EPM July/August 2017

A SMOOTH TRANSITION NATOLI REVEALS HOW TO MAKE THE TRANSITION FROM R&D TO FULL SCALE AS SMOOTH AS POSSIBLE PLUS: JULY / AUGUST 2017

• WINNING FORMULA • AGE OF AUTOMATION

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Contents July/August 2017 | Volume 17 Issue 5

Regulars

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6

Features

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EDITOR’S DESK

CLINICAL TRIALS

With increasing antibiotic resistant bacteria will we see the tide turn for R&D efficiency?

Step-by-step guide to fund lower priority trials, how collaboration can speed up trials, the challenge of monitoring adherence and how a new EU regulation will affect early phase clinical trials.

6 ANALYSIS

20

How to succeed in pharma outsourcing and accelerate innovation in healthcare.

OPINION

24

Looking at the questions arising in the pharma community as a result of the political uncertainty.

REGULATORY AFFAIRS Discussing how marketing authorization can be supported with non-clinical overviews and the effect Brexit will have on pharmacovigilance.

14 ON THE COVER Natoli reveal anticipatory experiments that can help make the transition from R&D to full-scale as smooth as possible.

30 LAB DIARY Listing the four considerations that are important when integrating solutions.

COATINGS & CAPSULES Highlighting the important points to remember when coating oral solid dosage forms.

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EMERGING MARKETS

28

The potential for dry powder inhalers is clear in emerging markets, with ‘advanced simplicity’ highlighted a driver for growth.

26 SERIALISATION Level 4 serialisation is explained, the challenges and opportunities when preparing for serialisation are outlined and the impact on packaging is assessed.

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AL RI RT O VE AD

Productive R&D drives intelligent drug delivery Phillips-Medisize and Medicom Innovation Partner argue that strategic development of a drug delivery device boosts pharmaceutical industry R&D productivity, shortening development lead times while providing enhanced value for all stakeholders.

Pharmaceutical companies face higher price pressure on better – but more highly priced – products as healthcare costs strain national economies increasingly. Phillips-Medisize’s chief technology officer Bill Welch and Kevin Deane, executive vice-president at Medicom Innovation Partner, observe that strategically developed drug delivery devices will drive improve patient outcomes, creating more value for the healthcare system, which in turn will improve pharmaceutical industry R&D productivity. For late-stage developments, the average yield on R&D expenditure has dropped from 10.1% in 2010 to 3.7% in 2016, as drug development costs rise.

Drugs are delivered to patients increasingly by complex devices, as opposed to traditional oral administration. As the number of internetconnected devices rises, the healthcare industry, and specifically drug delivery, will inevitably be caught up in this societal change, too, according to Welch and Deane.

stakeholder interviews, user research and client workshops. Rapidprototyped delivery devices can be a useful workshop tool, as well as a means of to identifying further opportunities.

Phillips-Medisize starts each development path with a strategy stage, with market differentiation, execution and constraints-to-execution phases. The company says its approach achieves shorter lead times than conventional ones, which omit the strategy stage, plunging straight into development.

The lack of a strong device strategy means the drug risks becoming a ‘me too’ solution; in this instance investing up front in a sound strategy generates a solid return.

All development team members are involved with the entire project, saving time that would otherwise be consumed in transferring knowledge from one team member to another.

Maximum value Addressing productivity, Welch and Deane say pharmaceutical R&D productivity should be enhanced by focusing less on efficiency and more on effectiveness, with patients benefiting from the greater value offered by more innovative drugs and better information.

Modern drug delivery devices achieve maximum value within each individual therapy strategy, ensuring more effective treatment, potentially also reducing documentation. Medicom is proud of its approach to identify how specific delivery devices can support patients and obtain improved care results.

Welch and Deane suggest drug delivery device producers should approach the market with differentiated, rather than lower-value ‘me too’ solutions that simply replicate others’ achievements. Only then can plans be drawn up for launch and further development of identified high-value therapies.

Strategy development should be completed within two or three months and should use existing approaches as building blocks, supported by

Time is also saved by handling device development parallel with development of technology platforms that provide the required technology.

Welch and Deane say early planning of specific drug delivery devices for individual types of therapy “will often hold the key to unlocking greater value”, creating better understanding and benefiting patients and the support they obtain from the various stakeholders – with potential spinoffs into more differentiated products. Integration of drug and device development and manufacturing is the key holistic approach and the driver towards obtaining significant improvements in R&D productivity, they conclude.

Intelligent multiple sclerosis solution Medicom gives an injection delivery device designed for treatment of multiple sclerosis as an example of a product developed with the company’s drug delivery strategy approach that maximises added values. It is a solution that improves ‘event-driven’ patient interaction and information sharing with healthcare professionals (HPCs) on specific MS therapy needs, to an extent that “off-theshelf devices are simply not able to deliver”.

W W W. P H I L L I P S M E D I S I Z E . C O M

Turning the tide?

editor’s desk

Research and development efficiency has been in decline for many years, but now with bodies, like the FDA, aiming to accelerate approval times and a critical need for new therapies to combat antibiotic resistant strains of bacteria will we see the tide turn?

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ith demand for drug delivery technologies rising on a global scale1,2 and emerging markets offering increased opportunities to pharmaceutical companies in several areas is it any wonder research and development (R&D) has taken a back seat?

The decline in R&D efficiency has been a continuing trend since the 50’s, as noted in the article by Scannell et al. in Nature Reviews Drug Discovery3 and, is also one of the sections highlighted as ‘in crisis’ within PricewaterhouseCoopers’ (PwC) ‘From vision to decision Pharma 2020’ report.4 Although these reports were published a few years ago, there hasn’t been a significant upturn in R&D efficiency of late either, which can be partially equated to the low proportion of drugs being approved by regulatory bodies.

However, in the current pharma landscape, more heavily focused on personalised medicines along with the rise (and rise!) of antibiotic resistance, plus a renewed stance from regulatory bodies, such as the FDA, to streamline and accelerate approval processes this may change.

Rising resistance Recently, we have been inundated with headlines about increased incidences of antibiotic-resistant gonorrhoea, including a plea from the World Health Organisation (WHO) that ‘new drugs are needed’.5 “The bacteria that cause gonorrhoea are particularly smart,” explained Dr Teodora Wi, medical officer, human reproduction at WHO. “Every time we use a new class of antibiotics to treat the infection, the bacteria evolve to resist them.”

The R&D pipeline for this specific disease is very sparse with only three new candidate drugs in development.

According to WHO,5 development of new antibiotics is not a particularly attractive prospect for pharma companies as treatments are short-term and have a limited efficacy lifetime due to the bacteria developing resistance. This means that more money will be required at regular intervals to develop newer antibiotic therapies that can combat the evolved disease.

Obviously, there are more cases coming to the fore in this potentially devastating problem with the current state of affairs being only the tip of the iceberg. This was emphasized by the BEAM Alliance, which has requested urgent action on the issue be taken by political leaders at the G20 summit.

“If nothing is done to thwart the progression of anti-microbial resistance, it will equate to a potential global economic burden of up to $100 trillion by 2050,” Florence Séjourné, president of the BEAM Alliance stated, citing estimates from the 2016 O’Neill-report.6 In a report from business intelligence provider GBI Research, covered by EPM earlier this year,7 it was revealed that the antibacterial drugs market is expected to reach $35.6 billion by the year 2022.

It is anticipated that this growth will be a result of new companies emerging in the market as well as the approval of new products.

So, what is on the cards for the future? There is a definitive need to nurture R&D, improve pipelines and see development but maybe we will see these changes within new, smaller companies rather than the more traditional big pharma. Regulatory bodies need to address factors that may cause delays to approvals, for which we have seen promising inroads being made by the FDA. The public and health sector need to be better educated about the consequences of overuse of antibiotics. Finally, funding for small to medium-sized companies is crucial as these may prove to be the vanguard in our battle against antibiotic resistance.

Felicity Thomas

References: 1. https://www.globaldata.com/asia-pacific-drug-delivery-devices-marketset-leave-north-america-behind-2026/

4. https://www.pwc.com/gx/en/pharma-life-sciences/pharma2020/ assets/pwc-pharma-success-strategies.pdf

2. http://www.prnewswire.com/news-releases/global-drug-deliverytechnologies-market-analysis--trends-forecast-report-2016-2025growing-demand-for-drug-delivery-devices-in-emerging-markets--research-and-markets-300393573.html

5. http://www.who.int/mediacentre/news/releases/2017/Antibioticresistant-gonorrhoea/en/

3. Scannell, J.W., et al., Nat. Rev. Drug Discov., 2012;11:191–200. https:// www.nature.com/nrd/journal/v11/n3/fig_tab/nrd3681_F1.html

7. http://www.epmmagazine.com/news/antibacterial-drugs-market-toreach-by-research-/

6. http://www.epmmagazine.com/news/beaming-a-light-on-the-issue-ofantibacterial-resistance-all/

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ANALYSIS

Winning formula Focusing on the keys to success for contract drug manufacturers, Arnaud Sergent Serge Hovsepian (partners), Nohmie Ben Rekassa (principal) and Ben Faircloth (partner) from L.E.K. Consulting detail the differentiation strategies that have proven themselves in the marketplace and provide a roadmap for investors.

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harmaceutical companies are increasingly outsourcing ‘noncore’ activities to cut costs and focus their energy, capital and management on sales, research and marketing, the two activities considered key for their value chain. The volume of worldwide outsourcing has almost doubled since 2006, bringing significant growth opportunities for contract manufacturing organizations (CMOs) and attracting substantial investment.

Contract manufacturing is a complex market, with companies exposed to a range of unpredictable factors, including changing government reimbursement policies or outright drug bans, such as the one that affected the analgesic dextropropoxyphene in 2010. Positions can also be affected by more predictable factors, such as branded drugs becoming generics and new product launches. Companies that succeed find ways to differentiate and protect their business by positioning themselves in sectors where underlying drivers are attractive and barriers to entry are high.

Opportunities and risks in the outsourced manufacturing market

CMOs can also be impacted by developments in a specific therapeutic area; they can be vulnerable to changes in the regulatory environment specific to a class or a product, or the launch of a new competitive product.

One example of the potentially unpredictable nature of the market is in France. Here, the state health insurance system, under pressure to shrink its deficit, decided in April 2010 to reduce reimbursements to consumers of dry cough syrup from 35% to 15% of the retail price, and to end reimbursement for children below two years old. The drop in demand caused by this decision affected makers of all syrups, generated overcapacity in production lines and negatively impacted the syrup contract manufacturing market as a whole.

Strategies for a hyper-segmented market

Contract drug manufacturing is growing fast, driven by the expansion of the overall drug market and the outsourcing trend among pharmaceutical companies. The development of generic drugs has particularly benefited this market, as manufacturers outsource as much as 80% of their production to CMOs. Branded pharmaceutical companies are also increasingly outsourcing their more mature molecules, although they typically continue to manufacture their newly launched drugs themselves for strategic reasons.

