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Contents June 2017 | Volume 17 Issue 4

Regulars

Features

EDITOR’S DESK

EXCIPIENTS & APIs

Looking at safety issues within pharma

The importance of the manufacturing route and excipient selection

ANALYSIS

What will the upcoming general election mean for pharma?

8 OPINION

PURIFICATION & FILTRATION

11 Examining Brexit’s effect on IDMP and whether biosimilars are interchangeable

14 ON THE COVER Siemens Financial Services reveal how digitalisation can have a positive effect on costs and margins

34 LAB DIARY Common headaches for those in the lab

Updates on serialisation from the NEXUS ’17 event

How do managers in the pharmaceutical industry ensure plant reliability?

REGULATORY AFFAIRS

EVENT FOCUS – NEXUS ‘17

3M reflects on some of the challenges facing biotech and how it is rising to them

32 QUEEN’S AWARDS A brief run through of some of this year’s winners

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editor’s desk

E C A P S E F A S A After recent events, it seems that more than ever protective measures are made to ensure pharma is a safe space for companies and patients.

s we begin the process of healing after the devastating terror attack on vulnerable people in Manchester and the shock of the recent cyber-attack affecting vast amounts of systems across Europe subsides, the questions arise of how do we manage these disturbing and disruptive problems and what preventative measures should be taken for future protection? One of the key challenges that has faced the pharmaceutical industry is that of counterfeit medicines. Back in 2006 charges were brought against 19 people for illegal racketeering in support of terrorist operations by the US Attorney’s Office.1 In this case, it was alleged that portions of the profits made from the sale of counterfeit products was used to fund foreign terrorist organisation Hizballah. However, we must also consider the possibility that within counterfeiting there is also an opportunity to infiltrate the product with other chemicals to cause damage to other human beings. To fight counterfeiting, we have seen the introduction of regulatory legislation, such as the EU Falsified Medicines Directive (FMD). This will provide tougher rules about the packaging of medicines, inspections and controls of API producers and will require strengthened record-keeping for distributors. Through these measures, public health protection will be improved. With these tougher measures, however, comes the issue of how IT will manage the vast amount of data that needs to be compiled in order for companies to ensure full compliance with the directive. Here in lies another potential risk for the pharma industry. As we recently saw, ransomware can cause mass disruption across multiple sites with little or no warning. Speaking to Microsoft, the BBC reported that the recent cyber-attacks “should be treated by governments around the world as a ‘wake-up call’.”2 There are already certain standards in place, such as the global SAFE-BioPharma initiative, created by the biopharmaceutical industry and its regulators. This helps to protect cyber-transactions in biopharmaceuticals and healthcare through the use of identity credentials.3

However, we must not close doors and borders through fear of attack. A globalisation of science is necessary in the fight against global health threats as was stressed by Dr Carmen Peña, president of the International Pharmaceutical Federation (FIP) during the 6th Pharmaceutical Sciences World Congress. “The bringing together of different fields of expertise, sectors and nationalities will help solve health issues. Integration will become the key word in the success of the pharmaceutical sciences,” she said. “Integration also means that borders between clinical trials and postmarketing surveillance are shifting to allow faster access to innovations while limiting risks for patients.” So, what does the future look like? With track and trace already hot on the agenda, we should be able to rest assured that pharma is doing all in its power to make the industry as safe as possible. By 2019 most countries will have regulations in place in some form or another that will offer an extra line of security. Extra security online, such as the SAFE BioPharma initiative, will help to prevent serious issues in the face of ransomware attacks, but vigilance with IT is always recommended. In essence, it is imperative that we do not fold to these acts of terrorism, while being vigilant and ensuring preparations are made to keep patients and companies as safe as possible from threat, it is also vital to continue to work globally in combatting health issues. Thanks, Felicity References: 1. http://www.prnewswire.com/news-releases/nineteen-charged-with-racketeering-to-supportterrorist-organization-70737752.html 2. http://www.bbc.co.uk/news/technology-39915440 3. https://www.safe-biopharma.org

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ANALYSIS

All change? In light of the upcoming snap general election, we pick through the three big parties’ manifestos and various industry analyses of the policies.

heresa May’s call for a snap general election came at a time when there were clear fractions forming within government over the impending departure of the UK from the EU. As soon as the election was called we have seen many comments on what a prospective new government should be looking to achieve for the UK’s health sector and pharmaceutical industry. So, how do the big three political parties’ policies hold up to the requirements and demands of pharma?

Health in crisis: Tackling the NHS It has been widely reported that the NHS is at breaking point, after years of under-investment,1–3 the British Medical Association stated: “it is crucial that the health service has the unrelenting focus of prospective parliamentary candidates.” The UK BioIndustry Association (BIA) called upon political parties to provide solutions in support of the UK’s life sciences.4 “In particular, parties should think creatively about how to harness the unique strengths of the NHS, as a single integrated system, to bolster UK life sciences in the face of global competition for investment.”

Additionally, both the Conservatives and Labour highlighted the importance of fast access to medicine, although the Liberal Democrats were a little vague on how they would realise their ambitions to see the highest standards of care delivered by the NHS. A key factor for this, raised by the ABPI is the agreement of a new long-term voluntary Pharmaceutical Price Regulation Scheme (PPRS), which should be done in partnership with the pharmaceutical industry. “This should balance investment in new medicines, value for money for the NHS and the need to maintain a strong pharmaceutical industry.”8

“

The new Government must be decisive in making sure the UK keeps its position as a location of choice for the global pharmaceutical industry.

Life after Brexit: Global investment and relationships

”

With the UK’s departure from the EU a key topic in the election campaigns, it is important to examine how global investment and jobs will be secured and how we can ensure a new relationship with our closest neighbours.

In response to the party manifestos,5–7 the Association of the British Pharmaceutical Industry (ABPI) revealed its hopes that the new government will secure a world-class NHS for UK patients. As stated in its manifesto: “The Government elected in June 2017 should set out a clear plan for how the NHS will support the health of the nation. This should include how patients can access the medicines they need.”8

In light of Brexit the BIA noted: “The fundamentals of UK bioscience remain strong. The UK life sciences sector is a dynamic, globally focused community, unfazed by new challenges and staffed by great management teams used to working with uncertainty and risk — whether it be scientific, financial or environmental […].”9

Labour’s proposed increases to corporation tax is a cause for concern, according to the ABPI. In its opinion, these tax increases “would have unintended consequences for the UK’s global competitiveness.” However, the increase in R&D spending proposed by the party of 3% of GDP was appreciated by the ABPI, which also welcomed the party’s negotiation plans to nurture a relationship with the UK and the EMA for the future. Highlighting an ambition for the UK to be the most innovative country in the world, the Conservatives approach is supported by the ABPI. However, caution was urged in relation to the immediate doubling of the Immigration Skills Charge. “A tax on talent risk cutting off the fuel that supplies the pipeline of highly skilled workers our pharmaceutical industry needs,” the ABPI stressed.

