® are trademarks or registered trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions. Daikyo Flurotec Closures® is a registered trademark of Daikyo Seiko, Ltd. in Japan.

For complete contact information please visit www.westpharma.com. © 2016 West Pharmaceutical Services, Inc. #9798 0816

FORMULATION

Solvent business Dr Ed Connor and Bruce Peat, Peak Scientific Instruments take an in-depth look at method implications on lab gas supply for residual solvent analysis using HS-GC-FID

It’s a gas: Nitrogen is widely used as a carrier gas for RSA and is used for the HS-GCFID of spironolactone and can be generated in the laboratory using a gas generator

nitrogen as an alternative In the manufacturing or processing of drugs and carrier gas to helium, pharmaceuticals, any with small changes to solvents used in production methods along with must be absent from shorter columns allowing the end-product as this identical analysis times. can be harmful to those consuming pharmaceutical The ASTM method, F products. Residual solvent 1884-04, for residual analysis (RSA) allows Work to rules: Peak Scientific’s Bruce Peat (left) and Ed Connor (right) say that analysis methods solvent analysis in identification of by- are highly regulated, meaning labs can’t freely choose which gases they use in particular methods p h a r m a c e u t i c a l products of manufacturing packaging material, does with concentrations tested, analysed and Class 3 solvents: Solvents with low toxic not define a carrier gas. This means that labs monitored to ensure levels present are below potential. Solvents with low toxic potential can choose the most optimum and efficient gas the limits set by the International Council for to man; no health-based exposure limit is for their analysis. There are clear advantages Harmonisation of Technical Requirements for needed. Class 3 solvents have Permitted Daily to be found from opting for hydrogen carrier Pharmaceuticals for Human Use (ICH). The Exposure (PDE) of 50 mg or more per day. gas for GC in this circumstance, with faster United States Pharmacopeia (USP) and ASTM RSA is the most common use for GCs in the run times allowing higher sample throughput have developed methods for identifying residual pharmaceutical industry and the world’s as well as the aforementioned benefits of solvents with the use of a headspace (HS) leading instrument manufacturers have created removing gas cylinders from the lab. extraction alongside gas chromatograph (GC) custom solutions with headspace and GC, FID and MS combinations tailored to meet a lab’s with a flame ionisation detector (FID).

Analysis methods in the pharmaceutical particular demands. These instruments require industry are highly regulated, meaning that labs Residual solvents are classified according to highly pure gases, meaning that laboratory are unable to freely choose which gases they managers have the choice between traditional their toxicity as follows: use in particular methods. For labs looking to gas supply methods or gas generator supply.

Class 1 solvents: Solvents to be avoided. simplify their overall workflow, a gas generator Known human carcinogens, strongly suspected The method for RSA, in accordance with the can help significantly. Generating gas in the human carcinogens and environmental USP, requires the use of either nitrogen or lab can improve productivity through providing hazards. helium as carrier gas and the FID will require a round-the-clock gas supply, without the Class 2 solvents: Solvents to be limited. hydrogen flame gas along with air or Zero Air need to changeover cylinders, wait for gas Non-genotoxic animal carcinogens or flame support gas. Nitrogen is widely used as a deliveries or having to manage stock levels. possible causative agents of other irreversible carrier gas for RSA, and is used for the HS-GC- The removing of cylinders from the lab has toxicity such as neurotoxicity or teratogenicity. FID of spironolactone and can be generated in clear benefits for lab efficiency and the use of Solvents suspected of other significant but the laboratory using a gas generator. Recently, nitrogen carrier gas does not necessarily mean reversible toxicities. there has been increased focus on use of slower analysis compared with helium.

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39

28 SEPT - 29 SEPT 2016

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ASEPTIC MANUFACTURING

Keeping it clean Chargepoint looks at the use of vaporised hydrogen peroxide (VHP) in aseptic transfers

T

he demand for advanced pharmaceuticals to meet the needs of the evolving human race has brought about the necessity for biotechnology innovation.