Although the overall outsourcing market is growing, CMOs are not all growing at the same rate. The contract drug market is highly

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segmented with each category having different growth characteristics; as a consequence, each segment has to be analysed separately. A segment is characterised by the typical size of the production run, the nature of the active pharmaceutical ingredients (APIs), the galenic form and the step of the product lifecycle to which it relates.

To help mitigate the impact of such risks, CMOs need to identify and position themselves in segments where growth prospects are strong and where they have, or can build, a differentiated position. They can do this in four different ways: in terms of scale, optimising their manufacturing capability to support either very large or very small production runs; in terms of product segment, having the capability to manufacture products with complex or hard to handle APIs; in terms of galenic form, offering a galenic form in which the market lacks capacity or capability; or finally by developing life-cycle management support competencies, which they can offer to pharmaceutical companies directly, alongside manufacturing (see figure 1).

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programmes for existing drugs. These essentially translate into new formulations and/or galenic forms of existing products that have additional customer benefits, such as faster delivery or taste masking. Part of the development process includes ‘scaling-up’ from making prototypes to full industrial production. A CMO which has helped on the ‘scale-up’ has an advantage when it comes to capturing the associated manufacturing contract, which will typically run for several years, thereby cementing the business relationship with the pharmaceutical sponsor. CMOs seeking to pursue this route have two options: they can either position themselves at the tail end of sponsors’ portfolios, specialising in reformulations of generics, or they can support branded drug launches, which often require investment in bespoke plant or material to support innovative manufacturing techniques and/or production scale-up (see figure 2).

Fig 1

Scale: Size is a significant differentiating factor, as the biggest players achieve considerable economies of scale. However, small can also be beautiful: the ability to deliver very short production runs is a differentiating factor, as it requires considerable manufacturing flexibility. Building a global organization able to deliver large-scale contracts requires substantial financing and commitment, while being able to cater profitably for short runs also requires highly flexible, small scale industrial capability.

Those providers positioned solely to support mid-sized production runs face the biggest challenges.

Product segment: CMOs can focus on drugs with high underlying growth and whose API is complex to source or handle. Examples include high potency drugs such as cytotoxic medicines used in chemotherapy and controlled substances such as opioids that are used to control and alleviate chronic pain. The APIs used in these drugs often have specific licensing, authorisation requirements and environmental or safety needs while having to be manufactured in a ‘cleanroom’ setting. Sourcing can also be complex. For example, in France, morphine has to be sourced through Francopia, a subsidiary of Sanofi, CMOs need to identify and position which has a licence from themselves in segments where the French government to growth prospects are strong and be the country’s exclusive where they have, or can build, a supplier. The requirement differentiated position. to establish a close relationship with Francopia is thus an additional barrier to entry for CMOs who want to manufacture opioids. In contrast, companies focusing on lower potency drugs are exposed to more competition and possible over-capacity in some galenic forms.

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Galenic form: Demand is rising for sophisticated, specific galenic forms such as liquid stick packs, blow fill seal, multidose preservativefree drops, pre-filled syringes, aerosols and other forms combining the drug with the delivery system, because they provide a range of benefits, including optimal drug efficiency, improved adherence by patients, safer use and limited side effects. These advanced forms are difficult to manufacture and not every CMO is able to produce them profitably. One example is preservative-free eye drops, which are seeing increased growth because they are safer for the cornea than multidose droppers containing preservatives and are cheaper than unidose packages. However, they require an expensive, highly customised production line that acts as a barrier to entry for many CMOs and keeps demand ahead of supply.

Companies focusing on the most common, traditional galenic forms, such as tablets, have to deal with overcapacity in the market, especially if they don’t have a robust product segment strategy.

Fig 2

Multiple specialisations as the path to success Specialising in a single segment can mitigate the risks, but cannot eliminate them altogether, so successful CMOs often have multiple specialisations to insulate them against individual market risks.

Having only a limited share of sales dependent on the product ‘at risk’ gives the CMO enough time to find other ways to fill its production lines, but developing multiple areas of specialisation is no simple task.

To successfully diversify risk, areas of specialty have to be uncorrelated, which implies limited synergies, increased investment and the identification of appropriate commercial opportunities.

The growth of the outsourced manufacturing market shows no sign of slowing and the underlying drivers — a buoyant drug market, increased activity from generic players and more outsourcing — are all positive.

Navigating this market, however, is complex and market players will need to become more specialised and even multi-specialised in the years to come. For investors, the market growth offers attractive returns, provided there is a clear understanding of where a CMO’s competitive advantage lies. Where expertise is developed based on a careful read of the market, the rewards can be substantial.

Product life-cycle support: Some CMOs have built in-house development capacities which have allowed them to partner with generic drug companies in the development of generic formulations or with branded drug makers in the development of life-cycle management

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Specialising in a single segment can mitigate the risks, but cannot eliminate them altogether, so successful CMOs often have multiple specialisations to insulate them against individual market risks.

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ANALYSIS

Giving innovation a boost Dr Marisa Miraldo, associate professor in Health Economics at Imperial College Business School, London, discusses ways to accelerate innovation in healthcare for the benefit of patients, healthcare providers and industry.

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he decline in innovation in research and development (R&D) in the pharmaceutical sector is well documented. Over the past decade, only around a quarter of new drug launches in the UK1 and a third of new drug approvals in the USA2 have been truly innovative drugs (using a new approach to fighting disease).

This slowdown in innovation particularly affects diseases that are less profitable or more complex.

Mental health conditions like dementia and depression, for instance, affect almost 40% of the population but are facing a critical shortage of new treatments.

A boost is needed To make substantial advances in tackling disease and improving public health, a new approach is needed to boost innovation in areas of critical need, whilst reducing the complexity and cost of drug development. Currently, fewer than one in 10 drugs tested in clinical trials ever makes it to market, and it costs over $1 billion and takes around 12 years to develop a new medicine.

Ultimately, however, the acid-test of an innovation is the impact it has on public health.

Ensuring an innovative treatment is widely adopted by the medical community remains a fundamental challenge.

To tackle these challenges, the main focus has been on understanding the factors that influence innovation success or failure in the R&D process, and on identifying strategies to promote the spread of innovation in clinical practice.

A global study has analysed R&D activity data for 62 countries across most disease areas. This has helped researchers to understand how and why healthcare innovations succeed or fail in the clinical phases from discovery to market launch. For example, it has been found that new drugs with considerable competition in the R&D pipeline are more likely to succeed.

Conversely, competition pressure from products

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already established in the market leads to a greater likelihood of failure in the early stages of R&D. What’s more, companies who have forged strong collaborative models appear to do better in phase I and II clinical trials.

For example, research is underway at Imperial College to examine the factors that influence the uptake of innovative cancer treatments in UK hospitals. In interviewing senior surgeons, it was revealed that, rather than being due to the practices of specific hospitals, it is often the knowledge and attitudes of individual surgeons as well as their networks that affect the uptake of innovative treatments. Most surgeons appear to be resistant to innovation because of a lack of supportive evidence from randomised trials. To increase uptake, more information from industry on the availability and use of new treatments and therapies is required.

Better collaboration, key to success New framework Much progress is being made by researchers to develop a new framework3 for evaluating and pricing drugs that is meaningful to society and properly rewards innovation. This requires a broader approach to assessing a new drug’s value, using factors that go beyond clinical benefit and cost effectiveness to include dynamic efficiency. These additional criteria should reflect both the current and future benefits to society, and the preferences of future generations in tackling different diseases.

An innovation that is not quickly embedded in health systems and clinical practice is essentially a wasted innovation. So, another area of research has been to investigate how the uptake and spread of innovations are shaped by factors within healthcare systems, such as collaboration and competition between hospitals, formal and informal networks of clinicians, and attitudes to best practice guidelines.

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Research is providing valuable drivers and barriers to innovation in healthcare. The key to success is better collaboration between industry, regulators, doctors, and hospital managers.

This will drive rapid and widespread uptake of innovative treatments, and ultimately ensure that treatments reflect the latest medical knowledge and that patients with the same condition receive the same standard of care.

Moving forward, further practical ways are being developed to boost innovation in healthcare — for example, creating R&D incentives for industry in areas of high patient need, and developing initiatives to promote rapid uptake by clinicians.

This work will help to bring a step change in the standard of healthcare.

References: 1. http://bmjopen.bmj.com/content/4/10/e006235.full 2. https://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DrugInnovation/ ucm534863.htm 3. https://spiral.imperial.ac.uk:8443/ handle/10044/1/42922

OPINION

With bated breath As pharma anticipates the forthcoming Brexit negotiations and future uncertainty, Stephie Castling, senior marketing executive from Denny Bros, examines the regulatory concerns coming to the fore in the industry.

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s the country holds its breath over Brexit negotiations and an uncertain future, the pharmaceutical industry is understandably starting to ask questions.

One of the current concerns is around the future of the EU’s Falsified Medicines Directive (FMD).

The directive has been on the table for a number of years now as a crucial way of preventing fake drugs getting through the system. In early 2016, the European Commission published The directive is a delegated regulation still clear and that enforces two safety features be placed on the makes perfect packaging of most human sense in the medicines by no later than fight against 9 February 2019. These counterfeiters. two features are a unique It is still relevant identifier — namely a twoand should still dimension barcode — and an anti-tampering device be adhered to and both will guarantee regardless of the authenticity of medicine the political for the benefit of patients landscape. and businesses alike.

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Prior to the Brexit vote, the progression towards compliance with this delegated regulation was going smoothly. My hope is that this will not change.

Earlier this year, we were hit with the news that the European Medicines Agency (EMA), the watchdog for

approving and monitoring the safety of drugs across the continent, was preparing to leave London in the wake of Britain triggering the process to exit the EU — Article 50.

Uncertain times in one way, but our message is a far more certain one.

Is it still applicable?

Over the last few months, I have heard a few whispers questioning whether the EU FMD would still apply when Brexit negotiations are complete!

From our point of view, we shouldn’t be worrying about politicians around the table. The directive is still clear and makes perfect sense in the fight against counterfeiters. It is still relevant and should still be adhered to regardless of the political landscape.

My hope is that most companies will continue with the directive’s guidelines. Against that, our worry is that some won’t prioritise this as much as they should, that they will hide behind the Brexit negotiations and put off taking action until much nearer February 2019.

This would be wrong on so many levels.

With many solutions in the offering for companies to assist in regulatory compliance there really is no excuse for a last minute panic. At Denny Bros, for example, we provide a range of pharmaceutical labelling solutions that support compliance with the EU FMD, including tamperevident labels and the ability to incorporate a unique serial number to identify and authenticate individual products.

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The directive provides a perfect platform against fraudsters with the unique identification code logged onto a central database by the manufacturer and medicines verified at the point of dispensing across Europe.

It is obviously going to help companies, both in terms of profits — through a better inventory and the ability to streamline a product — but also, most importantly, it will prevent fakes from getting onto the market.

We shouldn’t be adopting a wait-and-see approach and I remain confident that the majority of companies will act now rather than wait for the future.

Challenges and concerns Like with so many walks of life, Brexit will continue to pose challenges and concerns in the coming years.

