EPM October 2016

PACKING A PUNCH: I HOLLAND ON HOW TO GET MORE OUT OF TABLET TOOLING PLUS: • LIFE IN THE COLD CHAIN • BREXIT IN THE PHARMA BOARDROOM

OCTOBER 2016

Contents October 2016 | Volume 16 Issue 7

Regulars

8

Features

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21

COMMENT

AT THE COLD FACE Experts talk cold chain logistics

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28

ANALYSIS

BACK TO SCHOOL

12

25

OPINION EPM talks to the firm developing ultra-concentrated insulin

16 REGULATORY AFFAIRS

18 COVER STORY I Holland on getting the best out of tablet tooling

50 PHARMA AT THE MOVIES Reece Armstrong looks back at The Constant Gardener

Why patient education is crucial for adherance

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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.

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editor’s desk Help or hindrance?

In 2016 it seems that we’ve jumped a new hurdle in tackling AMR – it’s a little bit like the stages of grief – you have to reach acceptance.

That’s not to say that as an industry we’ve been burying our heads in the sand. Many of our brightest minds have been striving to address the problem for years.

But beyond the industry, healthcare providers, the national press and the public at large are now starting to get on board with the scale of the problem.

Actually it’s the pharma sector which is responsible for kicking off a good year.

In January’s World Economic Forum, 80 companies from pharma, medtech and biotech signed the Davos Declaration – a new pledge to work closely with governments around the world to tackle the problem.

Hot on the heels of that news, May saw the release of the UK’s O’Neill review – a longanticipated, highly detailed report on the scale of the issue, and recommendations going forward.

So where are we now? The O’Neill team have highlighted the need to maintain momentum into 2017 and beyond, and it’s a valid point.

AMR in the public eye poses a similar threat to global warming. The mainstream media have done a great job in supporting the cause this year, but as time goes on we’re in danger of the subject falling into the doldrums of ‘slow news day’ editorials.

In the battle against climate change, scientists were frustrated when the media started using images of polar bears as the flag bearers (no pun intended) for a greener world. The problem with a polar bear is that it implies something distant, too distant to really worry about - somebody else’s problem.

And perhaps the threat of AMR falls into the same category, at least in media terms.

The emergence of the O’Neill review, whilst extremely useful, has a comforting effect on the public at large – the experts are dealing with it. We don’t need to worry.

But of course, people do need to worry. Or rather, they need to be thinking differently about antibiotics. The most urgent steps to be taken involve dramatically curbing their use in medicine and agriculture. But how do you take a household item out of the household?

That’s the first challenge.

Nevertheless, thanks to the media coverage of the past couple of years, we can now say that most people know there is a problem. That seems to be where we are in 2016 – we’ve reached that critical ‘acceptance’ step. But do enough people truly understand the problem?

If we return to the global warming example, we’re talking about an issue which has been making headlines for far longer than AMR. You’d think the general public would be pretty well versed on the matter, right? Wrong!

In just the same way that many people believe that global warming is a result of the hole in the ozone layer, a recent WHO study found that 76% of people think antibiotic resistance happens “when the body becomes resistant to antibiotics”.

66% of people apparently believe they’re at no risk of infection as long as they take antibiotics as prescribed, and most worryingly of all, 64% believe “medical experts” will solve the problem before it becomes too serious. It’s that polar bear problem all over again.

We’ve achieved a lot this year, and we have some focus and direction in fighting the good fight. But the mainstream media must continue to deliver a consistent and coherent message if we’re going to get everyone’s support.

Dave Gray

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ANALYSIS

Ten ways to shine a light on dark data and find value in it John Culkin, director of information management, Crown Records Management looks at how businesses can benefit from finally taking control of the great unknown

J

ust hearing the words ‘dark data’ can be enough for managers in pharmaceutical sector to feel a little uneasy - but despite its rather menacing name there has never been a better time to tackle the phenomenon head on.

When you think of the recent explosion in data it’s hardly surprising that businesses worry about how dark data - defined as ‘information assets that organisations collect, process and store during regular business activities, but generally fail to use for other purposes’ - will affect them in future. So why are so few doing anything about it?

The threats provided by an explosion in data are obvious; businesses which don’t know what information they have or how to find it are opening themselves up to the possibility of a data breach and in danger of falling foul of data protection regulation as it continues to evolve.

In pharma the problem is particularly acute. Regulation demands strict quality in manufacturing and research for safety reasons. However, raw clinical data or clinical

trials are often in incompatible format, which then loses the ability to infer interesting insights from it.

Like all large organisations dependent on many complex systems, pharmaceutical companies will strive to meet their compliance needs - however they are still likely to have data hidden in their systems that is either not necessary to keep or could contain potentially useful information.

By finding and exposing the data and finding all the places it hides, gains can actually be realised. But the bottom line is organisations need to know what dark data is and where it is in the first place. If you don’t understand it how can you possibly be in control of it, let alone realise value hidden in it?

People fill their attics and garages with ‘useful’ things that could be needed in the future. The corporate equivalent is when people say ‘keep the data just in case’. How much money around the world is wasted due to those few words?

Top tips to prevent dark data accumulating – and derive benefit from it 1. Perhaps the first place to start for those in pharma is to realise that data may go to waste or sit unused if it is not properly managed – or if systems are not properly designed in the first place. This can include data which may contain potential insight for the future.

2. All industries are likely to see an explosion in data as the Internet of Things takes hold – and for pharmaceuticals it seems inevitable. The vast amount of data that genomics and personalised medicine will

generate

in

future

massively

increases the volume of data being stored, creating further challenges.

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3. Reducing the amount of dark data kept is crucial; so don’t accept that because data storage is cheap everything can be kept.

4. Develop policies and continuous training for all staff about managing data (including data on local drives, laptops, shared drives, removable devices and mobile devices).

5. Understand which regulations require what data to be kept for how long.

Don’t keep it longer than necessary unless clear benefit can be derived from it. A quarter of respondents in a Crown Records Management survey this year

said they were ‘not confident’ they knew how long they were legally obliged to keep data. This is a major concern.

sources – this is about documenting ‘where’ and ‘why’ the data lives and how it was derived.

6. Don’t believe all data in enough volume is “Big Data” and therefore has value.

Much of it will not be useful in big data projects, especially as it’s often unstructured and in various formats.

9. Have an Information Governance programme in place supported by the most senior management levels and practiced every day.

7. Use File Level Analysis software, to analyse the content of data rather than just its creation and expiry date. It can help a business understand information content, type, size and location.

8. Map data sources generated by internal systems or received from external

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10. Talk and communicate with people because not everything will be officially documented or known about. Workarounds and short-term fixes often become routine in the business place, so make people aware of the impact of not being able to manage everyone’s data effectively - it affects everyone.

Managing Brexit in the pharma boardroom

ANALYSIS

Executive coach Alan Denton of The Results Centre looks at how executives in the pharmaceutical sector can tackle the impact of Brexit

Alan Denton of The Results Centre

A

s an industry, the pharma sector was largely pro remain in June’s EU referendum. However, it has also been one of the industries least affected by the fallout – so far. Seen as a safe bet for investors during times of economic uncertainty, pharma was one of the few sectors with no real fall in share prices after the summer’s shock result.

example, how many senior leaders have really examined the views and wishes of their stakeholders? What possibilities lie dormant within your own team, company or the pharma sector as a whole? What would happen if you were able to expose these before they came to the vote?

How could you create a culture that engages your people in delivering something amazing?

As people will always need life-saving drugs, most areas of pharma are relatively immune to macroeconomic conditions. Furthermore, with around 40% of UK sales taking place in the US, the weaker pound has made our products more competitive.

Above all, how can you, as an executive or a manager, take the current situation, where the UK has changed forever, and utilise it (and the thoughts and ideas of your people) to create something bigger, better and brighter? This means opening up new dialogues on a range of post-Brexit issues from R&D to drug regulation and investment.

However, it’s not all good news. The long term implications could be negative in terms of investment into the life sciences industry, drugs regulation and approval, investment in R&D and having access to skilled workers, although with the long lead time of most research projects, the effect is unlikely to be immediate. The truth is, we can’t be sure what the next few years will bring for the pharmaceutical sector, but industry leaders need to be prepared.

It’s time to keep your head As an executive coach working across a range of industries including pharma, if I had to cite one quality that will be crucial in the times ahead it would be mindset. As a leader, if you take the right attitude, you can navigate most changes – including the uncertainty of Brexit. Rudyard Kipling’s classic quote ‘If you can keep your head when all about you are losing theirs’ has never been more apt.

Whatever your personal opinion, now that the die has been cast, leaders need to accept what’s done, change perspective, heal rifts and resentment - and look at the possibilities. So, what can coaching bring to this debate and how might it help?

What do you see in the mirror?

The referendum provided a mirror which was held up to the whole country, and dependent upon your point of view, reflected division, protest and disconnection or an opportunity to return to the nostalgia tinted time when Britain was ‘great’.

Coaching is a similar process. It provides an opportunity to reflect; to look in on yourself as a leader, your business and your people. For

It’s a time for leaders Now is the time to both show leadership and develop leaders in your organisation.

Reacting to Brexit will require a myriad of skills and talent. Senior teams will be tempted to wait until they have a plan before involving others.

Instead, this is the perfect opportunity to give leaders-in-waiting a seat at the table. This could include: • creating a junior leadership team to provide ideas/challenge the senior board • opening up decision making to wannabe leaders to experience issues first-hand • providing leadership shadowing • giving major projects to leaders waiting in the wings to show faith in their potential and allow them to make their mistakes and learn from the process.

Coaching can play a key role in accelerating the development of emerging leaders. It creates an opportunity to reflect and learn. It supports self-awareness of strengths to build on and areas to develop.

It allows budding leaders to engage with the real issues; to deliver their best ideas and their best self to implement them. So seek out your wannabe leaders, nurture them and reap the rewards.

Whatever you may feel personally, the referendum result reflects a desire for change. Whether that change will be for the better remains to be seen. What does matter is that leaders step forward, take responsibility and create a positive future for their organisation and the pharma industry.

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ANALYSIS

S c ie n c e

Technolo Ad

y r o vis

gy

p u o Gr

Research group unveils cutting edge task force Research services provider Envigo has announced the launch of STAG - or Science and Technology Advisory Group – a new division tasked with driving forward emerging areas of research and developing new technologies.

The STAG group will operate across all of Envigo’s services – including pharmaceutical development, research models and services as well as crop protection and chemicals testing.

The idea behind the new group is to develop “the next generation” of research services, technology and science. As such, the group will sponsor internal programmes designed to develop new or improve existing capabilities.

Selected external partnerships will also be explored – including collaborations with academia through postdoctoral sponsorship, placement and combined research – along with offering science and technology development services to customers.

Brian Burlinson, deputy chair of the STAG, commented: “We are encouraging our scientists to put forward new projects for funding, acting as an internal innovation incubator, but also, we are going out to

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market and asking our customers if they have research problems they would like us to develop into commercial solutions.

been preliminarily approved for development – with more in the pipeline” added Burlinson.

However, it’s not just about today’s problems, as we are also partnering with universities, both on developing new science and offering work placements to graduates. Our ethos is to instil a culture of new science that permeates all areas of the business.”

Another central goal of STAG is to work closely with Envigo’s customers to develop new screening assays – utilising the company's advanced science and technology to meet on-going R&D demands.

Since its inception the group has already reviewed 16 internal applications and spoken with several external partners.

One area that is showing a number of promising projects is non animal testing (NAT) for toxicology – in vitro or silico – as these solutions have the dual benefits of de-risking drug development and meeting the desire for reduced animal use.

“The aim is to generate a balanced portfolio of projects into an annualised programme. Five projects have already

One recent example is the development of in vitro assays that enables the testing of 100 or so compounds per month for potential endocrine disrupting effects. A key benefit of these assays is the capability to put fairly large numbers of compounds through the screens with very little material needed for use.

Beyond customer contracts the group is also planning to independently develop new assays and technologies that Envigo can potentially sell to customers in the future.

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STAG will also take on a longer term role in the process of attracting talented scientists, particularly high calibre university graduates, including PHDs, who possess specific, specialised skill sets that mirror scientific and technological projects planned or in development at Envigo. This will be achieved through the Science and Technology Advisory Group forming close collaborations with academic institutions and arranging for five or six selected students each year to take up work placements at the company.

Envigo has already entered into such an arrangement with Kings College London for students with cardiovascular and pharmacology expertise.

The STAG will have a core membership of six to eight representatives for the first three years from a range of technical disciplines across the company. However, after this period the STAG committee membership will rotate on two year cycles to ensure a regular impetus of new ideas and thinking.

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OPINION

Bioterrorism: a very 21st Century threat EPM sat down with Ted Fjällman, CEO of Prokarium, a company tasked with developing vaccines against bioterrorist threats, to find out more about this growing danger Q: What is the true threat of bioterrorism today?

A: In 2001 there were attacks in the US using the dry spores of Bacillus anthracis commonly known as anthrax, where 30,000 people had to be treated, 22 became ill and five people died. Three buildings had to be decontaminated also, with a total direct cost in excess of $1 billion. In August 2014, a laptop owned by a Tunisian physics and chemistry graduate fighting with ISIS/Da’esh was found to contain a 19-page document on how to develop bubonic plague from infected animals and turn it into a weapon.

And ISIS/Da’esh and other terrorist organisations now have access to advanced laboratories taken over in Syria and Iraq, in some cases specifically designed by the fallen regimes for production of weapons of mass destruction.

While the anthrax attacks were posted in letters, Yersinia pestis, the bacterium responsible for bubonic plague, can be made into an aerosol and could be spread with a crop-dusting airplane. If released over a densely populated area or during a major event, it is estimated that 1.9-3.4M people could need treatment, 450,000 could become ill and 380,000 could die, with citywide decontamination costing $1.8 trillion.

Quarantine of cities is harder today, due to greater international travel, so if treatment is not available swiftly, biological diseases will continue to spread.

The increase in DIY-bio videos online and the access to community biolabs where the skills to grow micro-organisms can be learnt, increases the risk that a small number of people and possibly even individuals could plan and carry out a biological attack.

However, access to the disease organism is one of the most difficult hurdles for the terrorists. Sadly many diseases do exist in wild animal populations and given the skills the disease organisms could be cultivated.