Vaccines are widely believed to hold the key to the burgeoning AMR crisis and a failure to act to invent technologies to speed up the manufacture of vital drugs could be catastrophic.

Quality of the end product has always been paramount and efficiency of the process is equally as important.

As the pressures of modern living on the scientific, medical and technological sectors grows, maintaining the highest standards is more important than ever.

The techniques to ensure sterility consist of high classification cleanrooms and barrier or isolator technology, along with sterilisation or decontamination processes to ensure the product and technology in critical manufacturing areas are kept at the required sterility assurance level (SAL).

A containment device widely used within the pharmaceutical industry to achieve product transfer is the split butterfly valve (SBV), which was developed more than 20 years ago.

The widespread use of SBVs within the manufacturing process has evolved from a part in the transfer of highly potent powders to a major role in the transfer of sterile ingredients.

As a result of the utilisation of SBVs and the ever-growing demands on manufacturing, ChargePoint Technology has created a device that it claims, is revolutionising the aseptic transfer market.

The fundamental feature of the AseptiSafe SBV is the two halves, namely the Active (Alpha) unit and the Passive (Beta) unit. Each half consists of half of the ‘butterfly’ disc which is sealed against the main body via an elastomeric seal to create the sterile barrier.

In operation, the two disc halves are locked in place to form a single sealed unit and the previously exposed interfaces are then sealed together.

Set the standard: the pressures of modern living on the scientific, medical and technological sectors grows, maintaining the highest standards is more important than ever

The active unit is the driving half of the valve and once operated, either manually or automatically, the disc will open to allow the transfer of material through the valve with the valve closed unlocked and undocked once the transfer has taken place.

“

Quality of the end product has always been paramount and efficiency of the process is equally as important.

”

The area of concern exists with the small area where the outer circumferences of the disc interfaces (that are exposed to the room environment) seal together and rotate into the open critical area.

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This is known as the ‘ring of concern’ which is common in any aseptic transfer device and the highly specialised SBV created

by ChargePoint Technology – called the AseptiSafe bio – uses a technique to eliminate that concern and, in fact, ensure the highest standards of SAL are met.

This new approach involves partially docking the two disc faces creating a sealed chamber which can be bio decontaminated prior to final docking. The active portion of the valve is designed in a unique way: the sides of the valve body form walls, when the passive section is introduced, a sealed chamber is created, allowing a matchless decontamination process to take place..

ChargePoint Technology has taken this a step further with the selection of H2O2 -hydrogen peroxide gas as the decontamination media.

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“We then take the indicator spores and see if we can grow something from it, if we can’t then we know the process has worked and the bacteria has been killed, the area is contaminant free proving our patented system works.”

During docking a sensor on the active portion of the valve identifies that the passive valve and transfer container are located in the partially docked position.

Gassing valves located at either side of the valve then open and allow the gas to be transferred through the sealed chamber biodecontaminating the internal surfaces of this area.

This decontamination process goes through four distinct phases to ensure that not only has the space been decontaminated but the H2O2 gas has been fully removed.

The timed sequence of the process is: • Setting the humidity level for the introduction of VHP/VHPV (Dehumidification/Conditioning) • Introduction of VHP/HPV (Conditioning/ Gassing) • Bio-decontamination/Dwell period.

Where biological deactivation occurs.

• Aeration. Removal of VHP/HPV to less than 1PPM. This time includes any out-gassing from material.

The times taken for this process vary between six and 30 minutes dependent on the gassing system utilised, chosen to ensure the effectiveness on the size of space which is gassed.

Half time: The fundamental feature of the AseptiSafe SBV is the two halves, namely the Active (Alpha) unit and the Passive (Beta) unit

H2O2 has for the past 20 years given fast and safe decontamination to areas that may be contaminated with bacteria.

In the 1980s, after almost a century of using aqueous hydrogen peroxide for disinfecting heat sensitive medical devices and surgical apparatuses, the American Sterilizer Company, now STERIS, discovered H202 has a quicker sporicidal time when in vapour form in smaller concentrations.