For one, health secretary Jeremy Hunt has indicated that he expects that the UK will leave the EMA organisation — a move that has led some to believe it will have a detrimental effect on British pharma. However, that is an issue that may have to wait for another day with so many unanswered questions remaining about the UK’s future relationship with the EU. Regardless of the future, the standards set out by the EMA should be adhered to for safety reasons and common sense business practice. The same very much applies to the EU FMD.

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08.06.17 15:30

REGULATORY AFFAIRS

A changing landscape Dr Prashanth BSB, head of safety and medical writing for ELC Group, talks to EPM about the ramifications Brexit may have on the pharmacovigilance landscape.

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he legal framework of pharmacovigilance (PV) for medicines marketed within the EU is provided for in regulation (EC) no 726/20041 with respect to centrally authorised medicinal products, and in directive 2001/83/ EC with respect to nationally authorised medicinal products (including those authorised through the mutual recognition and decentralised systems).

The EMA has also released good PV practice guidelines (GVP)2 to facilitate the performance of PV activities. These GVP modules replace the volume 9A3 guidelines.

The EMA requires that all applicants name a qualified person for PV (QPPV), and set up a PV system master file (PSMF) that describes all aspects of their PV system. The GVP also details requirements for signal detection and management, literature screening and risk management, with requirements which are often more stringent than FDA regulations.

The EMA (unlike the FDA), now requires all serious adverse events — both those labelled and those unlabelled — to be submitted within 15 calendar days to the EMA and other national regulatory agencies, as well as submission of all case reports of non-serious adverse events within 90 calendar days of receipt by a marketing authorisation holder.

In the US, all pharmaceuticals, including drugs and biologics, as well as medical devices, are subject to federal regulations, enforced by the Food and Drug Administration (FDA).

During clinical development of a product, the FDA is focused on development of a safety profile and requires, similarly to Europe, the submission of expedited reports for serious and unexpected adverse events and confirmed signals occurring in association with the drug or biologic under development.

Unlike Europe, the FDA is focused on new molecular entities and on serious and unexpected adverse events occurring after marketing. Also, unlike Europe, not all newly approved pharmaceuticals are required to have a risk management plan in place at the time of marketing.

The FDA has a robust signal detection programme in place, and pharmaceutical companies and manufacturers of medical devices are subject to these regulations.

Brexit On 29 March 2017, the UK government served formal notice under Article 50 of The Treaty on European Union to terminate the UK’s membership of the EU. Based on Article 50, the EU Treaties shall cease to apply to the UK and the UK exit will take effect in March 2019 (subject to the unlikely possibility of the withdrawal agreement being concluded sooner and unless all member states agree to extend the period).

In October 2016, the prime minister further announced plans for a repeal bill.

The proposed effect of this bill is to convert the current body of EU law into British law.

The intention is that this will mean more ‘business as usual’ as the same rules and laws will apply to businesses and workers after Brexit as they did before.

life sciences sector are likely to be substantial.

This is because the UK would no longer keep access to many of the benefits of the EU system, such as the centralised procedure for marketing authorisations, the EU portal for clinical trials and the PV database.

Pharmacovigilance The EU PV system is coordinated by the EMA, which will need to be relocated from the UK following Brexit. UK companies will therefore need to revise their PV reporting system as a single person cannot perform the PV function for the EU and UK, and as the appropriately qualified person should both reside and operate in the EU. Furthermore, uniform product safety laws, as applied currently across the EU [e.g., the general product safety directive (2001/95/ EC)], are likely to continue post-Brexit in common with those of the EU and globally, so as to maintain the competitiveness of UK goods and suppliers.

It is still, however, uncertain what the exact ramifications of Brexit are going to be and we therefore suggest the best policy at this time is to be prepared by keeping up to date as the process develops.

References:

However, notwithstanding the effect of the repeal bill, of arguably greater importance is the current position of the UK not to be part of the European Economic Area (EEA) postBrexit. As the UK does not intend to remain in the EEA or be part of the European Free Trade Association (EFTA), the effects on the

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1. http://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=CONSLEG:2004R0726:20120702:EN:PDF 2. http://www.ema.europa.eu/ema/ index.jsp?curl=pages/regulation/ document_listing/document_listing_000345. jsp&mid=WC0b01ac058058f32c 3. http://ec.europa.eu/health/documents/eudralex/vol9_en

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REGULATORY AFFAIRS

Outside support

Dr Rajendra Wable, subject matter expert-medical writing and regulatory affairs at Sciformix Corporation, discusses how marketing authorisation applications across Europe, Australia and other countries can be supported with non-clinical overviews.

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he origin of the non-clinical overview (NCO) is from the twin

As companies’ internal teams do not have the capacity to sustain their

directives 75/318/EEC and 75/319/EEC issued on 20 May

clinical regulatory writing and submission work, outsourcing these

1975. Directive 75/319 article 2 indicates that the marketing

processes to an external provider can be a cost effective and flexible

authorization application should provide an assessment of the

option to author NCOs as part of the CTD dossier submission (CTD

pharmacotoxicological data and annex of directive 75/318 refers to

Module 2.4). NCOs look primarily to provide integrated and critical

such assessment as an ‘expert report’.

assessments of the pharmacologic, pharmacokinetic and toxicologic

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evolution of the active ingredients.

Today much care and resource must be applied to non-clinical data to ensure that the three elements of overview, written summary and tabular summary tell the same story and give the same interpretation,

The evolving regulatory landscape

especially if the authors of each part are not the same.1 As such, the complexity of regulatory writing is at an all time high, and the intensity

For any generic applications in the EU it is necessary to show that the

and skill level required is constantly expanding.

finished product in application is essentially similar to the innovator finished product, as required by directive 2003/63/EC annex part II(2)

Furthermore, over the past decade regulatory submission requirements

(b).2 This is so that all pharmacotoxicological information and clinical

have grown substantially, in part due to the increased product registrations

experience data can be transferred from the innovator product to the

in the EU, Australia and other countries. Many organisations from small

generic product for this application, provided through submitting NCOs.

to the top pharmaceutical companies struggle to fulfil their non-clinical

12

regulatory writing and submissions in a timely manner and therefore

Many other health authorities have similar requirements including, TGA

require assistance from external sources.

(Australia), MCC (South Africa) and LATAM countries (Brazil, Mexico,

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etc.), to fulfil the criteria for generic marketing applications. NCOs are

Supporting client needs

also required to demonstrate a well-established use for a medicinal product, with acceptable efficacy and safety levels, as prescribed in Directive 2001/83/EC.3

FSPs can quickly establish teams of expert regulatory writers in toxicology and pharmacology, along with medical reviewers to support client needs. Once the vendor is familiarised with the organisations preferred

Challenges for pharmaceutical organisations

processes for NCOs a standard practice can be implemented and a template created, that will be accepted across all regulatory regions.

When authoring NCOs, the literature search and selection of

“

publications, to be included in the integrated assessment, can be a sticking point for many pharmaceutical companies.

Many organisations from small to the top pharmaceutical companies struggle to fulfil their nonclinical regulatory writing and submissions in a timely manner and therefore require assistance from external sources.

”

These templates should look to follow the requirements set out by the EU directives and the ICH, particularly for the overview of in-vitro and in-vivo non-clinical testing strategies, primary and secondary

A literature search is often a lengthy

pharmacodynamics, safety pharmacology, pharmacokinetics and

process due to the sheer amount of

toxicity data in various animal species like rats, mice, dogs, rabbits

safety and efficacy data available for

and cynomolgus monkeys.

well-established generic molecules.

However, by using a functional service

NCOs look to include important information for the reviewer on the

provider (FSP) to undertake these

safety of excipients and the impurities in the product. Additionally, a

activities a pool of highly-skilled and

summary highlighting important safety topics and how the information

knowledgeable resources is readily

supports safe use of the products as per the proposed product label or

available. Additionally, FSPs generally

the summary of product characteristics (SmPC) should also be included.

have access to widely acceptable literature search tools like Embase, Medline as well as some specific

toxicological databases like Registry of Toxic Effects of Chemical

In summary

Substances (RTECS), the Hazardous Substances Data Bank (HSDB), Developmental and Reproductive Toxicology Database (DART), and

For pharmaceutical companies to achieve 100% compliance with

Chemical Carcinogenesis Research Information System (CCRIS), etc.

NCO requirements for their entire generic product portfolio utilising an external provider can be a cost-effective approach.

After the NCOs are authored they need to be reviewed by an external

“

independent non-clinical expert who provides the declarations (CTD

With the ever-changing regulatory landscape, by choosing to invest

module 1.4.2) which is to be submitted alongside the CTD dossier.

more resources to discrete non-core competence activities, a strong partnership can be built with a vendor that is able the assist through

For pharmaceutical companies to achieve 100% compliance with NCO requirements for their entire generic product portfolio utilising an external provider can be a costeffective approach.

”

Additionally, external vendors can spend

the whole authoring and submission process, using a flexible approach

more time analysing relevant regulations and

to adapt to individual companies’ needs.

recommendations of products for particular therapeutic areas by international societies when authoring NCOs. For example, in the area of antibacterial molecules, when authoring NCOs, recommendations from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are highly

References:

relevant to consider in addition to EMEA

1. International Pharmaceutical Product Registration, Second Edition. Edited by Anthony C. Cartwright and Brian R. Matthews CRC Press 2009

regulations.

2. Official Journal of the European Union — commission directive 2003/63/EC. 2003

With their additional resources FSPs are able to maintain high quality reporting within agreed timelines for volume surges of up to 200%.

(Internet) available at: http://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/ dir_2003_63/dir_2003_63_en.pdf [accessed 23/05/2017] 3. Official Journal of the European Union – Directive 2001/83/EC of the EU Parliament and

Finally, additional time can also be spent assisting in drafting responses to

of the council of 6 November 2001 on the community code relating to medicinal products

questions from health authorities, such as requests for supplementary details

for human use. (Internet) Available at: http://www.ema.europa.eu/docs/en_GB/document_

about specific non-clinical testing issues, or biological characterisation

library/Regulatory_and_procedural_guideline/2009/10/WC500004481.pdf [accessed 23/05/2017]

of impurities.

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COVER STORY

A smooth transition Speed to market is a significant concern in tablet manufacturing, however, moving too quickly may cause problems, delaying production.

Here, Dr Charles Kettler (director, Natoli Scientific) and Robert Sedlock (director of technical training and development for Natoli Engineering with over 20 years’ experience in the tablet compression industry) reveal anticipatory experiments to help make the transition from R&D to full scale as smooth as possible.

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significant concern in tablet manufacturing is speed to market. Moving too quickly, however, may cause delayed production, lost product and missed deadlines. To reduce potential headaches, companies are embracing the principles of quality by design (QbD) and using automated data gathering and tablet analysis during research and development (R&D).

This allows organizations to reduce product development and delivery stress and loss.

Even under ideal circumstances, tablet development will encounter unknown variables before a final product is realised. To reduce problems, performing several simple experiments and creating characteristic profiles enables R&D and production to accurately evaluate new drugs as oral solid dosages. Experimental data is used to characterise formulation performance with both patients and manufacturing organisations as ultimate customers. Understanding these compaction and compression characteristics is fundamental because they often drive changes in production requirements.

