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REGAINING CONTROL OF THE SUPPLY CHAIN

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Contents May 2018 | Volume 18 Issue 3 REGULARS

5 EDITOR’S DESK

Taking a closer look at the race to dominate the artificial intelligence (AI) space.

6 A SMALL DOSE

A brief round-up of some of the developments in the industry.

9 ANALYSIS

Looking at the importance of supply chain visibility and the lessons pharma could learn from the collapse of Carillion.

15 OPINION

Exploring the hidden challenges of clinical packaging.

18 REGULATORY AFFAIRS

Revealing the key differences companies should be aware of in light of the GDPR and the best approaches to balancing the risk of patient re-identification.

22 COVER STORY

In this article, Natoli Engineering details the challenges faced by the R&D team when evaluating the ideal compression profile for a tablet and how the right tooling can help.

58 TECH TALK

Discussing how best to monetise your mHealth app.

FEATURES

24 BIOPROCESSING

Examining the challenges of flow rate and pressure in biopharmaceuticalmanufacturing applications and the potential contamination risk of single-use bioprocess bags.

29 ANTI-COUNTERFEITING

Assessing the reasoning behind the FMD directive and the next steps for companies, as well as expert opinions on serialisation and the key challenges to achieving compliance.

36 BIG DATA

Looking at the importance of blockchain in logistics, how to best prepare for big data, the RWE continuum and the advantages of implementing aggregation.

44 COATINGS & CAPSULES

IĂąaki Bueno from Idifarma tells us more about the ins and outs, challenges, advantages and latest developments in coatings and capsules.

47 LYOPHILISATION

Case study on how to develop the best freeze-drying recipe for a cytotoxic product.

48 SPOTLIGHT ON INNOVATION

Here, Dexter Tjoa, Tjoapack, explores the future of pharma packaging.

50 TABLET PRODUCTION

Taking an alternative view on continuous manufacturing in OSD and a case study using a predictive model to help solve sticking issues.

56 STERILE PACKAGING

Discussing sterile transfer systems, industry standards and what the next steps to evolve these systems need to be.

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lobally, we have witnessed many races by various nations to be at the forefront of the latest technological advances — the nuclear arms race, the space race, the race to 5G and so on. For healthcare and manufacturing, in particular, the latest race for technological domination is that for AI.

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EDITORIAL

editor felicity thomas felicity.thomas@rapidnews.com deputy group editor dave gray david.gray@rapidnews.com head of content, life sciences lu rahman, lu.rahman@rapidnews.com

With China investing massively and the US setting up meetings with AI trailblazers, the European Commission has also made clear its bid to boost the region’s competitiveness in this field.1

reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

PRODUCTION art robert wood

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As the race to dominate the artificial intelligence (AI) space steps up a gear, I take a look at how AI finds use in pharma and how different regions plan to invest in this exciting area

In a factsheet,2 the European Commission explains that ‘AI refers to systems that show intelligent behaviour: by analysing their environment they can perform various tasks with some degree of autonomy to achieve specific goals.’

For pharma, probably the most apparent way AI can have a substantial impact is through the management of data. By applying AI in this way, it may be possible to gain faster and more accurate disease diagnosis and, in the cases of drug discovery and clinical trials, improve success rates and increase safety.

EDITOR’S DESK

According to research from Oracle Health Services in partnership with Informa Engage/Pharma Intelligence more than 60% of drug safety experts are planning to use AI to improve the speed and security of adverse event case processing.3 “With the increase in adverse events reported, and the flat growth in resources to manage safety case processing, pharmacovigilance teams are under extreme pressure to do more with less,” asserted

Bruce Palsulich, VP of safety product strategy for Oracle Health Sciences. “Fortunately, adverse event processing is becoming faster and smarter with the help of AI and the cloud.”

Across the Atlantic, the US Food and Drug Administration (FDA) is actively developing new regulatory framework to promote innovation in the AI space and has recently approved a medical device (combining a special camera with AI) that enables earlier disease detection.4 “One of the most promising digital health tools is AI, particularly efforts that use machine learning,” stated Dr Scott Gottlieb, FDA commissioner. “AI holds enormous promise for the future of medicine… We expect to see an increasing number of AI-based submissions in the coming years.”

The European Commission’s approach, alluded to earlier, involves increased investment, both private and public, into AI. The three-pronged approach proposed will involve boosting the EU’s technological and industrial capacity and AI uptake across the economy, preparing for socioeconomic changes and ensuring an appropriate ethical and legal framework. “…AI is transforming our world,” said vicepresident for the Digital Single Market Andrus Ansip. “We need to invest at least €20 billion by the end of 2020.”1 So, the race is on and whichever country or region becomes the AI superpower, ultimately the winner should be the patient with quicker access to treatments and earlier diagnoses.

REFERENCES: 1 | http://europa.eu/rapid/press-release_IP18-3362_en.htm 2 | http://ec.europa.eu/newsroom/dae/ document.cfm?doc_id=51610 3 | https://www.epmmagazine.com/ analysis/nearly-two-thirds-of-drug-safetyexperts-plan-to-use-ai/ 4 | https://www.fda.gov/newsevents/ speeches/ucm605697.htm

6 ‘Super’ drugs for superbugs…

‘A major wake-up call for everybody’ is how Public Health England (PHE) has described the world’s worst-ever case of super-gonorrhoea only just about being cured with a singular antibiotic — ertapenem — after it was not curable with the regular treatment.

So, as we seem to be moving in reverse against antimicrobial resistance is there anything out there that may offer hope?

In fact, there have been a few ‘super’ drug breakthroughs recently with researchers successfully treating drug-resistant bacteria in a clinical setting. Here is a brief rundown of some of the exciting newws happening globally:

TOPPING THE CHARTS…

A small dose BREAKING THROUGH IN BRITAIN: A team of researchers at Lincoln University — in collaboration with groups from Liverpool University and researchers from the Netherlands, Belgium and Singapore — have just provided evidence in a rodent model that an improved, synthetic version of a natural antibiotic called teixobactin can treat MRSA and vancomycinresistant enterococci.

These simplified versions of the natural antibiotic have the potential for commercial production.

USA PUTTING UP A UNITED EFFORT: Of late, there have been a few studies into various potential options from US researchers. One, from a team at Rhode Island Hospital in Providence, is a family of molecules

Data and analytics company, GlobalData, has released its list of the top performing pharma companies by market cap for the year 2017, featuring some interesting positional changes and shifts from the prior year. Here are the top 10:

Johnson & Johnson — retaining its position in the top spot for 2017.

Roche — moves up a place into second.

Pfizer — drops down a place switching with Roche.

Novartis — no change for the Swiss pharma giant.

AbbVie — rising three places this year and increasing market cap by more than 50%.

Merck & Co — takes a drop by one place even though its market cap is increased.

Novo Nordisk — another climber, rising from 12th place.

SOURCE: https://www.globaldata.com/top-25-global-pharma-companies-market-cap-end-2017/

Amgen — gone down a couple of places from its position last year.

Sanofi — the same for Sanofi which goes from 7th to 9th.

Bayer — rising from 13th to get into the top 10 and break the $1 billion market cap value.

7

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called retinoids. These compounds were found to not only kill normal MRSA cells but also the dormant/persister cells as well. The other comes from a team at the Rockefeller University which uncovered natural compounds in soil samples — malacidins — that work as calciumdependent antibiotics against MRSA in rodent models.

FUTURE PROMISE FROM FRANCE: French company Nosopharm’s new class of antibiotics — odilorhabdins, produced by symbiotic bacteria found in soil-dwelling nematode worms — work by targeting the ribosome and uniquely binding to a place on the ribosome that has not been used by other known antibiotics. In collaborative research, this new class of

antibiotics were found to cure mice infected with several pathogenic bacteria. The first inhuman clinical trials of the company’s lead candidate are expected in 2020.

HUGE HOPE FROM HONG KONG RESEARCH: In the University of Hong Kong, a team of medical chemists have found that the bismuth-based metallodrug — colloidal bismuth subcitrate (CBS), used to treat peptic ulcers — can paralyse multi-resistant superbugs, such as Carbapenem-resistant Enterobacteriaceae (CRE), and suppress the development of resistance to antibiotics.

This, in effect, should extend the lifespan of currently used antibiotics and as the drug is already approved by the US FDA it is hoped to be ready for human clinical trials soon.

CURIOUS CONSEQUENCES

and other strange side effects After a man claimed the painkiller, Pregabalin, completely changed his sexuality we scoured the internet in search of what we consider to be the top five weirdest side effects that may potentially occur when taking various medications…

1. Amnesia short-term memory loss can happen after taking some medications, although generally these effects go away once the patient stops taking the drug.

2. Colourful urine ranging from dark brown to alarmingly red, pink or even blue there are multiple drugs out there that can cause a change to the colour of

urine. A good guide to which compounds cause vibrantly coloured urine can be found at www. globalrph.com/urine.htm 3. Loss of fingerprints cancer drug capecitabine could be the culprit of this side effect. On studying the drug’s effects, a senior consultant in medical oncology at the National Cancer Centre in Singapore noted that it may cause hand-foot syndrome, which in turn leads to the loss of fingerprints!

4. Height reduction a common steroidal medication, Prednisone, may make you shorter, although in a systematic review of randomised trials, performed by a

team at the University of Montreal in Canada, it was found that in paediatric growth rates the reduction was on average about half a centimetre in the first year of treatment, which then tailed off.

5. Gambling urges some patients taking drugs to treat symptoms of Parkinson’s disease or restless leg syndrome have ended up with a gambling addiction.

GlaxoSmithKline, which manufactures the drug ReQuip (ropinirole), lists ‘impulse control/ compulsive behaviours’ in the warning and precautions for the drug, recommending patients talk to their doctor if they or their family notice any unusual behaviours while on the medication.

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9

ANALYSIS

REGAINING CONTROL

As more pharma manufacturers outsource elements of their process, Steve Cottrell, president at Maetrics, looks at the importance of supply chain visibility and how companies can regain full control.

P

harmaceutical manufacturers are increasingly outsourcing elements of the manufacturing process in order to boost capacity, improve speed-to-market and to capitalise on the availability of new suppliers in Asia. A recent survey found that 44% of pharmaceutical companies expected to outsource more business in 2017 than the previous year, and only 11% expected more business to be

By resolving tabletting issues that are typically overlooked at the development stage manufacturers can speed time to production and reduce costs.

brought in-house.1 A potential drawback of this surge in outsourcing activity is the difficulty manufacturers then face to maintain sufficient visibility and control of the supply chain once they have relinquished ownership of individual elements of their operation.

LAPSES IN QUALITY CONTROL Manufacturers are ultimately responsible for guaranteeing the control and monitoring of outsourced activities and the quality of purchased goods and

services. The increasing complexity and fragmentation of multitiered supply chains, as outsourcing takes away direct control and sight of all stages in the manufacturing process, is making it harder for businesses to achieve this. Factor in as well the lack of appropriate IT systems, limited personnel experience or capacity and resource constraints and it is clear to see why poor supply chain visibility is often unavoidable.

With Chinese firms now producing 40% of the world’s active pharmaceutical ingredients (API) it is understandable that they are increasingly sought out as suppliers to European and USbased manufacturers.

Their quality control levels, however, are not commensurate with those of Western markets so manufacturers risk attracting regulatory penalties if safety standards are not met.

The FDA and other regulators specifically address this matter,

emphasising that manufacturers must assure the ultimate safety of all operations and that their responsibility ‘extends to the control and review of any outsourced activities and quality of purchased materials’.2 Mergers and acquisitions are another example of how manufacturers are losing control over supply chain visibility, exposing their businesses to the associated operational risks in the process. With all efforts concentrated on signing on the dotted line and tying up deals, manufacturing operations are often scaled back and tight control and monitoring of day-to-day processes tends to slip. Personnel typically do not have the required capacity to perform adequate supply chain gap analyses and supplier assessments, as well as manage any quality issues that arise from deviations, out-of-specification (OOS) issues, nonconformances and below par investigations into supplier corrective action reports (SCAR).

Substandard quality and performance are the potential outcome. >>>

10

ANALYSIS

OPERATIONAL IMPACT Clouded supply chain visibility introduces operational risks because manufacturers are unable to ensure compliance, to fully understand demand and capacity or to effectively assess and respond to any disruptions in the supply chain. Productivity suffers as a result with delays in operations becoming unavoidable.

Unforeseen delays to operations can result from numerous risk factors. For example, when incoming goods fail to conform to required specifications or lack a certificate of analysis, production must be put on hold until the matter is addressed. Sometimes materials received might fail to perform in the manufacturing process despite meeting regulatory standards. This can be due to poor shipping temperature controls or data integrity issues that internal auditors were not trained to spot. Poorly written quality agreements can also delay operations, for example by leaving a legal loophole open which exonerates a supplier from notifying their client of a quality issue encountered during the manufacture of an API. REFERENCES:

1 | http://www.pharmavoice. com/article/2018-02outsourcing/ 2 | https://www.fda. gov/downloads/drugs/ guidances/ucm073517.pdf 3 | https://www.slideshare. net/E2open/survey-resultstrends-in-supply-chainvisibility

ONE VISION Supply chain visibility, when operating efficiently, gives manufacturers sight of and control over components or products in transit at all stages of the chain. It also gives them accurate and realtime access to data, for example on supplier inventory levels or customer demand capacity, which

allows them to respond quickly to fluctuations from the norm and run flexible and efficient production operations where quality standards are consistently maintained.

When asked in a recent ‘Trends in Supply Chain Visibility’ study whether anyone in their organisation had an end-toend comprehensive view of supply chain data, only 19% of respondents felt that this was the case. The majority felt that visibility data was fragmented and scattered throughout the business.3 No wonder then that achieving full supply chain visibility is now one of the top strategic priorities for professionals in all sectors. So what action do pharmaceutical manufacturers need to take to put their organisations on the path to enhanced visibility?

Firstly, supply chain stakeholders should be treated as partners; it’s important to work together to produce supplier and quality agreements that are clearly written and planned to adequately cover all interested parties and their respective legal requirements.

Encourage the sharing of information between stakeholders, which will be easier to achieve by investing in the right IT infrastructures, allowing real time data to be leveraged and shared at all points in the supply chain.

Any potential interruptions, such as falling supplier stock levels, can then be identified and rectified as soon as they occur.

Recording and reviewing detailed records of the quality and timely receipt of materials is paramount.

Regularly monitor suppliers using periodic scorecard assessments, SCAR and investigative reviews, and ensure that you perform on-site audits, paying particular attention to the qualification and re-qualifications audit, and forcause investigations.

Interruptions to supply chain activity can also originate from external factors such as political disorder or environmental disasters so keep an eye on global developments to be in a position to respond promptly.

Many manufacturers, rather than facing these challenges on their own, choose to bring in specialist consultants with the requisite experience of tightening up supply chains to mitigate risk while boosting business efficiency.

This route allows companies to benefit from adopting the SQ outsourcing model, which enables cost savings of up to 48% by managing costs per audit versus full-time equivalent (FTE) resources. It maintains a higher level of compliance and inspection readiness while allowing internal resources to focus on other business needs.

Taking these steps will help your business regain full control and vision over all elements of your supply chain ensuring that not only can you identify problems as and when they occur, but that you are well placed to solve them quickly.