As well as hydrogen peroxide’s natural power, it has been used as an ingredient to solve everything from teeth whitening, contact lens cleaning and mouthwash, tackling acne and even cleaning aquariums.

Christian Dunne, global sales manager for ChargePoint Technology, said: “Small

For a bio-decontamination cycle time, the timeframe is considered extremely fast compared to the conventional airlock approach to transfer into the aseptic core, which would typically be in the region of 30 minutes to one hour due to the surface area and volume being transported. droplets are dropped onto a hot plate and they are vaporised and blown into an air stream and into a space between our passive and active just before the valve docks and that’s when the elimination of bacteria in the area happens.

“When you have a potentially ‘dirty’ room, two faces are brought together and that traps the un-classified air. If you open the valve up there is risk contamination from the air can contaminate the product.

“Once we have created this chamber what we do is propel the hydrogen peroxide gas through and decontaminate the space. We prove its efficacy by putting biological indicators inside to validate the process.

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The applications for this type of sealed transfer are varied, although this system is now being successfully utilised in the product transfer for non-terminally sterilised products, adding bulk powders to formulation vessels, and also direct from process dryers into immediate containers and then into filling lines.

Manufacturers are benefiting from a closed handling method that not only achieves the required SAL along with a reduction or elimination of manual intervention but also the opportunity to reduce the resource associated with cleaning and validating large volume areas.

This is done by utilising a compact and efficient split valve system that is also capable of ensuring high level protection while handling toxic ingredients that pose risk to operators.

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Quality matters.

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08.10.15 11:32

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LEAN MANUFACTURING

Drive for innovation Germán Ormaechea, Telstar, outlines how the automotive sector has inspired lean manufacturing in drug manufacture

A

t the end of 2009 many ‘innovative drug makers’ faced slower growth and were forced to reduce costs, following years of high margins and continuous sales increases. Other markets, especially the automotive market, had been struggling with this same predicament for many years. This article analyses the evolution of the pharma industry in relation to this new market perspective.

The operational KPIs of the main pharmaceutical companies in comparison with other markets were at that time, completely disproportionate.

Measure

Production Lead Time (Days)

Pharma

Automotive

Aero Space

Computer

Consumer Package Goods

Company

Roche

J&J Pfizer

120-180

1-7

7-120

5-10

3-7

Finished Goods Inventory (Days)

60-90

3-30

3-30

5-50

10-40

Overall Equipment Effectiveness

10-60%

70-85%

50-70%

80-90%

70-90%

Labour value-add time

20%

60-70%

60-70%

60-70%

60-90%

Direct / Indirect Labour Ratio

1:01

10:01

10:01

10:01

10:01

Annual productivity improvement

1-3%

5-5%

5-10%

1-3%

5-15%

Merck

First pass Yield - Zero Defects

60%

90-99%

70-90%

90-99%

90-99%

Eli Lilly

Number of suppliers / FTE

24%

8

7

22

Spend / Supplier (in US $ Million)

GSK Novartis Sanofi-Aventis

Key to success The Japanese manufacturer closed the gap gradually, one improvement at a time.

Toyota focused on its production system: a total view of how to design, produce, and sell cars, standardising working methods and establishing a common set of principles and tools aiming for an integrated process that combines the concepts of waste elimination, built-in quality, and worker involvement supported by a cultural focus on problem solving.

AstraZeneca Bayer Abbot

BMS

Main issues within pharma sector

Amgen Teva

Source: McKinsey & Co., quoted in The Gold Street, December, 2009

Genzyme

Image 1: Source Kaizen Institute

(On the right the list of top pharma industries by 2009 revenue, on the left shows the average of the KPI’s from these companies in comparison with other industrial sectors) The challenges then and now still remain: low R&D productivity, rising costs, increasingly complex technologies and product portfolios, increasing competition from generics, growing regulatory constraints. As a consequence of these factors the results were steadily declining. Pharmaceutical and biotech industries quickly recognised that one time cost cutting was not enough to overcome their problems and to establish the basis for a required sustainable trend of cost reduction and quality increase.