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Suicidal terrorists can travel to outbreak zones, get infected and use themselves as weapons, but that is less likely to cause a large-scale epidemic. However, these suicidal terrorists could be a source for cultivating the disease organism (from e.g. sores), which is then weaponised by noninfected terrorist collaborators.

Q: What approach should societies be taking to help in the counter attempt?

A: While it is important to strengthen detection and control measures of materials coming into a country, it is not possible to police everywhere. Similarly, education of DIY bio community laboratories to detect and report any suspicious behaviour amongst users can also reduce chances of ‘homegrown’ bioterrorists emerging. But DIY bio enthusiasts do not have the resources or the inclination to police their fellow ‘biohackers’.

Thus it is very prudent to prepare for dealing with the possibility of a successful biological attack by terrorists. For this, we need to develop vaccines and treatments that can be manufactured simply and quickly and administered rapidly to an infected population. Stockpiling of the vaccines and therapeutic medicines (i.e. develop strategies for long-term storage/longer shelf-life) will be important. Finally, the military, police and public health workers should run smallscale demonstration exercises to test the rapid deployment and countermeasures in a representative population.

Q: And what is Prokarium specifically doing?

A: Prokarium is developing an oral, thermostable and easily manufactured vaccine platform called Vaxonella. Being oral means that Vaxonella-based vaccines are easy to distribute and even selfadministrable without needing skilled health

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workers for e.g. injections. Vaxonella is thermostable at 40°C for 12 weeks and has a shelf life of over three years when stored at 4°C. This long-shelf life means the vaccines can be stockpiled by governments and the thermostability means you could send the vaccine out to the general population without needing refrigeration. In addition, the manufacture can be scaled up quickly without the need for very highly skilled technicians, because Vaxonella does not require the costly and length purification steps that injectable vaccines do.

Using Vaxonella, Prokarium is now developing a specific vaccine against Yersinia pestis, the organism that causes plague. This will be tested in the clinic next year.

Q: Recently we reported that you were granted funding – what will this mean for your work?

A: Prokarium received a £1 million government innovation procurement contract from the UK Department of Health and the UK Vaccine Network, under a programme called Small Business Research and Innovation (SBRI), administered by Innovate UK. The contract allows Prokarium to conduct a clinical trial that not only will determine the potential of a plague vaccine, but also the potential of the platform to orally deliver other vaccines in the future. This clinical proof of concept for the Vaxonella platform sets the stage for strengthening the UK’s and the world’s capability to respond to epidemics and bioterrorist attacks based on many different diseases.

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OPINION

Shout it from the rooftops Suhasini Sharma, director of medical affairs at Sciformix Corporation explains how effective medical communication can pave the road to success in emerging markets

Suhasini Sharma, director of medical affairs at Sciformix Corporation

E

merging economies are gaini ng increasing importance in growth strategies of global life science companies, shifting their focus away from developed markets which have experienced a steady drop in growth opportunities. With predictions they will account for 40 percent of the worldwide pharmaceutical market by 2020. Varied demographics, government health spending and regulatory environments in individual countries of the emerging markets require global pharmaceutical companies to both create and implement specific and custom strategies to succeed in these markets. Many innovator companies are customising their product portfolio to suit these markets, focusing on older drugs going off-patent and using a strategy of “differential pricing”, and locally targeted marketing and product communication.

As a result, both generic and innovator companies are finding that they need to support launches of multiple products in short timeframes yet they don’t have the people, processes, technologies or expertise do so. By utilising the services of a functional service provider (FSP) to undertake activities necessary to support local marketing/product promotion plans, they can have access to a ready pool of highly skilled and knowledgeable resources in a country such as India, which can be deployed in a timely and need-based manner, optimising costs and maximising impact.

Challenges in emerging markets Regardless of the strategy adopted, marketing of healthcare products in less mature markets has unique challenges, including: • Lack of effective local regulations and ethical guidelines pertaining to healthcare product promotion/dissemination of medical information • Insufficient local resources • Diseases and healthcare priorities that are different from the western world • Variations in local medical standards of practice • Language and cultural differences • Varying levels of digitisation and access to internet/ online resources Companies have to develop strategies and programmes that address the unique environment of each country to ensure maximum uptake of their products and achieve clinical positioning that is not only credible and scientifically well-founded, but impactful and largely applicable across countries.

Medical communication Medical Communication forms the backbone of pharmaceutical product promotion. When a new product is launched in the market, physician prescribers have to be informed and educated about its features, benefits, efficacy, safety profile and comparison with existing treatments. A host of print and digital material such as

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product monographs, brochures, leave-behind literature, CME slide decks and training modules are created so that the product knowledge can be widely and quickly distributed to the prescribing physicians.

Medical affairs support Medical Affairs is a key function in pharmaceutical companies and provides scientific support to both internal and external customers for the development and marketing of the company’s products. Medical affairs activities that may be of particular importance in emerging markets are: • Collection of local epidemiological and clinical practice data in different disease/therapy areas and creating disease registries • Developing evidence-based practice guidelines for the local use for diseases/healthcare issues of local importance • Providing continued medical education/information to healthcare professionals, including the use of e-learning resources and methodologies • Building relationships with key opinion leaders (KOLs) through clinical events, meetings and support for investigator initiated research activities and publications • Designing and conducting patient awareness/ support programmes

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“

Companies have to develop strategies and programmes that address the unique environment of each country to ensure maximum uptake of their products

Publication writing

”

While it is widely regarded as essential to get research findings published in peer-reviewed international scientific publications, the pharmaceutical industry and researchers in the emerging countries also aspire to get published on international platforms. Organisations can require assistance with this kind of writing, especially if English is not their first language. Knowledge of international requirements and guidelines such as CONSORT for clinical trial reporting, and Good Publication Practices as well as ICMJE guidelines is essential for preparation of manuscripts for publication.

Medical writers well-versed in these requirements can help authors and investigators get their work published in international journals.

Summary Life science companies are affecting a model shift in their focus towards emerging markets given their growing economies and the steady decline of opportunities in the developed markets. Emerging markets present new challenges related to pharmaceutical promotion, hence, new medical communication strategies need to be developed matching each market’s unique structure. Outsourcing these activities and workflows to an experienced Functional Service Provider is an effective strategy which allows organisations to maintain uniformity of content and design across material at the corporate level while allowing their local affiliates to cater to local requirements.

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OPINION

Once more unto the breach, dear friends…

Nancy Dickie, senior associate at Winckworth Sherwood tells pharma firms what they need to know about Europe’s new data regulation

A

fter lengthy negotiations at EU level, earlier this year we finally received the new European General Data Protection Regulation (“GDPR”). It brings with it the risk of fines of up to €20million or 4% of worldwide turnover, for data breaches – meaning they must be taken seriously. Whilst not taking effect until May 2018, the GDPR is complex and seeks to introduce a cultural shift in data protection. It is prudent to start preparations early and in particular consider those changes that are most likely to impact heavily on the pharmaceutical sector.

It is impossible to ignore Brexit - whilst it will undoubtedly impact on data protection, in practice the UK will still have to adopt the GDPR or something close to it. Firstly, it is unlikely that the UK will have left the EU before May 2018 in any event. Furthermore the GDPR will apply to any business trading in the EU, regardless of where it is established.

What’s more, as the Information Commissioner’s Office has highlighted, to continue as a ‘safe’ destination for EU data, the UK will have to establish its adequacy in the same way as other non-European countries. Given the relatively tight timescales involved, again businesses should plan for GDPR now, whilst the detail of UK implementation plays out over the coming months or even years.

At the heart of the GDPR is a desire to bring greater accountability and transparency to how organisations must hold personal data, as well as establishing a “one stop shop” with a common set of rules applying across the EU, a change that will benefit pharmaceutical businesses operating on a pan-European basis and beyond.

Nancy Dickie, senior associate at Winckworth Sherwood

Businesses will need to consider the following key points: Consent

Privacy by design

Obtaining and using consent as the basis for processing will become much harder - consent will have to be informed, freely given, specific and unambiguously shown. So a ‘boiler plate’ clause perhaps hidden amongst other terms won’t work. This may have particular relevance in areas clinical trials where consent forms will need to be more specific and detailed, especially if there is a need to transfer data to the US.

GDPR requires businesses to understand and consider data protection in all new projects and technology and to demonstrate it has been taken into account. This has particular resonance in the pharmaceutical sector when new research projects are planned: as activity that is bound to be viewed as higher risk given the sensitive personal data involved, a privacy impact assessment will be necessary. PIAs were encouraged previously but are now baked into the law.

Genetic and biometric data These terms are now defined and health data continues to require particular treatment and specific requirements. Despite the aim of harmonisation, member states can legislate domestically in certain areas, including health and employment; for example an exemption for scientific research may be applied at national level. So unfortunately local data protection requirements will still vary slightly across borders a case of watch this space for the sector.

Individuals will have much greater rights, including increased rights to object to certain processing, the right to be forgotten, to have data corrected and to restrict how data is used. There are far more obligations to inform individuals where and how data will be held and used. Subject access rights will be expanded and the compliance period cut to one month.

Pseudonymised data

Data processors

This is defined as ‘personal data’ and is encouraged as part of ‘privacy by design’. Where data used for a clinical trial for example has been assigned a unique ID, it must still be processed in line with the rules even if no name attaches to it. Only genuinely anonymised data that cannot be traced back to an individual at all would not be personal data.

Currently, suppliers that process data, perhaps a payroll bureau, have very limited liability for data compliance. Under GDPR processors can be directly liable for some breaches.

Governance There will be increased expectations on businesses’ governance and record keeping. Given the amount of data processed by many pharmaceutical businesses, many will have to designate a Data Protection Officer.

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Individual rights

Information Commissioner The administrative burden of informing the ICO annually of a business’s data processing activities and pay the fee has been removed. Although in practice the increased record-keeping obligations balance this change.

Mandatory data breach notification applies to all data controllers who will usually need to inform the ICO within 72 hours of a data breach.

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REGULATORY AFFAIRS

How well do you know your patent rights?

Kushal Vyas, senior manager, intellectual property at ELC Group on unitary patents and the pharma sector

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atent rights are territorial, and inventors and companies have country-specific patent filing strategies based on their commercial interest in each country. Filing, prosecuting, maintaining and enforcing these patents in multiple small countries can be a very costly affair, compromising expenditure on research and protection versus returns.

Currently there are two options for filing patent in EU countries: 1. National patent in respective countries 2. EP bundle patent granted by the European Patent Office (EPO) National patents (NP) are cost-effective when the patent strategy is to only file in one or just a few countries.

For European bundle patents (EP), single patent application are examined by a unified procedure for all designated states applied for by applicant. EP patents, once granted, need to be validated in designated states by submitting translations and the necessary fees. Third parties can oppose EP patents within nine months post-grant. Enforcement by the patentee and revocation by a third party after this time is done on a national basis. Important considerations of the current enforcement via national courts include high costs, differences in law and interpretation, forum shopping, slow court processes and so on.

A Unitary Patent (UP) will be another option for members of the 25 EU participating states (excluding Spain, Poland and Croatia).

Examination of UP patent will be done by the EPO and will have unitary effect. Compared to the current EP patent, if an applicant opts for UP, validation into national office will not be required. The patentee will be able to renew with a single payment of fees. The UP will also provide uniform protection, and enforcement & revocation will be decided by a single UP court system for all member states, as opposed to an individual country-wise process. Country-wise licensing may still also be possible for a UPC patent. A key benefit of a UP patent is that it may make patenting less costly and uniform jurisprudence may bring more certainty. Patentee will have to decide whether to opt for UP or EP. It should be noted that the EPO is not an agency under the EU and it has both EU and non-EU member states. Only EU states may be party to the Unitary Patent and therefore non-EU states will not be covered by the unitary patent. EP patent holders opting for UP will have to be validated & enforced separately in non-EU EPO member states, and in Spain, Poland and Croatia. UP is expected to come into force in early 2017.

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The Unified Patent Court (UPC) will have jurisdiction for infringement of patents and supplementary protection certificates, revocations, and injunctions related to UP. The UPC will comprise a Court of First Instance and a Court of Appeal. The Court of First Instance will be composed of a central division in Paris, two sub-courts in London and Munich, plus several local and regional divisions in the Contracting Member States to the Agreement. The Court of Appeal will be located in Luxembourg.

Infringement actions may be started at the local or regional division in the participating state where the alleged infringement took place, or where the defendant is based.

Pharmaceuticals research involves considerable investment and ROI can be a long-term process. For each product, there are limited key blocking patents, and the validity of these patents is critical in order to achieve return on investment. Unified enforcement can therefore be very important for low-cost, speedy or single enforcements, injunctions and damages into multiple member states.

One risk of opting for UPC may be that UPC has jurisdiction for single revocation process across all member countries. Under current EP law, upon opposition, a patent can be revoked via a single procedure into all member states. Still most key pharmaceuticals patents have filed using the EP framework. However, opposition can be filed only within nine months of grant, and the procedure can take 5-6 years. Approval of a pharmaceutical product can itself take multiple years, and sometimes the nine-month objection deadline has expired before a third party identifies its opposition options. Once an EP opposition period is expired, the third party will have to initiate national revocation proceedings. Revocation under UPC may be faster and offer filing without time restriction.

In EU member states, there are instances wherein a patentee or challenger has received a favourable decision in a few EU countries and an unfavourable decision in other countries. National laws also differ in issues such as research exemption, second medical use, doctrine of equivalence, claims interpretation, SPC, and so on.

In summary, UP will reduce maintenance and enforcement cost and will give a patentee single enforcement options that are important for injunctive relief and subsequent validity. Along with benefits, however, it also brings a risk of losing patents by single revocation attack. In pharmaceuticals, once a key patent is lost, markets may become open to generics competitors. So, whether to opt for EP or UP? Pharmaceutical companies may have patent or invention-specific strategies. It is possible that some may not go for UP until the evolution of jurisprudence and legal certainty, while others may opt for UP due to the benefits of single process.

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Forward thinker

Q

Arecor is a company working on the next generation in diabetes care. CEO Sarah Howell sat down with EPM to talk about the future of the disease

What’s your priority as a company?

Our priority is to leverage our technology platform to develop superior treatments for diabetes care that will have a significant impact on improving the health outcomes and quality of life of people living with diabetes.

Over the past nine years at Arecor, we have attracted the very best scientific talent in to Arecor to develop an innovative and proprietary formulation technology platform that can be utilised to deliver superior biopharmaceuticals.