All three major parties have included increased spending on the NHS in their manifestos. The Conservatives have specified £8bn, Labour have offered £30bn and the Liberal Democrats have stated a figure of £6bn.

Additionally, the ABPI highlights a necessity for an increase in NHS spending to bring it in line with the G7 average. Currently, the UK spends a total of 9.9% of GDP on healthcare and should be aiming for about 11.3%.8 Examining the figures more closely, the party that will offer the required level of spending is Labour, but the ABPI urges caution over how the party plans to raise these funds. The Conservatives and Liberal Democrats offerings, however, seem to be more of a short-term commitment and may not deliver on a world-class health service.

Although, the party’s stance on science and innovation was praised by the ABPI.

Pharma industry is key to strength Whatever the result on 8 June, one thing is clear, the position of the UK needs to be maintained, if not improved, to ensure a bright future for the pharmaceutical industry and that patients are kept as a priority focus. As stated by the ABPI: “The pharmaceutical industry is key to the strength of the UK economy and the health of UK patients […] The new Government must be decisive in making sure the UK keeps its position as a location of choice for the global pharmaceutical industry.”10 References: 1. https://nursingnotes.co.uk/nhs-care-among-worst-europe-dueinvestment/ 2. https://www.theguardian.com/society/2014/oct/05/nhs-financescrisis-rising-demand-budget-cuts-30-billion-pound-deficit-2020 3. https://www.bma.org.uk/collective-voice/influence/nhs-breaking-point

Out of the big three political parties, only the Liberal Democrats have outlined a policy to perform a ‘second EU referendum on the terms of any Brexit deal’ with both the Conservatives and Labour committing to uphold the original Brexit outcome. With a very clear position on Brexit, the ABPI highlighted its disappointment at the lacking detail in the Liberal Democrats’ manifesto on how they would ensure patient priority and public health in Brexit negotiations. Also, the proposed increase to corporation tax by the party raised concerns that economic stability may be impacted.

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4. https://www.bioindustry.org/newsandresources/bia-news/proposalsfor-how-government-can-support-uk-life-sciences/ 5. http://www.epmmagazine.com/news/pharmaceutical-body-reactionto-labour-party-manifesto/ 6. http://www.epmmagazine.com/news/uk-pharmaceutical-bodyanalysis-of-the-liberal-democrats-man/ 7. http://www.epmmagazine.com/news/abpi-examines-the-conservativeparty-manifesto/ 8. http://www.abpi.org.uk/our-work/library/industry/Documents/ ABPI_GE2017_Manifesto.pdf 9. https://www.bioindustry.org/newsandresources/bia-news/biastatement-triggering-article-5/ 10. http://www.abpi.org.uk/media-centre/newsreleases/2017/Pages/UKpharmaceutical-industry-response-to-a-snap-General-Election.aspx

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OPINION

Plant reliability How do managers in the pharmaceutical industry ensure that their plant performs reliably and safely? Michael Dixey and Pete Hibbs of GGR Associates explain some of the reasons for poor performance and suggest how these problems may be overcome.

any pharmaceutical companies have invested heavily in recent years in new plant and equipment. Much of this equipment is running at higher speeds and for longer periods — often 24/7. Yet, despite this investment in equipment, plant performance may not be reaching target levels. Companies measuring overall equipment effectiveness (OEE) often find that plant reliability is little better than it was before the investments were made. In response, some companies focus on increasing the amount of preventive maintenance being undertaken, particularly in response to failures. Some upgrade their computerised maintenance management system (CMMS) or focus on shop floor data capture systems. Others make organisational changes. These seldom make a significant difference. No wonder senior managers feel that they are ‘between a rock and a hard place’! Yet the civil airlines learnt that increased maintenance and improved systems do not necessarily improve reliability. Indeed, their research work showed that certain types of maintenance are counter-productive and reduce reliability.

A typical analysis of these losses for a packaging line which is achieving 64% efficiency is given in figure 1. Less than 5% of the losses are due to breakdowns. Most of the losses for a packaging line are likely to be caused by one or more of the following: • Poor setting at start-ups or changeovers • Raw material or packaging variations • Process capability issues • Equipment design limitations • Poor line control philosophy • Process control issues • Incorrect or inadequate operating procedures • Inappropriate intrusive preventive maintenance • Operator ‘adjustments’ • Inappropriate cleaning or hygiene procedures.

LINE EFFICIENCY LOSSES

To understand why plant performance is poor, one needs first to look closely at the underlying causes. In many companies, most ‘performance losses’ are classed as downtime which, in turn, is equated with breakdowns. Breakdowns are viewed as being a maintenance issue. However, the reality is often very different. Most equipment in the pharmaceutical industry will run virtually forever if no raw materials, product or packaging are put through it. The majority of the causes of poor performance centre around the machine/material interfaces, and there may be many of these. For example, on a packaging line there may be several hundred of these interfaces.

Figure 1

Machine breakdown 3% Quality losses

Causes of poor performance

Slow running 5%

Minor stoppages 10%

Changeover losses 15%

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Effective running 64%

Few, if any, of these problems can be solved with improved preventive maintenance. Even the causes of genuine breakdowns can often be traced back to problems at the machine/material interface. To leave it to the engineers to solve these problems on their own is clearly inappropriate. Yet this is exactly what many companies do.

Possible solutions Many companies will have programmes such as Lean, World Class Manufacturing or Manufacturing Excellence. Within these programmes, they may be using one or more of the following methodologies for improving equipment reliability: • Total productive maintenance (TPM) • Reliability centred maintenance (RCM) • Single minute exchange of dies (SMED).

Each of these focuses on different aspects of performance. TPM was developed in the Japanese car industry. It tends to concentrate on operator-related issues — ‘ownership’ of the equipment and the basic disciplines, e.g. the 5Ss (an approach to organising the workplace, keeping it neat and clean, and maintaining the standardised conditions and disciplines needed to do an effective job). It also puts great emphasis on the need for continuous improvement, and can be a driver for autonomous maintenance. RCM is from the US airlines. It focuses on developing and optimising preventive maintenance routines. It also identifies where maintenance alone cannot deliver the required reliability. FMECA comes from the off-shore oil and gas industry. It is now most widely used at the design stage for equipment, with the purpose of improving the design to eliminate potential failures or to mitigate their consequences. SMED is from the press shops in the car industry. It focuses on reducing start-up and changeover times and losses. (In the authors’ experience, over half the waste in the pharmaceutical industry can be directly attributed to poor start-up and changeover procedures.) All four of these approaches have their strengths, but none address the complete range of problems which affect plant performance in most companies.

QUALITY EFFICIENCY

Working with a number of household-name companies, GGR Associates have developed an approach to overcome these limitations. It is based on the structure of RCM but incorporates many of the best features of TPM, FMECA and SMED (see figure 2). This approach which is called Fast-track RCM has three stages: • Failure analysis: An analysis of the ways in which the equipment can fail to perform together with the root causes. These are identified under seven headings, somewhat similar to TPM’s six losses. The categories include more than ‘breakdown’ failure modes: they cover intermittent stoppages, slow running, quality and product integrity issues, low yields, start-up and changeover losses, material problems, access and maintainability issues, safety and protection, etc. • Consequences and criticality assessment: The consequences and criticality of each of these failures are evaluated, including an assessment of both the probability and the severity of the failure modes (as in FMECA).