It was clear for the drug industry that there was a need to transform its business model, operations and overall cultural outlook for future success. In this sense, pharmaceutical companies such as AstraZeneca, Roche, Novartis and Pfizer started to look at the automotive industry and began hiring experts from Jaguar, Land Rover, Toyota and Renault in order to increase the efficiency of their operations.

At this stage the Toyota production system appeared to be the solution for the problems that the pharma industry was facing. However there are some differential aspects within the pharma industry that render the challenge of this change especially difficult.

Preserving the innovative spirit was and still is, one of the main drivers for the drug industry. Years of high margins and large budgets motivated a very low cost conscious culture in comparison with other markets. An additional constraint while applying lean is the complexity: independent functions, divisions, and geographic units leading to isolated structures and departments. Since lean is all about teams and cross-functional collaboration, a new cultural conflict arose for pharma.

Pharma companies typically have a complex variety of customers – patients, physicians, hospitals, public companies and the needs of each are increasingly segmented and variable. Customers in developed economies or emerging markets are serviced sometimes from the same central organisations with the complexity of understanding customer needs – one of the basic pillars for TPS. Many pharmaceutical companies have based their core business on the ability to deliver ALL possible solutions to their customers and experience inherent difficulties when developing a standardisation methodology. Product portfolios are therefore another constraint.

Why Toyota?

When Toyota created its lean production system in the late 1950s the Japanese company built a clear competitive advantage through a new business approach.

Taichi Ono implemented the Toyota production system to compete against Ford/GM’s massive production systems.

Toyota’s rise to the top from its humble beginnings as a textile machinery manufacturer is one of the most remarkable examples in history of managing for the long term. In 2007 Toyota sold a total of 9.34 million vehicles and in so doing overtook America’s General Motors to become the world’s largest automobile manufacturer.

Achieving results with lean methods Lean is undoubtedly helping drug companies to do far more with fewer resources.

These changes however cannot happen overnight (it took Toyota 50 years to refine its lean production system). Many pharmaceutical companies began the lean journey nine years ago in 2007 and some companies are only just starting.

As with other industrial sectors, the first lean approaches within pharma were applied to manufacturing lines. By standardising processes, the lean efforts were able

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45

to increase productivity, efficiency and flexibility of a global supply network for the required medicines. Concepts such as pull manufacturing, TPM, 5S, SMED, VSM started to be used in the manufacturing lines. Well-executed lean programs in pharma manufacturing companies soon realised results, such as reducing production cycle times by 60-90%, reducing inventory by 40% and cutting costs by 10-30%.

Lean practices and the set of tools providing lean are inter-dependent. The sole focus on one single practice cannot lead to success.

The next step was to move forward from the assembly lines into the offices. New product development, sales productivity and marketing effectiveness are now also improving by applying the same set of tools and principles to their processes.

The Toyota production system and its tools are normally represented by a temple combining all of the tools, visualising the interconnection between them. The temple aims to provide stability for long term improvements. The foundation is settled by the people, their culture, their safety, their daily behaviour and their common objectives. All the main Lean tools (5 Ss, JIT, SMED , visual management, Poka-Yoke, standardisation, TPM, VSM) are then the pillars supporting the roof, which shows the operational excellence that the company needs to achieve.

Typical Payoff – Savings!

Culture : Kaizen Spirit

100%

90%

90% 50%

50%

Inventory Cut By

Productivity Increased By

Defects Decreased By

Key factors for a successful lean implementation are management commitment and shared vision and culture. Very often the first obstacle when implementing lean is the lack of management conviction to the benefits it provides.

30% Throughput Time Decreased By

Manufacturing Costs Reduced By

Floor Space Reduced By

Image 2: Source Kaizen Institute

Supplier’s role The supplier base must also embrace this cultural change. The improvements needed cannot just be focused on internal operations, since material costs have a significant impact on the profit and loss accounts.

Toyota and other automotive companies usually work together with their supply base at their plants by providing resources and helping them to develop these systems. The pharmaceutical sector has not gone so far; however in recent years commercial tenders have started to include evidence of operational excellence in their requirements. Main pharma multinationals want to ensure that their supplier base is working according to the operational excellence principles. Consequently, the market is becoming more competitive and aggressive in this sense.