We are now a leader in this field and we are leveraging this technology platform to enable improved treatments for diabetes care via the innovative reformulation of approved proteins and peptides.

How do you see medicine evolving?

This is a very broad question and I will focus on the advanced delivery of medicines rather than other very exciting areas such as immunotherapies where significant advances have clearly been made over the last 10 years and I would expect this to continue. Moving forward, I believe we will see significant advancements from collaborations across industries that will bring technology and life sciences together to not only further understand the underlying causes, and hence, develop effective treatments for diseases but will also focus on how to effectively and conveniently deliver these medicines to patients thus improving compliance, reducing healthcare burden and ultimately improving overall health outcomes.

We see this as a key area within the treatment of diabetes for example.

Our mission is to bring together technology and life sciences to uncover new truths about health and disease.

How can you improve the patient experience?

Arecor’s mission is to leverage our innovative formulation technology platform to reformulate existing products to enhance the effectiveness and delivery of these medicines to patients. If we take insulin as an example, prandial insulin is used to control the blood glucose rise after meals for people living with diabetes. It is essential that insulin begins to act rapidly as possible

i.e. to mimic glucose control that is achieved physiologically in a healthy individual. In addition, it is known that the continuous delivery of insulin via wearable devices such as patch pumps results in superior blood sugar control (glycemic control), and hence, improved health outcomes.

However, currently available insulin pumps are intrusive, heavy and cumbersome which acts as a significant barrier to their use. Therefore, the delivery of a highly concentrated rapid acting insulin would enable the administration of a fast acting insulin in a miniaturised insulin pump which is a critical unmet need to break down the barrier to use and significantly improve the quality of life and health outcomes in these individuals.

OPINION

&A

What are the challenges to your work?

All of Arecor’s proprietary programmes rely on solving complex formulation challenges to deliver products that would otherwise not be possible using conventional formulation science.

For example, for the ultra-concentrated insulin programme there are a number of complex formulation challenges that have to date prevented the development of this product, however, with our innovative approach to formulation we are confident in being able to deliver this product to patients. The two main challenges in increasing the concentration of insulin are (i) it slows down its onset of action in the body upon administration.

As discussed earlier it is absolutely key that the insulin starts to work as quickly as possible upon injection to control blood glucose levels and (ii) it becomes more unstable, and hence, will not work as effectively. Both of these challenges can be overcome utilising Arecor’s formulation approaches Name one goal to achieve today to move your work onwards Today, our team of very talented scientists are working towards developing lead formulations that we are testing to confirm that they have sufficient stability and time-action profile upon administration (in-vivo) to be able to enable the miniaturisation of next generation insulin delivery devices. Demonstrating this in patients will be a key goal and take us a significant step closer to delivering this vastly improved insulin product to people living with diabetes.

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ON THE COVER

Best practices pay when it comes to tablet tooling management I Holland explains how to get more out of tablet tooling

T

he efficient and accurate management of punches and dies is vital to optimise profitability and productivity in modern tablet manufacturing. However, keeping track of tablet tooling is not an easy task and can be a daunting undertaking. There are clear trends within tablet production today; these include the increase of capacity, flexibility, speed of response and robust traceability with the core objective of maximised press uptime. Currently many tablet manufacturers accept that tooling is a consumable item to be written off as part of the costs of the business. Through the development of computer-based monitoring systems this way of thinking is changing and productivity per punch can be maximised more effectively.

Any problems within tool inventory management can have serious implications on the bottom line and manufacturers should have a complete audit trail covering tooling usage and maintenance. This is not only good practice but an important regulatory requirement in the majority of pharmaceutical environments. Without a robust management system that controls the procedure effectively there will certainly be adverse effects.

Tooling management systems – the key to increased tablet production The costs of tool replacement are often known, however hidden costs such as those created by the unavailability of tools due to avoidable damage or unforeseen replacement can be lacking, and by implementing a management system to monitor all aspects of the tooling being used increases production and reduces downtime and time to market.

Deployment of a tooling management system can significantly improve tooling inventory availability. The data can also provide information to effectively measure areas of performance by way of showing what and how many products have been produced and a summary of any production issues experienced. This can be used in a controlled tiered access system by all personal without specific technical expertise required.

One such management system that helps to combat downtime is I Holland’s Tool Management System (IH-TMS), which allows proactive monitoring of tooling rotations, inventory and maintenance. The

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software has been specifically developed to maintain efficient, wellorganised and in-depth monitoring of tablet production giving manufacturers a complete audit trail on tooling usage and maintenance.

It also incorporates an in-depth guide to tooling specification and troubleshooting so any problems flagged up can be traced and rectified.

In addition, it has the capability to archive tablet and tool images and drawings and incorporates an alarm to alert users of any problems including over compression, when maintenance is required and even when tooling replacements should be planned.

Within pharmaceutical manufacturing the importance of knowing where tools are, and what condition they are in, should be a priority. Without this information, either unnecessary tooling replacements are made, reducing productivity, or punches are deployed when they should be in maintenance or replaced. The latter scenario breeds problems with the end tablet when it is found that the tooling being used does not meet the highly demanding process of tablet manufacture. Rejected tablets, wasted formulation and press downtime is the usual result. In addition to this, not having a clear picture of tooling availability may lead to the loss of opportunities in a fast moving competitive environment.

Implementing a tooling management system like IH-TMS will fulfil the core requirement of enabling tablet manufacturers to manage their tooling in an ordered, traceable way, with minimal technical expertise required to use the system. Not only is it easy to use and allows all of the production team to monitor outcomes with only simple training involved, it is also extremely affordable demonstrating cost saving through increased tooling productivity and press uptime.

Companies throughout the world are set to benefit from the multilingual and adaptable system, which is available in different configurations to work flexibly and seamlessly within an established manufacturing facility.

Such management systems should also be compliant with protocols like the FDA’s Code of Federal Regulations – 21-CFR part 11, so important electronic records and electronic signatures can be traced.

Why does tablet tooling fail us?

There are many reasons why tooling becomes less effective leading to poor tablet production, one such problem being the impact due to damage and wear caused by abrasive formulations. I Holland has seen

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the issues created by this common problem resulting in time consuming and costly mistakes for the tablet manufacturer. If the correct procedures are put in place at the beginning of the process and a proven tool management system is implemented, tooling issues should be prevented.

Damage through handling can be another significant production failing. There are several stages of the tablet manufacturing process where damage can take place, including unpacking the tooling, loading/unloading the tools in or out of the tablet press, during tool cleaning/maintenance procedures and storage/transportation. If damage occurs it can lead to the production of poor quality tablets, and even further damage to both the tooling and the tablet press. It is important to understand the delicate nature of the tooling and operate good tool care, maintenance, storage and handling procedures, to keep this problem to a minimum. This should be done through adopting a planned process for tooling maintenace and storage.

A core feature of a system like the IH-TMS system is the ability to keep track of the tooling maintenance; the correct maintenance is critical in obtaining maximum life from punches and dies. In turn this allows the person in charge of managing the tool room to prioritise maintenance activity by creating a work-to list. By implementing an advanced management system, problems like wear to punch heads can be detected before they impact on production. Such a system can monitor the quality of tooling and processes that are already being used like the I Holland PharmaCare 7 Step Process, a logical, professional approach to tooling maintenance and storage which has already been adopted by many companies around the world as a Standard Operating Procedure (S.O.P). Implementing a planned professional process like the ‘7 Steps’ is key to getting the best from tooling.

Auditing-helping to trace poor maintenance procedures By auditing tooling and tooling procedures, poor handling and maintenance techniques will be flagged up through software like I Holland’s IH-TMS tooling system. A professional tooling and procedure audit is a simple way to directly detect and rectify this, ultimately saving many hours of reduced production through unplanned tooling maintenance and replacements. By combining tooling management software and maintenance procedures as an SOP, uptime can only increase.

3 Repair: Light surface wear, corrosion and damage on tooling can 3. be repaired and polished to a useable condition. Damaged tips can result in poor quality tablets and inferior embossing definition.

Equipment such as a motorized chuck and double ended polishing motor are used in conjunction with abrasive polishing accessories.

4 Measure: Measuring is essential after repair to ensure that critical 4. tooling dimensions have been maintained within an acceptable working tolerance. Measuring should be carried out at regular intervals even if repair has not been necessary, to check for natural wear due to the compaction process.

5.

5 Polish: Controlled, light polishing on a frequent basis will ensure the tools are maintained to a smooth finish, helping to maximise tooling life and reduce problems such as sticking and capping.

6.

6 Lubricate: Lubrication is important to protect, preserve and aid smooth operation of the tooling.

7 Store: Tooling storage and transportation to the production area 7. should be specifically designed to maximise security and safe handling to minimise damage and deterioration.

Application of the 7 Step Process will have a direct impact on the reduction of many common tablet and tooling problems, resulting in a better quality tablet, and can provide direct cost saving. A process like this should be monitored through a system such as the I Holland IH-TMS. Correct maintenance is critical in obtaining maximum life from punches and dies. A high percentage of punch and die problems can be conclusively traced back to poor handling and maintenance procedures. With the use of a monitoring system, which can record data in real-time and offer instant solutions, together with the application of a structured maintenance process, the direct impact on the reduction of many common tablet and tooling problems, results in a better quality end product.

Adopting these recommended ‘best practices’ will have direct cost savings to the tablet manufacturer as the maximum life from tablet tooling is extended and production is increased.

Through a site visit by a tooling expert, and a review of tool maintenance procedures, methods and the equipment used, problems can be traced to root cause. Quality tooling manufacturers like I Holland can advise on an informed and working solution, or the optimisation of current maintenance techniques. This helps to save not just money but also time by diagnosing the problem, and offering a solution.

Implementing a simple maintenance process The use of a maintenance process like I Holland’s PharmaCare 7 Steps will help in maintaining and storing punches and dies correctly to ensure tooling is clean, serviceable and within specification when required for production, resulting in a better product for longer, reducing costs and increasing profitability.

The 7-step process includes: 1 Clean: Clean is the most critical part of the process. Punch and die cleaning is essential for the removal of residue and to avoid product contamination and potential production issues such as sticking and picking caused by old product adhering to the surface of the punch tip.

This step can be used to highlight damage to punch tip edges and damage that may occur in the form of nicks and bruises causing burrs and occasionally chipping. Approximately 80% of damage to punches and dies is usually caused accidentally when handling the punches through the production and tool care processes.

2 Assess: Punches and dies should be visually inspected under magnification for signs of damage, wear or corrosion, and to validate the cleaning process to establish how the production process is running.

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COLD CHAIN LOGISTICS

Keep your cool Brian Keesee, executive director, US clinical services at PCI explains how to efficiently maximise the supply chain for biologics in clinical trials

B

iologics such as a drug, vaccine, or an antitoxin are synthesized from living organisms or their products and used as a diagnostic, preventive, or therapeutic agent.

Supply chain requirements of a biological are similar to those of a non-biological product – with the ultimate objective of delivering the drug safely, on time, to the right location, at the right temperature and at the lowest cost.

“

Even with qualified shippers, a monitor must be included to ensure product temperature, ideally one allowing immediate review of the data

”

With biological products often being more expensive than conventional drugs, and therefore of higher value, extra care must be taken ensure that all supply chain processes are robust and validated to avoid potential hazards.

Biological therapies have widely varying temperature requirements, calling for specialist Cold Chain or Ultra Low Temperature (ULT) storage, packing and distribution. Maintaining correct product temperature is paramount and a reliable, expert cold chain process is critical to product integrity.

that correct temperatures are maintained throughout the journey. Specialist suppliers can be costly; however, the risk of experiencing a temperature excursion can be far more costly.

Distribution Practice (GDP), an IMP for clinical trial use has to be stored and distributed from a fully licenced facility. In most clinical trials, the IMP will not be manufactured in the same country as the Qualified Person (QP) certification and will need to be imported.

Map transport routes and storage depots

A copious amount of Brian Keesee, executive information is needed to director, US clinical services When shipping to gain an import licence for at PCI countries outside of the a biological product. In EU, several factors may the UK, the Department require an in-country for Environment, Food and Rural Affairs depot to be used – including import (DEFRA) issues licences for the import of license requirements and transportation any animal- or human-derived product. time. Additionally, for some trials the Issues will occur if the product contains time between patients being screened materials not covered under general to receiving their first dose can be licences, where an individual product short – customs processes may make it application must be made. impossible to meet these timelines, so At the onset of a clinical trial, it is vital to establish the information and timelines for obtaining licenses to import the IMP into all countries involved. Compiling this in advance may impact the decision to perform a trial in a specific region, and should be considered alongside the regulatory authority requirements.

Plan ahead

When shipping biological products, selecting the correct transportation method is paramount. Most products of this type are sent by air; the quickest means of transport given the need to maintain product temperature. The selected transport system must be able to maintain the required temperature for the duration of the journey, including the flight, customs clearance and onward delivery.

In the EU, in accordance with Good Manufacturing Practice (GMP) and Good

Specialist couriers should be used for biologic shipments capable of ensuring

Effective supply chain for Biological Investigation Medicinal Products (IMP) can be addressed in three key phases:

local storage depots are essential.

The supply route should be considered on both an individual product and country basis. The product, cost and availability as well as site storage capacity and recruitment rates must be addressed to ensure a secure and cost-effective route that meets trial demands.

have the facilities to top up, dry ice or hold refrigerated product.

Even with qualified shippers, a monitor must be included to ensure product temperature, ideally one allowing immediate review of the data. While high quality shippers and monitors may add cost, using them reduces the risk of temperature excursions.

These three phases look at product supply chain where final packaging is already defined. Greater efficiencies could be made if an integrated design process is introduced in conjunction with the supply chain.

An integrated process where supply chain is considered at design or proposal stage enables the development of a streamlined and efficient strategy for each trial, capable of delivering product on time, at temperature and cost-effectively.

Selecting an experienced service provider early in the study development phase avoids frustrations common to shipping Cold and Ultra-Cold Chain products, ensuring the focus remains on the successful delivery of life-saving therapies.

Cold chain packaging for trial material logistics Selection and preparation of shippers is critical for temperature-controlled products. Shippers must be qualified to last the duration of the shipment and couriers should

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18/07/2016 16:16:45

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COLD CHAIN LOGISTICS

At the cold face EPM catches up with Kevin Lawler, vice president of worldwide sales at Pelican BioThermal to discuss all things cold chain

Q: How is the temperature-controlled packaging industry responding to the rising regulatory requirements within the pharmaceutical cold chain?

packaging is fit for purpose, cost-effective, all while being safe and reliable, understandably, a pharmaceutical critical prerequisite.