These anticipatory experiments result in less formulation changes prior to full-scale production. Changes to production-ready formulations are the costliest and most time consuming as they must meet FDA scale-up and postapproval changes (SUPAC) compliance or other regulatory guidelines.

The pharmaceutical industry benefits from using vendor partnerships for troubleshooting techniques and solutions. A quality tooling vendor can provide help to prevent tabletting issues with information provided in compactability, tabletability and compressibility profiles. The study completion and analysis outlined in this article also provide smoother transitions from R&D to fullscale production.

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Gathering powder performance data with single-station presses Single-station tablet presses offer crucial advantages during new tablet early formulation and pre-clinical development. When using a single-station press, operations that would otherwise occur automatically are performed manually, such as blending and the die filling process.

The advantage of a single-station press is it allows R&D scientists to perform tabletting studies on the active pharmaceutical ingredient (API). Having this data can assist in excipient selection. Use of these tablet presses also makes it easier to perform formulation studies. Each of these studies work harmoniously to provide data about a tablet’s planned components and how well they consolidate and compress.

Compactability profile This profile illustrates how readily a material undergoes changes in volume when compressed.

It is a measure of how a powder can be changed into a tablet and the resulting strength of the tablet. A simple plot of compression force against the resulting tablet’s breaking strength is often referred to as a manufacturability plot.

To compare various sized tablets, the compaction pressure is calculated by using applied force and punch cup area. A tablet’s solid fraction is an important parameter because small changes in solid fraction can impact tablet properties. Figure 1 illustrates a compactability profile for two excipients and a blend of the two generated on a

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single station tablet press. The three samples have a magnesium stearate level of 0.5% for lubrication.

Tabletability profile To better understand tablet tensile strength’s relationship to force used in tablet compression, it is vital to plot the tablet tensile strength against compaction pressure. Both variables are normalised to the tablet area to facilitate comparison of tablets of different size or tablets compressed on other tablet presses.

In the tabletability profile in figure 2, we see a typical formulation profile compressed on a single-station press. Each formulation contains a high drug load; one is a direct blend recipe and the other a wet granulated drug product. Tablets with a tensile strength of greater than 2 MPa are desired and as neither formulation is found to form a suitable compact at any pressure between 50 MPa and 300 MPa, further study should occur before expending efforts on a rotary tablet press.

Figure 3 illustrates the tabletability of the three samples measured for figure 1. It is clear that microcrystalline cellulose (MCC), with 0.5% magnesium stearate, provides the strongest compact. This is due to the MCC plastic deformation characteristics. The lactose monohydrate, with 0.5% magnesium stearate, also provides a robust tablet at reasonable compaction pressures. By blending the two excipients, it’s possible to add functions to the formulation’s performance, including plastic and brittle deformation characteristics. A 3-to-1 ratio of lactose-to-MCC provides a slightly stronger tablet than one made from pure lactose.

Compressibility profile The compressibility profile illustrates how readily a material undergoes volume changes when compressed, and affects tablet properties like dissolution, hardness and friability.

Analysing tablet compressibility data will ensure the tablet quality throughout the R&D and manufacturing processes.

Figure 4 shows the compressibility profile of the same excipients as figures 1 and 3.

Importance of the rotary tablet press in R&D The use of a rotary R&D press is the next step in planning tablet compression scale-up to meet client needs. Integrating this step into tableted product development allows additional study completion, and provides data at larger scale production, which can be used for further scale-up and production considerations.

As previously shown in figure 2, there is a stark contrast between compaction profiles of the direct compression blend compared to the wet granulation when completed on a singlestation press versus a rotary press (as presented in figure 5). The differences in moving to a large press with 30+ tooling stations will significantly change the compaction process even further. These changes can occur due to the pitch circle diameter of the tablet press turret,

increases in the tangential punch velocity and decreases in compression dwell time.

A simple strain rate study helps determine whether a blend produces an acceptable tablet at various turret speeds and dwell times. Figure 6 reveals that the strain rate-sensitive formulation will need almost twice the dwell time to produce a quality tablet compared to the wet granulation. With respect to API, completing these tests can be costly so what can be done to reduce these costs? Discuss tablet compression tooling options with reputable vendors. Tooling manufacturers offer modifications that may reduce or solve the problem of reduced strain rate.

Other areas to review: Communication and tooling Gathering and analysing data is important but lack of communication between departments is often an additional cause of missed deadlines. Strengthening communication and common goals relieves pressure from different areas to fix problems that may have gone otherwise unnoticed. Communication should remain open throughout the entire process — from R&D through final production. Strain rate studies may reveal potential issues with a production department’s ability to manufacture the desired number of tablets due to formulation issues, which may need to be addressed via compression tooling modifications.

Tooling vendors are an excellent resource for troubleshooting formulation issues so it is important to communicate issues as they occur. Formulation issues which cannot be changed due to regulatory implications may be resolved by a quality tooling vendor early in the process.

As some APIs are prone to sticking and picking issues, a tooling vendor should have a strong working knowledge of different steel types. By carefully selecting tooling steel, sticking and picking issues may be alleviated without using expensive coatings.

For example, tools with high chromium concentrations in the alloy — 16–18% — can enhance the release of tabletted materials. Other specialty steels enhance performance needs like even wear, corrosion resistance, or better compressive strength. Tooling modifications may also be a viable option. For example, both TSM-B and TSM-D tools can be manufactured with an increase in head flat diameter to increase dwell time.

This allows an improvement in tablet press speed, increasing production.

Formulations with a significant quantity of fine particles are prone to powder sifting between the punch tip and die bore. This results in excess heat generation which can initiate sticking and picking as well as cause binding of the lower punch in the die. Fixes may include machining a narrow tip width and deeper sharp relief for lower punch tips, which can help scrape excess powder from the dies.

Many picking issues are preventable, and may come from tablet design. Embossing design is a common culprit with problematic font selection, font size, location on the tablet surface and engraving cut depth or angle. Compound cup configuration, using practical font selection, incorporating pre-picking and character tapering can reduce the probability of picking prior to a product run.

With the emergence of better information gathering techniques, the inclusion of data analysis must become part of the process for acquiring QbD information. The tooling vendor remains the best resource to contact when problems are encountered that may be addressed by minor changes in tablet design or tool configuration. However, use of the tabletting profiles mentioned will aid in building suitable drug product component profiles that comprise much of a company’s tabletted products. As the profiles stated in this article are generated, gathered and catalogued, R&D scientists, production managers and others involved in submitting new drugs for review will be better equipped to make tablet design and formulation decisions with less outside consultation.

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15

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CLINICAL TRIALS

A model fund?

In this article, Ben van der Schaaf, principal at Arthur D. Little, gives a five-step guide to explore possible funding partnerships for lower-priority drug trials — a new model for big pharma.

T

oday’s clinical trials can cost biopharma companies upwards of $100 million1 before they even begin to consider additional investment in marketing and distribution of new life enhancing therapies. For those major drug companies that spent the last decade building a robust pipeline of early stage compounds and indications, these skyhigh development costs mean they have a wide portfolio of potential assets without the resources to get them through trials.

The result? Pharmaceutical businesses with strong R&D pipelines are losing billions each year in potential revenue while promising new therapies lay dormant, waiting for patents to expire.

Innovative big pharma strategists are looking to a new partnership model to claw back some of these costs, and allow more new therapies to proceed to the development and clinical trial stage.

Working with CROs, universities and patient advocacy organisations, drug makers can identify investors who see the value in their promising compounds and indications, and will provide the capital and share the risk involved in getting new therapies through the development stage, regulatory approvals and launched to market.

trials will attract external investors and be profitable once in market. Trials need to be relevant and complementary. Relevance of a trial is based on its potential market demand, and will predict the value of the development asset it gains regulatory approval.

Packaging several trials in the same therapy area is attractive for investors and will reduce upfront costs. Even trials in the same therapy area need to be complementary — geography, indication, trial duration, patients, etc. — to realise operational advantages and identify the right CRO to execute them.

The partnership must demonstrate a real transfer of risk if it is going to help the drug maker develop its assets without adding development costs to its bottom line. That means that actual risk needs to transfer from the biopharma company to other parties. A clinical trial with a 95% probability of success would not satisfy this requirement, as it would just be a financing arrangement packaged as an investment.

in biopharma, non-profit organisations and patient groups with a focus on a specific therapy area, or other investors with interest in a specific disease area or public health issue.

3. Establish an operating model and structure Once partners are committed to the project, the next step is to develop a legal structure and financing arrangement. The new entity could be a joint venture or special-purpose entity, established solely to operationalise and manage the execution of the included trials, with governance by representatives from all partners.

Setting clear goals for each partner and performing a full risk assessment are key steps to ensure the new organisation’s success. The risk assessment must include thorough due diligence and a well-defined exit strategy that ensures all partners agree the potential outcomes and have clear roles in delivering the final goals.

2. Attract partners

4. Operationalise and execute For the next two–four years this new entity will work to complete development on the selected potential therapies. This requires establishing processes and roles upfront to ensure efficient and effective operations.

Consider the following four areas before operations begin:

1. Identify relevance

A successful partnership will bring together the biopharma’s science and data; the CRO’s trial operation capability and capacity; and the investors’ funds, along with their knowledge of structuring and exiting these types of transactions. Finding the right CRO will be based on their location, track record and expertise in the relevant therapy area.

When reviewing the portfolio of deprioritized new therapies, drug makers must make tough choices about which clinical

Finding the right investors takes careful targeting and multiple approaches. These could be venture capitalists specialising

Finding partners to fund lower priority drug trials takes careful planning. Consider this five step investment roadmap as a guide.

a) Technical — have you established a protocol that can deliver the clinical data required to support an increase in product value?

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b) Commercial value — is the market assessment valid, and is there real revenue potential for the drug(s) coming out of it? c) Operational — are the trials in question designed in such a way they can be executed efficiently and on time, to deliver the necessary cost savings?

Are the proposed trials operationally complementary? d) Cultural — have the partners agreed shared norms and working arrangements that will ensure successful progress and a clear exit once the investment value has been realised?

5. Exit Partnerships must have a clear, pre-agreed process for closing out relevant trials, realising value for each partner in line with the contract, and effectively dispersing or disposing of accrued assets.

The pharmaceutical industry has a proven track record working in partnership at the drug discovery and marketing and distribution stages. Extending the partnership model to funding clinical trials is a natural next step for those drug makers with robust R&D pipelines, and will result in improved value creation for companies and improved quality of life for patients.

Reference: 1. https://aspe.hhs.gov/report/examination-clinicaltrial-costs-and-barriers-drug-development

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CLINICAL TRIALS

Better together Jennifer Goldsmith, senior vice president of Veeva Vault, examines why industry collaboration holds the key to faster clinical trials

A

s the clinical trial landscape becomes increasingly complex, the life sciences industry is supporting broad collaborations to define and implement common approaches that make running a trial easier. These collaborations are becoming a strategic priority for many companies hoping to create greater efficiencies in the race to deliver innovative therapies, drugs and medicines to market.