Image 3: Source : http://www.flad.com/content/epubs/Novartis_BSM_ LeanLabDesignWorkshopWhitePaper.pdf

Typically lean programmes fail when only some of the tools are applied providing spot benefits without providing the basis for continuous improvement. Only by applying the ‘so called’ three Kaizens will companies be able to progress on their journey towards Lean operational excellence.

1) Kaizen projects. Apply continues improvement projects using the Lean Tools in order to reduce costs and promote efficiency.

Examples of specific achievements Companies like Patheon have implemented lean programs, such as Patheon Advantage (PA) in its third year of deployment, with all 10 Patheon sites fully engaged. There are nearly 150 continues improvement projects on the books with an average project value approaching $100K savings.

Pfizer also launched its ‘Lean Lab’ programme back in 2009 starting at Pfizer’s biotech site in Ireland. The Pfizer lean story is an excellent demonstration of the benefits of real lean to significantly improve business processes also outside of manufacturing, namely within QA and QC departments.

By the end of 2014 Novartis had accomplished a major transformation involving process re-engineering and lean manufacturing principles in most of its plants. The programme was launched in November 2002 and the initiative achieved the reduction of cycle times and reduced spending significantly In 2009, GSK Bio (GlaxoSmithKline) applied several lean concepts to its vaccines business. The results were immediate in producing less waste and developing faster cycle times for decision making. The success story included the launch of the Cervarix (HPV Vaccine) 18 months earlier than planned.

The Kaizen Temple and management commitment are the key factors for success and sustainable improvement

2) Daily Kaizen. Change the person’s mindset for future success. Apply the Kaizen: ‘everyday, everybody, everywhere’ in order to generate small continuous improvement ideas.

3) Leadership Kaizen. Manage by example. Implement concepts such as Gemba Walk, layered audits... providing continuous support, promoting, offering guidance and teaching on the different tools.

Conclusion Since 2009 the pharma industry (especially the big drug manufacturers), have been on a lean journey working towards operational excellence forced by the evolution of world markets. The use of Kaizen has been demonstrated to be the main tool to achieve the desired results. All main companies are introducing this system to varying degrees and are bringing their supplier base with them.

The message is clear – the market must start approaching these methodologies even if R&D capabilities are considerable. Management teams need to make a clear step in this direction to drive the continuous improvement the market is now requesting – to deliver better and cheaper drugs.

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47

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CASE STUDY: TABLET PRESSING

Pressing needs Bmp production explains how the addition of a Prexima 300, IMA Active’s new tablet press, has improved its production processes

Looking ahead: According to bmp’s Ingo Küster the company is focusing on the acquisition of medium to large production contracts for solid dosage forms

‘There is nothing we cannot find a solution for,’ says bmp production, contract manufacturer and R&D-service provider for pharmaceuticals, nutraceuticals and medical devices.

“

“Our customers and their products are our first priority and our goal is to contribute to the success of their business”, says Ingo Küster, CEO. The company believes that a customer-oriented approach has proven to be successful in the past 23 years. Compliance with even the most restrictive standards along with flexibility are what Küster believes characterises the business and the services it offers. These include micronisation, mixing and production of tablets, capsules, granules packaged in sticks, blisters, jars and bottles.

We are committing ourselves to fulfil contracts under strict quality standards and to generate added value for the benefits of our clients

”

A €7 million turnover is generated by small, medium and large batches produced under international DIN ISO 13485 and cGMP as well as German AMG regulations. After service is taken just as seriously, whether handling, forwarding, commissioning or storage under controlled conditions is concerned.

Bmp had an old tablet press machine, which no longer matched its requirements. Prexima is designed to offer an innovative solution, to ensure optimal performance even with the most difficult-to-handle powder substances.

According to Küster, the Prexima has improved bmp’s production efficiency, even for large dimension tablets. He says that overall tablet quality is always assured as the machine keeps the tablets uniform in terms of weight and hardness.