A: Increasing regulatory requirements and compliance within cold chain to ensure the safe transportation of pharmaceuticals and biologics means temperature-controlled packaging (TCP) manufacturers must be at the forefront of industry innovation.

Q: How are innovations in TCP helping mitigate cold chain risks?

With the significant rise of biologics and biosimilars, the need for temperature control is ever increasing, where any minor temperature excursion within the cold chain can have costly consequences for patients and pharmaceutical companies alike.

The fact over half of approved new pharmaceuticals are going to be biologics or biosimilars, is proving another driver in the rising demand for tighter temperature control requirements making innovation in - (TCP) - increasingly vital.

It’s in direct response to the pharmaceutical industry’s rising requirement to protect more of their shipments with strict temperature controlled ranges.

The primary driver of this is due to a growing trend in new pharmaceuticals being based on biological compounds which require strict temperature controls, rather than chemical, which have less efficacy than biologics, but less strict temperature requirements.

Q: What are the main cold chain challenges to consider when transporting pharmaceuticals?

A: More complex distribution lanes, with emerging markets, geographies and increasing regulatory compliance conditions are some of the challenges when transporting temperature sensitive biologics/ biosimilars.

The increased need for last-mile pharmaceutical transportation is a growing trend, as well as requiring stringent compliance throughout the cold chain process to ensure the protection of highvalue, temperature sensitive, pharma payload endto-end on its journey from the manufacturing facility to the patient’s hands.

Industry innovations are also required in response to the rise globally of regulatory activity by agencies and organisations producing specific-in-country guidelines and regulations the pharmaceutical companies are required to support and be prepared for.

The TCP industry is governed by stringent GMP (Good Manufacturing Practice) standards, as well as GDP (Good Distribution Practices).

Standards bodies, including the International Organization for Standardization (ISO), ensure

A: A rise in the acceptance of innovative materials such as advanced phase change materials (PCM) and vacuum insulated panels (VIPs) for insulation purposes helps manufacturers and service organisations maintain temperature throughout the cold chain. These innovations avoid temperature excursions, which could render the pharmaceuticals unstable, causing them to lose efficacy.

resident ler, vice p Kevin Law at Pelican s ide sale of worldw al BioTherm

Emerging TCP featuring ‘hibernation’ capabilities combat customs delays. These new generation packaging systems can be placed in a refrigerated area, suspending or stopping the loss of energy retained by the shipper.

There has been a notable move away from incorporating older technologies, such as waterbased ones, which required seasonal packaging components, sometimes covering all four seasons, which in turn required seasonal instructions, which drives the need for further training and additional warehouse personnel.

Within pharmaceutical distribution and biological sample transportation, there is a move towards more advanced VIPs and PCMs instead of utilising the traditional, water-based systems.

Performance improvements and cost savings can be made and passed on through the supply chain process by reducing processes required and subsequent training.

The advent of innovative temperature controlled packaging allows TCP companies to improve packaging performance and technical tools that aid with performance modeling. These efforts are helping revolutionise the TCP industry, allowing it to respond more quickly to changing demands from their customers.

Convincing pharmaceutical firms of the importance of having the fit for purpose cold chain shipping systems, as part of their overall operations and budget considerations, is an ongoing challenge.

These modeling techniques included software, which allows companies to develop a temperature profile easily, which they might want to test against a specific shipping lane and packaging solution.

Newer technologies allow pharma companies to utilise shipping systems with a reduced number of components and coolants incorporated in the packaging process. This simplification is another contributor that provides elimination of pack-out errors, which are the cause of many temperature excursions.

Temperature indicators on PCM panels, which display when they are ready for use and packing, are also new to the sector. These further aid the protection process in cold chain by avoiding errors, which ultimately offers more efficient payload protection and reliable shipping solutions.

Q: How can cold chain distribution costs be reduced?

A: Currently the industry is moving towards newer technologies, looking at tools to assist in the management of more modern PCMs, which are more technologically advanced over managing traditional water based systems.

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It comes down to helping pharmaceutical manufacturers better understand the true cost of impact of moving to newer technologies and what impact that can have for their operations. Ultimately ensuring stability in the supply chain is critical within the pharmaceuticals industry where patient safety and efficacy are an absolute priority.

Q: What measures can be taken to reduce environmental impact within the industry?

A: Future trends will see the increase in the use of reusable packaging.

Although single use packaging still serves a purpose, particularly when it comes to more difficult to control or challenging lanes, when the retrievable infrastructure is in place, reusable, which is on the rise, can prove a more cost effective option per trip.

Reusable technology is becoming more and more accepted because it can really drive down costs per use. The packaging industry is working hard to try and change preconceived perceptions about reuse and its reliability.

Future developments will involve industry standards, which demonstrate ways to guarantee reusable containers are fully qualified, remaining fit for purpose after multiple uses.

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14/10/2016 16:02

COLD CHAIN LOGISTICS

Don’t go with the quo When it comes to the logistics of clinical trials, it’s time to challenge the status quo, according to Mark Sawicki, chief commercial officer at Cryoport

T

he biopharma market is in the early stages of its next transformation.

Clinical pipelines are being filled with ever more intricate targets and medicines, including next generation cell and gene therapies.

In addition, the diagnostics required to evaluate and progress clinical programs are relying on biomarkers and new assay systems that have increasing sensitivity and complexity. Consequently, logistics costs are rapidly rising to support these industry changes. In fact, the current clinical trial cold-chain logistics market is now estimated to be approximately $3 billion USD annually . Unfortunately, conventional shipping methods including shipping biomarker samples on dry ice are no longer sufficient in many cases. Dr. Dominic Warrino, technical advisor, large molecule sciences at Kansas City Bioanalytical & Biomarker Services (KCAS) has stated that “Approximately 30% of all biomarker samples shipped to KCAS for analysis have experienced temperature excursions.” It is now more critical than ever to look more deeply at the impact of shipping conditions, not only on sample failure, but the impact of the selected transport medium on assay or product performance.

More and more new clinically important biomarkers are being discovered in an ever more challenging array of matrices (CSF, synovial fluid, sweat, tears and whole blood among others), and as such, platforms are being developed and improved to detect biomarkers in these matrices at lower sample volumes and greater dynamic ranges. While each of these new platforms has advantages as well as drawbacks, sample quality is of paramount importance for all to produce reliable sample analysis, informed clinical decisions and effective personalised medicine.

While Quantitative Western Blot has greatly improved in both dynamic range and throughput in recent years, ELISA remains the gold standard for ligand binding assays (LBA) because is well understood, highthroughput and relatively inexpensive. However, it is often subject to deleterious matrix interference effects due to auto conversion of the signal-generating molecule. Electrochemiluminescence (ECL) platforms have a larger dynamic range than standard ELISA’s and also have the benefit of being capable of multiplex analysis. They are, however, still

subject to matrix interference effects. In all cases, strict temperature control and maintenance of sample quality can ameliorate some of these effects and increase the dynamic range of a particular assay. As new LBA platforms are developed (immuno-PCR, single molecule counting, proximity ligation assay, Bio-Barcode, etc.) with greater sensitivity and dynamic range, sample quality considerations will become ever more amplified.

LC-MS is a powerful technique for biomarker analysis that is increasing in use due to its ability for high-throughput analysis, detection of low level analytes as well as analytes for which there may not be a good LBA available. Poor sample quality may degrade an analyte, affecting detection levels and % CV within an assay.

Flow cytometry has become an increasingly useful tool for bioanalytical development, and is arguably the most sensitive to sample quality effects. Dead or dying cells, a loss, degradation or downregulation of cell surface markers due to improper sample preparation, storage or transport increases background, signal interference as well as greatly hinders assay performance.

The logistics market has responded to these challenges with new temperature management systems, including phase change materials, vacuum paneled insulators, and actively controlled temperature managed shippers, to move critical materials. These systems do have superior performance characteristics over traditional Styrofoam packaging. Unfortunately, it is likely not enough as a disproportionate number of samples that are critical to evaluating clinical performance are still being moved without a complete understanding of the impact of the transport carrier, packaging, or refrigerant being used. The industry has not conducted a systematic, comprehensive assessment on the impact of these systems and advances under dynamic conditions on the critical materials being moved (namely cell and gene therapies, critical biomarker samples, cell banks, tissue samples, clinical PK/ADA samples, etc.).

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Figure 1: standard deviation of biomarker activity by choice of packaging configuration

Figure 2: percentage of time a package type was in the improper orientation during both domestic and international transport. Both standard integrator and specialty couriers were utilised during transport

Cryoport, in conjunction with our partners, Heat Biologics and KCAS, is conducting a scientific study to evaluate the impact of temperature and transport packaging at deep frozen temperatures on critical biomarkers and cell-therapy cancer vaccines respectively. The study is focusing on the deep frozen space, namely samples typically transported either on dry ice (-80°C) or at liquid nitrogen (-196°C) temperatures. Early results demonstrate that recovery of nearly 30% of all biomarkers tested (8 of 30) were impacted due to shipping on dry ice and assay performance was impacted notably (Figure 1). We also observed significant pH shifts in the samples shipped on dry ice (shifts were observed up to 1.3 points down in the dry ice packages), regardless of container used, a phenomenon observed by others in the recent past to have an impact on sample integrity , . Dynamic temperature mapping experiments also indicated a significant level of thermal variability in both dry ice packages utilised versus cryogenic shipping (Table 1). These early results substantiate the concern the bioanalytical industry has expressed and support the call for a more comprehensive assessment in the coming months and years.

orientation is important as it impacts both dry-ice sublimation rates and nitrogen evaporation rates, thus reducing the overall hold time of the package. In the case of dry ice shipping, increased dry ice sublimation rate increases the amount of acidic carbonic gas and may accelerate pH shifts in the samples. In addition, package handling can damage the packaging integrity, introduce shear related stress on the sample being moved, and subject the sample to increased temperature volatility.

Styrofoam Shipper

Vacuum Panel Shipper

Dewar

STDEV

14.1

7.6

0.7

STDEV (+)

-57.9

-69.2

-192.9

Average

-72.0

-76.9

-193.6

STDEV (-)

-86.1

-84.5

-194.3

Table 1: Thermal variation of packaging during dynamic shipping conditions (in °C)

In addition to sub-optimal (and in some herein observed samples, statistically disqualifying) biomarker recovery and assay performance due to either temperature or pH shifts, one also needs to consider the impact of the transportation itself. As part of the study, we looked at the orientation and handling of the packages in transit. Out of the 33 packages shipped, 32 had multiple orientation events and the average time spent in a mis-oriented position averaged between 10-15%. The type of package was not consequential as all package types incurred such handling issues (Figure 2) and the handling issues occurred with both integrator and specialty courier managed packages. Mis-

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As per the study conducted, it is believed that all of these factors (temperature, pH, orientation, dry ice vs. LN2) play a role in the quality of biomarker and/or clinical samples and may not only impact the quality of the data generated for evaluation of more than 64,900 studies active as of the time of this submission, but will also impact release of pharmaceutical drug substance, drug product, and final dosage products which all rely on analytical assays for verifying product quality and performance.

Our study makes clear that packaging and logistics decisions directly impact sample quality and bioanalytical assay performance. Based on the early results we have observed, shipping biomarker samples at cryogenic temperatures does in fact reduce thermal variability, eliminates the risk of pH shifts, and improves overall assay performance in the biomarker panel tested. It is important to note that for all biomarkers tested the mean recovery rate and %CV of the samples shipped cryogenically were comparable to control, indicating that shipping biomarker samples cryogenically is safe for all biomarker samples, and for 30%, is critical for optimal recovery and assay performance.

We encourage the industry to take a step back and critically evaluate whether or not clinical efficacy, as well as bioanalytical or manufacturing issues may in fact be due to logistics choices. It is time for a wide ranging industry wide assessment on the most appropriate logistics methodology and standards for maintaining appropriate sample integrity, activity, and performance.

1 Pharmaceutical Commerce, March 15, 2016 2 Nature Methods 10, 278-279 (2013) 3 Clin Chem Lab Med 53, 809-13 (2015)

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NEC, Birmingham

DRUG DELIVERY & ADHERANCE

Back to school Chris Evans, vice president, innovation, West Pharmaceutical Services believes patient education is the missing piece of the adherence puzzle

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everal biologics coming onto the market offer the potential to make a difference in the lives of patients with incurable-butcontrollable conditions such as diabetes and Crohn’s disease.

These innovative therapeutics aim to improve patients’ quality of life by not only reducing symptoms, but also offering new independence enabled by at-home treatment.

Many of these new drug formulations are being paired with self-injection systems that may require a little extra training for effective use and, therefore, need innovative approaches to patient education. The typical illustrated instruction sheets can be greatly assisted by “look-alike” training systems that allow patients to practice administering Training initiatives are medications before actually doing it with a way drug packaging a live product.

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and delivery system manufacturers can add significant value

West recently announced a collaboration with Noble, a patient onboarding innovator, to develop validated training solutions for self-injection systems.

Together, West and Noble will offer multisensory education programs and technologies for patients using West’s SmartDose Electronic Wearable Injector and other self-injectors.

Collaborations like this can positively impact patient safety, medication adherence and satisfaction. Additionally, they can improve data and feedback collection to lend valuable insights regarding potential product refinements.

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Such training initiatives are a way drug packaging and delivery system manufacturers can add significant value to their pharmaceutical customers’ drug development cycles.

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Custom training systems deliver feedback to patients An essential element of training for self-injection systems is customising them to offer precise feedback so the patient is assured they’re following the instructions correctly. Delivery system education programs can help ensure patients administer the right dose in the right place with the least amount of discomfort to improve the patient experience and maximising the benefits of both the drug and the delivery system.

Feedback can include sounds and lights that indicate correct use of the trainer. They can also indicate incorrect use in the form of negative feedback, in real time, thus prompting patient or user correction. Auditory and visual cues are particularly important in this era of global drug procurement, If instructions with because they cut through language pictures are worth a barriers and regional contrasts in thousand words, how healthcare delivery.

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many is a copy of the actual drug delivery system worth?