Centralising information-sharing and establishing an easy, consistent process for document access and information exchange can dramatically reduce administrative burden and increase operational efficiency in trials.

In addition, companies gain visibility across all of their studies, and investigator sites can have a consolidated view across multiple trials with multiple sponsors. This level of visibility wasn’t possible before within SIP.

There is a growing imperative across the industry to collectively define approaches that could create greater efficiencies in trial processes, especially as sponsors increasingly outsource their research and development (R&D) work to CROs. With more stakeholders in the mix, as well as different processes and systems used across the clinical trial ecosystem, the ability to share information and make timely decisions has become burdensome. For example, study teams regularly use manual processes to manage documents and data — often sharing information via email — which limits collaboration, creates redundant work, and significantly lengthens trial timelines.

A centralised model of information exchange is a good example of how the life sciences industry is transforming the clinical model in four key areas:

To address some of these challenges, TransCelerate BioPharma (a nonprofit organisation) has introduced the Shared Investigator Platform (SIP) initiative, with the aim of providing the industry with a centralised platform that is focused on collaborating with investigational sites and interoperable with various clinical solutions. The SIP’s goal is to streamline communications between investigators and sponsors, and reduce duplicate information requests during trials.

As part of this effort, the cloud-based content management solution, Veeva Vault SiteExchange, will be integrated with the SIP to enable clinical teams to access and exchange information with sites before, during and after trial execution. The cloud application will help sites consolidate study-document requests, alerts and notifications.

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Creating a universal and flexible operating model.

Enabling a collaborative clinical ecosystem.

Gaining better insight from metrics and measurement.

Shifting to modern, unified systems.

Standardising on a common operating model Creating a common framework that standardises trial processes, while still enabling flexibility to support individual study needs, will help to eliminate the rework that takes place with each new trial and reduce the time to full study optimisation.

To date, rigid information systems have exacerbated the challenges to embracing a common model because they limit the flexibility of business processes and force people to find workarounds to complete their tasks at hand. For example, today’s trials require more data collection and protocol amendments, and include novel therapeutic areas and multiple partnerships. Clinical study teams must often adjust to mid-study changes,

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and if the systems they work within are not flexible enough to easily accommodate change of any sort, people revert to managing activities and tasks outside the system, creating manual processes and information silos, which can extend the duration of a trial.

A common industry process for exchanging documents and information can drive significant operational improvements in running trials, reduce the need to seek non-standard workarounds and, ultimately, speed time to market. Access to information on one centralised platform means investigator sites no longer need to log in and out of multiple systems to share important information with sponsors. Sponsors also gain a complete view across all their studies, and can post and retrieve documents quickly and easily.

Improving collaborative processes Operational and information silos between functional areas, as well as sponsors and partners, have historically made collaboration difficult. As clinical trials expanded in scope and complexity, sponsors built dedicated teams internally, with specialized functions to handle specific parts of trials.

Teams drove toward efficiency in their areas of specialisation, with limited visibility into end-to-end trial processes and inability to conduct effective handoffs between groups.

Similar challenges exist between sponsors and partners. Each commonly has its own processes and systems in place, making information difficult to access and harder to share.

The growing call for information to be shared across both company and geographic lines is driving the need to collaborate and contribute information that can be easily accessed and disseminated.

Linking all stakeholders together on a common platform provides greater visibility — and greater collaboration — across the end-to-end trial process. Enabling real-time access to information, and the ability to transfer knowledge more easily, engenders trust that all parties are working towards the same goals and outcomes.

Enabling better metrics and measurement Visibility into how trials are performing relative to other studies is another common challenge among investigators, sponsors, and CROs. Lack of comparable data makes it tough to judge what is working or how to improve trial performance.

Increasingly, sponsors and CROs want to have single, consolidated views of their clinical trials across their portfolios, regardless of which specialised providers have participated in contributing data or documents to trials.

However, inconsistent metrics and varying means of measurement often make it impossible to harmonise the data to gain the insight they need.

Investigators typically deal with multiple sponsors and requests for documentation and information, which they manually track. When the collection of documents and the data around these documents is easier to manage and track, sponsors can better understand the progression of their trials and where delays may be occurring. Sponsors can also benchmark their trials as they relate to the timeliness and quality of how sites are executing.

Setting common operational metrics and measurements is an important aspect of a more unified, collaborative clinical landscape. A standard

set of metrics and measures improves the ability to extract quality insight and identify trends across the industry. For example, a clinical team can determine whether a problem is isolated to one study, one site, one therapeutic area, or another common denominator. This type of information then becomes a strategic asset to perform predictive analysis across multiple sites and studies, using real-world evidence and historical operational metrics to better inform trials moving forward.

Modernising and unifying information systems Limitations in available technology created the silos that companies are now trying to eliminate. Systems were implemented to support specific functional activities, not end-to-end trial processes. As a result, most clinical teams work in many different systems, and often without the benefit of direct collaboration between teams, either internally or externally. The systems also have Collaborations are very different purposes. While one system building greater manages content, another manages the data understanding being produced. Therefore, content and data among clinical trial are collected and managed from multiple sources, even though the information is all stakeholders, and the industry is focused associated with the same study.

“

on finding new ways

Now life sciences companies are bringing of working together together previously disparate systems in the for the benefit of cloud to support the end-to-end trial process. the patient.

Open APIs, standards and emerging native cloud solutions allow companies to better support a unified clinical environment and sustain collaboration among internal and external partners. In addition, next-generation cloud applications can manage both content and data to eliminate information and process silos. Clinical information systems that are inherently integrated by leveraging a single platform will be essential to propelling the industry toward a unified clinical environment.

”

Groups are also establishing approaches to facilitate better engagement and collaboration between sponsors and their partners by using technology platforms. Now clinical and other functional groups can access much of the same information and data throughout the drug development lifecycle with cloud technologies and sharing tools, helping to foster more collaborative working processes. The flexibility and collaborative nature of next-generation clinical systems creates an environment where people are enabled to work within their processes, as well as ensure information can be traced and viewed across the trial.

Collaboration and the cloud Collaborations are building greater understanding among clinical trial stakeholders, and the industry is focused on finding new ways of working together for the benefit of the patient.

With a common framework supported by technologies designed to enable greater sharing and information exchange, collaboration among sponsors, CROs, IRBs, investigator sites, and others in the trial process, becomes easier.

Cloud technology is helping to drive the transition from traditional operating models to more efficient, agile and collaborative processes — empowering life sciences to innovate faster and accelerate drugs to market. That’s a breakthrough for the industry and for patients.

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19

CLINICAL TRIALS

EYE ING UP ADHERENCE A recent partnership to address the challenge of monitoring adherence in ophthalmic clinical trials was formed between Aptar Pharma and Kali Care.

Here, Sina Fateh, MD, founder and CEO of Kali Care and Sai Shankar, director, Business Development — Connected Devices, Aptar Pharma, discuss this alliance further.

P

atient adherence to therapy is a long-standing issue across the full spectrum of the healthcare industry. According to the World Health Organisation a mere 50% of patients in developed countries with chronic disease are adherent to their therapeutic regimen.1 This lack in maintaining a prescribed therapeutic schedule leads to medicines being less effective than anticipated and a significant increase in financial burden on national healthcare systems.

One such area where adherence to a therapeutic regimen is vital is in a clinical trial. The expense of a trial means that should the patient population not follow the recommended schedule of treatment they will be deemed as unusable in the clinical write up. This in turn means that more patients will need to be sourced and the trial process started anew.

With soaring clinical trial costs and complexity, numerous industries are constantly seeking new approaches to improve efficiency and productivity, to get to commercialization sooner and for less cost.

Ophthalmology is not excluded from this and given the fact that we have a globally ageing population, most of whom will need some form of eye care (glaucoma, posterior segment, cataract recovery, for example), patient adherence at the clinical stage and thereafter is of utmost concern.

By replacing usage assumptions and self-reporting the monitoring system improves accuracy and time efficiency in clinical trials. The Kali Care system manages this through integrating smart sensors, data analytics and cloud services.

Helpful for eye care and beyond This partnership addresses the megatrends in the pharmaceutical industry, which includes precision medicines, outcome based insurance payments and comparative effectiveness research. All require objective adherence data, targeted delivery and personalised messaging.

In the ophthalmology space specifically, any eye disease requiring an eye drop can benefit from the Kali smart system. Beyond eye care, this technology can also be applied to other drug delivery routes of administration such as topical dermal and nasal.

Challenge of adherence in ophthalmic clinical trials

Through this partnership, it is hoped that Aptar’s regulatory expertise can help to move Kali Care forward through approval and compliance processes. Aptar’s ophthalmic device knowledge and ability to support complex projects in addition to Kali Care’s monitoring technology will be applied to packaging for clinical trials.

To address the challenge of monitoring adherence in ophthalmic clinical trials Aptar Pharma entered into a partnership agreement with Kali Care,2 which is a technology based company based in Silicon Valley.

The first clinical trial incorporating Aptar Pharma’s drug delivery devices and Kali Care’s monitoring solution is anticipated within the second half of 2018.

When using eye drops as a drug delivery method, there are many challenges to overcome in relation to patient adherence. Will the patient remember to use the drop at the correct time/on the correct day? Will they apply the drop correctly, ensuring enough of the therapeutic content is administered?

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A way to more accurately collect patient adherence that is also done in a time effective way is obviously beneficial. To this end, Kali Care’s digital monitoring system has offered an innovative solution.

References 1. http://www.who.int/chp/knowledge/publications/adherence_report/en/ 2. http://kali.care/#empower

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CLINICAL TRIALS

Clear and clinical?

Bruno Speder, head clinical regulatory affairs & consultancy, SGS Life Sciences, gives an overview of new EU regulation 536/2014, introduced to provide a single European submission and approval procedure for clinical trials, and discusses the effects it may have on the performance and reporting of early phase clinical trials

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U regulation 536/2014 has been enacted to provide a new authorisation procedure for clinical trials in Europe. It will enable a single integrated regulatory authority and ethics committee submission for new investigational medicinal products to be made via a single European Medicines Agency submission portal.

The new regulation includes a twostep approval process, consisting of assessments of the scientific part of the submission file (part I) and of the local requirements of the application file (part II). The objective of this is to create a more streamlined submission and approval process and timelines for clinical trials while also increasing consistency for safety reporting requirements. Additionally, it will expand the scope of the EU’s EudraVigilance scheme, increase transparency and notification requirements for new drug approvals, and confirm the scope and modified definitions required for low-intervention trials and auxiliary medicinal products.

Online electronic submission of information will make the process simpler, with data and supporting material more transparent and easy to analyse. However, two areas that will be affected are approval timelines and transparency of the required data to be supplied.

Phase I trials Phase I clinical trials are designed to assess the safety and pharmacokinetics of investigational drug compounds and are conducted over a short time period in healthy volunteers, typically one– two months. Such trials can have very complex designs, are normally performed in a specialised clinical pharmacology unit at a single location, and require extensive logistical and planning procedures.