• Failure mode, effects & criticality analysis (FMECA)

PROCESS

An alternative approach

• Recommended actions: The recommendations are made with the help of a comprehensive logic diagram. The actions available are many and include cleaning and lubrication routines, preventive maintenance tasks (emphasis on condition-based maintenance), changes to operating procedures or setting and changeover routines, training, improved documentation (SOPs), changes to the specification of materials including packaging and its storage, plant modifications, necessary rectification work and spares recommendations. Figure 2 Possible failures

FMEA

Structured approach Nature of failure Decision logic

FMECA

RCM TPM

Fast-track RCM

Probability of failure Severity of failure Cleaning & lubrication Operator ownership Analysis of losses Changeover losses

SMED

The analysis is performed by a small team that knows the equipment well, working under the guidance of a facilitator — similar to TPM — and involves both operators and technicians as well as relevant specialists such as quality control. The focus is on improving overall plant performance and ensuring that product integrity is maintained at the very highest level. Unlike TPM, Fast-track RCM is performed on a machine-by-machine basis, rather than as a site-wide initiative. This makes the approach much easier to manage. The approach is also quicker to use than ‘classical’ RCM (e.g., RCM2/MSG-3), typically taking about one-third of the time. Its application has led to step changes in performance levels in a wide range of industries.

Conclusions Performance improvement initiatives are usually started with much enthusiasm but tend to be short-lived and have limited impact. This is often because the techniques and methodologies being used do not address the wide range of issues faced by production and engineering management. The authors recommend that Fast-track RCM initiatives always start with one or more pilot projects to demonstrate the effectiveness and relevance of the approach. Once this has been established, it can then be rolled-out on a phased basis to all areas where there is scope for improved performance.

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REGULATORY AFFAIRS

In imperfect harmony? The UK’s separation from the EU could have implications for regulatory harmonisation, and increase administrative workloads at a time when responsible teams are already overstretched and experienced talent is hard to find. Dr Jutta Hohenhörst of Schlafender Hase asks what impact this could have on IDMP preparations.

he global market is currently experiencing a turbulent period, as national elections continue, governments change and the UK edges closer to Brexit. One of the practical concerns for life sciences is how this might affect the regulatory landscape, and momentum behind specific regulatory developments such as the phasing in of ISO Identification of Medicinal Products (IDMP). Although the benefits of harmonised product information, reporting and safety standards, and improved traceability internationally, are still in everyone’s interests, the worry is that authorities’ attentions will become diverted by other priorities. Where life sciences firms are required to invest significant amounts of time and budget in preparing for emerging requirements, there is a need for clarity and reassurance. European Medicines Agency (EMA) timelines for IDMP have already shifted, with an impact on firms’ preparations. At this rate, even though they have had longer to get their processes and data in order, they risk a last-minute rush because they haven’t maintained focus. This could jeopardise the quality of their output, as well as any benefits of their own derived from improvements to the way they manage data. Even the EMA is distracted now that Brexit negotiations are underway. It has mooted plans to relocate its London headquarters to a new base on mainland Europe, despite encouragement to remain. Whatever the outcome, there is a good chance that at least a proportion of its 900 employees will review their position; some have already moved to other national agencies. Right across the industry, skilled and specialist employees are worried about what happens next and where they will end up due to proposed new controls on resident permits and the free movement of labour across Europe. This comes at a time when a number of life sciences disciplines already face a talent gap, unable to fill growing teams because relevant experience is lacking.

Maintaining stability and direction

Letting technology take the strain

Where does this leave regulatory compliance progress, especially around IDMP? Clearly it still serves everyone’s interests that this comprehensive international standard for product data exchange is supported and effective. However, this is an ambitious project and it will take a lot of time to align all the right pieces, to deliver the desired quality. Whatever the delays and distractions, there is plenty of work to do now to prepare for what’s coming.

Beyond structured databases and formal document management systems, there are likely to be assets stored on people’s desktops, attached to emails, or kept in folders on servers without a common naming convention. If documents are PDFs, and do not contain selectable text their content will be difficult to extract and re-use — machines will be unable to read it. Use of non-unicode fonts could also interfere with machine readability. Different languages, varied spellings, corrupted content could all compromise consistency and accuracy as organisations work towards a definitive record of correct, current product information. Product information files may have been broken up by regulatory teams too, multiplying the scope for variation.

Forward-thinking firms are treating the hiatus as an opportunity to quantify the data preparation task that lies ahead. They can’t invest in specific IDMP software solutions until the final requirements and guidance have been published, but that doesn’t currently matter because the real effort required is in the initial groundwork. Whatever else is moveable, the need for consistent, accurate data will be a constant. How should companies move forward, to deliver something meaningful and of value that will serve them well in any eventuality? Firms need to start by identifying all the source content regulators might want, using known IDMP requirements as a guide; the different formats it is held in; and where it resides in the organisation. By creating a comprehensive inventory of files and file types, organisations can start to understand the size and scope of the task that lies ahead and begin to work out how best to tackle it. Challenges include identifying and locating the most up-to-date versions of documents and data. Few organisations have a single, centralised system for holding content, so bringing it together or comparing one version with another is unlikely to be easy. If the company has been subject to mergers and acquisition activity, and/or has amassed different legacy infrastructures over the years, all of this will add to the complexity of content management. Across the wider ecosystem, contract manufacturers, CROs, local representative offices, translation companies and other service providers will also need to be surveyed for contributing product information.

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The best way companies can tackle all of this reliably and efficiently is to harness automation wherever possible in preparing and checking content. It is now possible to accurately compare files even if they are in different formats, which can save organisations vast amounts of time. Once all documents have been accounted for, cross-referenced and checked, and labelling and other patient content verified as correct and up to scratch, firms will be in a strong position to meet the IDMP requirements. The final step will simply be to compare pre-compliant content with the new specifications once the last details have been finalised — ideally with an ability to filter and flag key words to ensure that quality checks will be efficient and reliable. Whether the real driver is IDMP submission or something more operational that serves the needs of the business, the output will only ever be as good as the source content. So, whatever happens in the international market and whenever the final compliance deadlines fall, any groundwork companies do now will be well worth it.

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REGULATORY AFFAIRS

Along (bio)similar lines Narasimharaju SN, senior manager — regulatory affairs and Mac Kella, senior regulatory affairs executive at ELC Group assess whether bio-similars are really interchangeable in the EU. Biological agents have revolutionised therapy and transformed treatment paradigms due to improved short- and long-term clinical and public health outcomes, and general patient care of chronic and debilitating autoimmune disorders. Recent or impending expiry of patents for some key biologics has led to development of bio-similar products. With growing numbers of these products there are now more options for healthcare providers and patients not only to access biological products earlier but also to possibly switch from costly originator versions to bio-similar alternatives.