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12

ANALYSIS

Never too big to fail... …and other lessons that can be learned from the collapse of Carillion. Here, Mark Tempest, VWV partner in the Insolvency and Restructuring and Pharmaceuticals and Life Sciences teams, looks at the construction giant’s case in more detail and what pharma and life sciences should consider in order to protect themselves.

C

arillion’s failure is likely to have a significant impact on the many businesses and individuals connected to it — from its employees, hundreds of sub-contractors and suppliers through to individual trades, and across a multitude of sectors. Its liquidation has left a trail of losses on big contracts and accumulated debts of over £1.5 billion. The ramifications will be felt far and wide, not just by those with a direct relationship but also by those who contract with and supply to those businesses, such as recruitment and marketing service providers.

For many suppliers to Carillion, the contract would have been one of their largest, if not the largest. These businesses face an uncertain and potentially catastrophic future. They will most probably be left in the unenviable position of being owed substantial debts (for which they must claim in the insolvency process as creditors and are likely to receive very little or nothing at all by way of a dividend) and a loss of future revenue. At the same time, any recourse normally available to them against a solvent company is unlikely to be appropriate or legally possible.

The reaction of pharma and life science businesses might understandably be to be thankful they are not in the construction industry, or directly connected with it. However, businesses

in any other sector can and should consider potential parallel situations within their own industry — there are lessons to be learnt that apply outside of construction.

POINTS OF INTEREST FOR PHARMA AND LIFE SCIENCES Turning to the pharma and life sciences sector, why is the Carillion collapse of any interest? Well, first, if further evidence were needed, it shows that no business is too big to fail. CROs, CMOs and other product and service providers have contracts with big pharma that account for a significant proportion of their business.

Others supplying products to big retail pharmacy chains, some of whom have been lengthening their payment terms in recent years and paying themselves a prompt payment discount if they settle within three months, are likewise heavily exposed to those trading relationships. A loss of those contracts is likely to have a dramatic negative impact on cash flow and viability of those smaller businesses.

But could a big pharma company really fail? Evidence from other sectors, not just the construction industry, suggests that the answer must be ‘yes’. What if they suffer severe reputational damage from the way a clinical trial has been conducted, or the way clinical trial data has been presented?

What if a product on the market leads to multiple claims after a

major bout of adverse reactions?

Alternatively, what if they suffer a late stage clinical trial failure for a potential blockbuster that leads to a collapse in share price and confidence? Seemingly robust retail pharmacy chains are coming under increasing financial pressure from the government’s pharmacy budget cuts, or they may also suffer a damaging reputational issue such as a failure in the standard of care provided when dispensing medicines.

Businesses need to consider and plan for the insolvency of business partners, however unlikely that may seem. They need to protect themselves and prepare for the worst.

Company directors also need to understand their personal duties (and potential liabilities) in the face of their company’s resulting financial difficulties.

WISE WORDS AND PRACTICES It is not easy for a business to manage its exposure to one significant customer. Very often that contract is highly-prized and doing anything that might undermine the relationship is unattractive. At the same time, a large contract may well take up time and resources to such an extent that identifying and establishing alternative relationships is simply not achievable. A lot of businesses will be content to enjoy the benefits

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of the business for as long as they can and defer worrying about the implications of it disappearing to another day.

Having said that, it is worth reviewing contracts carefully, and regularly. If you supply goods, such as APIs, excipients, finished products or packaging, you should ideally have a well-drafted ‘retention of title’ clause. Such a clause will give you, as a supplier of goods, priority over secured and unsecured creditors of the buyer if the buyer does not pay for the goods and goes into an insolvency process. It should ensure that you retain ownership of goods and give you the ability to reclaim possession of them.

Changes to insolvency legislation and processes mean that many older contracts are often simply not fit for purpose. A well-drafted contract will include provisions governing what is to happen on the insolvency of either party; it should, for example, clearly state whether the contract is to terminate automatically or only at the instigation of one of them.

There is no doubt that there is a limit to what can be achieved through documentation, and if practicable any party entering into a commercial contract should ensure that it maintains a robust credit control system. Where a supplier has any concerns over the financial position of another business it is entering into a trading relationship with, it should also consider obtaining alternative forms of security (e.g., a bank guarantee or letter of credit) and taking out credit insurance.

Finally, any business contracting with anyone — even with a big pharma company or a multiple retail pharmacy chain — would be well advised to prepare for the worst and minimise the potential fallout should the unthinkable happen. This means getting advice

from experienced insolvency professionals to review contracts and options available in the event all or a significant part of their revenue dries up, or they find themselves with a large noncollectable debt. A ‘wait and see’ approach will likely mean that a business is ultimately forced into a much more difficult position at short notice with fewer and more limited options. Acting at the outset of the relationship, or before problems arise, is always the best advice.

Any business contracting with anyone — even with a big pharma company or a multiple retail pharmacy chain — would be well advised to prepare for the worst and minimise the potential fallout should the unthinkable happen.

13

Opinion

15

Ultimately, to properly understand clinical packaging and achieve eďŹƒciency and compliance, it needs to be viewed as part of the bigger picture.

LOOK AT THE BIGGER PICTURE Operating clinical studies with a silo mentality with undoubtedly yield poor results. With various risks associated at each stage of the clinical supply chain Adrian Collins, production manager, Almac Clinical Services, explores the hidden challenges of clinical packaging and how they may be overcome‌

F

rom small, single-arm trials to large, complex studies involving a range of research centres, in multiple countries, the last 25 years has seen a dramatic evolution in clinical trials and the processes that support them. As a result, the development and delivery of IMP (Investigational Medicinal Product) to clinical sites and the patient is changing continually.

Despite these changes, one thing that remains unaffected is the objective to supply clinical trial patients and sponsors with safe, flexible packaging to meet the varying needs of individual clinical trial protocols without impacting the stability of the IMP. Safety and flexibility are two vital ingredients within the planning of a study which are often overlooked, or not given the consideration they deserve early in the process. Indeed, failing to consider potential packaging challenges at the study’s planning phase, has the potential to compromise the timing, safety and success of a trial. >>>

16 THE HIDDEN CHALLENGES There are risks associated at all stages within the clinical supply chain, but those hidden challenges at the planning stage can mean the difference between a successful study and no study at all.

Special considerations in clinical packaging include: l Visibility

— clinical supply is a vital, but often unseen timeline factor. Ensuring this element isn’t overlooked in the planning stage of a study is essential for delivery.

l

l

Unstandardised — product, protocol and patient needs differ based on the unique nature of each study, which in turn demand a specialised solution Change — study size, scope, clinical direction, patient demand and regulatory compliance is variable for each study and is particularly evident in multi-country studies, there is, therefore, a need for continual monitoring of the entire supply chain in order to accurately meet study demand.

l Institutional

learning — historical product and/or programme learnings can be lost when personnel move or company structure changes.

Strong relationships and succession planning are essential to ensure knowledge retention.

OPINION

It is never too early to begin planning your clinical trial packaging and distribution strategy and questions must be asked at the outset of any study regarding the quantity required, stability and expiry date of the IMP, if blinding is necessary and, ultimately, if material and timelines could impact production. To ensure success, and overcome the hurdles posed by the above challenges, these questions may seem obvious but are fundamental to developing effective packaging strategies and ensuring appropriate resource capacity is available.

OVERCOME THE CHALLENGES There are many factors that, if addressed early enough and approached in an integrated manner, can help to create an optimised operation.

Firstly, ensuring full visibility of kit design during the initial planning stage is critical as this influences the materials, quantities and specific tooling requirements needed.

Additionally, the lead-times associated with the specific kit design will impact durations and deliverables, it is important that this is agreed as part of a wider project.

The stability and dose form of the drug is also a key consideration and can often restrict the choice of packaging for the kit.

Blinding — and the complication it can introduce to packaging — should be explored at the earliest opportunity. Without knowing that the samples of both IMP and comparator products are available, or if blinding is even possible (and if so, that there is a process for it), timelines and more critically, study design, could be jeopardised. This lack of foresight became evident when a study comparator provided by a sponsor was too large for the selected shell for over-encapsulation.

A solution was quickly identified which involved recruiting and securing a new proven source comparator, along with a smaller tablet presentation to fit the preferred shell, resulting in no major adjustments to the clinical protocol.

Planning for the unpredictable is essential.

As we know, change, often unforeseen, is inevitable. A flexible study design is vital to enable modification if there was a change to elements such as: study size, visit schedules, clinical site, patient demand or regulatory compliance. In these cases, applying

scrutiny to plans means that alternative packaging scenarios can be considered.

In one sponsor’s case, early planning of the packaging design resulted in a switch from a visit kit to multiple weekly dosing in a compact wallet design.

This not only made patients’ lives easier but resulted in the reduction of overall clinical supply units from 300K to 108K, saving an estimated six weeks and approximately £600K. Finally, one must consider the challenges presented when demand surpasses supply in active studies. This is a serious consequence of disjointed supply chain planning that fails to align site activity with production processes, leading to a risk of stock outs. Similarly having slower than expected demand can also pose challenges. Patient recruitment and retention is one of the most important aspects of a trial.

Having measures in place to protect against stock outs and being able to react quickly and accurately needs to be a priority during the planning phase of a study; not left as a costly knee jerk reaction when the problem unexpectedly occurs.

CONCLUSION Ultimately, to properly understand clinical packaging and achieve efficiency and compliance, it needs to be viewed as part of the bigger picture. Operating with a silo mentality will yield poor — potentially catastrophic — results. Clinical packaging not only needs to be part of the conversation at the outset of trial planning, but its role within the drug development process properly scrutinised and pro-actively managed to overcome any challenges posed mid-trial.

Managing an integrated supply chain means preparing for every eventuality with effective forecasting, maintaining clear dialogue with third parties and embracing innovative ways of identifying and solving problems.

Clinical packaging strategy isn’t something you can buy off the shelf. It is something that requires both considerable effort and expertise. If approached correctly and early, it can safeguard patient safety, reduce significant cost, ensure regulatory compliance and champion successful studies that will no doubt contribute to future leaps forward in drug discovery and advancements in human health.

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18

REGULATORY AFFAIRS

As the General Data Protection Regulation (GDPR) take effect this month, Mark Stevens, managing director, Formpipe Life Science, looks at the key differences companies should be aware of and how they can attain compliance.

GETTING A HANDLE ON GDPR G

DPR is the outcome of many years of negotiation aimed at harmonising the EU countries’ approach to data protection issues and is scheduled to take effect in all member states on 25 May 2018. The consequences of failing to comply won’t begin and end with a fine but will risk the reputation of non-compliant organisations.

The fundamental principles tackled by GDPR are not new, it simply strengthens existing legislation protecting individuals and their personal data. The five key differences relate to: 1. The appointment of a data protection officer. This will become mandatory for qualifying organisations.

2. Breach notification. GDPR requires a data controller to notify the Information Commissioner’s Office (ICO) without undue delay, and not later than 72 hours after becoming aware of a data security breach.

3. Data protection by design/by default. Organisations need to consider data protection compliance when implementing new processes or methods of handling data.

4. Changes to the use of consent. Consent has never been the only justification for processing data lawfully but is a common one. With GDPR, it will be a condition that is undoubtedly harder to get right.

5. Changes in sanctions. Fines for non-compliance have been replaced and sanctions re-categorised into two tiers. The first is for violations relating to internal record-keeping, data processor contracts, data security and breach notification, data protection officers and data protection by design and default. These will carry a fine of up to two percent of annual worldwide turnover or €10 million, whichever is greater. The second tier will cover violations relating to breaches of the data protection principles, conditions for consent, data subjects’ rights and international data transfers. The penalty will be up to four percent of annual worldwide turnover or €20 million, whichever is greater.

Safeguarding data integrity and demonstrating compliance with an array of legislation is second nature to most pharmaceutical organisations, yet GDPR still represents somewhat of a game changer for the sector.

Relieving some of the immediate pressures of GDPR can be achieved by retiring inadequate, legacy technology into cloud-based, archive – or preservation systems.

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A CULTURAL SHIFT The introduction of GDPR represents a wider cultural shift in the way we view personal data. Legislation is mirroring ever-increasing consumer demands, and regulators are keen to adopt a more holistic approach to data management and information governance.

The DPA was introduced in 1998, with the Internet in its infancy and smartphones a futuristic concept.

People now view data as their possession, and GDPR reinforces this sense of individual ownership; raising the risk profile of data management within organisations and acting as a catalyst to expand responsibility beyond the compliance department.

GDPR gives the ICO powers on par with super regulators like the Financial Conduct Authority and Competitions and Markets Authority. Any organisation that controls or processes personal data is required to comply with GDPR. Most pharmaceutical businesses will have transferable frameworks and resources that can be adapted to comply with the legislation. This doesn’t mean it’s not a daunting feat.

GETTING YOUR HOUSE IN ORDER The ICO advocates a 12-step programme to achieve GDPR compliance best practice.1 First is awareness: GDPR impacts every aspect of an organisation, so it’s important all stakeholders understand its significance and feel empowered to help safeguard compliance. Once a culture of awareness and accountability is in place, understanding where personal data came from and what it’s used for are logical next steps.

Re-evaluating processes in light of GDPR, from how privacy information is communicated to how personal data is deleted, should be prioritised. Existing breach-reporting protocols need to be a key area of focus too, alongside reviewing current privacy notices and checking processes and procedures against the new rights of individuals.

Subject access requests also need to be carefully considered. Technology has a key role to play in this, with adding or adapting systems essential to staying on the right side of regulators.

Once you’ve established your business has a lawful basis for processing personal data, findings need to be documented and, where necessary, privacy notices updated or created explaining the extent of personal data processing and justification for it.

Reviewing how consent is obtained, recorded and managed, as well as documenting any changes, should be prioritised by pharmaceutical organisations. The personal data of children deserves extra consideration.

Other considerations the ICO highlights include complications for businesses operating in more than one EU member state, which are required to determine the appropriate lead data protection supervisory authority.

TRANSLATING THEORY INTO PRACTICE On top of general changes that need to be introduced by data controllers and data processors, there are several sector-specific considerations for pharmaceutical firms. For instance, with pharmaceutical businesses typically operating in chains with multiple touch-points involved in the creation and management of a drug portfolio, it’s essential to know who owns this information.

There is no precedent, but responsibility at each stage will presumably remain with the data controller. There will be arguments on both sides, but the only certainty is that no one will want to pick up the bill for non-compliance.

Putting effective contracts in place will help define responsibility and practical activity, thus becoming increasingly important under GDPR. Clinical trial organisations that come into direct contact with individuals and those individuals’ personal data will

need to manage this data to ensure it is being used with maximum effect, whilst also ensuring GDPR compliance.

In practice, these organisations will already be acting in a compliant way to meet DPA regulations. However, the introduction of tougher legislation represents an opportunity for firms to embrace more robust, electronic and efficient solutions.

DON’T PULL THE PANIC CORD Whatever organisations are currently doing, time is officially up. GDPR is here and it’s here to stay. If they haven’t already, data controllers should be auditing existing processes and systems to check compatibility with the intricacies of the new laws and, if needs be, investing in the resources required to rectify any shortcomings.