Delays to a regulatory approval could impact heavily on these plans.

Timelines for the review of data from such trials vary across the EU. Drug approval regulations currently in force in Belgium and the UK are very short, and specify a 15-day review period. Under the new regulation, these timelines will — in theory — be aligned with the standard EU timelines, but in practice the timelines for phase I single country trials will remain as is.

Identification and recruitment of suitable clinical trial volunteers can partly be performed using a generic screening process. As the new EU regulation 536/2014 defines the start of a clinical trial as the ‘first act of recruitment’ instead of ‘first patient first dosing’, which could eliminate the possibility of the use of generic screening. The new

regulation will allow for alternative ‘start’ procedures to be specified in the clinical trial protocol.

In addition to the notification of the start of a trial, the end of the recruitment period must be specified; as well as the end of the trial, any temporary halts and restarts of the research process, and any early termination of the trial. Serious breaches of regulatory procedures and unexpected events that occur during a trial also need to be reported and any relevant third-country inspection reports that are available must be included in the final report. However, any effects that this new regulation has on timelines for the overall drug development process from discovery to market are likely to be negligible.

Transparency requirements The EU’s transparency requirements for clinical trials are specifically set out in the regulation along with the form and content of information presented in published documentation. Among other details, this information includes the main characteristics of the trial, identification of the investigational medicinal products, treatment population and number of subjects, inclusion and exclusion criteria, and main objectives and endpoints. A published conclusion

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of the assessment and decision on the trial is also required, as is any information that has been updated during the trial in respect of the start and end dates of recruitment.

As Phase I trials are conducted with healthy volunteers, and not ‘patients’ as such, an increase in data transparency is not expected to have any effect on clinical trial recruitment. Requiring data transparency this early could deter companies from doing studies in Europe.

Not a lot will change for monocentred, single country studies in practice. In theory, there will be longer review timelines, however, several countries have indicated that for these types of studies they will keep the currently applicable timelines. The main issue will be the integration of the review by the Ethics Committee and making sure that the assessment is made by people experienced with the specificities of Phase I studies.

The major impact of the new regulation will be the transparency requirements, which will also be applicable to Phase I studies.

However, these transparency requirements are not fully compatible with the specificities of Phase I studies and could lead to losing the competitive advantage Europe offers as a place to perform these trials.

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COATINGS & CAPSULES

Coating compliance Jason Teckoe, technical director, Colorcon EMEA, discusses the important considerations when coating oral solid dosage forms

Considering coatings

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ablets remain the most common solid oral dosage form for many reasons, including ease of manufacture, convenience for the patient, accurate dose administration and good stability. Good ablet design can be used to provide product differentiation, avoid medication mix-ups and deter counterfeiting. It can also impact patient of coating compliance.

The choice depends on the chemical properties and chemical nature of the tablet’s core ingredients…

Every drug is different so there is not a ‘one-sizefits-all’ coating.

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So, what are the reasons for including a coating on an oral solid dosage form? Purely from an aesthetic point of view, uncoated tablets are undistinguished. In addition, a rough-looking tablet can appear to be of poor quality; not an attribute you want, especially in a medicine.

From the patient’s perspective, coating makes the tablet appear easier to swallow and aids in visual differentiation, thus reducing the potential risk of medication errors. Coating also reduces tablet friability and overcomes any damage or dusting issues often associated with uncoated tablets.

From a manufacturer’s perspective, the coating helps to protect the tablet, provide a desired release profile, mask the taste of a bitter drug, minimise the impact that environmental conditions may have on drug stability, extend the product shelf life, aid packaging and help differentiate the product.

Recent focus on medication errors has led regulatory bodies to consider tablet differentiation more prominently, encouraging manufacturers to think more about the patient’s perspective and whether they are likely to follow the recommended dosing regimen outlined in their prescription.

The FDA, for example, has released two industry guidance documents on this topic,1,2 intended to champion the patient’s perspective, improve patient compliance and medication outcomes. Adding a coating to a previously uncoated tablet would improve patient compliance and bring the tablet in line with the FDA’s recent recommendations.

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When beginning a project that involves a coating system, it’s vital to discern which considerations are important for your product. Selecting the right coating, however, can be surprisingly tricky, and getting it ‘wrong’ can impact patient compliance or even compromise drug efficacy by negatively affecting the drug release profile.

The core is key: The tablet core is key, as it’s the substrate the coating will be applied to; so, starting with a suitable surface is critical to achieving a good finished product appearance.

In solid oral dose development, compatibility of the active pharmaceutical ingredient (API) will drive the selection of the excipients. Excipient choices for a formulation are typically driven by functionality requirements and compatibility with the API. The choice of coating depends on the chemical properties and chemical nature of the tablet’s core ingredients, including the API or where it needs to be released in the body, sensitivity to the environment, and the physical properties of the API. Every drug is different so there is not a ‘one-size-fits-all’ coating.

API sensitivity: When coating an API that is moisture and/or temperature sensitive this presents physical challenges to overcome. To assist with these challenges, Colorcon offers specialist coatings such as Opadry QX that can be applied at high solids and low coating bed temperatures; whilst Opadry amb II, which provides moisture barrier properties, and is less prone to generating reactive impurities during accelerated storage conditions.

Coatings with a pH dependent release profile (enteric coatings) are typically used when a drug is acid labile, irritating to the stomach, or requiring targeted release in the small intestine for optimal bioavailability.

These coatings employ the use of a pH-dependent polymer such as a methacrylic acid copolymer, which is designed to remain intact and protect the tablet or multiparticulate dosage form in the lower pH of the stomach and dissolve immediately in the elevated pH of the small intestine.

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Special requirements: The paediatric and geriatric groups are specialized patient groups that have unique requirements related to product performance and differentiation.

For paediatrics, taste-masking and the ability to swallow medications is important, so liquid dosing, mini-tablets or multi-particulates are often used, as they provide easier to swallow dosages and allow for dose adjustment based on patient age and size.

In addition to dosing and taste-mask properties, manufacturers also need to ensure their coatings are safe for use in the paediatric population. They need to confirm the raw materials contained in the product are suitable and ideally have existing precedence-of-use in a relevant paediatric application.

Meanwhile, the growing number of elderly patients, with inherent polymedication challenges, points to a need for increased product differentiation based on size, shape and colour of tablets, to enable patients, or their caregivers, to know they have taken the correct medicine at the right time.

Odour masking: Some tablets also have a surprisingly bad odour, which can have a negative effect on patient compliance. If the patient has a poor impression of their medicine the moment they take it out of the packaging, it could be destined for failure.

Moreover, if patients get beyond the aesthetics and the smell, they often find that uncoated tablets are more difficult to swallow, as they can get stuck in the throat and start to disintegrate the moment they are exposed to moisture.

tion ula rm

In addition to the coating composition, the coating process parameters are also important. Ensuring good mixing and physical movement of tablets in the coating pan and optimizing the thermodynamics of drying for the product all play a significant role in achieving a high quality, uniform tablet appearance with the desired functionality.

Generally speaking, most Coating film coatings can be used in Quality continuous equipment, but some provide better results than others, with each having its own advantages and challenges.

HPMC systems have a higher comparative viscosity, which leads to a lower percentage of coating solids, around 12 to 15%. This reduces throughput rates and results in a narrower working window in terms of process parameters such as airflow and inlet temperature. PVAbased coatings which are used at around 20% solids, overcome this limitation and tend to work better at higher temperatures and airflows; both systems therefore provide challenges to attain optimal results for all tablets.

Co a t i ng Fo

Acetylsalycylic acid (Aspirin) tablets and proton-pump inhibitors (PPI) such as omeprazole, use an enteric coating like Colorcon’s Acryl-EZE, aqueous enteric coating system, to protect the patient from the drug and vice versa in the low pH conditions of the stomach.

& Equipm cess en o r P t

Tablet Subs tra te

To meet the industry’s need for faster and more flexible coatings, especially for continuous manufacturing, Colorcon’s Opadry QX, quick and flexible film coating, allows for a higher percentage of solids (up to 35%) and results in a smooth, uniform tablet appearance. But perhaps the most significant advance this coating offers is the manufacturing flexibility, as it works well with all equipment types across a wide range of process conditions. This is especially important as companies may move product between different manufacturing locations and equipment types can vary between sites.

A more palatable dose There are a few ways to try and make an uncoated tablet more palatable (e.g., adding colour, taste-masking ingredients or changing the shape to aid swallowing) but by far the simplest and most effective way is to add a film coating.

When considering coating an oral solid dosage form, try to remember the key aspects of the product’s core composition and how the coating can support and protect it while also creating an aesthetically pleasing tablet.

Probably, and most critically, think about the patient who will definitely appreciate a pill that is easy to swallow!

References: 1. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/ucm331810.pdf 2. https://www.fda.gov/downloads/drugs/guidances/ucm377938.pdf

Continuous processing Continuous processing is a growing trend in the pharma industry and being encouraged by regulatory agencies. This is not a new technology, but it is a new mindset for the pharmaceutical industry moving away from traditional batch processes.

The end goal of using continuous processes is not necessarily about achieving high volume throughput, but about adopting lean and consistent manufacturing processes that build quality into the manufacture of the product, rather than testing at the end of the process. One attribute that all continuous coating processes offer, compared to batch processing, is faster and more frequent presentation of tablets to the coating spray zone; this results in shorter cycle times to achieve consistent coating coverage.

Creating an efficient continuous coating process not only depends on the equipment used, but also on the formulation of the coating.

A wide choice of film coatings is available, based either on hypromellose (HPMC) or more recently polyvinyl alcohol (PVA) polymers and the choice will depend on the specific needs of the application.

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23

EMERGING MARKETS

Keep it simple ‘Advanced simplicity’ will drive growth for inhalers in emerging markets, Peter Schmelzer, CEO of H&T Presspart tells us more.

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he number of blockbuster respiratory products going off-patent has opened up opportunities for generic inhalers, and demand for asthma and chronic obstructive pulmonary disease (COPD) treatments is on the rise in the developing world, not just the mature markets.

Indeed, emerging markets clearly represent an area of unmet need when it comes to respiratory care.

In Latin America, COPD deaths have risen by 65% in the last decade,1 while in India, a recent study collecting data without spirometry assessment suggested that 12 million people were affected by the disease1 — in China, chronic respiratory diseases are the second leading cause of death.1 More and more people in emerging markets are entering the middle classes with new money and new demands. Also, as access to medication improves in developing countries, citizens and their doctors are demanding better treatments.

Growth opportunity We have seen that the generic capsule-based dry powder inhaler (DPI) segment in developing markets shows a lot of promise and demand is rising. However, when it comes to these products, patients in developing markets have not been best served by strategies employed by major pharmaceutical companies in the US and Europe, which have developed DPIs customised exclusively for one specific active pharmaceutical ingredient (API).

Global generic players also have customised devices for specific DPIs and have spent heavily in leading emerging markets. However, the healthcare markets in most of the fastest-growing economies in the developing world are highly fragmented.