Regulatory requirements In accordance with regulatory frameworks laid out by the European Medicines Agency (EMA), the US Food & Drug Administration (FDA), the World Health Organization (WHO) and other authorities with higher regulatory requirements, development of a bio-similar has to be accomplished by rigorous and comprehensive comparability exercises. This is to assure similarity of the bio-similar with the reference medicinal product in terms of quality characteristics, biological activity, Interchangeability safety and efficacy, which includes is a medical the absence of any clinically important practice of differences.

“

changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting…

The EMA has pioneered the legal, regulatory and scientific framework for approval of bio-similars, with 29 products approved via centralised procedure for use in the EU. However, the agency’s evaluations do not include recommendations if a biosimilar can be used interchangeably with its reference medicine. This decision is the sole responsibility of each of the EU Member States’ competent authorities. Recently, experts from national agencies in the EU issued their position statements welcoming the switch to bio-similar products and raising concerns over the scientific purpose, feasibility, utility and usefulness of over-complex and often un-surmountable interchangeability requirements, and how these fit with economically sustainable placement of these products onto the market.

”

It has been claimed that the switch from the reference product to the corresponding bio-similar may have an impact on the efficacy and safety. Ideally, changes in safety and efficacy might be associated with a switch from reference product to bio-similar if either of the products

has a higher inter-individual variation in pharmacokinetics. However, such a difference has not been observed with current bio-similars.

Immunogenic issue Considering the above, the remaining potential problem is immunogenicity. A biological product is immunogenic if the immune system of an individual will recognise it as a foreign substance. It is not always possible to avoid immunogenicity of biological medicinal products. A bio-similar is allowed to be as immunogenic or less than but not more immunogenic than the reference product. Immunogenicity caused by a switch between a bio-similar and its reference product may, in principle, be caused by two mechanisms. First, the immune system may react to a structural difference between the products. However, such a reaction is highly unlikely with licensed bio-similars, as the products have been shown to have comparable structure and immunogenicity in pre-licensing clinical trials. Increased immunogenicity has, in rare cases, been associated with manufacturing changes of a given biological product. The other possibility is that the reference product is immunogenic and the immunoglobulin class or specificity will change upon the switch to a bio-similar.

Changing one for the other Interchangeability is a medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting, and in any patient, on the initiative or with the agreement of the prescriber. Automatic substitution is a practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber. The term ‘switching’ is related to the decision taken by the treating physician to exchange one medicine for another with the same therapeutic intent in patients who are undergoing treatment. Several EU national regulatory authorities, including those of the Netherlands, Finland, Scotland, Ireland and Germany have already taken national positions to endorse the interchangeability of biosimilars under the supervision of the prescriber. Due to the medicinal product complexity the automatic substitution of a reference biological product by a bio-similar product is not allowed by any of the EU member states. The decision of substitution or switching lies in the hands of the doctor and not the pharmacist.

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COVER STORY

Bonus!

The value of digital Chris Wilkinson, head of sales for Healthcare for Siemens Financial Services in the UK, looks at the value of new-generation digitalised technology within the pharmaceutical industry.

ew-generation digitalised technology (also known as Industry 4.0) is enabling manufacturers across a range of sectors to improve performance through increased manufacturing productivity, more accurate planning and forecasting, enhanced competitive capabilities and greater financial sustainability. In the pharmaceutical sector, for example, digitalisation and data analytics can reduce the high levels of downtime typically experienced by pharmaceutical plants. Although, the various dimensions of productivity differ between industries and countries, increased manufacturing productivity — the ability to either produce the same number of products for less, or more products for the same — has a clear and calculable positive effect on costs and margins.

International research This effect — which we have called the ‘Digitalisation Productivity Bonus’ — is the focus of our latest research,1 which captures testimony from over 60 international industrial companies, expert management consultancies and academic specialists based in 11 countries. The resulting model estimates this productivity bonus for different industries. The potential ‘Global Digitalisation Productivity Bonus’ (all manufacturing sectors) is estimated to be between 6.3% and 9.8% of total annual revenue by 2025. Additionally, the research looks specifically at the potential gains for the pharmaceutical manufacturing industry. Applying the model to this sector in each of the 11 countries covered provides an estimate of the digitalisation productivity

bonus to be gained as a result of investment in digitalised Industry 4.0 technology.2 The resulting totals are an estimate of the potential financial gain for the pharmaceutical industry as a direct result of improvements in manufacturing productivity from digital transformation. In the global pharmaceutical manufacturing industry, it is estimated that conversion to digitalised technology could deliver a digitalisation productivity bonus of between $67 billion and $105 billion.3 The digitalisation productivity bonus is a critical starting point for CFOs in the pharmaceutical industry. Nevertheless, there are other commercial benefits to be accrued from the move to digitalisation.

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Pharmaceutical plants typically experience high levels of downtime. According to one analyst, digitalisation and data analytics could reduce this by 30% to 40%4 significantly improving overall equipment effectiveness (OEE). Internet of Things (IoT) communication between machines and machine-learning artificial intelligence (AI) deliver seamless processes, predictive maintenance and automatic corrective actions.

Regulatory benefits The pharmaceutical manufacturing environment is highly sensitive and tightly regulated. The smallest of errors can result in life-changing patient outcomes and have a disastrous commercial, legal and reputational impact on the manufacturer. For these reasons, ‘Pharma 4.0’ can often deliver amplified operational and competitive value. A few years ago, a global pharmaceutical giant had to recall over a half a million tablets because of packaging and human-monitoring errors in the plant.5 Digitalisation and automation are now ensuring the company will not experience a similar error in the future and suffer the financial ramifications and negative brand impact it suffered in the past. The company has introduced digital sensors and robotics and invested in high-availability computing to guard against data-transfer issues between units. This has created a fully automated production line that has the by-product benefits of making it much easier to maintain cleanroom processes, capture and manage electronic batch records, and analyse process performance (through root-cause analysis) to identify and implement improvements. Further points of value for Pharma 4.0 are being gained in the field of regulatory compliance. One manufacturer has installed digital sensors for visual, environmental, temperature, and chemical monitoring throughout its manufacturing process.6 This has now automated compliance reporting that previously involved expensive manual monitoring, although halfyearly manual tests are still made by an outside agency to audit and verify the automated reporting. Not only has this released crucial funds for investment elsewhere in the business, it has also provided the means for alerts when any of these factors move outside of defined tolerances, triggering early intervention that minimises the cost of potential contamination, formulation errors, and consequent process shutdowns.