Big change brings uncertainty, and this has the potential to breed panic. This may cause businesses to make rash, ill-informed decisions or assume that all problems can be fixed by implementing new software, processes and/or procedures. Although well intentioned, this will provide a short-term fix at best and prove a costly mistake should the new systems be deemed inappropriate

by GDPR auditors.

Relieving some of the immediate pressures of GDPR can be achieved by retiring inadequate, legacy technology into cloud-based, archive — or preservation — systems. This is a costeffective solution that takes data from one system and houses it safely and compliantly, while replacement systems are thoroughly investigated, data categorised and informed purchasing decisions made.

Understanding how historical data needs to be preserved to support compliance best practice in relation to multiple sets of legislation is therefore crucial to reach sensible and controlled decisions.

REFERENCE: 1 | https://ico.org.uk/media/1624219/preparing-for-thegdpr-12-steps.pdf

20

REGULATORY AFFAIRS

Based on considerable experience of managing companies’ early submissions, Pooja Phogat, regulation and compliance expert at Kinapse, advises on the best approaches to balancing the risk of patient re-identification with the need for greater data utility.

ACHIEVING THE DESIRED END GOAL…

T

he European Medicines Agency (EMA) Policy 0070 provides important guidelines and processes supporting the agency’s vision for a public database of clinical research findings.1 The goal is to increase industry transparency, yet without compromising trial participants’ privacy.

With the EU’s new General Data Protection Regulation (GDPR) now imminent,2 the impetus for life sciences firms to cement their data management strategies has further increased.

Initiatives by other regions such as North America3,4 around the external publication of clinical findings provide an additional driver for improving approaches to managing outwardfacing information.

FALTERING FIRST STEPS Early attempts by companies to fulfil Policy 0070 requirements have left quite some room for improvement.

A common approach has been to redact public-facing content. However, the value of a heavily doctored clinical study report (CSR) is questionable.

Redaction is also a painstaking process.

With other anonymisation methods, several priorities can be addressed simultaneously — the delivery of higher-value output; strong measures to protect patient privacy (information is simply hidden in plain sight); accurate risk measurement;5 and support for process automation.

Not surprisingly, this is the road EMA is recommending.

RECOMMENDED PRACTICE Based on our work in helping life sciences companies prepare early Policy 0070-compliant submissions, Kinapse has identified the following optimal compliance approaches:

1. Look forwards.

Policy 0070 is an evolving requirement, so the most effective strategies will be those that take into account longer term requirements — as well as what is being demanded of firms now.

Policy 0070 was first introduced in January 2015, with guidance on CSR anonymisation published in March 2016, and the first submission made public that October. Phase 2 of Policy 0070, which will require that life sciences companies provide anonymised copies of all of their clinical trial data, is coming down the line, albeit that there isn’t currently a known timeline for this next stage. It is something companies should prepare for nonetheless, as it will require a more systematic and repeatable process than most companies have in place currently.

2. Get going.

Do not wait to start planning how to tackle document anonymisation.

Once companies submit a marketing authorisation application to EMA, the guidance specifies that they should ideally take no more than 180 days to provide the equivalent anonymised content for the designated EMA portal, where anyone can look at it. Four and a half months might sound like a long time, but it isn’t really. While there are about 100 different ways we can address a company’s anonymisation needs for a given submission package, those options are reduced the closer firms are to the public submission’s deadline. The tightest timeframe Kinapse has worked to so far has been two months — although we still delivered as planned, this was far from ideal.

3. Manage expectations.

EMA Policy 0070 compliance is not something the majority of life sciences companies can easily manage themselves. The requirements are new,

and expertise is in short supply. It’s also easy to underestimate the need for collaboration between different stakeholders.

Using a specialist service provider offers greater efficiency and reliability, not least through the chance to centralise activities. It is probably also the best route to accessing enabling technology and tools — including smart algorithms/machine learning, which over time produce faster and more accurate results by building on each anonymisation cycle.

Anonymisation methods geared to de-identification generally rely on IT to maintain data integrity, measure and manage risk, and provide auditable evidence of measures that have been taken. These techniques can deliver benefits starting at 60% improvements in time and cost efficiency compared to non-technology enabled anonymisation processes.

Managed service providers will also keep abreast of data security as they process documents, keeping companies compliant with GDPR and other data safeguarding measures. For clinical trial sponsors, this all adds up to the lowest-risk and most efficient option for managing compliance.

4. Forget redaction.

Other than in exceptional cases, defaulting to redaction as a strategy is a false economy. It is not in the spirit of clinical data transparency and it adds the least value for everyone concerned.

As international requirements dovetail with EMA’s ambitions, and as Policy 0070 enters its next phase, redaction’s limitations will be exposed. This will mean that any money spent on redaction processes and work now will not count, and companies will have to invest afresh in alternative anonymisation strategies.

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Keep in mind that EMA has now established a dedicated anonymisation taskforce6 to help sponsors come up with ideal methods and techniques for maintaining data utility.

5. Seek out a like-minded partner.

Once companies have accepted the need for professional help, they will need to decide what kind of outsourced service is appropriate for their requirements. Some service providers offer advisory services, but not the practical operational delivery — or the other way round. Some are light on technology; others focus too much on automation, with a risk to quality control. The optimum combination is likely to be an end-to-end service.

Early attempts by companies to fulfil Policy 0070 requirements have left quite some room for improvement.

REMEMBER THE END GOAL Finally, accept that the demands of EMA Policy 0070 are considerable.

But remember too that putting off the inevitable or cutting corners could result in greater costs and pain.

Keep a clear sense of purpose — that greater goal of transparency, increased public trust and accelerated clinical breakthroughs — which key stakeholders can buy into.

REFERENCES: 1 | European Medicines Agency policy on publication of clinical data for medicinal products for human use, EMA, October 2014: http://www.ema.europa.eu/docs/ en_GB/document_library/Other/2014/10/ WC500174796.pdf 2 | How will GDPR impact Life Sciences organisations, Kinapse, February 2018: https://kinapse.com/insight/gdpr-lifesciences/ 3 | Public release of clinical information, Health Canada, February 2018: https:// www.canada.ca/en/health-canada/ programs/consultation-public-releaseclinical-information-drug-submissionsmedical-device-applications. html?wbdisable=true 4 | What’s not shared—building on the FDA’s transparency momentum, BMJ blog, January 2018: https://blogs.bmj. com/bmj/2018/01/31/tianjing-li-whats-notshared-building-on-the-transparencymomentum/ 5 | Questions and Answers on the External Guidance of Policy 0070 on Clinical Data Publication, EMA, September 2017: http://www.ema.europa.eu/docs/ en_GB/document_library/Regulatory_ and_procedural_guideline/2017/04/ WC500225881.pdf 6 | EMA Technical Anonymisation Group (TAG): Call for applications, March 2017: http://www.ema.europa.eu/docs/en_GB/ document_library/Presentation/2017/03/ WC500224906.pdf

22

COVER STORY

Time f r change In this article, Dale Natoli (president) and Kevin Queensen (technical service support, Tooling and Tablets), Natoli Engineering, detail the challenges faced by the R&D team when evaluating the ideal compression profile for a tablet and how the right tooling can help.

O

ne of the challenges tablet manufacturers have faced for many years is the lengthy amount of time and high costs associated with pushing a solid dose product through the research and development (R&D) process. Developing and validating a new solid dose product can, therefore, be daunting for the R&D team.

A critical step in any tablet development process is determining the compressibility of the formulation, which means collecting data on how the formulation behaves in relation to variations in compression force and dwell time — both of which affect the final thickness, density and hardness (tensile strength) of the tablet. These parameters help determine the ideal compression profile for a tablet during R&D and ideally will lead to trouble-free mass production.

KEY DIFFERENCES Transitioning product from an R&D tablet press to a production press during scale-up has been an ongoing challenge in the tabletting industry for many decades. When developing a new formulation, scientists use a small-scale tablet press to study and understand their product’s tabletability.

These small-scale systems are useful at the research level, but formulations do not always successfully transfer to the larger-scale manufacturing machines due to differences in turret size, turret speed, pitch circle diameter, feeder assemblies and pressure roll diameter.

Compression dwell time is a crucial function that can be affected when scaling up from R&D to production.

Generally, R&D presses are 10 to 16 stations whereas a production press ranges from 30 to 100 stations, which represents a significant difference

in pitch circle diameter and effective length of the feeder aperture. These differences considerably affect dwell time as it is dependent on head flat diameter, turret speed and turret pitch circle.

So, what is dwell time? Specifically, dwell time, expressed in milliseconds, is the time in which the punches achieve maximum penetration in the die under the main compression rollers and the punches are no longer moving vertically. In other words, dwell time is the time a punch spends in the same position or stage of the tablet compression process.

SIMULATING PRODUCTION PRESS DWELL TIMES The simulation of production press dwell times on a small rotary R&D press can be accomplished by using punches with a smaller-than-normal head flat.

By carefully choosing the head flat and press speed on the small-turret R&D press, one can simulate the dwell times experienced on a productionscale press at a given speed. As many tabletting issues are related to dwell time, this can help mitigate and resolve issues that often get overlooked in the development stage.

However, changing tooling in an R&D tablet press to test which head flat will produce the most robust tablet and possibly solve potential tabletting issues in R&D can be a lengthy and labour-intensive process. For example, the research team can face significant downtime when changing out different sets of tablet compression tooling on the tablet press. An additional challenge is the cost of purchasing these different sets of tooling, each with a different punch head configuration.

The newly available Quick-Release Tooling (Figure 1) from Natoli Engineering was designed to mitigate the operational differences between R&D and production presses.

Each tooling set comes with a punch barrel, three interchangeable heads (standard head flat, extended head flat and complete dome — Figure 2) and one customisable punch tip.

The three interchangeable heads can be swapped without tools of any kind.

R&D teams can test different dwell times during the research process without needing to buy additional equipment.

FIGURE 2

Natoli Quick-Release Tooling comes with a set of three interchangeable punch heads. Punch heads are available to meet TSM or EU specifications in either B or D sizes.

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23 FIGURE 1

By being able to change the punch heads with speed and ease, the R&D team can evaluate dwell times with respect to both press speeds and head flat profiles — critical components of dwell time. This in turn allows for a more detailed analysis of a formulation’s compressibility as well as greater troubleshooting capacity in the early development stages.

Once this detailed analysis has been performed in the early development stages it will enable the R&D team to determine the ideal dwell time for a specific formulation or product. In some studies, it has been suggested that the length of the dwell time can help with tabletting issues, such as picking/ sticking and capping. However, in recent studies performed at the Natoli Institute at Long Island University it has been shown that some formulations respond negatively to longer dwell times. The results of these studies are set to be published soon.

Additionally, the ability to achieve a specific dwell time is invaluable for continuous manufacturing because as the powder is fed at a specific rate, there is little ability to adjust press speed to achieve the ideal dwell time or to resolve related tablet defect issues.

By changing the head, it is possible to achieve the ideal compression profile for the product while keeping the press speeds at the specific requirement relative to powder feed and desired tablet output.

Other tablet considerations, such as size, shape, and cup configuration, can be evaluated when changing the

By resolving tabletting issues that are typically overlooked at the development stage manufacturers can speed time to production and reduce costs.

punch tips in the early development stages. Once these considerations are assessed then the optimal tablet shape and cup geometry can be discerned. Not only does this afford the teams the opportunity to examine different tablet geometries for postcompression processes, such as coating, but also means that the various tablet geometries can be assessed for potential defects, such as sticking/ picking, capping and edge erosion/ chipping.

SUMMARY Tablet manufacturing issues arise from a multitude of variables such as operator training, calibration and maintenance of equipment, quick delivery parts, tooling and tablet design in addition to the formulation to be compressed.

By resolving tabletting issues that are typically overlooked at the development stage manufacturers can speed time to production and reduce costs. As revealed earlier an important consideration is that of being able to simulate production press dwell times during the research stage of development, which can be a lengthy process. Any innovation that could shorten this process and reduce costs would be a great benefit to tablet manufacturers.

The new Quick-Release Tooling affords research teams to be able to test different dwell times with speed and ease and without requiring several different tooling sets. Also, teams are able to simulate dwell times on a smallturret R&D tablet press before scale-up to a production press, which in turn means that tabletting challenges can be mitigated or solved during the early development phase.

Natoli will be introducing the new tooling set during this year’s ACHEMA exhibition — the showcase of the process industry.

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BIOPROCESSING

At the heart of it…

In this article, Glenn Hiroyasu, Americas development manager for Quattroflow Fluid Systems, examines the challenges of flow rate and pressure in chromatography, virus filtration, TFF and inline blending processes and illustrates why the quaternary diaphragm pump is ideal for use in biopharmaceutical-manufacturing applications.

E

very iteration of unit operation in biopharmaceutical manufacturing must adhere to an unbending set of operational parameters if the desired outcome — a viable, contaminant-free drug suitable for human or animal consumption and administration — is to be realised.

…a better choice is the quaternary diaphragm pump, the operation of which greatly reduces the chance that pulsation and shear will compromise the safety and effectiveness of the final product.

Four of the more common unit operations within the biopharmaceutical-manufacturing universe are chromatography, virus filtration, tangential flow filtration (TFF) and inline blending. For these operations to be implemented successfully, though, the operator must be aware of their specific operating characteristics, all of which revolve around fluid transfer.

THE UNIT OPERATIONS — A CLOSER LOOK Chromatography columns Chromatography columns contain complex target-product adsorbing media that need careful handling.

Protein A resin, for example, can cost as much as $10,000 a litre, making proper feeding of the resin extremely important.

Some chromatography systems require buffer gradients to achieve purification of the proteins. Quite often more than one buffer is required, which creates the need to use two or more pumps.

Because of this, precise pumping is required to achieve the right pH/

conductivity conditions for specific adsorption and high-resolution purification.

Virus filtration Virus-filtration systems are used to ensure the viability and safety of the drugs that are produced through the removal of potential contaminants from products that are created using cell cultures.

The operation of most virusfiltration systems use constant pressures with variable flows.

These flows change as the virus filter becomes clogged. When this happens, the flow rate will not decrease in a linear fashion, which will adversely affect the performance of the filter, product yield and overall quality.

TFF Also known as cross-flow filtration, in TFF the biologic feed stream flows tangentially across the filter membrane at positive pressure.

As it passes across the membrane, the portion of the feed stream that is smaller than the membrane’s pore size passes through the membrane.

TFF is different from what is known as normal-flow (NFF), or ‘dead-end’, filtration because the tangential motion of the fluid across the membrane prevents

molecules from building up a compact gel layer on the surface of the membrane. This mode of operation means that a TFF process can operate continuously with relatively high protein concentrations with less fouling or binding of the filter.

Inline blending Also known as continuous blending or inline mixing, inline blending systems create a new standard for just-in-time-production and reflect the next step in the evolution of continuous-production technology.

In this process, liquid ingredients are fed proportionally to one main stream and are instantly mixed since they are being transferred within a common manifold.

To obtain exactly the right product, this process requires good metering and volumetric efficiency capabilities that can facilitate the automation of the system. When this inline blending is continuous, the blending is instantaneous and there is no space or time available for corrections.

THE ‘PUMP’ CHALLENGE Various pump technologies have been tested and used for the common unit operations. Two of the more popular are lobe and peristaltic (hose) pumps. Both, however, feature operational inefficiencies that may make them insufficient for use.