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Local players make up a sizeable chunk of the market in developing countries, with well-established channels of generic production and distribution. We have also seen a number of new entrants coming into the inhaler field.

As such, there is a growing demand in the emerging markets for a DPI which can be used with a variety of API but is easy to use and affordable.

Companies who aspire to capture these growth opportunities must therefore ensure that they have functional excellence in place. Quality is critical when it comes to manufacturing not only APIs but also the components and delivery systems.

As well as manufacturing excellence, the firms that will succeed will be those that can accelerate the development, global scale-up and

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commercialisation of products for respiratory patients in the developing world. They will need to come up with designs that minimise manufacturing assembly and production costs, whilst maximising ease of use.

To address this challenge, H&T Presspart moved into the DPI space through a pact with Portugal’s Hovione. Through this partnership, we have launched PowdAir Plus, primarily designed as a ‘generically available’, customisable device for the developing world. It features an all-plastic, four-component design to keep costs low. It automatically opens the capsule once the tray is closed, removing the need for patients to pierce the capsule and reducing operational steps. By enhancing ease of use, the design also removes the risk of errors that may affect treatment efficacy.

Design features that help tackle the persistent issue of poor adherence are extremely important for asthma and COPD treatment. Despite significant advances in inhalers, many patients continue to experience poor disease control, with adherence being a key factor. According to WHO, patient adherence for those on long-term therapies for chronic diseases is only at 50%, with rates in asthma and COPD varying from 22–78%. As well as impacting patient quality of life and outcomes, non-adherence is associated with higher healthcare utilisation and costs — pertinent in emerging markets.

Specific emerging market needs As for specific regions, players looking to benefit from the coming growth in the emerging markets should consider opportunities in India, Pakistan and Bangladesh but also take into account the needs of patients when designing their inhalers.

For example, humidity can The potential for DPIs affect the performance of the in emerging markets is device, while patients expect clear. The winners will be to use their capsule-based DPI for up to six months, not one the companies who can offer aspirational devices month as in the West.

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driven by advanced

Latin America, the Middle East simplicity, ease of use and Africa are also seeing and affordability. increased usage of asthma inhalers and while the volume sold in China is currently low, the country is expected to become one of the highest consumers of generic inhalers, driven by rapid urbanisation and industrialisation, as well as improved access to healthcare.

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The potential for DPIs in emerging markets is clear. The winners will be the companies who can offer aspirational devices driven by advanced simplicity, ease of use and affordability.

Aspirational design While cost and functionality are crucial, companies that fail to recognise the growing aspirations of consumers in emerging markets are missing a trick. Consumers in these markets are not prepared to accept cheap, but inferior products, and the desire for higher-end, high-quality products is growing. So, alongside quality and functionality, companies need to consider aesthetics.

In the same way that we have seen a move towards more stylish insulin pens, inhalers are part of daily life and patients are looking for sleek and compact designs that are both attractive and highly portable, as well as being robust.

References: 1. WHO. Chronic Respiratory Diseases. Available at: http://www.who.int/gard/publications/ chronic_respiratory_diseases.pdf

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SERIALISATION

Level up!

With serialisation efforts in full swing connecting the dots across the full supply chain is becoming important.

Here, Christophe Devins, CEO and co-founder of Adents, and Chuck Sailer, a serialisation solutions expert for Adents, explain why Level 4 serialisation is uniquely positioned for data sharing.

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ith the US Drug Supply Chain Security Act (DSCSA) scheduled for enactment this November, and a similar EU mandate just two years away in 2019, comprehensive serialisation efforts are in full swing on both sides of the Atlantic.

The most effective and comprehensive serialization solutions support the requirements of all levels of technology

A complete serialisation solution is composed of various software and hardware components, each focused on an area of responsibility referred to as a ‘Level’.

According to ISA95 standard, there are five levels of track, trace and serialisation technology.

The most effective and comprehensive serialization solutions support the requirements of all levels of technology, connecting challenges at the plant/site levels with the enterprise level.

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While an extensive amount of effort has been expended on line-site implementations in a ‘bottom-up’ approach, it is now critical to connect the dots with sufficient infrastructure both at the enterprise level and along the ensuing supply chain.

Indeed, from manufacturing to dispensation, there is a great need to exchange information between trading partners and stakeholders — at any level of the supply chain — to address both regulatory requirements and business operations. In that regard, the core principles of a Level 4 system make it uniquely positioned to deliver data sharing capabilities up, down and across the supply chain.

What is a Level 4 System?

While lower levels are connected to plant/site operations, Level 4 is referred to as the ‘Enterprise Level’. These sorts of cloudbased solutions can be thought of as a viewing portal into a specific portion of the overall supply chain. From manufacturing to dispensation, the full gamut of stakeholders benefit from sharing information at various points throughout a product’s lifespan.

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Essentially, a Level 4 System consists of a variety of functional areas for handling an assortment of business processes, global compliance, inter- and intra-organisational connectivity, reporting, identity access management, application programming interfaces and other enterprise-level functions. A best-in-class cloud serialisation and traceability solution should use multiple standard data exchange protocols, exchange patterns, data security, and data integrity techniques.

Perhaps the most accurate and succinct definition of a Level 4 system is that it manages the business-focused activities of manufacturing, warehousing and distribution.

What are the elements of a Level 4 Solution?

User interface: The user interface (UI) must be clean, crisp, modern and responsive to the existing system’s dimensions — meaning it should be 100% responsive for mobile phone usage and ‘scale up’ for large monitor displays.

Centralized location: A chief concern at Level 4 is providing functional areas to handle business logistics. Centralisation and secure connectivity is a must. It is common for various user and system roles within a given organisation to require access to various functional areas or APIs provided by Level 4.

For example, warehouse and distribution centre workers will need to perform business processes on data collected at the packaging line (Level 2) and aggregated by a site-level system (Level 3). Before these workers can do their jobs, Level 3 must send relevant data to Level 4. In this scenario, without a proper Level 4, warehouse workers and distribution center workers would be operating on different networks and unable to share important data. Therefore, the Level 4 system is centrally located and accessible by authenticated and authorised users and systems.

Security: Identity Access Management (IAM) plays a critical role in this requirement. Not all actors — whether human or electronic — will have the same access to Level 4 functionality and API operations. A secure Level 4 will use multifactor authentication (MFA), certificates, API keys and HTTPS, at a minimum.

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Electronic signature: FDA Regulation CFR 21 Part 11 clearly states that all changes within systems dealing with pharmaceutical operations must record electronic signatures for any changes made to the data.

This mandate will likely also be included in pending EU stipulations.

Level 4 systems are at the heart of a new and exciting digital paradigm for manufacturers, trading partners and patients

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Auditing: It is critical that all Level 4 actions taken by any actor (human or electronic) be audited. Audits include actor identifiers, dates and times, underlying objects changed and values before and after change.

Business processes: Any Level 4 system should be able to execute business processes, defined as any problems that a customer must solve to be compliant with government regulations and/or their own standard operating procedures. Examples include packing, shipping, dis-aggregation, global compliance reporting, printing and sending/ receiving files or data to and from other systems.

Label printing: In a warehouse or distribution centre, it is not uncommon for labels to get destroyed, or for rework to occur requiring additional label printing. Therefore, a Level 4 solution that assures compliance must accommodate instances of both reprinting and, should a revised serial number be required, new label printing.

Centralised logging: This describes the ability to collect and centralize logs from site-wide Level 3 systems as well as the Level 4 system itself, and to provide insight into that data. Centralized logging provides valuable, system-wide usability metrics and faster problem resolution. Centrally locating logs is the first step toward using newly mined data for competitive production/business advantages.

Reporting: Reports are always a requirement in any enterprise level software system and can be thought of in two classes — industry reports and customer driven reports.

Message intermediation: Level 4 is where message interoperability between two or more systems occurs, transforming AJAX into XML, XML into CSV, or one XML format into another XML format before data is moved to another system.

There are advantages to deploying any modern system to the cloud, including high availability, unlimited scalability, durable storage, database management (including identity access segregation) and metrics mining (i.e., big data) capabilities.

How do Level 4 Systems help ensure global compliance?

All these features and capabilities are desirable in any enterprise application.

The cloud makes them a reality with very little effort and at a tremendous cost savings when compared to onsite physical hardware alternatives.

Government laws and regulations come and go, and are subject to changes. DSCSA, SFDA, Turkey, Europe, Argentina, Brazil, South Korea and India all have very different requirements. Therefore, a certain amount of flexibility must be factored into any system, Level 4 or otherwise, to meet these demands.

Some governments require systems to send properly formatted data directly to a central system. Others take a more manual approach such as email of (S)FTP. Whatever the case, the Level 4 system must be able to accommodate. Regardless the workflow scenario, there must be a suitable facility within Level 4 to record actions.

Here, the ability to inspect the aggregation of a batch/lot or object identifier, such as an SSCC or SGTIN, is vital. This process entails a variety of identifiers, including: Disposition Packaging level (pallet, case, item, etc.)

Genealogy (children, parent, grandparent, etc.)

Last known location (GLN or LAT. LONG. pinned on a mapping API) Current location (GLN or LAT. LONG. pinned on a mapping API)

The cloud fit and Level 4

Data integrity, security, and resiliency benefit greatly from built-in features of the Cloud infrastructure. Data centres thousands of miles apart can be set up in minutes. Multiple data centres ensure data is protected from loss, and is available to all dependent applications. Backing up, restoring, and ensuring consistency among data centres is clean and concise.

Another benefit of the cloud is the maturation of DevOps. Building, testing and deploying software on the cloud can follow predictable and repeatable processes that were not easily achievable just a few years ago.

Principles and practices of solid DevOps methodologies ensure a high level of quality and dependability.

New and exciting digital paradigm Clearly, cloud technology (Level 4) presents many advantages for pharma companies to manage compliance globally in terms of data generation, exchange, storage and security. However, the real value goes beyond compliance. Cloud technology will be the cornerstone of the digitisation of the supply chain.

Serial number management: Although Level 4 isn’t the primary stage for recording product serial numbers, some degree of serial number management at Level 4 is useful — depending on the specific serialisation recording system being used.

Coupling Level 4 serialisation and track & trace systems with business intelligence tools and Industry 4.0/IoT will accelerate the digital transformation of the supply chain and allow the pharmaceutical industry to develop new capabilities, such as end-to-end collaboration, granular supply chain visibility and data-driven decision making.

For example, if a manufacturer uses a solution from our company called ‘Adents Supervisor’, this system would be its ‘system of record’ for serialisation numbers. Here, it is useful for the Level 4 solution to review serial number ranges to inspect and audit Supervisor’s issuance of serial numbers. It is also desirable to have the Level 4 system configure serial numbers and communicate new and updated information back to the Level 3 system.

Imagine this — patients who have the potential to access full product information, including origin and authenticity, as well as the capability of manufacturers and trading partners to monitor the supply and plan logistics down to the unit-level to avoid disruptions, manage adverse events and improve profitability. Clearly, Level 4 systems are at the heart of a new and exciting digital paradigm for manufacturers, trading partners and patients.