Why are these training systems suddenly more important? Patients are selfadministering care in their own homes more than ever. Yet, a recent study by Noble analysed by Auburn University indicated that more than 60% of patients self-reported that they didn’t completely read the instructions for their self-injection systems before using them the first time.

If instructions with pictures are worth a thousand words, how many is a copy of the actual drug delivery system worth, especially when it is enabled to show right and wrong in terms of operation? With that in mind, manufacturers of injectable drugs can greatly benefit from offering this level of patient education.

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Insight for manufacturers The second element of training systems afforded by the latest technology is data tracking and analysis. Drug delivery systems can be programmed to store or transmit statistics on patient learning – what goes well, what mistakes they make – back to the manufacturer who, in turn, can analyze and make design improvements.

This data is incredibly valuable – even more so when coupled with analysis from human factors studies. West works closely with Insight Product Development to conduct human factors testing and examine the usability of drug delivery systems. Combining feedback from training systems with insights from real-world usage studies leads to the development of self-injectors that are user-friendly and meet patient’s lifestyles needs throughout their treatment journey.

Addressing patient motivation The missing piece in patient education, as the Noble-Auburn study shows, is motivating patients to take the time to complete their training.

Well-designed training systems can not only offer feedback, but also validate that the patient completed training and demonstrated competency in using the drug delivery system.

To help address barriers to adherence, West collaborated with HealthPrize Technologies to develop a connected health offering that is designed to improve and reward medication adherence with unique technologies in a gamified environment. The offering integrates HealthPrize’s Software-as-a-Service (SaaS) medication adherence and patient engagement platform into injectable drug delivery systems with an app that tracks and rewards patients for taking their medication. This type of rewards-based patient motivation and engagement can be tied into delivery The idea behind it system training regimens as well.

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is timeless: Enriching patient wellness by improving medication adherence

While the technology creating these exciting new patient-education programs might be cutting-edge, the idea behind it is timeless: Enriching patient wellness by improving medication adherence. Drug manufacturers need partners who are constantly innovating to deliver on this over-arching goal that ultimately benefits all the partners involved in drug development and procurement. Creating a digital health ecosystem that accounts for all pieces of the adherence puzzle—from education to ongoing treatment—is the next-generation means to get there. The combination of West’s experience, internal capabilities and external collaborations provides a full-service offering to customers that supports both drug product lifecycles and patient adherence.

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ADVANCES IN PACKAGING Unusual shapes require a high level of creativity, knowhow and experience from label manufacturers.

Going in blind Labelling expert Faubel on how individual solutions for blinding clinical trials are now gaining momentum

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bout 5,000 clinical studies are initiated every year. Drug candidates are tested in the form of capsules, tablets, drinking solutions, salves, injections, sprays and even plasters depending on the area of application.

In addition to the product under study, participants may receive a placebo, a comparator as well as an additional or substitute drug.

Given this complex initial Complex situation situation, the requirements Research companies in the for the packaging pharmaceutical industry are often faced with the challenge and labelling of appropriately blinding the of study study medication. The varied medications assessment of treatment results often labelled as informational, are extremely judgment or ascertainment high

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bias - is thus restricted.

Furthermore, blinding can improve compliance in study participants and the willingness to remain in the trial, while reducing the use of additional care or treatment measures.

Either the primary packaging masks the shape, size, colour, texture, weight, smell and/ or the taste of the drugs, or the secondary packaging takes on this task. Blinding is a substitute for repackaging, which is often not possible. Blinding can take place on a single- or double-blind basis; the term tripleblind is also used occasionally. The degree of blinding is determined by whether individual or multiple participants in the trial are unaware of the allocation of test subjects to treatment or control groups.

“Given this complex initial situation, the requirements for the packaging and labelling of study medications are extremely high”, said Anthony Morrow, business development 30

manager at Faubel, serving customers in Northern Europe. Drinking solutions are often packaged in bottles or cans, capsules and tablets in blisters, wallets or tins, salves in tubes, jars or sachets, injections in vials, syringes, ampoules or bags, sprays in aerosol cans or inhalers, and plasters in boxes.

As with labels, boxes can be complemented by optional properties such as tamper-evident elements using seal labels or attachment bands. One advantage of using boxes is that they can be further processed without using tools or even configuring the packaging line.

Efficiency in blinding Labels for flexible use Many primary packaging methods, e.g. syringes or tubes, can be simultaneously blinded and marked using labels. Not only are labels incredibly flexible in their design, format and scale, their material and adhesive properties can be adapted to filling, storage and transport conditions. Film, paper and ink give the package an opaque and lightproof cover. When it comes to multinational clinical studies, different country languages usually need to be factored in. In this case, the use of a booklet label is ideal, one that can hold up to 113 pages. Unusual container shapes require considerable effort in project-related development from packaging suppliers.

Overall concepts integrating various secondary packaging materials are often used like for blinding syringes, for example.

The requirements on blinding solutions for clinical studies will continue to grow. The possibilities described cover only a fraction of the day-to-day requirements with which packaging manufacturers are confronted.

It is generally recognised that this constant confrontation with legally-mandated requirements, individual customer demands, new materials and innovative technologies is driving the capacity to develop. “After all, only those who can offer their customers sophisticated concepts can guarantee efficiency in blinding and the usability of treatment results, thus saving contract-research institutes and research-based pharmaceutical companies effort, time and money on a sustainable basis”, Morrow said.

Boxes – overall concepts Complete masking of shape, size and weight of the primary packaging and the colour of the trial products can be achieved by using tailormade boxes. These can be used in single- and double-blind studies primarily for cans, vials, bottles and bags. Boxes can be produced from rigid cardboard. Recently it has even become possible to make boxes from plastic using 3D printing. This way, a vast array of different shapes can be produced in extremely limited series. A built-in control window enables drug identification in case of emergency, meaning on first opening it becomes clearly visible.

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The success of a clinical trial is improved by first-class blinding for study medications.

ADVANCES IN PACKAGING

Information nation How to maximise space and get the right information on pharmaceutical packaging –

Rupert Taylor, global category manager healthcare & personal care, Essentra

by Rupert Taylor, global category manager healthcare & personal care, Essentra

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or the past two years, the EU Falsified Medicines Directive (FMD) has been one of the most talked about topics relating to pharmaceuticals in Europe. The directive addresses one of the biggest threats to consumers: counterfeit medications within the supply chain. The legislation, which will enforce the inclusion of serialisation and tamper evident features on pharmaceutical packaging, will have a huge impact on the industry. From 2019, pharmaceutical manufacturers will need to alter everything, from packaging to IT systems, the processes used to manage the supply chain to business In meeting the new structures. regulatory requirements,

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manufacturers should not compromise the consumer experience or hinder patient adherence

However, despite the challenges manufacturers will face, it is vital that the transition for consumers remains smooth. In meeting the new regulatory requirements, manufacturers should not compromise the consumer experience or hinder patient adherence.

After all, ultimately the goal of the FMD is to ensure that people have access to authentic pharmaceuticals, so – when taken properly – the medication can improve their lives in some way. It would clearly be detrimental if this new legislation resulted in an increase in patients’ incorrectly consuming medication.

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Patient adherence is the extent to which a person’s behaviour – for example, taking medication – corresponds with agreed recommendations from a health care provider. Alarmingly, this is already a major challenge for global health: the challenge is so significant that the World Health Organisation (WHO) has reported that there would be more worldwide benefits from improving adherence to existing treatments than from developing new ones. In fact, approximately 50% of patients with chronic diseases in developed countries do not take medications as prescribed, and this is even higher in developing countries.

According to the WHO, one of the factors that contributes to patient adherence is a lack of knowledge. Too often patients misunderstand the treatment instructions or have a lack of perception of the health risks related to their disease and the relevant medication. It is vital that as companies seek to meet the new FMD legislation they don’t inadvertently exacerbate the challenges of patient adherence, for example by adding features that reduce the space available for essential information. As

a leading global provider of healthcare packaging, Essentra believes that all pharmaceutical firms should invest in packaging materials to make information as clear and accessible as possible.

Packaging can be altered in a number of ways to enhance consumer interaction. One way to increase the amount of people who take their medicine correctly is to provide more detail. There is currently a trend towards long form instructions, as consumers not only want more information but also more variations of it, for example the same information in different languages or the use of graphics as well as words.

Popular ways to increase space for information without compromising the size of the packaging include the use of extended content labels, booklet labels and leaflets. Extended content labels are an efficient way to add additional information to medicine bottles, allowing patients to peel the labels back to access more information. These labels can be ‘peel and read’ or ‘peel and reseal’ – the difference being that the latter can be resealed multiple times throughout the lifetime of the product.

Similarly booklet labels are ideal for medicine bottles, allowing patients to scan through multiple pages of additional information on the product. Lastly for the maximum amount of space, medicines cartons can contain multi-fold leaflets inside. These can deliver several pages of information in multiple colours and, as they can be set out in a booklet format such as is done with Essentra’s Plurium leaflet, patients can open and flip through pages easily to find exactly the information they need to know.

Every patient with the same prescription will be in contact with the same packaging which, if adapted correctly, can have a major impact on influencing adherence. By making small changes to extend the amount of information made available to consumers, packaging can both inform and support patients. With the EU FMD coming into place in 2019, the chances that patients will receive the correct medicines should increase – pharmaceutical companies must now ensure that patients take these authentic medicines correctly.

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ANTI-COUNTERFEITING

Fooled EU As manufacturers await the implementation of the falsified medicines directive, Nadine Lampka product manager, pharma-security at Schreiner MediPharm examines the state of play

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he countdown has started: The EU Large number of unreported cases requirements for protecting medicines against likely to exist counterfeiting will become mandatory in three years’ time. Consequently, pharmaceutical For instance, counterfeiters using increasingly manufacturers are preparing to meet these professional methods produce detailed copies requirements with variable marking and sealing of of medicine packs and fill them with ineffective, their sales packs, and seeking innovative solutions harmful and even toxic imitations. More than to safeguard the pharmaceutical supply chain. But a million people around the world die of the beware of misunderstandings: product marking is Nadine Lampka product manager, consequences every year, according to Interpol. In only secure if, in addition to a 2D code, products pharma-security at Schreiner 2015, for example, German customs investigators have counterfeit-proof authenticity features. Only MediPharm confiscated 150,166 counterfeit medicines worth a combination of DataMatrix code and anti1.01 million, equating to a 26% increase compared to the year before, counterfeiting technologies can comprehensively protect a product although German customs authorities actually check only 2% of all against fraud, misuse and counterfeiting. Ideally, authenticity features goods at the time of being imported. Counterfeiting affects the entire should be selected so that both consumers and specialists are involved in product range of the manufacturers and all forms of sale, from online the authentication process. and wholesale distribution all the way to the pharmacy. Thus, effective Counterfeit medicines are a common threat and an international challenge to all stakeholders involved in the pharmaceutical supply chain.

The World Health Organization (WHO) estimates that in industrialised countries up to 7% and in developing countries 30-70% of all medicines are fakes. As the profit margins are clearly higher than those generated with drugs such as heroin or cocaine, global counterfeiting syndicates are increasingly involved as well. All forms of administration are affected, such as tablets, infusions, injections, ointments and solutions, whether or not they require medical prescription. This poses a major risk to the safety of patients. Counterfeits are particularly wide-spread in developing countries in Africa and Asia, as a result of the growing number of internet pharmacies. Using diverse methods, fraudsters either circumvent the legal distribution chain or take advantage of its complexity to channel in products that have been falsified in terms of their identity, ingredients or origin.

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actions for counterfeiting protection should always be based on a holistic approach to product and patient safety. This requires strategic security management on company level in the respective pharmaceutical manufacturer’s operation.

Enhancing security of the supply chain By means of EU Directive 2001/62/EC, the so-called Falsified Medicine Directive (FMD), legislators and pharmaceutical manufacturers intend to safeguard the supply chain in Europe. Since February 9, 2016, a threeyear transition period has been in effect to implement EU Regulation 2016/161, which concerns protecting medicines from counterfeiting.

The delegated act from Brussels supplements the Falsified Medicines Directive 2011/62/ EU by technical and organisational details pertaining to the required security features. Effective February 9, 2019,

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every manufacturer must provide prescription medicine packs with an individual serial number in the form of a 2D code (DataMatrix) and a tamper protection feature. Thus, patients shall be protected against falsified medicines. As the requirements set out in the valid version have been known since October 2 2015, the roadmap for those who need to take action is clear. The level of the counterfeiting risk determines whether or not a medicine has to be provided with these security features.

Serialisation plus authenticity feature Serialisation by means of 2D codes, as required by the EU Directive, opens up additional opportunities to the industry. It controls internal logistics processes more efficiently and offers clear identification of every individual medicine pack. However, further actions are necessary to convert an easy-to-copy serialization code into an authenticity feature for effective verification. Deep industry knowledge combined with specialized know-how in materials and printing technologies are prerequisites for developing tamper protection and anti-counterfeiting solutions for the pharmaceutical industry. Effective security solutions for diverse threat scenarios can be divided into three categories: Firstly, a label may clearly indicate first-opening and tampering. Secondly, integrated technologies of various security and detection levels provide effective protection against counterfeiting. Last but not least, track and trace system solutions serve to identify and trace products, and thus indicate gray market activities. All functional components can be customized and combined with each other. This results in complex security labels that effectively put a stop to the counterfeiters’ game and offer a wide range of added value to the pharmaceutical company.

Covert features from high-security printing are suitable for checking customs inquiries, for pharmacovigilance or for complaints. For this purpose, manufacturers integrate specialty pigments into the packaging or label. Only a special detector can prove the presence of these pigments during authentication. These robust and colorless markers can be invisibly incorporated into any design and implemented using diverse techniques. A customised formulation with an invisible “fingerprint” represents the highest level of counterfeiting protection, as it can neither be copied nor seen.

Overt features enable fast authentication by sellers, pharmacists and consumers without any extra tools. Optically variable holograms, for instance, are based on microscopically small, diffractive structures in the film layers, which make the feature unique and thus achieve a high level of counterfeiting protection. Pharmaceutical manufacturers increasingly complement this feature by security color-shifting inks. Providers of professional solutions rely on specialty inks that may only be used by security printing companies. Manufacturers achieve a particularly high protection level by combining these color effects with special printing techniques, “latent images” or thermo-reactive inks. Overt features are typically used for allowing laypersons to perform intuitive checks, but require detailed knowledge of the authenticity features. Here interactive, digital technologies can be helpful as well and make information about the security feature’s properties accessible to the end user for verification.