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Lobe pumps Since many biopharmaceutical materials are contained in a lowviscosity aqueous solution, lobe pumps may not be a good choice because slippage can occur during their operation. Slip will also result in increased shear damage and energy consumption, and if used in a TFF filtration system, there can be noticeable heat addition to the product that requires significant cooling efforts to protect the product from overheating.

Lobe pumps also have mechanical seals, which do not provide full containment unless special (and oftentimes expensive) seals and seal barriers are used. The sterility required in biopharmaceutical handling means that no outside contaminants can be introduced into the purification process, which is something that pumps with mechanical seals cannot reliably ensure.

Finally, the necessary contact between a lobe pump’s internal parts can lead to wear and the generation of particles that can result in product contamination.

Solid particulates can also cause severe damage to the lobes, resulting in damage to the entire product batch.

Peristaltic (hose) pumps The obvious shortcoming of peristaltic pumps is their method of operation, which will undoubtedly produce pulsation — an undesirable in biopharmaceutical manufacturing. Peristaltic pumps also have limited flow and pressure-handling abilities.

They can also release some small quantity of hose material — in a process known as ‘spalling’ — into the pumped product, which

can compromise its purity. If the spalled hose material makes its way to the filter, it can foul the filter, making its operation less efficient than required, which will also lead to contamination.

In the end, the shortcomings of lobe and peristaltic pumps come down to two main things: ● If there is shear, which is common in lobe pumps, you will damage the pumped material ● If there is pulsation, a certainty with peristaltic pumps, you won’t have even flow, which means you won’t have accurate flow THE SOLUTION An effective counter to the operational shortcomings of lobe and peristaltic pumps can be the quaternary diaphragm pump.

In 1986, Frank Glabiszewski was an engineer for a German filter manufacturer who was growing increasingly frustrated with the operation of the pumping technologies that were commonly used in chromatography and TFF applications.

His search for a solution led him to consider the operation of the human heart. With that vision in mind, Glabiszewski and his engineering partner, Josef

Zitron, invented the quaternary (four-piston) diaphragm pump technology. As the use of quaternary pumps has increased, the technology has been modified (disposable plastic heads and wetted parts) to make it applicable in the burgeoning single-use biopharmaceutical-production marketplace.

The four-piston diaphragm technology creates a gentle pumping action through soft ‘heartbeats’, producing four overlapping pumping strokes of the pistons that efficiently reduce pulsation.

The method of operation allows it to gently, safely and securely convey low-viscosity aqueous solutions and biopharmaceutical materials that are highly sensitive to shear forces and pulsation while being pumped.

Of course, not every pump technology is completely perfect for every fluid-handling application.

In this instance, the design and operation of the quaternary diaphragm pump limits it to handling fluids that have a maximum viscosity of 1,000 centipoise and that contain particulates up to 0.1 mm In diameter.

25 CONCLUSION The importance of biopharmaceuticals means that any and all products must meet strict demands regarding their manufacture, with no damage to component materials during critical chromatography, virus-filtration, TFF or inline-blending operations. While lobe and peristaltic pumps have been popular for these unit operations, a better choice is the quaternary diaphragm pump, which greatly reduces the chance that pulsation and shear will compromise the safety and effectiveness of the final product.

Quattroflow offers a complete family of stainless-steel quaternary diaphragm pumps for use in biopharmaceutical manufacturing, many of which can also be outfitted with disposable plastic wetted parts and pump heads.

26

BIOPROCESSING

Contamination risk?

With a trend moving towards more use of single-use bioprocess bags to transport biopharmaceutical solutions Dujuan Lu, PhD (technical client manager/global lead, SGS Life Science Services) and Kate Comstock (senior marketing specialist, Thermo Fisher Scientific) assess whether or not contaminants leach out from these bags, potentially creating a risk to patient safety.

S

ingle-use bioprocess bags are increasingly being used for the preparation, storage and transport of biopharmaceutical solutions, intermediates and final bulk products. These bags are made from plastic materials, and there is the risk that contaminants, additives and degradants may leach out into the cell culture media and remain inside final drug products.

It is therefore an important part of the safety risk assessment process that any such leachable is both identified and quantified.

Leachable contaminants pose a risk to the cell culture process itself and can be toxic to cells used in biopharmaceutical production.

Moreover, leachable contaminants may directly pose risks to patients, either through direct toxicity or because they may alter the efficacy of the medicinal products.

EXTRACTABLE STUDY SGS, in collaboration with Thermo Fisher Scientific, carried out an extractable study on plastic single-use bioprocess bags using different solvent systems, including acidified water, alkaline water, phosphate buffered saline (PBS), and mixtures of organic and aqueous solvents. The aim was to bracket and mimic the pH values, ionic strength and hydrophobicity of common process fluid solutions, then multiple analytical techniques were used to give a comprehensive profile of the extractables.

These included headspace analyses using GCFID & GC–MS for volatile organic compounds, liquid injection GC-FID & GC–MS analysis for semi-volatile organic compounds, and LC-UV & LC–MS analysis for non-volatile organics.

The analysis was carried out on commercially available plastic bioprocess bags. Extractions were performed on the bags using water at both pH3 and pH9, PBS, 1:1 mixtures of both isopropyl alcohol (IPA) and ethanol with water.

Bags filled with the five different solutions were placed in a shaker at 50 °C for seven days, and the extract solutions then analysed using the different techniques.

ANALYSES Headspace GC–MS analysis was used to identify and quantify volatile organic compounds using an Agilent 6890N machine.

Cyclohexanone was found in all of the extracts; this was also found using liquidinjection GC–MS analysis. The overlap in extractable profile by these two techniques reiterates the completeness of the volatile and semi-volatile organic compound profile determined via this method.

IPA was detected in all of the aqueous extracts via headspace analysis. The presumption was that vapour from the IPA/water extract in the bags could migrate into the aqueous solvents within other bags inside the same shaker.

Further studies were carried out, with the bags containing aqueous solvents and those with organic solvents being separated within the shakers, and this time, no IPA was detected in the aqueous extracts. Therefore, in future it will be important to keep the extracts separated to prevent this type of contamination. Covering the bags with aluminium foil without separating the bags also greatly decreased the IPA levels in the aqueous extracts.

Only by understanding what might be extracted, and the quantities that are likely to be extracted under what conditions, can the risks that extractables may pose to patients be assessed and quantified.

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RT: 4.50 - 46.00

NL: 5.00E9 TIC MS 03282016006

5000000000 4500000000 24.10 4000000000

Relative Abundance

3500000000 3000000000 2500000000 2000000000 1500000000

FIGURE 1

1000000000 500000000 5.02 0

7.43

8.83 9.79 12.27 14.73 16.36

5

10

15

25.70

19.10 22.62 22.84 20

27.00

25 Time (min)

42.85 43.87

31.88 32.95 34.33 36.01 38.48 30

35

40

45

RT: 4.50 - 46.00

NL: 5.00E9 TIC MS 03282016016

5000000000 24.10

4500000000 4000000000

Relative Abundance

3500000000 3000000000 2500000000

5.04

2000000000

FIGURE 2

1500000000 1000000000 500000000 0

7.42 5.85

8.51

5

10.86 11.88 10

16.36 15

23.63 19.46 22.84 20

25.71 27.00 25 Time (min)

31.62 32.59 34.14 35.41 37.74 39.16 30

35

43.45

40

45

RT: 4.50 - 46.00

NL: 5.00E9 TIC MS 03282016010

5000000000 24.10

4500000000 4000000000

Relative Abundance

3500000000 3000000000

24.37

2500000000 2000000000

Ethylhexyl

1000000000 500000000 0

4.99

7.42

5

16.37 7.76 11.51 13.72 14.73 10

15

27.01

n

FIGURE 3

1500000000

18.99

23.64 25.72

22.85

27.34

20

25 Time (min)

31.90 32.98 34.28 36.00 37.73 30

35

42.47 43.43 40

45

RT: 4.50 - 46.00

NL: 5.00E9 TIC MS 03282016020

5000000000 24.10

4500000000 4000000000

Relative Abundance

3500000000 24.37

3000000000 2500000000 5.08 2000000000 1500000000

FIGURE 5

FIGURE 4

27.01 1000000000 23.64

500000000 0

7.44 5.88 5

8.17 9.80 11.44 10

14.26 16.36 15

18.99 20.85 20

25.72 25 Time (min)

27.35 30.69 33.12 33.70 30

36.30 36.50 39.09 35

40

43.25 44.28 45

GC–MS analysis was used to identify and quantify semi-volatile organic compounds, using a Thermo Scientific ISQ LT single quadrupole GC–MS system with National Institute of Standards and Technology (NIST) library, and a Thermo Scientific Q Exactive high resolution accurate mass (HRAM) GC– MS/MS system to aid identification. The aqueous extracts are usually solventexchanged with dichloromethane (DCM) before injection, but emulsification can be problematic with liquid–liquid extraction if there is a high amount of alcohol in the samples. The effect of solvent exchange was therefore studied by injecting the ethanol/water and IPA/ water extracts both with and without DCM extraction, as shown in Figures 1–4.

Better peak shape and higher recovery were observed in the samples with DCM extraction, regardless of emulsion and phase separation issues.

The highest concentration of extractables was found in the IPA/ water extract, particularly hydrophobic compounds. The major peak in every extraction was bis-(2-ethylhexyl) phthalate, or DEHP, which is the primary plasticiser used in these plastic bags. The majority of the rest of the extractables were phthalates, degradation products from DEHP, and lubricants.

LC–MS analysis was used to identify and quantify non-volatile organic compounds, using a Thermo Scientific Q Exactive high resolution accurate mass (HRAM) LC–MS/MS system.

Identification of unknown compounds in the LC–MS analysis for non-volatiles was more challenging as there is currently a dearth of standardised spectral libraries and LC–MS spectra vary from vendor to vendor significantly.

Instead, a high-resolution accurate mass (HRAM) full scan and MS/MS data acquisition with polarity switching was used to aid structure elucidation.

This technique ensured the detection of structurally diverse compounds, provided a comprehensive extractable profile, and increased the analysis throughput.

27 As can be seen in Figure 5, 20 extractables are evident in the IPA/ water extract, significantly more than was seen in any of the other four solvents, both in terms of number of peaks and concentration. To identify the compounds, the HRAM data was processed using Thermo Scientific Compound Discoverer small molecule structure analysis software.

This gives structure predictions and then performs an online library search against ChemSpider (RSC) and mzCloud (HighChem), as well as a local extractables and leachables compound database search. Again, the major peak observed from all extracts was DEHP. Higher concentrations of hydrophobic compounds were detected in the IPA/water extract. There were two extractables in the IPA/water extract with the same molecule weight and chemical composition, but which eluted with different retention times, indicating that they were structural isomers.

An MS/MS analysis indicated a different fragmentation pattern. Running both full scan and MS/MS analysis will be required to get the full picture.

IMPORTANCE OF COMPREHENSIVE INVESTIGATIONS The study highlighted the importance of carrying out careful, comprehensive investigations into how plastic bioprocess bags being used for biopharmaceutical products behave when in contact with liquids that might extract compounds from them. Only by understanding what might be extracted, and the quantities that are likely to be extracted under what conditions, can the risks that extractables may pose to patients be assessed and quantified.

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ANTI-COUNTERFEITING

For all practical purposes As the falsified medicines directive is set to come into full force early next year, Christian Taylor, serialisation business consultant, Zetes, looks at the key challenges and practical questions relating to achieving compliance in more detail.

T

he falsified medicines directive (FMD) 2011/62/EU will come into full force on 9 February 2019. With approximately 1% of medicines sold in developed markets being counterfeit, the global counterfeit drug market is worth $200 billion a year.1 The legislation aims to prevent counterfeit or unauthorised prescription medicine entering the legal supply chain, providing greater protection for patients.

With less than a year to go until the regulation comes into force, wholesalers and logistics providers know they need to do something now to become compliant. But, some may not know exactly what that looks like in practice…

WHAT DO THE REQUIREMENTS MEAN FOR DIFFERENT PARTS OF THE SUPPLY CHAIN? At the beginning of the supply chain, the pharmaceutical manufacturer has responsibility for serialising cartons, sealing the product and then uploading the unique identifiers to the European Hub, known as the European Medicines Verification System (EMVS).

At the end, the dispensing pharmacist must be able to scan, verify for authenticity and decommission that product against a national hub, known as the National Medicines Verification System (NMVS). If the pack matches the information

in the repository, the pack is decommissioned and dispensed to the patient. Alternatively, if there is a warning related to the pack, the package will not be dispensed to the patient and an investigation will be made to see if the medicine is falsified.

This leaves the middle of the supply chain, where there is also a requirement for wholesalers and logistics providers to implement a ‘risk based’ approach to verification and decommissioning of product passing through their operation.

They will also have to

decommission products on behalf of some of their customers who do not operate within a healthcare institution or a pharmacy but who nevertheless use or supply medicines on an occasional basis.

To achieve compliance by February 2019, wholesalers will need to implement a system that enables verification, decommissioning or recommissioning of packages, linking with the respective country’s national hub. >>>

30

There’s no denying that the benefits of the FMD regulation far outweigh any of the complexities.

ANTI-COUNTERFEITING

WHAT’S INVOLVED FROM A PRACTICAL SENSE? In simple terms wholesalers and logistics partners need three components: 1. The ability to scan 2D data matrix barcodes, either using mobile handheld devices, desktop scanners or automated imaging technology.

2. A software application that enables the pack, once scanned, to be verified instantaneously against data held on the National Medicines Verification System (NMVS), managed by the local National Medicines Verification Organisation (NMVO). In some cases, such as for ‘Article 23’ organisations wholesalers will also need the software to decommission or recommission product. Decommissioning could also be required where the product is being exported out of the EU, or where damage is incurred.

3. The ability to capture and record all events associated with verification and decommissioning for a period of up to 10 years. The immediate priority for wholesalers must be to comply in the most cost-effective and efficient way possible. For some, there could also be additional business value that comes with being compliant. The ability to manage a serialised warehouse brings greater track and trace capabilities and further safeguards businesses and patients alike.

REFERENCE: 1 | Pharmaceutical Serialisation: Compliance and Beyond, EY, 2016.

CAN COMPLIANCE BE ACHIEVED WITHOUT OVERHAULING LEGACY SYSTEMS? In short, the answer is yes. There is a concern that to introduce FMD compliance into the warehouse, a costly ‘rip and replace’ approach is required. This doesn’t have to be the case. For reduced complexity, speed and cost

effectiveness, businesses should look to partner with organisations that can provide a single source solution — warehouse process and technology integration expertise, a data/event visibility platform and seamless connection with a national medicines verification system.

Expertise of integrating with existing WMS or ERP systems is highly advisable. This can provide significantly reduced implementation times (crucial with such tight deadlines) at a much lower cost.

CAN A WHOLESALER COMMUNICATE WITH THE EMVO? No, Market Authorisation Holders (MAH) are the only organisations that are able to communicate directly with the European Hub (EMVO). However, wholesalers will not only need to have the capability to handle the product but also the ability to send data to and connect to their respective country’s national hub (NMVO) or potentially multiple national hubs if importing.

Any information that is reported by an MAH to the European hub will be sent directly to the relevant national hubs, which can then be accessed by wholesalers, parallel distributors and pharmacists.