Mass customisation Mass customisation is also important to the pharmaceutical sector in light of the increasing trend of individualised formulations. Although individualised-medication manufacturing raises important issues about quality, batch stability and risk management, some areas may benefit from being able to manufacture short runs of customised therapies at the kind of price previously associated with mass production. One manufacturer is currently trialling such digitalised processes with analgesic combinations.7

Digital information integration up the supply chain and down the distribution chain is also delivering greatly enhanced demand-supply management. One manufacturer that supplies a wide range of therapies has set up information links with all the hospitals in a single particular location.9 Links to these hospitals’ clinical information systems enables the gathering of aggregated anonymised patient data in a selection of specialities and uses predictive analytics to better plan manufacturing production volumes. This pilot The digitalisation has already demonstrated high levels of accuracy and is productivity planned for gradual rollout across the country through bonus is a critical to 2020.

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The best financial package

starting point for CFOs in the pharmaceutical industry.

While digitalisation drives financial sustainability, access to a range of smart and appropriate financing techniques — Industry 4.0 finance — is also critical to a company’s ability to sustainably invest in the new fourth-generation of digitalised technology and automation equipment. Industry 4.0 finance covers a range of requirements from the acquisition of a single digitalised piece of equipment, right through to financing a whole new factory. Financing techniques have now been developed to allow an organisation to, in effect, apply some or all of the digitalisation productivity bonus to fund the digitalised technology and equipment that makes the bonus possible in the first place. In simple terms, these financing methods seek to align payments for the new generation technology with the rate of gain from the Digitalisation Productivity Bonus. Broadly speaking, this can help make the upgrade to digitalised technology affordable and potentially cost neutral (or better) for the manufacturer. Industry 4.0 finance arrangements tend to be offered by specialist providers that have a deep understanding not only of how the digitalised technology works, but also of how that technology can be practically implemented to deliver the digitalisation productivity bonus as well as other benefits of digitalisation. At times, the financing arrangement will be an embedded component of the value proposition, offered right at the beginning of the sales cycle. In other cases, the technology provider will refer its customer to one or more finance providers to fund a sale.

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Complete solutions should be taken into consideration to identify the best finance package to effectively digitalise a manufacturing facility’s entire operation.

Complete solutions should be taken into consideration to identify the best finance package to effectively digitalise a manufacturing facility’s entire operation — from equipment to software to the production line to the whole enterprise. Between them, this range of Industry 4.0 finance techniques allows pharmaceutical manufacturers to access the digitalisation productivity bonus.

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References: 1. Siemens Financial Services, ‘The Digitalization Productivity Bonus’, April 2017. 2. The average bonus percentage range has been applied to the total annual revenue of the Pharmaceutical industry in selected countries across the globe (official data on revenue was taken from official third-party sources).

Integrating the chain Digital integration of the distribution chain (through distributors, then pharmacists and retailers, to the clinician and patient) offers pharmaceutical companies greater opportunities to combat fraud. One generics manufacturer8 became aware of several counterfeit versions of its products in certain countries. The company introduced an encrypted digital signature to its packaging that allowed genuine products to be tracked and traced down the distribution chain, with healthcare organisations able to verify the product through a secure portal in the cloud.

3. Average Digitalisation Productivity Bonus data derived from over 60 interviews in 11 countries with international manufacturers, international management consultancies and academic experts (expressed as a percentage of total revenues). 4. Strategy & “Digitization in Pharma” (19 October 2016). 5. Source: original research, US. 6. Source: original research, Germany. For general points, also see Manufacturing Chemist, “IoT, Industry 4.0 and the pharmaceutical manufacturing sector” (8 December 2016). 7. Source: original research, UK. 8. Source: original research, India. 9. Source: original research, UK.

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Investing in the Future of Pharma Opened in May 2017, the GEA Pharma Solids Center (GPSC) represents our continued commitment and ongoing support to the future of the pharmaceutical industry. With a total footprint of 1100 m2, the GPSC epitomizes the state-of-the-art in oral solid dosage (OSD) form testing, development, and optimization, and oﬀers a full range of batch and continuous manufacturing technologies. From product development and process enhancement to real-life simulations and test and loan machines, we provide a comprehensive range of services that are designed to improve production eﬃciency and expedite time to market.

The GPSC oﬀers • customer demonstrations and trials on our batch and continuous equipment • training sessions and classes • hands-on laboratory experience • pharmaceutical product development assistance • CQAs evaluation • testing of new concepts (equipment and advanced controls) • scale-up from laboratory to production • process development/refinement to increase the understanding and capability of GEA equipment.

ASEPTIC MANUFACTURING

A clean sweep Richard Lewis of Biopharma Group looks at the rise of low maintenance, automated aseptic processing lines.

ontemporary procedures to ensure the cleanliness of vials, for use in aseptic processing environments appear to be at the forefront of technology more than ever before.

This may, in part, be associated with increased attention from regulatory agencies, and the drive towards compliance as a result. The presence of micro-organisms and other contaminants can have severe consequences, for example, should foreign material enter the blood stream, following administration of an injectable drug product. Manually washing vials can be cumbersome and inefficient, with large variations in the level of cleanliness batch-to-batch and vial-to-vial; an inconsistency which poses issues during validation. Proper and thorough vial washing, depyrogenation, is therefore critical to ensure the safety of patients. The purchase of pre-sterilised containers however, can be cost prohibitive as a long-term solution.

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Industry standards, therefore, continue to seek alternative equipment designs, negating the reliance on moving parts, to minimise potential containers (i.e., glass vials) becoming compromised.

Proper and thorough vial washing, depyrogenation, is therefore critical to ensure the safety of patients.

Continuous aseptic processing Continuous aseptic processing, therefore, has significant advantages, which is why it has fast become a recommended practice within manufacturing facilities, and a popular solution to this conundrum. In less than 30 minutes, a container can move from the vial washing machine, into the sterilisation/depyrogenation tunnel, and finally towards the filling/stoppering/capping machine — no operator intervention or re-contamination occurs during any point of the aforementioned cycle.

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This has led to a focus on units composed principally of static parts, in some cases as few as two moving parts may need to be present: Inside the wash chamber itself The central column and the out-feed mechanism Instruments such as those described can be used as both ‘standalone’, and integrated in to full aseptic production line. Of course, equipment must be used in such a way that strictly adheres to any cGMP guidelines, to satisfy the strictest of process and cleaning (CIP/SIP) or software compliance (CFR 21 Part 11), too — another favourable facet of the technology.

The story does not simply begin and end at this stage though, due to the complexities associated with aseptic processing. To effectively lower risks of container contamination, companies and operators alike, seek to establish integrated processing lines. An example of other salient techniques/mechanical devices encompassed within these ‘lines’ to curtail the possible propensity of particulate generation are outlined, below: • Depyrogenation tunnels • External vial washers • Rotary vial washers

While it is now becoming more accepted that aseptic process equipment is the way forward, it is essential to know which to choose to achieve the best results. For instance, some devices include gears, belts, chain, grease points, to name a few, which may actually become a source of particulate generation, and ultimately, contamination; an occurrence that should always be avoided.

• Automated loading/unloading systems • Filling and capping units These items should be carefully considered to ensure best practice within aseptic processing lines is maintained.