Maintenance has also been simplified – limited surface contact with the product reduces cleaning time and prevents contamination.

“

Thanks to the addition of this technology bmp has been successful in expanding its production of pharmaceuticals

“We have a privileged relationship within IMA, who supports us with good advice – this time more than usual. IMA product managers communicated excellently with our technicians and their designers worked side by side with us to define the project’s specifications,” says Küster.

He believes modern facilities and machinery, combined with well trained and highly motivated staff are the foundations of the company.

Thanks to the addition of this technology bmp has been successful in expanding its production of pharmaceuticals by increasing business with existing customers and by acquiring new customers and production contracts. It also plans to extend our range of machines. The next step will be the installation of a case packer machine followed by two new capsule filling machines.

The company recently installed a Prexima 300, IMA Active’s new tablet press machine.

“We are focusing on the acquisition of medium to large production contracts for solid dosage forms,” adds Küster.

“We are committing ourselves to fulfil contracts under strict quality standards and to generate added value for the benefits of our clients,” says Küster.

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”

49

A M R PHA THE AT CKS FLI

Reviewed: Awakenings Hollywood royalty star in this true story about a drug and its side effects.

Based on the memoirs of British neurologist Oliver Sacks, the film represents a voyage of discovery, combining both comedy and tragedy.

The film: The year: The budget: Box office takings: Rating: Leading lights: Written by: Directed by:

Awakenings 1990 $31 million $52.1 million 7.8/10 IMDB / 88% Rotten Tomatoes Robert De Niro, Robin Williams, John Heard, Julie Kavner, Penelope Ann Miller, Max von Sydow Steve Zaillian Penny Marshall

Synopsis Dr. Malcolm Sayer, a ficitonalised version of Oliver Sacks, portrayed by the late Robin Williams, is a doctor at a New York hospital.

His work with patients of the 1917–1928 epidemic of encephalitis lethargica, leads to the discovery of certain stimuli which seem to garner a response from the patients.

However one patient, Leonard Lowe (Robert De Niro) is less successful with the stimuli approach.

Sayer learns about a drug - L-Dopa - and its success in the treatment of Parkinson’s disease. Believing the drug may be useful in his own work, Sayer conducts a trial with Leonard.

Initially, the treatment appears overwhelmingly successful, with Leonard awaking from his catatonic state. As a result, Sayer seeks funding from donors so that all his patients can receive the drug and begin the same recovery.

As Leonard continues to receive treatment, he falls in love with Paula, the daughter of another patient. But life in the hospital

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soon becomes frustrating for him, and increasingly he desires his freedom. As he agitatedly confronts his doctors about this, Sayer notices Leonard displaying certain tics, which begin to concern him.

Why you should see this film

Unfortunately, this is where the success story ends for L-Dopa. The tics turn into spasms and difficulty walking. Meanwhile the other patients see his deterioration and realise that they will likely suffer the same fate.

Metaphorically, while the ‘awakenings’ themselves were only temporary, the doctor at the heart of the story alludes to the fact that he has had an awakening of his own.

Realising the fleeting nature of life and good health, he begins to enjoy his own existence more vigorously.

Leonard requests that Sayer film him, in the hopes that he may in some way be able to contribute to future research and treatment.

Leonard ends his blossoming relationship with Paula, and soon returns to his catatonic state – as do the other patients receiving the treatment.

Pharmaceuticals L-Dopa was first tested as a treatment for Parkinson’s disease in the 1950, by Swedish scientist Arvid Carlsson. It is still used in treatment of the disease.

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This is an emotionally-packed re-telling of an important discovery in the history of medicine.

In addition, despite the events taking place in the late 60s, there are some interesting correlations with modern day pharmaceutical tactics. For example, Leonard requests to be filmed for the purposes of future research, despite knowing that he himself will not get well. In a real world setting, video footage like this could prove extremely useful in finding ways to improve care. For example, US biotech Celgene recently initiated a video project for patients with psoriasis, in the hopes that they may be able to improve their relationships with healthcare providers – and drive home the point that no two cases are the same.

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