Digital security features use computer-generated and highly encrypted encodings as human-readable numbers, 2D codes or special random patterns to enable Internet-based authentication in the pharmaceutical supply chain all the way to the end user. In addition, digital technologies offer direct interaction between the product and the person performing the check, and can thus serve to provide information and to support promotional activities. However, due to the possibility of copying them, numbers and encodings A customised formulation alone are not counterfeit-proof. with an invisible Companies should therefore always combine them with additional features. “fingerprint” represents Copy protection patterns, for instance, the highest level of provide clear proof of authenticity with a counterfeiting protection high-resolution, cloud-like printed image.

Its delicate details are not discernible by the naked eye and, for technical reasons, a reproduction by counterfeiters is impossible at this level of resolution and will automatically result in a loss of printing quality. These variations can be clearly identified with handheld readers or smartphones and respective software, exposing them as a copy.

Creating a fingerprint

Qualification and implementation process

Ideally, holistic counterfeiting protection should always consist of a combination of overt security features with digital and covert technologies.

The requirements of the EU Directive to enhance the security of medicine packs meet with proven technologies on the manufacturers’ side. An analysis of the threat scenario and the product to be protected, as well as the development of an appropriately adapted security strategy, provide an important basis for selecting the security technology best suited for the respective task. However, the subsequent qualification and implementation process should not be underestimated. In addition to the high complexity involved in the system integration of code printing, checking and acquisition, administration and transfer to a database, solution providers have to rely on established know-how of integrating anti-counterfeiting and tamper protection. The experts not only consider the technical requirements and the particularly high quality criteria of the pharmaceutical industry, but also the demands made on security manufacturing, warehousing and distribution. Tamper protection and anti-counterfeiting measures are tasks requiring comprehensive, in-depth security management. Thus, effective measures to protect products against counterfeiting should always be based on a holistic approach to product and patientsafety.

Overt features for intuitive checks

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ANTI-COUNTERFEITING

Fooling the fakes Denny Bros’ senior marketing executive, Stephie Castling, explains how to stay ahead of the fraudsters

Stephie Castling, Denny Bros’ senior marketing executive

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errorist activities are making headline news and increasing people’s general sense of vulnerability. But what about the dangers they could be facing from their over the counter medicines or internet medicines?

Clever counterfeiters are keen to make a profit whatever the cost to human life and business.

Counterfeiters are keen to sniff out opportunities and often copy high-value, high-turnover, high-demand drugs. They prey on weaknesses in the supply chain and are responsible for 170,000 deaths worldwide each year which can be related back to counterfeit medicine.

To minimise the potential impact on pharmaceutical profits and consumer health, manufacturers need to be one-step ahead of fraudsters by being proactive in applying anticounterfeiting technology to their products.

According to the Pharmaceutical Security Institute, total incidents (worldwide) of pharmaceutical crime increased by 51% between 2011 and 2015 - a statistic that manufacturers cannot afford to ignore.

Of course the EU’s Falsified Medicines Directive is bringing the issue sharply into focus as the 2019 deadline approaches. All pharmaceutical medicines will have to have a unique identifier, such as a two-dimension barcode carrying a serial number, and an antitampering device.

A robust chain of custody is what is called for in order to render the counterfeiters’ job useless. Once pharmaceutical products are provided with a unique identification code (which is logged on a central database by the manufacturer) medicines will be verified at the point of dispensing across Europe.

The pharmacist or dispenser would scan

the product triggering an update of the manufacturers’ database and closing the record on that product so that it is no longer live; thus shoring up the supply chain against fraud.

Many labelling companies are already advising pharmaceutical manufacturers on the best, securest solutions for their packaging and labelling needs. Companies not only need to seek advice on whether their current packaging is meeting the forthcoming legislative requirements, but is it effectively addressing other issues too.

Typical problems include how to accommodate the specifications for different countries in any new labelling strategy. For example, the UK requires a dispensing label while in France a label with French braille is needed. Practical challenges also present themselves such as how to introduce a tamper-free device that is not too difficult for elderly patients to open.

Pharmaceutical industry partners can advise on how best to mix the overt versus covert ratio of anti-tamper and counterfeiting printing solutions suitable for their products.

There are key differences between overt and covert protection. Overt features are clearly visible and do not require detection. Covert solutions offer an extra level of security and could include UV light or temperature-revealed hidden text.

High-level covert solutions will contain some form of taggant that is only visible or detectible through more sophisticated handheld readers, which range from laser pens to dedicated readers with controlled distribution.

These may include acoustic tags and Radio Frequency Identification (RFID) tags.

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Guaranteeing a product’s authenticity brings with it numerous business advantages: a better managed inventory system, an ability to streamline product recalls thus minimising their financial impact, being able to demonstrate that compliance with product security is paramount, increased brand protection and heightened public safety through better traceability in the supply chain.

Clever strategies would encompass deliberate print imperfections incorporated into labels, the use of microtext (only legible through a magnifying glass), 2D matrix codes revealing encoded data in text or numeric form and complex holograms.

Another deterrent to counterfeiting high-value pharmaceuticals, is to hide RFID tags under labels or within the packaging.

The product can then be scanned and tracked by RFID readers to match the data to The EU’s Falsifi ed medical databases. Business productivity can significantly Medicines Directive be boosted too, as taking an is bringing the inventory with a RFID handheld issue sharply reader is 25 times faster than into focus as the with a barcode reader.

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2019 deadline approaches

The industry is adapting well to the challenge of staying ahead of the counterfeiters as more manufacturers include anti-counterfeiting devices within their products.

Incisive and well-informed decision-making by management in partnership with key suppliers is what may make the difference between counterfeiters snatching a huge share of their market or manufacturers being able to out-run and out-think these stealthy imposters.

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1. According to the International Policy Network

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DATA

Information overload?

David Northmore, vice president, EMEA, MarkLogic, explains how a data hub can resolve IDMP data integration challenges

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ocused on improving patient safety, the new EU ISO IDMP standards are set to create a few IT headaches for pharmaceutical firms as they race to get their data in order. The first phase of IDMP came into force in July 2016, and any firm operating in the EU that fails to demonstrate IDMP compliance risks a fine of up to 5% of annual EU revenues. And while it is not yet legally binding, the USA, Canada and Switzerland have also signalled their support.

Implemented by the EMA, the goal is to simplify the exchange of data between all stakeholders by providing a universal system for identifying drugs. This includes how they should be used, consumed and packaged and is applicable to all stakeholders including pharmaceutical drug researchers, developers, manufacturers, distributors, registration authorities, product safety analysts, and quality control specialists.

But achieving this unified view of medication formula and dosage requires a data strategy rethink.

Much of this information currently lies in multiple, unconnected data silos such as billing, clinical, manufacturing and supply chain management systems. The flurry of pharma M&As over recent years presents additional data challenges, creating even more system fiefdoms and silos that have to be joined together to provide an integrated, consolidated view for reporting and regulatory purposes.

To add a further layer of complexity, around 70% of this drug data is unstructured or semi-structured – for example, clinical dossiers, protocols, package inserts and regional label submissions. Add to all of the above the fact that the IDMP standards are not yet finalised and the data challenges become even greater. Maintaining compliance against a moving target is tough!

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For IDMP compliance all of these different types of information need to be stored, classified and made available in the same way as traditional transactional data.

The traditional approach to this data conundrum would be to use a rigid relational database linked to a Master Data Management system and a data lake to hold all the data. But the relational model is not designed to handle unstructured data and is too inflexible to accommodate changes without resorting to many man hours of data wrangling - extraction, transformation and loading (ETL). Costs go up, timelines increase and business agility is stymied. In some cases, ETL work can account for a staggering 60 per cent of a project’s overall costs.

Some early industry estimates suggest that the cost of transitioning from the current XEVMPD requirement to IDMP is conservatively forecast to exceed 38 million across a sample of 14 European Federation of Pharmaceutical Industries and Associations (EFPIA) member companies.

It would take many thousands of man hours to manually curate a multinational pharmaceutical firm’s data, using a relational model, in readiness for IDMP compliance: identifying and collecting all the data sources and then manually linking the relationships between these data sources. Automating this process using an Enterprise NoSQL database with in-built semantics and the ability to learn as it goes is far more costeffective. One proof of concept we have done for a customer suggests it would be possible to dramatically reduce the number of man hours needed to build such a system.

Building an Operational Data Hub, using an Enterprise-grade NoSQL database, to integrate all of these data silos delivers a solution that is specifically designed for rapidly changing, multi-structured data applications. A data hub is a virtual filing cabinet that can hold a single

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unified view of all drug-related data, both structured and unstructured.

Effectively a complete drug lifecycle management system, every single ‘event’ that happens is recorded, meaning that firms and regulators have a system of record for all drug-related data and can easily understand what is going on with any drug, anywhere in the world, and at any point in time.

Once this 360-degree single view is enabled, it is easy to find the data needed for IDMP compliance - and to see commonality between data sets. This is important for producing safety summaries from data captured on drug trials, and actual data once the drugs are licensed, for example. Having this single source of truth makes it much easier to plan in the case of an adverse event: find out what a particular drug is approved for in a given region, review information on previously identified adverse events, identify any potentially counterfeit batches, and determine whether the batch may be incorrectly labelled. This data not only helps firms to identify other drugs with potentially similar effects, but also means they can react quickly to streamline recalls and perhaps even isolate the recall to a single country.

Choosing the right NoSQL database that comes with integrated search and semantics capabilities and full enterprise-grade ACID compliance is essential. In a database with ACID capability, even the largest datasets are processed consistently and reliably so none of the data is ever altered or lost. Importantly, the system can also be quickly adapted, extended and enhanced to meet changing business and regulatory requirements.

Because IDMP is all about looking at the relationships between data, all relevant information needs to be harmonised within and across enterprise boundaries and natural language processing/standard vocabularies supported. This is where integrated semantics and search come into play. Asking a question in a number of different ways

and getting the same answer consistently is a must. Members of the pharmacovigilance (PV) and manufacturing departments, for example, need to be confident that they will surface the same answer from the system to the same basic question on a historical product recall, regardless of how they have framed the question: a single source of truth. The semantic capabilities also need to be flexible enough to handle the fact that drug vocabularies invariably change throughout the average product lifecycle of 5-10 years.

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A database that supports bitemporal data management is also rapidly becoming a must-have for the pharma industry. With its roots in the financial Achieving this unified view services sector, bitemporal allows firms in of medication formula and heavily regulated industries to minimise dosage requires a data risk through “tech time travel”—time strategy rethink. stamping and rewinding documents to identify changes by looking at data as it was over the course of time. This capability can help pharmaceutical firms with reporting as well as helping them to demonstrate and maintain compliance with, for example, the IDMP standards as they evolve.

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There is no time to lose. The pharma industry needs to act now to get its digital filing in order to meet the emerging IDMP standards and ultimately to help enhance patient safety.

An operational data hub is the perfect prescription for curing the data pain points associated with IDMP compliance. Benefits include improved operational efficiencies, faster data retrieval, and more informed decision-making. And of course the ability to avoid large – and wholly avoidable - regulatory fines.

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STERILISATION

Playing it safe How sterilisation tests provide important information on pharmaceuticals, packaging and product safety – by Isa Alkan, sales director, Schoeller-Bleckmann Medizintechnik

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erminal sterilisation protects filled pharmaceuticals from microbes and ensures they are safe to use. However, the sterilisation process is subject to differing requirements depending on both medication and primary packaging, posing various challenges to pharmaceutical manufacturers.

How high can a steriliser’s temperatures be without damaging the efficacy of temperature-sensitive drugs? What pressure conditions are needed to maintain the containers’ stability? Sterilisation tests help to determine each product’s processing parameters, from supporting pressure to loading procedures, thereby ensuring pharmaceutical product safety.

Plastics – a challenging material

Especially for new products, pharmaceutical manufacturers increasingly rely on customised packaging solutions made of plastic. These are often developed in close cooperation with primary packaging manufacturers to fulfill very specific design and marketing requirements. During terminal sterilisation, however, plastic containers may burst, warp or lose strength, making them unusable. Potential negative impacts on the product’s final validation entail long delays and additional costs for the manufacturer. As a result, pharmaceutical and packaging producers must Isa Alkan, sales director, Schoeller-Bleckmann create the ideal sterilisation conditions for different types Medizintechnik of medication and containers. Here, invaluable support At first glance, a syringe reveals little about how is provided by suppliers of sterilisation equipment complicated its production is. It actually involves a with a wide range of product-specific processes and comprehensive very complex process, from developing the solution, choosing and sterilisation tests. filling the packaging to designing the container. Even after filling, the process is not yet completed. For instance, depending on the Terminal sterilisation is precisely tailored to pharmaceutical requirements. active ingredients, many countries require terminal sterilisation Depending on the medication and the approved procedure, different of pre-filled syringes to ensure the safety of both product and cycle times, temperatures and sterilisation media are needed to ensure patient. Parenterally administered pharmaceuticals, such as heparin the containers remain sterile and intact, and the filled ingredients preparations in syringes and infusion solutions in bags or bottles, maintain their integrity. This can be accomplished by various different generally place high demands on the sterility of the packaging. All sterilisation methods. Among the industry’s most common and preferred these products need to remain free of microbes to prevent infections methods are the vacuum-steam process, the steam/air mixture process, after administration. Terminal sterilisation of the packaged drugs and the hot water shower. Modern combined systems incorporate eliminates microorganisms to the maximum extent in accordance multiple processes within a single steriliser, thereby offering much with official regulations. greater flexibility in terminal sterilisation.

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Finding the right process for each product Solid and porous equipment, pre-filled ampoules and blister-packed products are sterilised using the vacuum-steam process. The air is completely evacuated from the pressure chamber and containers, ensuring saturated steam to penetrate even into the tiny cavities of porous items like plastic stoppers. The latter are subsequently heated and sterilised by inflowing pure steam. Depending on the type of load, the process finishes either with vacuum drying or jacket cooling.

Open, semi-sealed and completely closed containers such as vials and pre-filled syringes, as well as mono- and multi-chamber bags are sterilised by the steam/air mixture process. It allows products to be removed in a dry condition at the end of the cycle. The direct inflow of steam, which is circulated by fans inside the chamber, provides for heating and sterilisation, while cooling is accomplished by internal heat exchangers. Supporting pressure can be adjusted as desired, thus preventing deformation, excessive stopper movement and container breakage throughout the entire cycle.