The important thing for organisations to consider at this time is that currently, no one is handling the data of individual products on the line.

To be compliant and report to the national hubs, wholesalers and logistics partners are going to have to review current processes and ensure they can handle data for any single packet within their warehouse.

WHAT ABOUT ARTICLE 23?

Article 23 is yet to be fully defined, it will cover any prescription medicine destined for nonhealthcare institutions. Ultimately,

those organisations wouldn’t have the authority to log into the national hub to decommission a product. Wholesalers delivering to these places will hold the responsibility of verifying and decommissioning prior to delivery.

BEYOND COMPLIANCE; FUTURE PROOFING SUPPLY CHAINS Ultimately, serialisation can be seen as the entry level for track and trace, enabling businesses to capture all of their supply chain events. The ability to capture and store data this way — creating complete real-time visibility and greater traceability will unlock efficiencies throughout the entire supply chain. It is very likely that legislation will progress in the coming years. It can already be seen in other countries that have undergone serialisation, which have now moved on to track and trace. Behind this legislation, there are distinct efficiency and quality advantages to be found.

If organisations embrace these regulatory changes — using them as an opportunity to optimise their supply chains, update data flows and break down silos — they can create true business value.

There’s no denying that the benefits of the FMD regulation far outweigh any of the complexities.

If wholesalers and logistics partners use this opportunity to improve capability within the warehouse, they will open up the ability to build comprehensive and agile visibility infrastructures. This will not only ensure compliance by the specified date, but these infrastructures can be built upon further, putting wholesalers in a better position to react to any further regulation changes with ease.

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According to the Global Health and Aging Report by the World Health Organization (WHO), “The number of people aged 65 or older is projected to grow from an estimated 524 million in 2010 to nearly 1.5 billion in 2050, with most of the increase in developing countries.”1

to self-inject a therapy without medical supervision or additional equipment. Enabling patients to self-administer during the course of their normal daily lives, such as at home, at work or even in a café, can significantly improve their quality of life and potentially increase therapy compliance.

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The WHO attributes this significant increase in the elderly population to extended life expectancy, which will also involve a change in the major cause of death from infections to chronic noncommunicable diseases.

Particularly in high-income countries, conditions that are often related to obesity, including hypertension, high cholesterol, diabetes and heart disease, are having a major impact on the aging population, along with chronic diseases, such as arthritis, cancer and dementia.

From the pharmaceutical industry point of view, however, biological drugs are very challenging to stabilize and administer, especially in a syringe or other drug delivery device, due to their complexity, sensitivity and viscosity. These challenges require a new generation of glass containers that enable give functionality to drug delivery systems, thus ensuring reliability and patient safety.

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Ompi, the Stevanato Group subsidiary specializing in glass primary packaging, has leveraged its expertise in the manufacturing of cartridges and syringes in a ready-to-fill format called EZ-fill to develop a breakthrough solution that addresses some of the most challenging needs in drug delivery systems.

EZ-fill has the widest range of sterile, depyrogenated and ready-to-fill glass containers for pharmaceutical applications.

In this scenario, where healthcare costs continue to climb due to the aging population biological drugs have revolutionized disease treatment and the companies who develop them have grown in parallel with this. Global biological drug sales are expected to grow from $161 billion in 2014 to $287 billion by 2020, with a projected annual growth rate of 10.1%, according to Roots Analysis.

Biological drugs, especially monoclonal antibodies (mAbs) and recombinant proteins, allow the pharmaceutical industry to treat critical diseases that were viewed as incurable in the past.

It is clear that the reasons behind this escalated growth include the progressive switch from blockbuster medicine to personalized treatments and the growing trend to treat patients outside hospitals, especially those who suffer from a chronic disease requiring the use of auto-injectors and wearable devices.

Drug delivery systems, notably wearables, auto-injectors and pen injectors, have the potential to generate a significant reduction in total healthcare costs by allowing patients

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Nexa is the top-of-the-range solution in the EZ-fill platform.

EZ-fill World, your primary packaging market standard In this evolving market context, pharmaceutical companies are moving away from a traditional, top-down model towards a flexible approach that offers personalized, safe and effective treatments, often based on highly potent drugs. This quest for flexibility translates into production in small batches and cutting down on non-core activities for the sake of efficiency.

Reduced time-to-market Over the years, its proven advantages have led this processing technology to be adopted as a standard by numerous glass primary packaging manufacturers. Pharmaceutical and biotech customers can benefit from an easy, flexible and streamlined process as they can immediately fill the ready-to-use vials or cartridges and shorten their time to market.

Increased quality: Ensuring patient safety Patient safety is at the heart of container design and engineering. Through the separation of all containers in the secondary packaging, Ompi EZ-fill ensures maximum integrity of the container during the transportation phase and in the buffering/ in-feeding operations, while ensuring no glassto-glass contact. This allows for an effective mitigation of the risk of breakages, cosmetic issues and particle generation. This in turn brings significant advantages, both from the mechanical and the performance point of view, because it dramatically reduces production stops and rejects during inspection.

REFERENCES: 1 | Global Heath and Aging, World Health Organization, 2011 2 | Large Volume Wearable Injectors 2014-2025, Roots Analysis

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ANTI-COUNTERFEITING

Are you ready… …for serialisation? After a preview of TraceLink’s second annual Global Drug Supply, Safety and Traceability survey has revealed disparity in terms of readiness for the falsified medicines directive between pharma companies and CMOs, three experts give us their perspectives on serialisation.

I

n a preview of the results of TraceLink’s second annual Global Drug Supply, Safety and Traceability survey, it emerged that business leaders throughout the EU pharma industry do not have true insight into each other’s readiness when it comes to meeting the falsified medicines directive (FMD) serialisation deadline.

The results showed that in the EU: ● Only 4% of pharma companies with EU FMD requirements have not yet begun preparations for serialisation. ● However, not one of the EU FMD pharma companies that feel ‘very ready’ for serialisation are fully integrated with their contract manufacturing organisations (CMOs).

When EU FMD CMOs were asked about their serialisation readiness: ● 94% of CMOs serving customers with EU FMD requirements stated that they felt somewhat or very prepared for serialisation, 42% of them have not yet begun their preparations. ● Over half (53%) of those that responded felt that brand owners were ready. ● Nearly half (48%) said they had integrated with pharma companies. ● This again contradicts the responses from pharma companies with 68% reporting that they felt somewhat or very prepared for serialisation.

With the deadline for the EU FMD now less than a year away and pressure mounting on businesses to start implementing their serialisation solutions and integrating with partners, this disparity between internal and external perceptions of preparedness has the potential to create more tension in the sector.

Three experts from businesses that have successfully implemented serialisation programmes, reveal what they think are the challenges around serialisation, what is causing scepticism in the industry and what can be done to resolve it.

PARTICIPANTS: Dexter Tjoa — director of corporate strategy, Tjoapack ● Michael Unbehaun — manager of engineering projects and serialisation team lead, R-Pharm ● Staffan Widengren, director of corporate projects, Recipharm ●

THE CHALLENGE FOR CMOS AND CPOS Tjoa: When it comes to serialisation, timing is crucial and is the obvious challenge. There are no shortcuts to compliance and less prepared CMOs and CPOs are now facing an uphill struggle to meet track and trace deadlines. It is vital that they decide to put in the necessary work or engage with well-prepared trading partners who can provide a compliant solution for them.

Unbehaun: During the planning and implementation of R-Pharm’s serialisation project, we encountered several challenges linked to resourcing and access to expertise. We found that there were gaps in technical and IT knowledge and vendor service availability was poor due to the demand created by time constraints.

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We found that there were insufficient process definitions and security across the site, with issues identified in areas from master data management and production planning to regulatory change management and data integrity gaps. When testing and subsequently implementing our solution we found that there were decreases in line efficiency and extended ramp-up phases that had to be considered.

These roadblocks all required additional dedicated resources for the project to be a success. Lesser prepared businesses that haven’t built some flex into their serialisation budgets would be well advised to do so.

Widengren: One of the biggest challenge we’ve encountered at Recipharm in our preparations for serialisation has been the on-boarding of smaller and mid-sized virtual market authority holders and brand owners. There remains a lack of understanding among these companies when it comes to the complexity of connecting with their partner CMOs and the EU-Hub subsequently.

A HEALTHY DOSE OF SCEPTICISM Widengren: Scepticism when it comes to readiness has many root causes. There remains a lack of understanding among some marketing authorisation holders (MAHs) and brand owners as to the complexity of implementing a serialisation programme.

There’s also a belief (or hope) in some quarters, that the EU will extend the implementation deadline as happened in the US. Extending the deadline in the EU would require agreement from all member states as opposed to a singular central government in the US. Given that some countries are very advanced in their preparations, this agreement is very unlikely.

The recently passed track and trace law in Russia is also likely to affect serialisation programmes across the EU. The requirements are

33 still uncertain however the law has allowed for intermediate deadlines for implementation and the governing body in Russia has inferred that these may be very short — potentially being sooner than those of the EU’s FMD. Tjoa: Industry readiness has been widely discussed and the lack of preparation has been evident, particularly in the FDA’s decision to delay the active enforcement of the Drug Supply Chain Security Act (DSCSA). It is therefore easy to see why companies throughout the supply chain would be unsure of each other’s levels of preparedness for serialisation requirements.

The industry has, in many quarters, underestimated the task of serialisation. Companies have been slow to react and are now scrambling to get their programmes in place as they begin to recognise the scope of the task at hand and the urgency to get started.

Unbehaun: Insufficient knowledge of each other’s related organisational and technical procedures can lead to a high-risk project readiness situation between CMOs and MAHs. RESOLUTION BEFORE SOLUTION Unbehaun: To resolve these issues, it is important that the MAH is building up the right level of transparency on project milestones and deadlines together with the CMO. The MAH should be able to specify and monitor the CMO’s progress and level of readiness in relation to single projects steps, including equipment, IT and organisational readiness. For this to be possible, a decision tree with the most important milestones including escalation situations is helpful.

Tjoa: As a rule, serialisation takes an unprecedented amount of cooperation and information sharing between all trading partners and the pharmaceutical industry is struggling to tackle this task. However, as we move past the initial implementation phase, companies will begin to realise the obvious efficiency benefits to this kind of transparency. As a result, we will inevitably see communication between partners improve.

For more information To read the full 2017 Global Drug Supply, Safety and Traceability Survey Report, visit https://www.tracelink.com/global-drug-supply-report/2017-report.

The results of the report and their implications for the pharmaceutical industry will also be discussed at FutureLink Munich, which will take place June 5-7, 2018. The event will see leaders from across the pharmaceutical and healthcare industries gather to discuss regulatory compliance and shaping the future of digital drug supply with information sharing networks.

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ANTI-COUNTERFEITING

A LONG WAY TO GO… Five years on from the adoption of the EU falsified medicines directive (2011/62/EU) and the challenge continues. Here Vincenzo Salvatore, Healthcare and Life Sciences Focus Team, BonelliErede (Milan), looks at the reasoning behind the directive and what the next steps are to achieve the ultimate goal of protecting public health.

T Early attempts by companies to fulfil Policy 0070 requirements have left quite some room for improvement.

he illegal marketing of falsified medicines is constantly increasing and is a serious threat to patients’ health.

Falsified medicines should be distinguished from other illegal medicinal products and from products that infringe IP rights: A falsified medicine is commonly defined as a fake medicine that passes itself off as a real, authorised medicine.

Over the last few years, national governments and international organisations have implemented several initiatives to address this phenomenon and mitigate the risk of exposing patients to falsified medicines, i.e., to medicinal products that (according to the definition approved by the World Health Assembly of the World Health Organisation, WHO) deliberately/fraudulently misrepresent their identity, composition or source. Falsified products usually contain substandard, falsified ingredients, no ingredients, or ingredients (including active substances) in the wrong dosage. A few years ago, the WHO also set up the International Medical Products Anti-counterfeiting Taskforce (IMPACT), which is tasked with developing principles to serve as a model for national legislation to combat falsified medicinal products.

The fight against falsified medicines is particularly challenging, as experience shows that they can reach patients through both illegal routes and the legal supply chain. This latter circumstance requires that national and international legislative measures be adopted to monitor not only the manufacturing process and identify the various means of product tampering but also to reinforce the obligations on all economic operators (manufacturers, wholesalers, distributors, etc.) in the supply chain. An obligation imposing them to cooperate in detecting and reporting all possible infringements to the competent national authority is essential to reach the goal. For legislative measures to be effective, they need to be accompanied, as is the case in Europe, by strong deterrents. These include significant financial penalties on stakeholders that fail to fulfil their legal obligations and greater cooperation from customs officers to check imported medicinal products.

The EU falsified medicines directive (Directive 2011/62/EU, adopted on 8 June 2011) is one of the most important tools adopted at European level: It sets out the rules to tackle the alarming

increase in falsified medicinal products in the EU. The directive was recently implemented at EU level through the adoption of Delegated Regulation (EU) 2016/61, which will apply in less than a year: on 9 February 2019.

The recently adopted delegated Regulation sets out what safety information must be included on the packaging of prescription only medicinal products.

Establishing and strengthening a robust regulatory framework at national and, to the best possible extent, international level is the most effective way to ensure a safe market. There is still a long way to go — especially if you consider that only 20% of WHO member states have effective, well-developed regulatory systems, compared to the approximately 30% that have no or very limited regulation.

Implementing effective technologies, raising awareness and a good enforcement system all have to be identified as essential elements — to be used in combination — to achieve the goal (i.e., to better protect public health).

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BIG DATA

Bridging the gap In a world where manufacturers must not only prove their product’s safety and efficacy prior to launch, but also ensure commercial success, real-world evidence (RWE) is crucial. Here, Dr Chitra Lele, chief scientific officer at Sciformix Corporation discusses the RWE’s continuum and how it could bridge the gap between clinical development and patient access.

R

eal World Evidence (RWE) is defined by the FDA as ‘clinical evidence regarding the usage and potential benefits or risks of medical products derived from analysis of Real World Data (RWD)’.1 RWD is the data collected from sources other than traditional clinical trials. These data are being obtained from electronic tracking systems used to capture patient experiences during care.

RWE is increasingly crucial for life science companies to ensure patient access and commercial success. Generating and leveraging RWE requires technical expertise along with strategic insights for informed healthcare decisions and optimal outcomes.

However, as the sources of RWD are disparate and the quality can vary greatly, accessing, analysing and drawing conclusions from the data is more challenging than ever. Going forward, RWE will become increasingly more patient centric, as highlighted through the growing emphasis by payers and regulators for advances in this area.

RWE IN CLINICAL DEVELOPMENT AND POST APPROVAL RWE has a role in both preand post-approval. In the clinical development stage RWE can enhance the effectiveness of randomised clinical trials, for example in the initial phases (Phase I and Phase II) it can aid in the identification of patient sub-populations and in

understanding patient pathway, disease progression, treatment preferences and patient related outcomes (PRO’s). RWE facilitates operational aspects of drug development by optimising patient recruitment and patient access.

Post-approval RWE can assist in generating further insights to improve safety and effectiveness of products, prescribing patterns and adherence, along with real world health outcomes.

A value-based, patient outcomes approach is driving the role of RWE in formulating a product’s evidence requirements across the development continuum.