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EXCIPIENTS & APIs

The ideal route Jonathan Knight, VP New Product Development at Cambrex, dissects the route used to manufacture APIs, highlighting those steps that can make a process ideal.

uring a drug’s clinical development, the focus is very much on producing API material — with an emphasis on speed — and the route used to manufacture the molecule is rarely altered past Phase IIa. It may be that only as the demands for product increase throughout the clinical stages, and into commercial manufacturing, that the synthetic route is scrutinised, and process chemists and engineers look to adapt it. Frequently, there are issues with synthetic routes where innovator biotech companies simply have not had the time, or resource, to dedicate to route development. These include the use of expensive key intermediates; poor and expensive registered processes; detrimental environmental footprints; and challenging steps to scale up using commercial scale equipment. Route evaluation is common for contract manufacturing organisations (CMOs) once the market has been established for a drug, several years after launch.

Route evaluation The economics of the route are driven by the cost of starting materials, the number of synthetic

steps, yields, process time and robustness of the process. Manufacturing on a smaller scale, with steps that may involve chromatography, chiral resolutions or multiple functional group protection and de-protection steps may be acceptable, but once the volumes of batches become higher, in many cases, these must be removed. When assessing a route, the obvious place to begin is to look at the cost and availability of the key starting materials, as well as the overall cost of goods, to see if these are limiting factors. One must also be aware of any patent restrictions that should be avoided, and the potential to protect the intellectual property of a new route which could give an enormous commercial advantage. The environmental impact of the route is also a factor to be taken into consideration. The use of chlorinated solvents on a large scale is increasingly restricted, and the cost of energy and waste becomes of greater importance as process volumes and manufacturing scales increase. Using alternative solvents which reduce the impact on the environment and demand less energy are obviously beneficial.

The robustness of the route and the reproducible purity of final products is of paramount importance. Having steps that require multiple work up procedures and purifications not only increases the overall process time spent in the plant, but can also potentially reduce overall yields. With ever tightening rules on elemental impurities in final API material, removing a metal-catalysed step can bring great improvements, particularly if that step is near to the end of the overall synthesis.

well as robust, reproducible and high yielding.

What is an ideal process?

For ease of manufacture, reducing the number of isolation steps within a process is desirable, so being able to telescope processes throughout the synthesis can reduce the overall process time of each batch, and reduce the quantity of solvents used. Being able to utilise standard plant equipment efficiently throughout a process avoids unnecessary investments to manufacturing facilities, and can reduce bottlenecks and delays where certain steps may be scale-limited by availability of equipment. Additionally, having a manufacturing strategy that limits and manages the waste produced by a particular process is important, and using solvents that can be reused and recycled within a process — albeit according to stringent regulatory parameters — can be greatly beneficial in terms of the economics.

Cheap, readily available starting materials that can be converted in the fewest number of synthetic steps which are atom efficient— by which molecular weight is constantly added to the target molecule rather than being taken away — are fundamentals to efficiency. Additionally, the route should be convergent, rather than linear, as

Identification of the key drivers for change from the outset is important, be it any of the factors discussed. There may not be a perfect process, and practicality may dictate compromises within route development, but it is important to set key project goals, and to consider all aspects of a process to strive to meet them.

As well as purity, the physical characteristics of the end-product may determine a need to change a process. If the end-product is difficult to handle, for example, carrying a high electrostatic charge, it may be that the final recrystallisation solvent used needs to be changed.

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EXCIPIENTS & APIs

Pick of the bunch Doug Millington-Smith, principal applications specialist at powder characterisation company Freeman Technology, considers the value of multivariate powder characterisation as a solution to the demand for comprehensive data.

ell-established techniques for material characterization may not provide the differentiation required to quantify variations in batches of excipients that contribute to variation in downstream process behaviour. A fundamental part of quality by design (QbD) is the need to establish a design space of acceptable raw material properties which requires understanding of a diverse range of excipient properties.

The importance of excipients to patients and producers Patients clearly want to be treated with effective drugs, but this is not their only concern. Any therapeutic agent is more acceptable to those who rely on it if the side effects are minimized and the delivery system is as palatable as possible. If drugs taste better, and are easy to take, patients are more likely to continue using them. For instance, large tablets are often coated to make them easier to swallow, flavours and sweeteners can be used to mask unpleasant tasting active ingredients, and colours may be added to improve the aesthetics and aid identification. Optimising these properties through the management of excipients is important in helping patients adhere to their treatment schedule. Excipients are equally important in pharmaceutical manufacturing, where their properties can be as vital to therapeutic performance as those of the active ingredient. Excipient properties are key to aspects such as product stabilisation and shelf-life, for example. The manufacturer can also choose to boost the effectiveness of the active ingredient by manipulating excipient properties to enhance solubility, reduce viscosity and increase absorption, among other things. Powder and solid doses, in particular, use a wide range of excipients to solve manufacturing problems. Anti-adherents, binders and lubricants are used to provide mechanical strength, prevent the ingredients from agglomerating and to protect tablets from sticking to the punch and die faces during processing.

Many excipients have been used for decades and their general characteristics closely defined. However, inter-batch variability can lead directly to variability in processing resulting in reworking or even scrappage. With recent QbD initiatives making it necessary to optimise production processes to ensure the consistency and reliability of final products, a robust method of quantifying the variations in batches of excipients that contribute to differences in downstream process behaviour is an absolute necessity if a design space of acceptable raw material properties is to be established. However, even well-established techniques for material characterisation (such as particle size analysis) do not always provide the required differentiation and typically only evaluate one physical property of the particles.

Reproducible properties measurement The FT4 Powder Rheometer (Freeman Technology, UK), uses powder characterization techniques and fully automated test protocols to deliver a comprehensive and reproducible database of process-relevant powder characteristics. As well as characterising the rheology, or flow properties, of powders, the inclusion of a shear cell allows the powderâ&#x20AC;&#x2122;s shear strength to be determined and quantification of how a powder shears with respect to the surfaces of process equipment can be undertaken using a wall friction kit. Bulk powder properties, such as density, compressibility and permeability, can also be measured.

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The benefits of such an approach are easily illustrated. Consider a pharmaceutical manufacturer sourcing alternative supplies of an excipient based on a specification that covers only particle size and bulk density. A new material matching this specification is sourced but, when fed into the plant, problems arise and efficiency plummets: blockages become commonplace and final product quality is inconsistent. In a case such as this, the excipient specification is clearly inadequate, incorrect, or insufficiently detailed, and does not reflect and reference all the powder variables that impact in-process behaviour. Analysing the conditions throughout the manufacturing process and identifying the key properties that correlate with these conditions is necessary.