The hot water shower is particularly suitable for liquids in closed containers, such as blow-fill-seal products and closed IV bags. Fast heating and cooling cycles reduce thermal stress on temperaturesensitive products to a minimum.

All process parameters considered Liquids and packaging are subject to highly variable thermal and mechanical stress. In case of too high pressure within the containers, walls may soften or bag seams burst. To prevent syringe and vial stoppers from shifting within the containers, a so-called supporting pressure is generated in the steriliser. Thermally instable pharmaceuticals risk to spoil when exposed to high pressures and temperatures, thus losing their effectiveness. Hence, precisely tailored sterilisation parameters for liquids and containers are crucial. But how can the necessary formulations be determined?

market launch. Even if the test results are negative, they will certainly not lead to the cancellation of production. Instead, packaging and pharmaceutical manufacturers can target their efforts more accurately and accelerate the further development of their respective products.

Moreover, specialised testing centers are also available to manufacturers who either do not own the right equipment or whose machines are already working at maximum capacity. Outsourcing sterilisation tests to experienced equipment manufacturers is an alternative that saves both time and money – while manufacturers and patients are always on the safe side.

The SBM process X-pert center Schoeller-Bleckmann Medizintechnik (SBM), based in Ternitz, Austria, is a subsidiary of Bosch Packaging Technology with more than 35 years of experience in the pharmaceutical industry. Its portfolio includes standard modules and customised solutions for the pharmaceutical sterilisation of products and equipment, as well as professionally conducted tests performed on-site at the “process X-pert center”. Here, pharmaceutical manufacturers and packaging suppliers can analyse the sterilisability of their products, determine the best process and most suitable equipment, and optimise formulations, cycle times and equipment concepts.

At the “process X-pert center”, SBM offers all three sterilisation procedures: vacuum-steam process, steam/air mixture process, and hot water shower. Two state-of-the-art sterilisers, including a combined system incorporating the vacuum-steam and steam/air mixture processes, provide the flexibility needed to develop precisely tailored sterilisation processes for the most diverse products. Via sight glasses, products can be observed during test phases and additionally allow photo and video documentation. Test runs are further documented by experienced experts who also advise customers on optimal sterilisation parameters, from temperature settings to loading. The services of SBM also include the professional storage and disposal of the products.

Pre-tests including essential process parameters like loading, temperature, pressure, heating and cooling speeds, as well as product storage are key. Depending on container quantity and complexity, test runs can take from a few hours to several days. They precisely map the sterilisation processes required by different products – and in case of doubt, they identify whether a new product or primary packaging material can be sterilised at all. Pharmaceutical and packaging manufacturers not only receive extensive documentation and practical guidance. The tests also provide them with important indications to further optimise their products and sterilisation processes.

Negative results provide useful insights The required sterilisation procedure for approved drugs has normally already been defined. In this case, test results can deliver valuable insights regarding which variables have to be adjusted in order to achieve even more efficient process and cycle times. The same applies to containers. Packaging manufacturers receive a detailed analysis of a container’s characteristics and potential weaknesses, resulting in important clues on how the packaging might be optimised. In case of a projected production line expansion, an evaluation of the loads capacities ascertained by comprehensive testing helps to determine the suitable size of the installation. Pharmaceutical manufacturers can thus invest in expansion projects according to their exact requirements, while saving time and avoiding unnecessary costs.

If correct procedure and parameters are still to be determined, test runs can be conducted as a kind of “stress test” to answer questions regarding sterilisability and packaging quality, as well as the most suitable procedure. Manufacturers save a great deal of time and effort during qualification and validation, and can accelerate the product’s

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39

STERILISATION

The heat is on Lee Oakley, sales director at Priorclave on making sterilisation a more energy efficient process

T

he intensity of saturated steam created by boiling water within a sealed pressurised chamber creates the perfect ‘killing’ environment to eradicate contaminants. And it is this basic principle of creating saturated steam that is behind every laboratory autoclave and research grade steriliser.

An autoclave is standard in virtually all pharmaceutical research or development labs where it is used to sterilise everything from bagged waste to petri dishes and various items of glassware.

It creates the perfect sterile finish for when items are to be re-used or for the safe disposal of laboratory waste.

Legislation, namely the Climate Change Act of 2008, (where the UK became the 1st country worldwide to commit to legally binding emissions targets) has led to the carbon tax1, whereby organisations are required to pay £12 per tonne of CO2 produced per year. This rate is set to rise to £16 per tonne this year, equally the use of water is metered in most organisations these days; therefore, it is a priority to produce more efficient, environmentally friendly products.

Reducing Costs Like so many industries, pharmaceutical manufacturers operate in an increasingly competitive business and are under constant pressure to lower the cost of their final output, without sacrificing quality. This can only be achieved by examining overall cost, from that initial and costly long-term research programme down the whole supply chain – from material purchase, through production, packaging and delivery into the warehouse and onto pharmacy shelves. Many areas seem to be constantly under review however one sector that seems to have gone virtually unchanged is in the research laboratory.

steel to heat and cool, no insulation or temperature-regulating steam jacket, it has a more simplified production process. It means a standard cylindrical chamber laboratory autoclave costs less to produce which ultimately is reflected in the initial purchase cost.

Using this brief comparative design analysis, it points to the cylindrical chamber autoclave being more energy efficient (there is a linear relationship between weight and energy consumption, as more steel to heat up in the pressure vessel means more energy consumed to achieve the same results in the same period of time.)

Steam generation

Balancing the sterilisation process round or rectangular

Another major factor which impacts on the annual running costs is how the steam is generated.

Pharmaceutical research laboratories many be able to conserve energy by making the right choice of autoclave and managing how it is used.

The booklet titled The Autoclave Knowledge Bank2 gives an insight to some of the things to consider before making that all important purchase.

Often choosing an autoclave is based on load capacity and hence chamber size with little regard to frequency of use. This can lead to selecting a rectangular chamber over a cylindrical design; the latter are the most common style of chamber since they are available in both front loading and top loading autoclaves.

Also cylindrical chambers3 easily manage intense pressure, and thus can be manufactured from lighter gauge steel - roughly one-third as thick and weighing much less than a rectangular chamber which also requires a reinforcing rib cage to prevent the chamber becoming round under pressure. Since the cylindrical chamber uses less stainless

40

Lee Oakley, sales director at Priorclave

It is important to appreciate the different methods of creating the steam, matching the source to the laboratory’s requirements, such as - does sterilisation take place virtually non-stop or is there a less demanding need such as once or twice daily, what is the quantity of media to be sterilised in a single pass and what type of media? How much to be sterilised and how frequently are two primary factors.

It can be a complex equation therefore it is always best to speak with an autoclave company that designs and manufactures as they have a wealth of know-how.

By reviewing this actual process one UK University achieved a signification reduction in direct energy costs and a massive overall saving in water usage of nearly 90%, resulting in an average overall saving of 56%.

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There are three main methods of generating steam: 1. Electrically heated – much like an electrical kettle heating elements are contained in-chamber within a water reservoir, this can be manually or auto-filled. This design tends to be the lowest cost option both in terms of purchase, installation and maintenance.

The big plus factor in favour of electrically heated autoclaves, which contributes significantly to lowering running costs, is that they are only powered up when required. This does not incur much time delay as modern autoclave designs are extremely fast to heat up and the important thing for sterilisation is the temperature of the items in the autoclave not the autoclave chamber itself.

2. In-built steam generator – this is normally mounted directly beneath the sterilising chamber.

This style of autoclaves is obviously more expensive to purchase and maintain and installation costs higher as they require plumbing and drainage facilities for the water supply. They prove ideal for laboratories that have a high throughput since steam is always on tap. However this can also be a disadvantage if chosen for sites with infrequent use; the generator may be operational 24 hours non-stop. Even if a short cycle is selected at say 17.00hrs to run for 2 hours, after 19.00hrs the generator will continue to run all night to top-up steam ready for the next cycle, whenever that is. This is a constant drain on electrical power and water consumption.

3. Direct steam – the autoclave has steam fed directly from the customer‘s own in-house steam supply.

Similar pros and cons as with autoclaves equipped with in-built steam generators although installation could be considerably more expensive due to additional pipework, regulators and drying equipment, etc. between the steam generator plant and autoclave.

However it is rare to find a steam generator house built solely to run autoclaves, and where direct steam is available it is usually because it is used for other, larger plant within the facility.

There can be significant losses of energy on long pipe runs from the boiler house to the autoclave and if the boiler is shut down or at low pressure for repair or routine maintenance then the autoclave will be out of use.

hard-water area the autoclave manufacturer recommended the fitting of a water softener, this resulted again in a very big reduction of salt requirements – a 92% cut compared to the previous operation.

The outcome was a financial saving in excess of £6000 p.a.

Making that saving In addition to carefully identifying the most appropriate Steam Source there are many other questions and parameters to consider when investing in an autoclave. It is essential to ask the right questions, get the right answers and to understand the real purpose of the autoclave.

It often helps to put together a written specification, this will help a supplier offer the right equipment, either from a standard range of autoclaves or a bespoke build. Ask the supplier to explain why a particular model is being recommended and discuss steam generation options as this can have a big impact on daily running costs.

“

It is essential to ask the

When York University’s Biology Department made the change to the right questions, get new autoclave the laboratory acquired a the right answers and machine with a larger capacity but with a to understand the real smaller footprint creating more free-space purpose of the autoclave. within the actual laboratory as well as totally freeing up a room, which previously housed the generator. Since the new autoclave has an inbuilt generator which heats water on demand, costs are cut significantly compared with the previous autoclave design. The new autoclave is called into action two to three times a day, five days a week and by heating water-ondemand it is estimated to save the University £7.58 per run; potential energy cost-saving of nearly £6,000 pa.

”

1

Carbon Tax - fee intended to make users of fossil fuels pay for climate damage http://www. carbontax.org/whats-a-carbon-tax/

2

The Autoclave Knowledge Bank – a free book available in print or to down load that gives background information to help make an informed Laboratory autoclave purchase. http://www.priorclave.co.uk/a/api/resource/?id=154

3

Large cylindrical autoclaves: views various designs http://www.priorclave.co.uk/products/front-loading-autoclaves/

Research university improved ‘green’ credentials Internationally renowned for the strength and quality of its research, teaching and state-of-the-art facilities, the Department of Biology at York University provides outstanding and opportunities for studying diverse subjects such as cancer, immunology and tissue engineering, to novel agricultural products, environmental studies and bio-archaeology.

Owing to the nature of the research work undertaken, this area of the University is classified as a Containment Level 1, so only those with authorisation can gain access to the laboratory. In order to maintain the highest level of decontamination risk-potential, after experimental procedures involving seed and GM investigation, all waste is carefully sterilised for safe disposal using steam autoclaves.

It replaced an older 350 litre powerdoor autoclave with a Priorclave front-loading laboratory autoclave. The previous smaller capacity machine required a separately housed 45kW generator that ran constantly 24/7 to provide the required level of steam for sterilisation.

Side by side analysis of running costs between the new ‘self-contained’ autoclave and the original model fed with steam via the external generator show an overall saving of 56%, the major contribution to this massive saving is associated with cost of water supply and disposal, amounting to a reduction of 88% and 89% respectively. Since the University is in a

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FREEZE DRYING UPDATE

Play it cool Freeze drying equipment supplier Biopharma Process Group explains what quality by design means for lyophilised pharmaceutical products

Q

uality by design (QbD) for lyophilisation is about building a robust process that proactively flags critical points and ensures consistent delivery of the best quality product, not only by minimising risk but also through greater understanding of the process itself. Regulatory bodies require details of the lyophilisation cycle for product registration but a well-designed cycle also has economic benefits since the best quality cycles are most efficient in terms of energy, time and other resources.

QbD terminology and what it means for lyophilised products For the final product, a “(Quality) Target Product Profile” (or (Q)TPP) must be established, this will define the product’s desired characteristics. For generic products, a profile may be straightforward to define, but for new products, this might not be so simple, as there is less “Prior Knowledge” about the product at the early stages of R&D. A benefit of the QbD approach is that it is not attempting to robotise the process; in fact, it places significant value on “Prior Knowledge”, recognised as an important factor in reducing risk for the product – a QbD core aim.

A product’s (Q)TPP might include quantitative limits or ranges for parameters such as moisture content or activity / potency, as well as descriptions or categorisation of more qualitative phenomena such as appearance, colour and homogeneity.

Once a (Q)TPP is established, the “Critical Quality Attributes” (CQAs) for the product are defined. Not every attribute is necessarily critical to the product quality, so some work needs to be done to establish what is /isn’t critical.. Again, for generics, this can be a simple process, since information will exist about the originator’s material. However, for new product, the process of identifying the CQAs can be involved. One approach is to assign an order of importance to the various attributes, which can help focus the process onto the critical parameters and de-risk the product with respect to these parameters.

This approach works similar to the “Theory

of Constraints” model, where parameters that are initially deemed to be low risk are made subordinate to those that pose higher risk; a solution is provided to deal with higher risks, which should result in the constraint being lifted or minimised; if the constraint is then transferred elsewhere in the system, reiteration may be required.

For lyophilisation, this might involve first establishing the liquid state stability of a formulation and understanding its sensitivity to cooling rate or freezing temperature, which should de-risk the filling, loading and freezing process. Focus can then be given to de-risking primary drying, which is arguably the highest risk (or constraint) part of the process and the longest step in any cycle. Considering primary drying, much can be done before carrying out practical lyophilisation cycles – many well-established equations for heat and mass transfer can be used to establish a range of input variables before entering the laboratory.

Combined with Prior Knowledge – particularly regarding the risks from the formulation and the equipment, outlined below – mathematical modelling can be a powerful tool in one’s LyoQbD armoury to mitigate risks.

Risk mitigation: Selecting excipients for the formulation Choice and balance of excipients in a formulation has a significant bearing on its lyophilisation process parameters. Various additives offer protection for different processing stresses, and formulation development aims to create balance that

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results in best possible final product. One challenge is in knowing whether the risks to the product may be better limited by keeping options open with regard to the formulation while completing process R&D, or to carrying out formulation development as a separate exercise. It has been demonstrated that essential parameters of the active ingredient(s) be investigated prior to starting lyophilisation cycle development, such as solubility in the chosen solvent(s), pH-stability profile, and any chemical incompatibilities identified.