RWE may potentially explain facets like head-to-head comparative effectiveness, differentiation in sub-population and effects of switching.

For example, data from an observational study among insulinnaïve patients with uncontrolled Type 2 diabetes was used to assess health outcomes of Toujeo (insulin glargine) compared to basal insulins.2 RWD pooled from US insurance claims databases was used to demonstrate effectiveness of Eliquis (apixaban) among non-valvular atrial fibrillation (NVAF) patients.3 RWE IN PATIENT ACCESS RWE can play a positive role in improving patient access by providing payers with information on the effectiveness in the real world and the cost-effectiveness in comparison to other drugs on

the market. RWD can improve health outcomes for patients and help pharmaceutical companies to develop a more efficient and streamlined commercialisation process.

The scope of RWE in market access includes achieving optimal price and full reimbursement, favourable recommendation from health technology assessment (HTA) authority and inclusion in various formularies at hospital, regional and national levels. As an example, RWE from US insurance claims helped Zytiga (albiraterone acetate) receive recommendation

by National Institute for Health and Care Excellence (NICE) for prostate cancer patients.4 Performance-based risk-sharing arrangements (PBRSA) involve conditional reimbursement by payers based on health outcomes and help improve market access for manufacturers. RWE provides insight into the impact of new intervention in the ‘real’ patient population; focusing on the efficacy to effectiveness translation. Smart contracts can be used to trigger drug reimbursement from insurers only for responders, thus enabling risk sharing between the stakeholders, based on RWD sharing via blockchain technology. RWD is also important for high-priced therapies; wherein ‘micro-pricing’ agreements are fulfilled based on attaining continuous outcomes and quality of life targets. There is an example of a pay for performance

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agreement in the cardiovascular area; wherein reimbursement will depend on reduction in heart failure hospitalisations.5 CLINICAL DEVELOPMENT TO PATIENT ACCESS: THE RWE CONTINUUM Previously, there was a difference in the evidence requirements for clinical development and patient access. The continuum of RWE looks to bridge this gap with value-development plans. In the now saturated pharmaceutical market, manufacturers must not only prove their product’s safety and efficacy prior to launch, but also present evidence-based recommendations on the way the product’s value is determined, demonstrated, communicated and realised in the market.6 The plan should be formulated during the proof-of-concept phase, and later include new information over the

product lifecycle as it evolves.

RWE allows for more accurate conclusion about medications to be drawn and provides new insights.

EVOLVING RWE Going forward, drug pricing will be based on health outcomes rather than payment per pill. The current constraints of using and leveraging RWE will be mitigated by the use of technologies like big data, machine learning and blockchain technology. The evolution of the Internet of Things (IoT) means that the future sources of RWE are likely to be much more diverse. Furthermore, blockchain technology will enable more secure storage of patient health data and the direct transmission of anonymised

e enc r e r diff s a ents fo a t w ere uirem patien h t , eq ly nd ous ence r ent a f RWE i v Pre e evid elopm um o u v h in t cal de contin gap… s i i e clin ss. Th dge th i e acc s to br k loo

data to pharma companies, helping to incentivise the right health outcomes in the system.

Also, precision health economics outcomes research (HEOR) through big data can aid healthcare decision-making tailored to specific clusters, so as to provide the most optimum and cost-effective individualised treatment.7 RWD obtained from wearable technology can be used by regulatory and HTA authorities to determine drug effectiveness.

Perhaps the biggest impact of these future trends will be felt in the emerging markets by ‘leapfrogging’ the aforementioned innovations.

SUMMARY With increasing emphasis on using RWE seamlessly across the entire product lifecycle, from development to patient access and back to discovery and development, there’s a distinct advantage to having cross-skilled teams. Solid experience in clinical trials with a strong orientation to the needs of real world studies and the peculiarities of RWD is the need of the hour.

Since the volume of work to be done in RWE, HEOR and MA is growing, largely due to vast amounts of data being available and the advances in data analytics, partnering with service providers with the required domain understanding and robust analytical and scientific writing skills is becoming more prominent. Partners who have the right blend of clinical development and patient access experience will be well-poised to provide value-added support to their clients.

37 REFERENCES: 1 | FDA. Real World Evidence. 2018. Available online: https://www.fda. gov/ScienceResearch/ SpecialTopics/ RealWorldEvidence/default. html [accessed 27/02/2018].

2 | Sanofi, 2017. Switching to Toujeo in a real-world setting produced a similar number of severe low blood sugar events as insulin Degludec. (Internet) http:// www.news.sanofi.us/201711-30-Switching-to-ToujeoR-in-a-real-world-settingproduced-a-similar-numberof-severe-low-blood-sugarevents-as-insulin-degludec [accessed 27/02/2018] 3 | Bristol-Myers Squibb Press Release, 2017. BristolMyers Squibb and Pfizer Present Observational RealWorld Data Analysis on the Effectiveness and Safety of Eliquis (apixaban) 4 | Ramaekers, B.L.T., et al, 2017. Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic CastrationResistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal PharmacoEconomics (2017) 35: 191. (Internet) https:// doi.org/10.1007/s40273016-0445-5 [accessed 27/02/2018] 5 | Omar Ishrak. Medtronic.

2018, Jan 8. 36th Annual J.P. Morgan Healthcare Conference, San Francisco.

(Internet) file:///C:/ Users/ppal/Downloads/ Release0463fc6ed125-459e-a1e04f83a78b9ad9_2324263. pdf [accessed 28/02/2018] 6 | Business wire, 2016.

Cigna Implements Value-Based Contract with Novartis for Heart Drug Entresto (Internet) https://www. businesswire.com/news/ home/20160208005778/ en/Cigna-ImplementsValue-Based-ContractNovartis-Heart-Drug [accessed 28/02/2018] 7 | Richard Borrelli, 2008. Health Economics, Outcomes Research and Brand Strategy-Canadian Pharmaceutical Marketing, An IMS Viewpoint.

(Internet) http://www. stacommunications.com/ journals/cpm/2008/04April%202008/023-IMS.pdf [accessed 22/01/2018]

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BIG DATA

DISRUPT OR BE DISRUPTED? Why blockchain will change your world Here, Scott Allison, president, Life Sciences & Healthcare, DHL, and Keith Turner, CIO Chief Development Office, Life Sciences & Healthcare, Service Logistics, DHL Supply Chain, look at the importance of blockchain in logistics.

I

n the life sciences and healthcare industry, everyone is anticipating farreaching change with the introduction of mandatory global serialisation for pharmaceuticals. New rules to ensure product integrity all the way from manufacturing to consumption may save as many as a million lives each year — Interpol’s estimate of patient deaths caused by counterfeit drugs.

We would argue, though, that more profound change is just around the corner — a level of transformation that will impact the entire life sciences and healthcare industry. Now is a great time to investigate the possibilities of a rapidly maturing technology known as blockchain. Applied the right way, this technology will take track and trace serialisation to the next level, cutting costs, elevating security and trust, eliminating error-prone data movements and enabling real-time supply chain transparency.

WHY IS BLOCKCHAIN IMPORTANT TO LOGISTICS? Blockchain is an important part of today’s increasingly digitalised logistics.

It can authenticate and track every important event in the production and movement of a product in a way that makes fraud nearly impossible. This ability to authenticate products through

a seamless, uninterrupted chain of custody is especially interesting as a way to protect against counterfeiting of pharmaceuticals and ensure the greatest possible transparency along the supply chain.

WHO KNOWS ABOUT BLOCKCHAIN? DHL and Accenture have together extensively explored and evaluated the usability and scalability of blockchain in the life sciences and healthcare industry.

We have established a blockchainbased track and trace serialisation system in six distinct geographies worldwide, populated by more than seven billion unique pharmaceutical serial numbers and handling more than 1,500 transactions per second. Along the way, we have learned lessons from other industries already using this technology: the diamond, livestock and finance industries (blockchain is the technology behind Bitcoin).

WHAT CAN IT DO FOR LIFE SCIENCES? Blockchain is a distributed ledger — a database that permits data to be broadcast to all authorised stakeholders in the supply chain but forbids fake data.

Manufacturers, warehouses, distributors, pharmacies, hospitals, doctors and especially patients are rewarded with what we call ‘a shared version of the truth’.

When a life sciences or healthcare company creates a unique serial number for a unit of medication or piece of equipment, this number is scanned, captured and verified at the point of origin. Using blockchain, as each item moves through the supply chain, additional verified information is appended. These blocks of data cannot be tampered with and are collectively validated by all stakeholders. The result is an end-to-end system that is simpler and more secure than anything we have seen before. It is more private, more transparent and more efficient, with less risk and it meets and exceeds global serialisation requirements.

This is just one of many use cases that will be highlighted in our upcoming trend report on blockchain.

WHEN CAN WE IMPLEMENT THIS SYSTEM? Right now we are moving our blockchain-based track and trace serialisation system out of the lab and into the supply chain.

This technology is ideal when the supply chain involves many parties that are geographically spread, with high potential for mistrust and a pressing need for security, privacy and fraud prevention.

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BIG DATA

Reducing the odds In this guide, Manuel Duval, PhD, from Scientist.com looks at how pharma and biopharma companies can best prepare for the impact of big data in healthcare.

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he ultimate goal of the set of technologies collectively referred to as big data is to provide the means to improve the accuracy of the decisions and to decrease the latency of making them. In competitive business environments, applying big data is not a choice; it is a necessity to sustain the organisation and achieve growth. In the healthcare area, it is a moral obligation, reducing uncertainty and delivering optimised treatments.

In short, big data is the means of reducing the odds.

Big data has been primarily enabled by the ability to collect and consume census-scale data sets with respect to some problem space. Before the advent of big data, analysts relied on sampling from a population and, depending on the size of the samples, were able to come up with some conclusion bound with some level of uncertainty.

At the base of the big data stack is the physical layer — the very large cluster of racks in data centres operated by numerous cloud service providers (CSP) accessible via broad network access. Aside from analytics, the ‘big’ attribute of big data also has meaning in information technology: above a certain threshold in terms of size (tera, petabytes and beyond) data sets cannot be handled with traditional data storage technologies. The prevailing solution in that area is the opensource Hadoop Distributed File

System (HDFS) technology whose specifications are maintained by the non-profit Apache Software Foundation.

From the perspective of a new or prospective big data user, the good news is that there is no need to become an expert in HDFS technology to take advantage of the power of big data. The other great advantage in contemplating big data usage is that it does not require capital expenditure. Instead, it comes from the operational side of the organisation and frees up the ‘big’ headache of procuring hardware. No more is it necessary to allocate a significant amount of time to plan ahead for the right IT infrastructure, hoping to target the right size. However, some planning remains necessary.

At first, procuring computing services could be loosely compared to purchasing transportation services. One does not need to invest in a vehicle that would not fit all-year various needs. Instead, one uses a ridesharing service that fits the current need. In addition, there is no need to consider parking, maintenance of the vehicle, dealing with the consequence of an accident or breaking parts. The same more or less holds true for cloud computing services with some minor differences: ● Data hosting: For big data, one needs a ‘home’ for the data sets the organisation plans

to mine. In that respect, CSP providers offer several options: (i) free data storage, but pay per analysis. This option is usually offered by large CSPs who provide extremely efficient data query solutions allowing users to mine terabytes of data in minutes or even seconds.

The CSP charges on the amount of data queried, not on the storage, which comes in handy when one has very large data to host but only needs to query sparsely; (ii) a mix of both — a renting space for your data at a discount with some additional fee when IO and CPU intensive queries are run. ● Resources availability: Some CSPs offer pre-emptive resources at a very large discount, which means that if the business deploys an application that requires long CPU time over numerous nodes but can be stopped and restarted without losing its state, it can procure pre-emptible virtual machines. In the event the CSP needs them because of a spike on its side, the user is alerted with short notice, enough to stop, and then restart when the resource becomes available again. Another point to consider is network access: large CSP provides multi-regional data centres in US, Europe and Asia.

When high availability and low data latency is required, it is preferable to procure CSP from the geographically closest data centre.

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● Portability and ranges of services: This is another critical aspect in selecting the CSP, depending on the business needs. CSP comes in three flavours: (i) IaaS, Infrastructure as a Service. This applies when the organisation only needs to procure computing, storage and network resources, regardless of OS and software. Some IaaS providers allow users to deploy their own virtual machine solution on top of the bare-metal hardware; (ii) PaaS: Platform as a Service: on top of the hosting operating system, users have the options to run services such as a web server application, file system management, database management etc. The users in that case are not involved in maintaining these applications and can deploy their own higher-level programs relying on these services and develop their own via CSP provided API; (iii) SaaS: Software as a Service: this is the turnkey solution when a specific application is hosted on the cloud by the CSP and the users consume it directly, usually via a web browser client application. Google Docs is an example of a typical SaaS. ● Applications: Some CSPs do provide advance machine learning solutions one could readily apply to its own data space (provided of course that the data is large enough). ● A ccess management: Regarding data security; the jury is obviously still out, and one could argue that data is safer when hosted by one of the major CSPs instead to be on premises depending on who administers the firewall.

That being said, when dealing with large data, user access management is evidently critical. Good CSPs provide users with management

solutions, referred to as identity and access management (IAM) allowing fine tuning of the user’s access to assets and resources. Most useful IAMs provide various levels of administration. ● Last but not least, precious time is usually allocated to develop applications and their persistence across different environments. Portability of systems is paramount and readily possible with technologies derived from virtual machines. Containers allow you to create an image of a full deployment stack and port it to a completely different environment. Another major advantage of containers is that they can be stopped and restarted quite easily, which allows some saving

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on resources usage. Once done with a job, one could stop the container, store it as an image in a free-hosting hub and restart it only when needed. Major CSPs provide a way to configure the environment to be scalable, allowing a true model of computing on demand.

In the healthcare area, it is a moral obligation, reducing uncertainty and delivering optimised treatments.

In short, big data is the means of reducing the odds.

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BIG DATA

Weighing it up In this article, Marco Baietti, commercial director at SEA Vision, weighs up the advantages of implementing aggregation, what the future holds and the current levels of adoption within the industry.

F Using both serialisation and aggregation, pharma companies will be best equipped to control the whole supply chain distribution system

or or against it, aggregation is something to consider as part of a serialisation set-up. In regulatory markets where it is not mandated, there are mixed opinions from businesses as to whether the benefits of aggregation outweigh the investment.

REGULATORY OUTLOOK Aggregation is currently mandatory in some countries and in others it is not a legal requirement but strongly recommended by regulators. Some countries in the early stages of developing their regulations will also require aggregation. Additionally, the US Drug Supply Chain Security Act (DSCSA) will require companies to aggregate in the next five years.

Europe’s falsified medicines directive (FMD) is the only large regulation not requiring mandatory aggregation, causing many companies supplying markets covered by the law to question their investment. In Europe, it is estimated that around 30–35% of the market is aggregating, with mainly small and mid-sized companies choosing not to at this stage. But, is this the right decision?

ASSESSING THE BENEFITS Obvious advantages of aggregation can be seen in the supply chain.

Aggregation allows product receivers to scan one code and understand what is in the whole shipment, simplifying the movement and handling of products.

Statistics show that around 2–3% of batches on the market need

to be reworked or recalled.