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SERIALISATION

The clock is ticking Are you preparing for serialisation? Carlos Machado, serialisation director at SEA Vision US, explores some of the challenges and opportunities companies are facing when preparing for serialisation and outlines some steps to success for those that are yet to make a start.

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It is important that companies recognise the enormity of the task at hand

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he upcoming serialisation deadlines in the US and EU should be one of the top business priorities for pharmaceutical manufacturers today. However, new industry research conducted by SEA Vision and Zenith Technologies, has highlighted that more than one third of companies in this space are not currently preparing for global serialisation requirements.

Companies need to turn their attention to meeting the demands of the US Drug Supply Chain Security Act (DSCSA) in 2017 and the European Falsified Medicines Directive (FMD) in 2019, if they are to achieve compliance in sufficient time. Of course, this is a complex task that requires both internal and external systems and processes across the entire supply chain to be adapted, meaning time is very much of the essence.

Never under-estimate impact Companies that fail to comply with the new regulations risk production downtime and loss of business in key markets. Our recent research revealed that 15% of companies believe it is too early to begin preparations, while over half said that they don’t have enough internal resource to dedicate to serialisation.

It is important that companies recognise the enormity of the task at hand, particularly if a lack of resource is delaying their preparations. Identifying a suitable partner to assist in implementing serialisation can help but remember, the clock is ticking.

Think long-term While compliance is the main driving force behind the need to implement a serialisation solution, it is possible to achieve wider business benefits by taking a long-term view. The regulatory changes provide the opportunity to review business processes, improve productivity and in some instances, provide a competitive advantage. The huge amounts of data that will be generated also creates the potential to increase visibility and information sharing across the supply chain. Despite this, only 44% of companies surveyed intend to use serialisation to benefit the wider business.

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It is likely that global track and trace requirements will evolve over time, therefore implementing a scalable and flexible solution that accounts for this will save time and money in the future. For example, consider upcoming global regulations and the potential need for aggregation in the future. Preparing for this now will mean you are ahead of the curve.

A well-considered strategy can be a differentiating factor between a good and a great serialisation programme. So how can companies who are yet to make a start guarantee success? Below are some tips that can help keep you on the right track: Consider your geographical reach — serialisation requirements differ across countries, therefore it is important to consider all of the markets you operate in or that you might want to enter in the future. Make sure you understand the various regulations to ensure you remain compliant.

Choose the right technology — a full serialisation set-up requires packaging, printing, data storage and transfer technology. It is not a one size fits all solution and requires a comprehensive strategy that is tailored to your individual needs. When choosing serialisation solutions, flexibility and scalability should be key, guaranteeing they are fit for purpose for the long-term.

Identify a suitable partner — companies that have identified a lack of internal resource to dedicate to serialisation may find external support useful. A third-party implementation partner can assist with the planning and roll-out of your solution. It can also help support seamless integration across multiple sites.

Establish a realistic timeframe — there are various complexities involved when implementing serialisation. As a result, it is important that time is built into your strategy to allow for test pilots to identify potential operational hurdles and rectify these before the upcoming deadlines.

Think ahead — take the time now to consider how future requirements will affect your business. Implementing a flexible solution will make it easier to adapt as legislation evolves.

With less than two years to go until the EU FMD enters into force, pharmaceutical manufacturers need to make serialisation a priority. It is not a task that can be completed overnight and the repercussions of failing to prepare can have a detrimental impact to the longevity of your business. Start now and you can ensure that you are on the right path to serialisation success.

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SERIALISATION

Crunch time Allison Gilpin, business unit manager, global serialisation and Ray Hook, manager global serialisation services, PCI Pharma Services, discuss the impact of serialisation requirements on packaging operations.

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eadlines for including unique product identifiers on prescription drugs are putting a strain on multiple parts of the industry, much of which is ill-prepared to meet the targets. Recognising this lack of readiness, the FDA has now extended its deadline for the US Drug Supply Chain Security Act (DSCSA) …serialisation for another year to alone cannot stop November 2018. counterfeiting.

European regulations A multifaceted will come in two years.

Companies cannot approach is afford to wait to adapt required. their supply chains to ease the complicated and challenging transition to serialisation. There is value in seeking support from suppliers which have taken a long-term, strategic approach to DSCSA requirements.

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PCI Pharma Services has been serialising commercial products for five years for US, European and emerging markets. Introducing serialisation across a large packaging operation has been challenging, but ultimately beneficial.

In this Q&A, Gilpin and Hook discuss the transition process, what they have learned and how companies can adopt multifaceted ways to combat counterfeiting.

When did you get started and how has the transition gone?

Hook: In the transition from our home-grown serialisation technologies to a scalable enterprise level vendor solution, our first Antares-based serialisation line went live in 2014.

Gilpin: It was a very big learning curve. An incredible amount of information, knowledge and experience is required.

Can you give a sense of the scale of the serialisation transition?

Hook: Effectively most items that become serialised will go through an entire launch process. The customer must make their artwork serialisation ready. They need to manage the inventory so non-serialised product goes out first. We then have to go through a significant batch

record and process change to move from non-serialised to serialised.

Gilpin: It’s a huge amount of work and it’s not just an engineering effort. It touches many functional departments, marketing, purchasing, project management, quality, regulatory, operations, and so on. Effectively where we had been making 100,000 units of the same thing in a batch, now we are making and tracking 100,000 unique items in that batch. Serialisation is a major paradigm shift for the industry.

How prepared is the industry?

Hook: A large proportion of the industry is not ready but has started to realise ‘we’ve got to get going’! Lots of people are starting to place orders for equipment. Their challenge will be that it is a 12-month cycle from starting to evaluate a solution to putting the first live line.

Manufacturers of serialisation equipment are seeing an increase in delivery lead times due to rising demand, even though they’ve scaled up their build capabilities. This is going to put late adopters in a tough position.

Gilpin: The staffing side is also a complex challenge.

It requires a lot of external and internal resources to get everything in place to meet serialisation requirements.

Many of our clients are relying heavily on consultant and contract resources to support their knowledge gap, but demand for those resources is also increasing exponentially.

numbers they’re entering. They don’t tell a distribution centre at all. The next normal verification step is when a pharmacist is about to hand a pack to a patient. Other than some special auditing, which is relatively low level, there are no checks throughout the supply chain in Europe.

Instead, Europe is mandating the use of tamper-evident technology on serialised packaging. These technologies, which destroy packs opened illegally, a substitute for the step-by-step verification of the US approach.

What other approaches are companies using to prevent counterfeiting?

Hook: Layering of anti-counterfeiting technology is popular, particularly in Europe. Companies are adding features such as photo-reactive elements to packaging to verify its authenticity by exposing it to light of a particular wavelength. People may also add microcode or intentional design defects that a counterfeiter may overlook when copying product packaging and leaflets.

Gilpin: Serialisation alone cannot stop counterfeiting.

A multifaceted approach is required. Layered technologies and a rotational approach to their strategy, paired with effective serialisation, significantly increases their chances to mitigate counterfeiting and diversion activity.

How do the incoming US requirements differ from those in the EU? Hook: The US uses a track-and-trace system — products are verified at each step in the supply chain. This addresses counterfeiting and helps the FDA eliminate bad actors from the supply chain.

Gilpin: In Europe, the Falsified Medicines Directive (FMD) process is very different. The manufacturer tells a European government the serial

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O Diary entry

LAB DIARY

#5

In this instalment, R&D software provider, IDBS, lists the four considerations that are important when implementing integrated solutions.

There are multiple stages in the drug discovery process. Each stage involves different kinds and amounts of data being generated, all of which need to be effectively captured, managed and analysed.

Many organisations use tailored software solutions or applications at each stage. However, integrating data generated across multiple solutions, from different providers, can be difficult and slow down operations.

To help, there are many integrated platform solutions available, creating a seamless data capture, analysis and reporting experience.

Using a platform rather than several siloed applications has many benefits, such as reduced admin time, increased transparency and data integrity.

Before implementing these kinds of solutions though, there are four things pharmaceutical organisations need to consider:

1. Usability We often hear ‘technology is only limited by its user’. The simplest software in the hands of a technological guru can work wonders, and the most advance software in the hands of a novice will be wasted — but what does this mean for pharma?

Pharmaceutical organisations looking to invest in the latest software need to consider who will be using the technology. The right balance between functionality and usability needs to be struck. It is vital for organisations to remember where scientists’ strengths and expertise lie — which is in scientific discovery, not software wizardry.

Organisations need to identify which software has the relevant functionalities and will produce the most return on investment, but also understand which solution will be easiest for scientists to use daily. Constant compromising on either usability or functionality does not have to be the norm, however. When vetting software vendors, organisations should look at the user interface and select a vendor that will provide thorough training for new users to ensure a smooth onboarding process or even better something that is so intuitive as to require minimal (ideally learning on demand) or no training.

2. Compatibility It is logical to partner with a technology provider that offers the latest software for your specific area of operation. However, there are other elements to consider, such as compatibility with the existing IT infrastructure and your potential provider’s track record within regulated environments, as well as selecting a solution that as much as possible future proofs the investment.

Not all vendors provide solutions that can smoothly integrate with existing systems. Organisations need to be smart and select a technology partner that will allow for seamless integration, which usually results from a mix of APIs with out-of-the-box integration applications.

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It’s also important that the technology partner has a series of certifications in place, such as SOC2. This ensures that the software has been tested multiple times and is free from any bugs.

3. Scalability Growing pains are a double-edge sword — it’s great that your organisation is expanding, but now you also have to update your software to facilitate this growth. Growing pains are especially poignant when different departments grow at different paces.

Organisations can save time and significantly reduce their costs by choosing a holistic cloud-based vendor over multiple solution providers.

Adopting a fully integrated Software-as-a-Service model is very cost effective as: • It enables organisations to pay only for what they need and use.

• Users can access the platform from anywhere with an internet connection, enabling them to access data in real-time and to continue their work, ultimately speeding up the research process • Sponsor organisations can protect their IP by ‘owning’ the tasks and tests within the platform.

• Collaborating parties can operate in a connected environment and can quickly adapt as research and regulations change and develop.

• IT departments can reduce their total cost of ownership (IT) and resource allocation.

In other words, a cloud-based model should painlessly scale as your organisation grows.

4. Security The pharmaceutical industry is increasingly using cloud software, but not to its full potential. Some organisations are still apprehensive about migrating their software to a complete cloud-based environment as there is a misconception that using one cloud provider for all data management needs is too risky — while dividing applications across multiple providers reduces risks. This isn’t true. Splitting software applications across multiple solution providers doesn’t dilute risk, but does dilute security, return on investment and efficiency. It also increases cost.

Partnering with a single provider increases an organisation’s visibility and reduces the number of authorisation access points. With one solution provider, organisations can clearly view who is authorised to input, share and analyse data. This reduces the admin and processing time to amend and update authorised users when necessary.

There is also a huge benefit to having one provider protecting an organisations’ precious IP. With a single unified support network, organisations can secure their data and focus their resources and energy on achieving their business objectives rather than handling the technology.

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