An example of multivariate analysis of bulk excipient batches Microcrystalline cellulose (MCC) has been used as a pharmaceutical excipient for many years, due to its abundance, ease of production and resistance to degradation. As with any excipient, however, variability exists between batches of supplied material that can, in turn, lead to similar variability in processing and the finished product. Particle size analysis was undertaken to test the three grades MCC (sample A, B and C) used as an excipient in the production of pharmaceutical tablets by direct compression. Data generated illustrated almost identical D50 values (100 µm) for each grade, and it was determined that all three samples were indistinguishable from each other in this context. All three samples were further analysed using an FT4 Powder Rheometer and the results are presented below.

Dynamic testing: Aeration Sample A and sample B exhibited similar responses, whereas Sample C generated a significantly higher Aeration Ratio (AR). This demonstrates that Sample C’s packing structure changes to a greater extent when air is introduced into the sample and typically indicates a lower degree of cohesive strength between particles.

Bulk testing: Permeability Again, sample A and sample B were similar whereas sample C generated a considerably higher pressure drop across the powder bed, indicating that it is the least permeable of the three. Low permeability means that any air that becomes entrained in the bulk is less able to escape. Considering the example of a tabletting process, greater air content within the dose would typically lead to weight variation as well as capping and lamination in the final product.

Shear cell testing Sample A exhibited markedly different behaviour when compared with the other two samples. It generated the highest shear stress values at low normal stress levels, but the lowest values when subjected to higher stress levels. This suggests that the way the powders perform in a given process would be heavily influenced by the stress levels they are subjected to, and demonstrates the need to characterize powders using process relevant techniques.

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If drugs taste better, and are easy to take, patients are more likely to continue using them.

It is also interesting to consider the results for sample B. The yield locus, generated by a best-fit line through the data points, is so steep that it intercepts the y-axis below the origin. This leads to a negative value for cohesion, and generates no result for flow function (as the minor Mohr’s circle cannot be constructed to produce a value for unconfined yield strength). This illustrates the risks of relying on parameters derived from Mohr’s circle analysis alone, as the mathematical model used to obtain these parameters may not always provide data for comparison.

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In summary, sample A exhibited the highest permeability and the lowest sensitivity to Aeration, and was less sensitive to changes in applied stress during shear cell tests. This suggests that it is the most efficiently packed of the three samples and is likely to exhibit more freeflowing behaviour across a range of conditions. Sample C generated the highest shear stress values, was most sensitive to aeration, and exhibited the lowest permeability, suggesting a greater sensitivity to the process conditions than the other samples and illustrating the need to understand the relationship between the process environment and the material properties.

The vital importance of powder flowability In quantifying clear and repeatable differences between three grades of MCC , the advanced powder characterization capabilities of the FT4 identified likely differences in their response to various process conditions. Although production conditions can be rigorously standardised and monitored, variations in the finished product can still occur. As a consequence of batch-to-batch variations, it is not uncommon for batches of the ‘same’ powder to perform differently in a process. For pharmaceutical manufacturers, these results demonstrate the importance of understanding the physical characteristics of a powder which correlate with good performance within their particular process, and perhaps just as importantly, those that are associated with problematic performance or poor product quality. Successful processing demands that powder and process are wellmatched. Multivariate testing delivers relevant data that can be matched with process ranking to produce a design space of parameters that correspond to acceptable process behaviour. Excipient suppliers and users now have the opportunity to intelligently and reliably select excipient batches that exhibit the characteristics necessary for a specific manufacturing process.

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MERGERS & ACQUISITIONS

A chunk of change Despite a downturn in M&A activity during the latter part of 2016, prospects are on the rise. In this article, we analyse what deals are on the table, coming to the table and those that are still in the kitchen waiting to be plated up!

n general, one thing that can always be relied upon is the fact that there will be merger & acquisition (M&A) agreements in the pipeline or being completed upon at multiple points during the calendar year within the pharmaceutical industry. It is usually, as they say, ‘a dead cert’. The trend for M&As, however, seems to be less than buoyant this year after the slowdown in 2016 due to the political uncertainties resulting from the Brexit vote and the US presidential elections.

Change is coming Yet, last month, we witnessed the possible beginnings of a change in tide with Thermo Fisher announcing a $7.2 billion deal to buy the Dutch drug ingredients manufacturer, Patheon.1 This transaction, which is expected to complete at the end of the year, will combine Patheon’s ability as a contract development and manufacturing organisation (CDMO) with Thermo Fisher’s capacity to supply to the biopharmaceutical industry, creating a ‘one-stopshop’ for drug manufacturers looking to outsource. Speaking about the deal, president and chief executive officer of Thermo Fisher Scientific, Marc N. Casper, said: “Patheon’s development and manufacturing capabilities are an excellent complement to our industry-leading offering for the biopharma market. Our combined capabilities will enhance our unique value proposition for these customers, create significant value for our shareholders and further accelerate our company’s growth.” Chief executive officer of Patheon, James C. Mullen, added: “Over the past several years, we have increased our capabilities to become a leading CDMO provider in a highly-fragmented market. We are confident that our combined offerings and Thermo Fisher’s proven track record of disciplined M&A and successful integrations will take our business to the next level.”

Sell, sell, sell This year, we have also seen the readying of Merck and Sanofi to sell or cut down their biosimilar and generics units, respectively. In Merck’s Annual Report for the year 2016,2 it was stated: “Merck is in advanced stages of negotiations to divest the Biosimilars business and the transaction

is expected to close in 2017.” Despite its work with Dr Reddy’s in India since 2012 within the biosimilars arena, no product has been brought to market to date. Sanofi’s approach was also outlined in their 2016 report3 and further iterated in the delivery of its annual sales and business growth analysis4 where it was stated: “As announced in our 2020 strategic roadmap, Sanofi has carefully reviewed all options for our Generics business in Europe and recently made the definitive decision to initiate a carve-out process expected to be completed by the end of 2018. Importantly, Sanofi confirms its commitment to Generics in other parts of the world with a greater focus on the Emerging Markets.” The strategy to slim down has also aligned with the company’s CEO asserting that Sanofi is in no hurry to do M&As, discussed during the announcement of the 2016 results.

On the cards A possible big M&A movement is that of the potential Dow Chemicals merger with DuPont. This mega merger received conditional approval from the European Commission in March, representing a significant step toward closing the transaction. The intention of the companies is to split into three separate publicly traded entities and, according to Dow, is expected to “create significant cost synergies of approximately $3 billion with the potential for $1 billion in growth synergies.”5 This conditional approval from the European Commission, however, has some provisos, with Dow and DuPont required to fulfil certain commitments that have been agreed upon with the European Commission in connection with the clearance. Adding to this, there have been reports that GlaxoSmithKline is looking to buy out Novartis’ stake in consumer health JV.6 The funds raised from this potential buyout are being penned by industry watchers as an aide to a possible takeover by Novartis of AstraZeneca, which would give rise to a shift in the oncology sector.