Aggregation can help to simplify this process. A good example of this is a pharmaceutical company that decided to implement serialisation only and needs to rework more than 15 million cartons per year during distribution. They are exploring automatic solutions to do this; however, this is likely to cost more than implementing aggregation.

In cases where two wholesalers exchange products, it is necessary to check that the codes and products are genuine and that they have been updated properly in the database. Without aggregation, the receiving wholesaler needs to open all the cases and reprocess each carton!

While aggregation is not mandatory in EU FMD, it is written into the regulations that if any product is stolen during transportation, it should be decommissioned within the database. Without aggregation, it is difficult to know which cartons have been stolen without scanning products manually.

POTENTIAL DRAWBACKS Despite the many benefits, the industry has been slow to adopt aggregation. The financial investment needed to achieve aggregation can be prohibitive.

Overall equipment effectiveness can be impacted by adding additional equipment to the packaging line. However, this can be off-set if the aggregation set-up has involved the purchase of new, more efficient machinery.

There will also be some downtime while the line is being equipped, which can be minimised by using an experienced partner. It is also recommended that aggregation equipment is introduced at the same time as serialisation systems to reduce both downtime and the overall cost of implementation.

During exception handling in the post packaging stage, it is sometimes necessary to split pallets to meet market demand and/or customer requirements or to take some samples from a case. When the cases and pallets are aggregated, it is necessary to de-aggregate and then reaggregate the cartons to account for any changes.

SUMMARY Manufacturers must take a global view of track and trace requirements to future proof their business and ensure they can meet demand from new markets.

Many in the industry believe that all the world’s pharmaceutical products will be serialised and aggregated in the next five to 10 years. In an ideal scenario, there will be a single, global track and trace regulation to simplify the market.

Using both serialisation and aggregation, pharma companies will be best equipped to control the whole supply chain distribution system. What is seen as a cost today, will repay pharmaceutical manufacturers with many benefits in the mid-term.

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COATINGS & CAPSULES

Getting our fill‌ Iùaki Bueno, formulation and manufacturing manager at Idifarma tells us more about the ins and outs, challenges, advantages and latest developments in coatings and capsules.

Q. WHAT TYPE OF FORMULATIONS ARE FILLED IN A CAPSULE? A. In principle, any type of formulation may be dosed into hard capsules, from blends or granules, to coated pellets, to other oral dosage forms such as tablets, micro-tablets and smaller capsules. It is also possible to fill liquids, provided that the material of the capsule (generally gelatine, although there are other alternatives) is not soluble in the solvent employed in the formulation.

Soft gel capsules have other advantages over other dosage forms: they are easier to swallow and aesthetically more pleasing.

Q. HOW DO YOU DECIDE ON CAPSULE SIZE AND FILL WEIGHT PER CAPSULE? A. Once the formula of the contents of the capsule is developed and the weight to be dosed is known it is easy to define the most appropriate capsule size.

The body of each size of capsule has a defined volume, so knowing the density of the mixture to fill we can establish the volume that will occupy the weight that we must fill in each capsule. In the case of mixtures (powder or granulate), knowing the tapped density makes it possible to determine the most suitable capsule size.

For pellets or micro-tablets, where there is no possibility of compaction, it is necessary

to use bulk density instead.

All capsule suppliers provide capsule size tables that facilitate the choice of capsule size.

Q. ARE THERE DIFFERENCES WHEN FILLING CAPSULES FOR CLINICAL STUDIES VERSUS COMMERCIAL PRODUCTION? A. There are no major differences, apart from the great potential that capsule filling provides for clinical trials, from filling just the API for first pre-clinical or clinical trials to filling other dosage forms in capsules (tablets or smaller-sized capsules, for instance) for blind or double-blind clinical trials.

Q. WHAT ARE THE CHALLENGES OF CAPSULE FILLING FOR LIQUID AND POWDER FORMULATIONS? A. The main challenge when filling liquids in hard gelatine capsules is to find the right solvent, which does not interact with the capsule material. From a technological standpoint, the capsule filling machine requires a specific station to fill liquids, and the capsules must undergo an additional band sealing process to prevent leakage.

As far as powder filling is concerned, the main challenge is to achieve a formulation with

good flow properties, which guarantees the correct filling of the dosing systems and therefore a good uniformity of mass of the contents of the capsule.

Q. WHAT ARE THE COMMON THINGS THAT CAN GO WRONG IN CAPSULE FILLING THAT MANUFACTURERS SHOULD BE AWARE OF? A. Capsule filling is a complex process. It is very important that the product to be encapsulated is well developed, with an acceptable flow and a reproducible batch-to-batch density to avoid problems of mass uniformity.

In addition, an automatic encapsulating machine is very complex equipment and each capsule format is composed of numerous pieces, which must be perfectly aligned and adjusted to avoid the opening or breaking of capsules. When capsules are broken they can release their contents, staining the entire batch produced.

Finally, hard gelatine capsules eventually undergo a crosslinking reaction which renders the gelatine less soluble and may affect the release of the capsule contents.

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Q. WHAT ARE THE ADVANTAGES OF SOFT GEL CAPSULES OVER OTHER FORMULATIONS? A. The main advantage is given to the state in which the active ingredient is found. The fact that the active principle is dissolved in non-aqueous media can increase its bioavailability, something especially useful in case of low soluble molecules (BSC II and IV). Another benefit of having the API dissolved is that, for certain pharmaceutical products, this may contribute to a lower tmax, achieving the desired therapeutic effect in a shorter time.

Q. HOW IMPORTANT IS CHOOSING THE CORRECT COATING? A. When considering coating an oral solid dosage form, you need to consider 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.

Choosing the right coating is very important, getting it ‘wrong’ can impact patient compliance or even compromise drug efficacy by negatively affecting the drug release profile.

Soft gel capsules have other advantages over other dosage forms: they are easier to swallow and aesthetically more pleasing.

Q. WHAT ARE THE LATEST DEVELOPMENTS IN CAPSULE PRODUCTION? A. The latest developments are aimed at increasing the efficiency of processes to make rapid changes of formats and products and increase the flexibility to encapsulate different products (tablets, micro-tablets, pellets, liquids...) or various combinations of them inside capsules.

Q. WHAT ARE THE REASONS FOR INCLUDING A COATING? A. Coating makes the tablet appear easier to swallow and aids in visual differentiation for the patient, 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.

For a manufacturer coating helps to protect the tablet, provides a desired release profile, masks the taste of a bitter drug and minimises the impact that environmental conditions may have on drug stability.

Commercially it aids packaging, extends the product shelf and helps differentiate the product.

Q. HOW DO THESE DIFFER FROM TRADITIONAL APPROACHES AND WHAT ARE THEIR BENEFITS? A. One of the main drivers is cost-efficiency, due to increasing competitiveness in the market.

Also, novel combinations can benefit from advanced capsule filling technologies which enable the entrance in the market of drugs that might improve patient compliance.

Choosing the right coating is very important, getting it ‘wrong’ can impact patient compliance or even compromise drug efficacy by negatively affecting the drug release profile.

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CASE STUDY : LYOPHILISATION

Recipe for success Who | Telstar What | Development of a freeze-drying recipe for cytotoxic product How | Differential scanning calorimeter and cryogenic microscopy analysis

THE COMPANY Telstar focuses on the design, manufacture, sales and support of high technology equipment solutions for the pharmaceutical, biotech and related industries with a range of product offerings, including GMP lyophilisers with integrated automatic loading/unloading systems.

THE CHALLENGE A customer wanted to develop a freeze-drying recipe for a cytotoxic product in a solution of water and tert-butyl alcohol as a solvent but did not have the tools and expert knowledge to successfully perform this task in a cost-effective way while also maintaining the initial product properties.

THE SOLUTION The company contracted Telstar’s services to develop the best freezedrying recipe in accordance with its requirements as well as those of the product, including a solution to the problem of powder ‘blow out’ from the vial and an upper ring of product in the vial wall.

The Telstar’s process to develop and design a freeze-drying recipe consisted of: 1) Differential scanning calorimeter (DSC) study to find out the thermal product properties 2) Cryogenic microscopy analysis to seek the critical temperature to freeze dry the product.

After gathering this information several freeze-drying tests are performed at the laboratory to optimise the recipe to obtain a good product, as quickly as possible.

Development problems The freeze-drying study of the product highlights two main process problems.

1) Explosion of product and powder ‘blow out’ of the vial This effect is a result of the fact that the freeze-dried cake is not cohesive enough to withstand being ejected from the matrix by the water vapour escaping from the sublimation front.1 Product ejection is more common in formulations containing organic solvents such as this product which contains tert-butyl alcohol so, it is believed that the explosion of product corresponds to the dilute solution part of TBT in water.

This fact not only shows the product mass lost in vials, but also an important contamination of the freeze dryer chamber.

Several conditions of temperature and pressure were studied together with a video camera to monitor the explosion moment.

Solution: Soft temperature and pressure of primary drying at freeze-drying recipe to avoid the aggressive ‘blow out’ of product.

2) Upper ring of product in vials After the freeze-drying tests some stains and sometimes rings of product appeared on the vial walls. There are various possible reasons for this effect: • Aggressive manipulation of the vials during the dosing and/or loading the freeze dryer.

• Blow up of frozen cake at the beginning of pulling vacuum.

• The low surface tension of TBTwater solution in contact with vial walls promotes liquid to rise and wet the walls.

Exploded product cakes

At the beginning of the vials dosage, this effect was observed together with a noticeable concave meniscus.

Therefore, the low surface tension was the reason for the product on the walls.

Solution: Study different treated vials and choose the ones which avoid the defect. Depyrogenated, siliconised, as well as other types of glass material affect the results of ring.

THE RESULTS Development defects were solved obtaining good cosmetic cake and cost-effective cycle duration. Product properties were not damaged after being freeze dried.

The improvement opportunities Customer has a robust freeze-drying recipe in which: • Product does not explode during cycle • Absence of cosmetic cake defects (upper ring) • Assure the quality and properties of product (it has been analysed by the client) • Optimised duration of cycle to achieve the correct product results.

• Saving product and money

REFERENCE:

1 | Lyophilized Drug Product Cake Appearance: What is acceptable?; Journal of pharmaceutical science, 2017

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SPOTLIGHT ON INNOVATION

What the future holds The introduction of new technologies over the last decade has paved the way for pharmaceutical packaging companies to explore new and innovative solutions, improve their operations and drive eďŹƒciencies across the supply chain. Here, Dexter Tjoa, director of corporate strategy, Tjoapack, explores the future of pharma packaging.

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raditionally, contract manufacturing organisations (CMOs) have assumed responsibility for both drug manufacturing and packaging of products. However, in recent years contract packaging organisations (CPOs) have taken a more prominent role in the pharmaceutical supply chain in response to growing demand for more efficient, and often intelligent, packaging processes.

Packaging requirements are growing increasingly complex as more innovative products are brought to market and regulations are introduced, evolved and sometimes removed across global markets. The Drug Supply Chain Safety Act (DSCSA) in the US and the EU’s Falsified Medicines Directive (FMD) have both created increased demand for pack redesigns and an overhaul of entire packing processes. Specialist packaging companies, with in-depth knowledge of market requirements and the flexibility to tailor solutions, have become a vital part of the supply chain.

Driving this growth are three trends which are causing fundamental changes across the pharmaceutical industry: postponement, serialisation and digitisation.

POSTPONEMENT Traditionally, CPOs provided a bulk packaging service where large volumes of pharmaceutical products were packed, then shipped before being stored in a warehouse until the product was required. Due to volatile market demand, this approach quite often produces a lot of waste product and can also incur high inventory costs in multiple locations.

as well as domestic regulations and the need to cater to different languages create a need for more flexible packaging processes, postponement is becoming more attractive to companies supplying to multiple markets. In this kind of environment, postponement offers huge opportunities to improve efficiencies, reduce costs and waste, and lower the likelihood of reworks being required.

In recent years, companies have started to explore late-stage customisation or postponement packaging, whereby blank marketagnostic product components are stored in a central warehouse and only customised for a specific market when there is demand.

The product can then be shipped within hours of receiving the order.

In the longer-term, postponement could overhaul the way that healthcare is delivered to patients, leading to patient specific packaging, ultimately increasing patient safety and adherence.

While there are some specialised CPOs that are already equipped to package products in this way, adoption of postponement packaging has been sporadic, with some companies reluctant to tackle its complexity or invest in new processes and infrastructure, which, for medicines, can be a substantial undertaking.

Nonetheless, as nuanced interpretations of the FMD,

SERIALISATION Serialisation has been widely discussed across the industry since the FMD and DSCSA regulations were first announced and the implementation of new systems to meet legislation will have a lasting effect on the industry.

The introduction of mandatory barcodes and the management and transfer of the huge amounts of data generated by serialisation has increased the complexity of pharmaceutical packaging

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and created significant costbarriers. Consequently, many drug manufacturers and CMOs have been slow to adopt serialisation.

However, it’s vital that companies look beyond these challenges and see the scope of serialisation systems, which will not only lead the industry towards a safer and more secure supply chain, but ultimately help to connect the whole industry, from manufacturer to patient.

Streamlining the exchange, interpretation and processing of data across enterprise systems and through entire supply chains has huge potential. Companies will be able to look at legacy data and optimise their logistics operations through real-time monitoring, resulting in accurate demand planning as opposed to assumption-based forecasting, as well as improved warehouse management, shipment visibility and more efficient distribution.

Ultimately this could mean a safer, more integrated and faster approach to bringing new drugs to market, to the benefit of patients and primary healthcare providers.

DIGITISATION OF THE SUPPLY CHAIN Serialisation is forcing businesses to move towards a more digital approach to data management and exchange, but it is not the only catalyst for change. To take full advantage of digital supply chain processes, companies first need to address their internal operations and capture data in a way that is readable, and usable, by computerised systems and analytics tools.

Better visibility of a business’ value stream could not only give organisations the ability to make

better informed decisions but will also pave the way for the implementation of automated processes and well-targeted and measurable process improvement projects.

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Companies who take a proactive approach to developing their packaging solutions and incorporating full track and trace and postponement into their operations will inevitably find themselves in a better position when these new digital processes become more widely adopted. It is important that the industry continues to drive these developments forward to fully realise the broader impact on supply chain management.

Specialist packaging companies have become a vital part of the supply chain, driven by three trends causing fundamental changes across the pharmaceutical industry: postponement, serialisation and digitisation.

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TABLET PRODUCTION

A fresh perspective When it comes to oral solid dosage (OSD) forms, continuous manufacturing is in high demand. But there is more than one way to look at things, as Fritz-Martin Scholz, product manager at Bosch Packaging Technology explains.

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SD forms like tablets, capsules and sachets make up roughly 60% of the total pharmaceutical products market. Increasing cost pressure and high-quality demands require efficient, modular and flexible processes. The trend towards highly potent and personalised drugs will have an important influence on production and process requirements, leading to small and flexible production quantities with the shortest possible time-to-market.

With OSD batch production, the pharmaceutical industry traditionally uses manufacturing processes, which have been established for many decades.

Accordingly, they have already been optimised and offer little room for improvement. As a result, pharmaceutical producers have turned their attention to continuous manufacturing. A paradigm shift is currently taking place, which will bring about fundamental changes in terms of infrastructure, as well as internal processes of pharmaceutical manufacturers.