Risk mitigation: equipment The lyophilisation process itself – so risk to the product and the robustness of the process – is significantly affected by aspects of equipment used, such as shelf cooling rate and the condenser trapping rate (sometimes known as the ‘choked flow’ point). If equipment limitations are known, this will help ensure smooth scale-up of the process. Specifically, the challenge is in ensuring that whatever laboratory process is developed, it can be replicated successfully at production scale.

Often the difficulty comes from the fact that details of manufacturing equipment is not known during early stages of R&D – this is often the case for a small company developing a promising product, where the lyophilisation process may be contracted out to a Contract Research Organisation (CRO) and/or a Contract Manufacturing Organisation (CMO).

If the CMO is known early in the R&D process, then the lyophiliser performance can be incorporated into the process, but if unknown then additional robustness will need to be built into the cycle.

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Risk mitigation: critical temperatures Scientific methods of determining critical temperatures of a formulation make it possible to design a high quality cycle. Key technologies are freeze drying microscopy (FDM), and thermo-analytical methods such as differential thermal analysis (DTA), electrical impedance analysis (Zsin ) and differential scanning calorimetry (DSC). Understanding at what temperatures a product exhibits changes in its appearance and structure when subjected to the lyophilisation process using FDM builds confidence in developing the formulation and lyophilisation cycle. Thermal and impedance analysis provides data to complement FDM and allows for greater understanding of how individual components of a formulation behave, which can often be related to productrelated issues such as micro-collapse, stability and reconstitution.

Building a design space: putting it all together A design space is a multidimensional combination and interaction of variables and process parameters that have been demonstrated to provide assurance of product quality. A successful, detailed study into all product and process variables makes it possible to establish a design space that provides repeatable, consistent and provable results. One of the challenges with the design space is that it might need to be more than 3-dimensional, which means it cannot be visualised. Practically, it is possible to divide the process into discrete steps, with each step

being assessed in terms of its risk, which would give several smaller design spaces that might then be 2- or 3- dimensional.

An example of how the design space might be constructed for the primary drying conditions for a lyophilised product (adapted after Mockus et al, 2011).

It can be seen that the boundaries of the Acceptable Space are defined by the limitations of the product (critical temperature), the equipment ( condenser trapping rate) and process efficiency (here, the mass flux through the duct between the chamber and condenser).

There may also be additional factors that might be superimposed on this diagram, or added as a further dimension in space to give a 3-dimensional ‘box’. One example is to use product resistance (as it increases with time) as the third axis, as it is well established that this can be a significant constraint – especially later in the sublimation process.

While a QbD approach can add significant robustness to a product, and while many of the aspects of the design box can be modelled mathematically (and tested by real laboratory studies), it remains an iterative process, and it is unlikely that this approach will ever completely

negate the requirement for testing in reality.

A further consideration with lyophilisation, is that risks change throughout the process – for example, in the early stages of sublimation, the condenser trapping rate might be the limiting factor to processing efficiency, while later in the process, the product itself (specifically the dry layer above the sublimation front) is likely to be the largest source of impedance to drying.

So, how might the QbD approach be integrated into lyophilisation formulation and process development in practical terms?

Figure 2 shows an example of a possible “QbD roadmap” for lyophilised products. Starting top left of the roadmap, under the principle of ‘Prior Knowledge’, one can set the desired parameters/ outputs. Once parameters are in place, work clockwise using a combination of candidate formulation assessment, mathematical modelling, and real-life lyophilisation, to ‘design in’ quality at each stage of a product’s design and development, whereupon if the robustness of the process with regard to the various risks is acceptable to the end user, then it can be considered a success.

Significantly, it can be seen that much of the roadmap involves desktop studies including an assimilation of Prior Knowledge, before practical work needs to take place, although it can be useful to gain an understanding of the product resistance (Rp) as it changes throughout the sublimation stage of the cycle, so this can be built into the Design Space.

With a “conventional” 2D space, one would tend to assume a high Rp value throughout the process, which may sacrifice efficiency in favour of risk mitigation; a 3D space that takes into account the changing risk might provide a solution to this issue, yielding a safe, efficient and robust process.

QbD “roadmap” showing possible stages of desktop study and practical work. Reference: L. Mockus et al (2011, Pharm. Dev. Tech. 16(6) 549-576

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BIOPHARMA MANUFACTURING

Risky business Heike Michaelis, director of the Emprove program at Merck and Frithjof Holtz, the company’s head of advocacy and surveillance for regulatory management explain how to make lighter work of risk assessments in biopharma manufacturing

Heike Michaelis

Frithjoth Holtz

I

n order to help ensure patient safety, biopharmaceutical companies must identify possible risks and mitigate exposure to those risks. Risk assessment programs are devised to do just that, helping to ensure safe and robust manufacturing processes.

Unfortunately, identifying and gathering the necessary data required as part of a risk assessment program can be incredibly time and resource intensive. Adding to the challenge is a lack of readily available, detailed information about consumables such as filters and single-use technology.

This article describes current processes and requirements for implementing such risk assessment programs, and offers recommendations for successful and robust quality risk management.

plans, companies can flexibly interpret and apply ICH Q9 guidelines depending on their specific activities, possible sources of risk and level of risk tolerance. For example, companies conducting sterile manufacturing must be aware of potential contaminants that can impact the safety of final drug products. As a result, these companies may have a lower tolerance for risk and therefore stricter adherence to ICH Q9 than other companies.

More guidance on enacting programs in accordance with ICH Q9 can be found in Technical Report No. 54, Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations from the Parenteral Drug Association.

Gathering data in support of risk assessment Building quality risk management programs A good starting point for development of a risk assessment program is the International Conference on Harmonization (ICH) Q9 Guideline on Quality Risk Management. This document is regarded as the “gold standard� for risk assessment worldwide. Widely referenced by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), ICH Q9 not only describes the steps that companies need to take to establish robust risk management systems, but also provides tools for success implementation of those systems.

ICH Q9 provides guidelines for many areas of risk management, from drug development to supplier management and drug production to packaging, labeling and storage. In developing risk management

Successful quality risk management depends on a strong understanding of the foundational science, components and processes of the risk under analysis. In the manufacture of drug products, this requires access to documentation and regulatory information describing all chemicals and consumables used in the manufacturing process. Such information facilitates qualification processes, selection of the best suppliers, supply chain transparency, preparation for approval and regulatory compliance.

Information gathered from the suppliers of chemicals and consumables should include details on how these products are manufactured, how quality is managed and how the manufacturer manages their own suppliers. These details are essential for ensuring a robust, transparent

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and reliable supply chain. Additional information needed includes the effect chemicals and consumables such as filters or single use components might have throughout the production process and the final drug product. Information such as that regarding elemental impurities (regulated by ICH Q3D) for excipients is important input for the end user’s risk assessment. For consumables, a comprehensive extractables report will assist end users as they run leachables tests with their drug product.

How the information is used depends on the chemical or consumable itself. For raw materials such as excipients, the information is not only needed for the drug filing. For consumables such as filtration and singleuse products or process chemicals, the information is used to qualify companies as suppliers, qualify the products for use in their systems, track and trace and better understand and characterise processes.

Obstacles to collecting risk assessment data Drug manufacturers often experience considerable discrepancies between the information they need to ensure compliance and successful quality risk management and the information that is readily available.

These companies often have their own internal requirements that are stricter than official guidelines.

This lack of clarity is especially challenging for consumables such as filters and single-use technology used in bioprocessing. Regulations around raw and starting materials provide relatively clear expectations of documentation expected from suppliers. In contrast, the regulatory landscape for single use is not as developed. As a result, when consumables are added to manufacturing processes there is no clear expectation for the type of information needed to complete risk assessment documentation.

At the very least, manufacturers need to know the risk of potential impurities from consumables – including extractables and leachables.

Regulatory associations are working on establishing a common ground for assessing risk from filters and single-use technology. In the meantime, current methods rely on complex processes of evaluating toxicological risk by reviewing in-house studies, scientific publications to determine levels of acceptable exposure from extractables and leachables. Not only is this approach to risk assessment time-consuming, but it requires expertise and specific equipment to verify stability of plastics, integrity of bags and proper operator training among other considerations for risk.

Faced with this level of uncertainty, it is essential for biopharmaceutical manufacturers to partner with trusted suppliers to facilitate quality risk management programs. A strong manufacturer-supplier partnership for risk assessment is crucial.

Recommendations for risk assessment success Suppliers have a vital role to play in helping drug manufacturers gain access to the comprehensive information needed in support of a risk assessment program. In the past, manufacturers had to contact multiple parties to collect the necessary information to support their risk assessment programs. We have created our Emprove risk assessment program to greatly simplify this process and save manufacturers time and effort associated with their own evaluation or testing. By providing extensive and detailed data about chemicals and consumables, the program addresses the challenges that manufacturers face in preparing for quality risk management.

anticipates future needs and delivers confidence, by informing risk assessment programs in a very effective way.

For drug manufacturers, it is important to understand the chain of custody of pharmaceutical raw materials. This aids in assessing the risk of falsification. For products in the Emprove program, we describe who produces, fills, labels, tests and releases the material. The original manufacturer is represented by a code. As original manufacturer data are confidential, customers can access this information through our online electronic original manufacturer tracking (eOMT) procedure.

Drug manufacturers leverage the Emprove program by accessing information for over 400 products, which is available 24/7 through an online portal. Manufacturers can access individual dossiers covering qualification, risk assessment and process optimisation or purchase the entire suite:

“

Suppliers have a vital role to play in helping drug manufacturers gain access to the comprehensive information needed in support of a risk assessment program.

• Material Qualification Dossier speeds approval preparation by supporting qualification efforts. It includes content on manufacturing processes, characterisations, certificates, justification, stability summary, and more.

• Quality Management Dossier supports the risk assessment by providing info on supply chain, supplier management and product stability

”

• The Operational Excellence Dossier supports process optimisation activities with/through elemental impurity information (ICH Q3D) and Analytical Procedures. For filters and single-use components a comprehensive extractables report is provided.

Information about intentionally added elements and results from testing of different batches for twenty four elements in line with the ICH Q3D Guideline for Elemental Impurities.

The information provided by the Emprove program is beneficial to large, well-established manufacturers as well as small, emerging companies who may be overwhelmed by the burden of developing manufacturing processes and evaluating risk from pre-clinical to full scale-up.

Conclusion While ICH Q9 provides strong guidelines for quality risk management, the success of these programs relies on access to documentation and regulatory information about all of the chemicals and consumables used in the manufacturing process. This process can become especially complex for consumables such as filters and single-use technology, where regulatory expectations are less defined and defining risk requires specialised equipment and expertise.

Faced with this potentially time- and resource-intensive process, biomanufacturers can greatly benefit from working with trusted suppliers who are in unique positions to provide risk assessment information.

This type of supplier-manufacturer partnership can efficiently provide manufacturers with the information they require to implement risk management and assure safe products for patients around the world.

Introduced in 2004, the program has been continuously extended and enhanced to encompass hundreds of raw and starting materials used by drug manufacturers. In June 2016, the program was further expanded to include products for filtration and single-use processing, making it the first program of its kind to include consumables for biopharmaceutical manufacturers. The program addresses current regulatory needs,

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A M R PHA THE AT CKS FLI

Ralph Fienne s stars in this adaptation of the John Le Carre no vel (image credit: Denis Makarenko / Shutterstock .com)

Reviewed: The Constant Gardener EPM’s Reece Armstrong examines the depiction of the pharma sector in the movie The Constant Gardener.

After his wife Tessa’s (Rachel Weisz) murder in Africa, British

Against his government’s wishes Justin seeks out the truth,

diplomat Justin Quayle (Ralph Fiennes) sets out to find out why

despite receiving multiple threats against his life. He continues

she was killed, revealing a conspiracy in the process that affects

Tessa’s goal to expose the conspiracy, finally obtaining a letter

the lives of millions.

that was written by the head of the Africa desk in the British government, implicating himself and the British government in

The film is told through a series of flashbacks that intermingle

the arrangement of Tessa’s murder.

with the events that are happening at present. The effect is one that allows the viewer to piece together parts of the puzzle.

The film is half a tragic love story and half a dark and unflinching take on the pharma industry, capitalism and government

Based on the novel by John Le Carre, the film takes an

influence. A side story that identifies one of his best friends as

uncompromising view of pharmaceutical industries and their

being in love with Tessa adds more heartbreak to the proceedings.

supposed practices of using less fortunate societies as guinea In an interview with director Fernando Meirelles, he spoke

pigs for medicines.

about the extent to which pharmaceutical companies exploited The film plays with the idea that there is an unethical agreement between pharmaceutical development and testing companies and the British and Kenyan governments.

A conspiracy is slowly revealed showing the damaging relationship between all of the major players, to the ill effect of the African

“

Africa as a testing lab because in the U.S and Canada companies have to pay to test drugs.

The film takes an uncompromising view of pharmaceutical industries

people who are being tested on. The drug being tested is dypraxa, a medicine for TB

50

countries such as Africa. He spoke about companies using

”

It raises questions into the monopoly that drug companies have over the products they are testing. Whilst the film might take an overly paranoid view, there is certainly a need for concern. For instance, recently the

and aids which has the nasty side-effect of killing some of

increase in EpiPen prices have caused outrage by consumers who

the inoculated. The deaths of those taking the drug are never

are forced to pay over $600 for the product. In another case Pfizer,

noticed and dypraxa results are doctored so the drug can go

who control a monopoly on a type of pneumonia vaccine have

into production and earn both the pharma companies and

refused to lower the price of dosages, restricting people’s access in

the government money in the first world.

lower income countries due to the high price of the vaccine.

Justin slowly discovers the ill practices going on and realises

A heart rendering finale shows Justin as a defeated man, but also

Tessa’s death had more to do with her threatening to reveal

as a man with empathy for third-world citizen’s. Like many of us,

the truth behind the drug. As he follows lead after lead Justin

Justin’s ignorance of issues in other countries were caused by

discovers his wife wasn’t who he thought she was and her

his position as someone detached from such problems. Perhaps

insistence upon finding out the truth behind dypraxa ultimately

the film’s greatest strength is showing just how much exposure to

led to her murder.

third-world problems is needed for us to take concern.

WWW.EPMMAGAZINE.COM

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