FROM BATCH TO CONTINUOUS In batch production, a set amount of raw materials is fed into the system at the start of a particular batch, and removed again at the end of each process step. Conversely, in continuous manufacturing, feeding of the starting materials and removal of the finished product

are done simultaneously. The typically separated production steps occur one after the other, without interruption, resulting in shorter throughput times, no intermediate storage, smaller plants, lower production costs and greater flexibility. The production volume is now controlled via the production time. Development costs also decrease, as scale-up becomes obsolete, which reduces development time and usage of API. Optimal quality monitoring ensures consistently high product quality.

Whether the change to continuous production pays off, depends on a number of parameters: active ingredients, required production amounts, and whether the product has already been approved or is still in development. Continuous manufacturing is nothing new in the pharmaceutical industry.

Current continuous production systems for wet granulation usually rely on continuous twin screw granulators. The subsequent drying in the fluid bed usually takes place package per package in separate chambers, amongst others to control the residence time, so that every particle sees the same amount of drying energy.

CURRENT CHALLENGES The biggest challenge of continuous production is the precise dosing of the starting materials. APIs and excipients

have to be continuously dosed in a constant mass flow rate of milligrams per second. Because all the available dosing systems show fluctuations over time at the achievable mass flow rate, it is mandatory to check the amount of active ingredient online using process analytic technology (PAT). Back-mixing is the only way to compensate these fluctuations, which in turn broadens the product’s residence time distribution in the system, making traceability more difficult.

In addition, the system requires a start-up phase before the steady state is achieved, resulting in startup and shut-down losses.

The changing characteristics of the granulate from the twin screw granulator present a further challenge, since the granulate density is different and often has a bimodal particle-size distribution.

This might cause segregation, which can, under certain circumstances, have a negative effect on the tablet properties.

REDUCED COMPLEXITY In response, Bosch Packaging Technology is investigating processes and systems that can overcome these challenges — for instance the Xelum platform.

The most important differentiation is that it doses active ingredients and excipients as discrete masses and not as continual mass flow.

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The system doses and mixes individual packages, so-called X-keys, step-by-step, which continuously run through the process chain and are removed successively. This way it is possible to reduce process complexity, and the system’s failure susceptibility.

Connection to line controls and flexible filling height control ensure smooth operation. Optimally placed nozzles for washing-in-place (WIP) can make sure the system can be cleaned in short time and largely automated.

At the same time, the necessary measurements of critical quality attributes can be carried out more easily, in part using soft sensors. If a steady state is not required, startup and shut-down losses can be reduced to a minimum. All starting materials can be traced back in the production line and can be clearly matched to the final dosage form, as back mixing occurs only inside of each X-key.

FIT FOR THE FUTURE Transferring processes from laboratory to production is often a challenge for pharmaceutical manufacturers. Thanks to continuous processing, this inherently risky and time-critical stage is eliminated. New products can be developed using either suitable R&D equipment or with the integrated automatic DoE function, which features software with the relevant test-automation support functions.

ADVANTAGES OF FLUID-BED TECHNOLOGY Although most available systems use twin screw granulators another possibility is the use of fluid-bed processors. In the fluid bed, granulation and drying take place in the same process chamber. This eliminates the need to transfer wet granulate, which has a positive effect on the system’s reliability.

With fluid bed granulation, pharmaceutical manufacturers obtain granulates with the desired characteristics — including unimodal particle size distribution, as well as excellent flow and tabletting properties combined with higher production yields.

Using the fluid-bed granulation process for existing products means that a technology transfer is not necessary, which significantly reduces the effort of changing to continuous processing. The same principle of dosing as a discrete mass also applies to the external phase. In the final processing step, the tabletting can take place in an integrated tablet press.

One thing is for sure: continuous manufacturing will take on an important role in OSD production alongside batch production.

Which process is used for which product has to be decided on an individual basis.

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The biggest challenge of continuous production is the precise dosing of the starting materials.

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CASE STUDY : TABLET PRODUCTION

53

WORKING THE PROBLEM Who I Holland and Novartis What | Sticking issues How | TSAR≈Predict model

N

ovartis, is a company providing innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines, over-the-counter and animal health products.

I Holland has origins that date as far back as 1910 when it was established as a general engineering and machining company by Messers Holland and Brewill. It is now a global manufacturer and supplier of tablet compression tooling.

THE PROBLEM The Italian division of Novartis approached I Holland and local agent Vis Viva with a sticking issue on an antiepileptic drug in the form of a coated tablet.

Novartis reported a strong sticking/ picking problem causing the press to be stopped several times during manufacture for cleaning and maintenance of the punches, which resulted in production downtime.

These two problems can be caused by various factors related to the physicochemical properties of the formulation components, the surface characteristics of punch face, as well as factors related to the machinery and the environment, for example, compression force and speed, temperature and humidity.

Sticking and picking halted production

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

by Novartis.

Picking was another problem encountered by the company — this is when compressed granule that has adhered to the detail on the punch face, results in ‘picking out’ of parts from the tablet face.

Understanding problems that can occur during manufacture will ultimately result in higher yields, less waste and money saving implications. To achieve this ideal, it is important to understand the product being made and how it interacts with the tooling used during the production process.

The removal of the tablet tooling from production for regular cleaning and maintenance was required due to the problem of sticking.

54 THE TRIAL Novartis had previously looked at the coating being used on the tooling to overcome the sticking/picking problem.

Proactively seeking a solution, the company tried several different coatings including HC (Hard Chromium), CrN (Chromium Nitride) and TN (Titanium Nitride). With unsatisfactory results from these initial trials, Novartis Italy contacted I Holland for expert advice and analysis of the problem with the support of local agents Vis Viva.

Sample tools were examined, with the tablet design and tool material selection and coating studied. I Holland used its TSAR≈Predict (Tabletting Science AntiStick Research) model. With sticking and picking being such a universally significant problem in the pharmaceutical industry, I Holland invested in a two-year research programme to develop a predictive model that could be used to reduce downtime and ultimately costs. The model comprises data on a range of parameters including surface chemistry, temperature, humidity, size of the granule, and whether it is elastic or plastic for example, to provide fast guidance to the tablet producer.

This reduces the need to carry out expensive in-the-field testing which is time consuming and requires the tablet manufacturer to take time out of tablet production to run trials with coated punches.

As well as using the predictive model, the tablet profile was examined. The type of profile required is influenced by several factors; the granule, embossing requirements, coating process, packaging and the company’s branding. If the design is to be heavily embossed with a lot of characters it is important to avoid tablet profiles with a deep cup, such as the ball or pill. Deep cup profiles can cause a softer core in the tablet which can in turn lead to sticking. It will also reduce the available space for the embossing itself; the use of a

CASE STUDY : TABLET PRODUCTION

profile that is shallower, with a reduced cup depth, will allow for a larger embossing area.

THE SOLUTION The tablet design, including the embossing, was examined and new and improved designs were created which included anti-picking features. Together with results from the TSAR≈Predict model, which selected the use of I Holland’s PharmaCote CN+(Chromium Nitride Plus) surface engineered anti-stick coating, new upper and lower punches were provided and implemented in production.

The selected anti-stick coating was used on the punches and applied to the tooling by using an electron beam process. This is one of the smoothest and most defectfree methods of applying a PVD coating as it does not create droplets during the atomisation process. The atomic particles are attracted to the tooling leaving an even surface which is far less susceptible to breakaway defects.

From the first trial of the new design and tooling using PharmaCote CN+, improvements were seen and all sticking/ picking issues were instantly resolved resulting in a 25% increase in production.

This was achieved over a five-day working week, with reduced hours, resulting in a full day’s production time saved.

Before the implementation of the new tablet design and tool coating, four batches of the tablet were produced during a 6-day working week. This included the extra time

required for cleaning and maintenance due to the original sticking/picking problem.

Once I Holland’s improvements were adopted, a further batch was produced in the same time-period with a total of five batches manufactured without the need to stop production.

As a result of this outcome, Novartis is now looking at further products to be analysed to improve production and reduce down-time.

THE CONCLUSION I Holland’s understanding of years of tabletting science has proven that when coatings are developed correctly, and their beneficial characteristics are matched to those of the formulation, they can help to prevent sticky formulations adhering to the punch tip faces. I Holland has deployed many advanced techniques to help improve the performance of its coatings. As a result, it has a proven range of anti-stick solutions based on that research. TSAR≈Predict gives a predicted particle adhesion force against each of the PharmaCote anti-stick coatings in I Holland’s range.

To improve tablet production efficiency, it is imperative to implement an effective tooling specification. To find the correct design for the product being produced, consultation with an expert tablet designer should take place in the early stages of the process. The design should not only be unique and visually appealing, but also robust and producible in a rigorous tablet manufacturing environment. By making just a few simple changes to a design it can stop future problems.

By adopting new sciencebased innovations, like those from I Holland, and investing in research and development, Novartis is proactively bringing important treatments to patients globally.

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56

STERILE PACKAGING

Reducing risk with sterile transfer ports In this article, Anneke Evers, senior director Sales & Market Support DPTE Sterile Transfer, Getinge, discusses sterile transfer systems, industry standards and what the next steps to evolve these systems need to be.

T

ransferring materials from one confined space to another in a sterile and safe way has been an important consideration for the pharmaceutical industry now for many years. In fact, in some aspects of pharmaceutical production, manufacturers are legally obliged to ensure almost completely particle- and germ-free environments, as defined by the standards of Good Manufacturing Practice (GMP).

A solution to this type of material transfer is in the form of the rapid transfer port (RTP). These systems are installed on enclosures such as an isolator or production line and enable the transference of material between two chambers of similar cleanliness or can connect two chambers of similar cleanliness without alteration of the environmental and containment properties. This means that clean material can be moved from one sterile zone to another through a non-sterile zone, using the DPTE container or single use bag which can be reconnected without risk because the inside of the container is still sterile.

THE FIRST SYSTEM OF ITS TYPE In the 1960s La Calhène (which was acquired by Getinge, a global medtech company, in 2005) built the first system of this type, initially in the nuclear industry sector, so that highly dangerous radioactive substances could

be transferred safely. This system was called the Double Porte pour Transfert Étanche — double door for leaktight transfer — (DPTE).

The DPTE system comprises two distinct parts: An Alpha port, which is installed on an isolator or filling line, and a Beta part, which is a rigid container or flexible DPTE-BetaBag, that docks onto the Alpha port.

Once connected, these two components form a safe and leaktight barrier so that transfer, introduction or extraction of sterile and/or highly potent material is possible without the risk of sterility of the material being compromised or contamination to the outside when using toxic materials. Therefore, overcoming the challenge of not contaminating the operators and the working environment around the isolator or filling line making potent drugs.

RELIABLE SOLUTION The benefits of this system being able to safely transfer radioactive material and providing high security in containment configurations has led to other industries, separate from nuclear, finding it advantageous. Nowadays, the system is used for many applications within the pharmaceutical industry and with more than 40,000 Alpha units sold to global locations is recognised as a successfully validated and guaranteed system.

As a result of its success many other transfer systems have become available on the market. In a comparative study of

the DPTE and five standard RTP systems manufactured for both the nuclear and pharmaceutical industries, multiple parameters were evaluated, including leaktightness, locking toque, security, ergonomics and multiple connections.1 From this study, the position of the DPTE as a reliable solution for leaktight transfers with guaranteed safety was affirmed.

CONTINUAL EVOLUTION In this age of increasing demand for drugs and a new era of biologics becoming more prevalent, reliable transference systems are also in higher demand. Single-use technology is of particular interest in the biopharmaceutical sector as it has the potential to reduce the crosscontamination risk. Here, the DPTEBetaBag can provide bidirectional containment without intermediate bio-decontamination.

Continuing the evolution of these systems to meet the ever more stringent regulatory requirements set out by the relevant authorities worldwide will mean an increased level of cleanliness and the lowest rates of particulates.

As a company at the forefront of sterile transfer technology, Getinge will look to reply to these requirements.

REFERENCE:

1 | Mounier, C. and Guilmet, C., Rapid transfer port systems – a comparative study, Clean air and Containment Review, Issue 20, October 2014, pp 26–29.

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58

TECH TALK

Show me the money In the latest instalment of Tech Talk, Novarum founder and BBI Group head of mobile, Dr Neil Polwart discusses how best to monetise your mHealth app.

W

ith mHealth apps forecast to generate $189 billion annual revenue to app providers by 2020, pharma companies hoping to jump on the mHealth bandwagon may soon find themselves facing an interesting question — how do I make money from the app?

Compared to time and risk factors involved in developing new pharmaceuticals, the ability to produce mobile medical apps can seem attractive.

Unfortunately, that often means apps are not perceived as justifying high value in return.

The mHealth market is rich with start-up companies often either ‘bootstrapped’ on the founders’ own funds or backed by venture capital firms looking for the next ‘unicorn investment’. As is often the way with technology start-ups, the business model is unclear, or even non-existent. In the mobile market, the typical strategy is to build a user-base first and worry about how to make money later.

Traditional approaches for apps to make revenue (like selling targeted advertising or in-app purchasing) are likely to cause ethical, regulatory and brand

perception issues for most pharma applications.

Of course, a well thought out mHealth strategy isn’t all about trying to get direct revenues.

Where a pharmaceutical is used for treating long-term chronic disease, potential exists for helping patients and clinicians to track drug use, symptoms and even biomarkers that would help build brand loyalty in markets where users play a key part in such decision making.

Over the counter pharmaceuticals and nutraceuticals are potentially even more sensitive to brand loyalty and value issues. These manufacturers might also look to how they can engage users on a recurring long-term basis.

Simple tools like reminders and reorder levels can also have a surprising impact on financial feasibility. For instance, if your average patient forgot to take their daily medication once every month, using an app to prevent that could see a 3% revenue increase. mHealth brings with it the promise of significant disruption. When the term was originally coined by Harvard Professor, Clayton Christensen,

in his book: ‘The Innovator’s Dilemma’, Christensen suggested disruptors are a product that addresses a market that previously couldn’t be served — or it offers a simpler, cost effective or more convenient alternative to an existing product.

Pharma companies need to be alert to the potential for disruptive influences in their markets and should also be acutely aware that large organisations often find it impossible to adapt to change at the pace needed to match these. By the time you become aware of disruptive threats it is often too late. The only real option to safeguard a market position is to acquire the upstart. A more proactive approach is to disrupt your own market before anyone else gets a chance.

In healthcare one of the most significant shifts is to emphasise outcome-based medicine and it follows that payers will start to expect pharma to adopt pricing models — not based on a population wide outcome, but on the outcomes for that specific patient.

As some insurers start to use mobile to incentivise healthy behaviours with long-term benefits, pharma companies may also want to look at how to incentivise patients. Mobile may provide a key tool for tracking either individual or anonymised average patient outcomes, the pharmaceutical provider which can adapt its models to enable this surely stands to reap the benefits when the healthcare economic models get reviewed One of the challenges product managers face is that there is a temptation to attempt to define, devise and develop the ultimate solution to achieve the maximum value, a process which is not only expensive and slow but almost invariably wrong. In the meantime, some previously unknown company develops a niche offering for a fraction of the cost and begins eroding parts of the market.

Mobile is increasingly impacting every aspect of our lives and even if a pharma business can’t see how to make revenue directly from mobile, it may need to embrace it to stop someone else usurping its target market segment.

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