Something in the air As stated by the law firm, Hunton & Williams, in their overview analysis of the M&A landscape for this year: “[…] we believe the global economic environment

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is generally favorable for M&A. Growth continues to be low and stable, monetary policy remains loose and inflation does not appear to be an imminent issue. This economic environment will encourage companies to seek expansion through acquisitions rather than just through organic growth, and they should have little difficulty financing those acquisitions. The 2017 M&A outlook could change So, despite the in an instant, but for downturn in M&A now, however, we activity during are broadly optimistic the latter part and look forward to an active year in both of 2016 […] the US and global there is a definite markets.”7 feel that more

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So, despite the big deals are on downturn in M&A the way activity during the latter part of 2016, resulting from the US presidential election, and the turbulence in the economic sector that Brexit may cause for the UK and Europe, there is a definite feel that more big deals are on the way and surely a plethora of smaller deals in the offering too.

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References: 1. http://news.patheon.com/press-release/corporate/thermo-fisherscientific-acquire-patheon-leading-contract-development-and 2. http://ar2016.merckgroup.com/sites/default/files/downloads/ en/merck_annual_report_2016.pdf 3. http://en.sanofi.com/Images/49288_20-F_2016.pdf 4. http://mediaroom.sanofi.com/sanofi-annual-results/ 5. http://www.dow.com/en-us/news/press-releases/dow-dupontconditional-approval-european-commission-merger-equals 6. http://www.fiercepharma.com/pharma/gsk-preps-10-3b-buyoutnovartis-consumer-jv-stake 7. https://www.hunton.com/files/News/1bb98d73-dcdb-4f7798bd-7b5999e07ed4/Presentation/NewsAttachment/0ff8c20a4b9d-47d5-a91a-7cd35b9d1fc1/2017-m-and-a-forecastfeb2017.pdf

EVENT FOCUS – NEXUS ‘17

The serialisation landscape Erik Haeffler, vice president of manufacturing services, Recipharm, examines the challenges and opportunities for a CDMO in the landscape of serialisation that contract partners must overcome.

ith growing concerns surrounding counterfeit medicines and the threat they pose to patient safety, the pharmaceutical industry is introducing varying serialisation mandates across the global market.

Serialisation goes far beyond the ability to apply barcodes to products at the packaging line level and implementing a robust process can be both time consuming and costly. As a result, it is imperative that contract manufacturers are well prepared for the introduction of the European Falsified Medicines Directive (FMD) and its counterparts across the rest of the world.

Challenges for CDMOs Serialisation represents a significant challenge for CDMOs; particularly those with manufacturing facilities and customers across the globe. While equipping packaging lines with new technology may seem relatively simple, managing the complexity associated with packing several companies’ products on the same line, as well as meeting the varying regulations of multiple markets, is not without its challenges. Failing to meet the required regulations on time can not only mean costly downtime and product shortages, but potentially a loss of business in key markets. Now is the time for CDMOs, particularly those serving the European market, to rise to the challenge and differentiate their offering by demonstrating proactivity in their preparations.

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Geographic and market requirements

Serialisation represents a significant challenge for CDMOs; particularly those with manufacturing facilities and customers across the globe.

Data requirements vary depending on the market that the drug product is supplied to. A CDMO must therefore implement a flexible solution that can be adapted to varied customer and market requirements.

For example, if production lines need to serialise products for more than one customer supplying to more than one market it may be beneficial to use the most complex data matrix (i.e., containing the most information) as standard. Some markets also require aggregation as part of their serialisation mandates and so this must be factored into the serialisation solution.

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Technical challenges In addition to the geographic complexities, there are numerous technical considerations that CDMOs need to address. Firstly, software and hardware selection is critical. In particular, the chosen software should offer the flexibility to adapt to future track and trace demands. In addition to the line level software, CDMOs also need to consider how to generate and manage serial numbers, particularly if they’re supplying to a market, like the EU, where the varying requirements call for randomised serial numbers and in both the EU and US, where the responsibility falls on manufacturers. They should also consider how the data will be securely exchanged with customers and the relevant authorities. Using a cloud storage system can help CDMOs to simplify the data exchange process by connecting to a large global network and provide the scalability that is necessary to cater to a diverse and growing customer base.

An opportunity: good practice for CDMOs While serialisation brings a number of challenges, it also creates the opportunity to improve business processes and establish your business as an industry leader. So, what does good practice look like? And, what should pharmaceutical companies be looking for in a contract partner? First and foremost, it is imperative that CDMOs have factored in enough time to plan, implement and agree on a solution that meets their customers’ requirements. If the CDMO has a dedicated taskforce it should be a The potential impact of sign that it has prioritised its serialisation being under-prepared is preparations and allocated sufficient vast and CDMOs should resources to the cause.

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be working closely with

It is the responsibility of CDMOs to have a detailed understanding of the complexities their customers to ensure of serialisation and the various markets they can cater for their in which their customers operate, which individual requirements. makes previous experience of delivering serialised batches desirable. However, perhaps most importantly, CDMOs should have a standardised solution which simplifies the serialisation process, while also being flexible enough to cater for the required markets and adapt to future changes to regulations.

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Final thought Introducing a comprehensive solution that will meet the varying serialisation requirements across the globe is no small task and the complexities associated with developing a robust process mean a thorough understanding of the global market is essential. Failure to comply with the new legislation on time could lead to product shortages and a potential impact on patients, as well as wastage, costly downtime and a possible loss of business due to reputational damage. The potential impact of being under-prepared is vast and CDMOs should be working closely with their customers to ensure they can cater for their individual requirements. As the saying goes, those who fail to prepare should prepare to fail. Erik Haeffler will be leading a speaking session on serialisation from a CDMO perspective at NEXUS ‘17, taking place in Barcelona, 7-8 June.

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EVENT FOCUS – NEXUS ‘17

Stay safe, stay connected In this article, Eric Tjoa, CEO and founder at Tjoapack, outlines a brief history of track and trace and explores the future for serialisation, including the opportunities that technology can bring to the sector and most importantly, patient safety

he tracking and tracing of medicines to improve the visibility of drugs throughout the pharmaceutical supply chain is not a new concept. In fact, the idea of serialisation has been discussed for over 15 years. However, what is changing is our understanding of technology and our mindset around the possibilities it can bring to the industry.

While the EU FMD is limited to the verification of medicines at the dispensing point and, therefore, does not allow for the tracing of drug products throughout the whole pharmaceutical supply chain, it is a positive step towards establishing a more secure system.

When Tjoapack started printing barcodes on single drug units around 28 years ago, it was too early for many people to understand the value of this kind of technology in the supply chain. Today, with the introduction of varying track and trace regulations across the globe, the need to develop a safe and connected pharmaceutical supply chain is coming to the fore.

The counterfeiting of medicines is an enormous problem and with increasing access to drugs via the internet and an extremely complex global marketplace, the situation is not getting easier. The mobility of people and drug products will only increase, while buyer behaviour and the way we access medicines is likely to evolve.

In the beginning: a brief history While companies have been discussing the need to identify and verify medicines to protect patient safety for some time, the pharmaceutical industry has been slow to adopt new technologies. In 1999, following a report by the US institute of Medicine, President Bill Clinton placed patient safety (including preventing errors at the point of dispensing medicines) on the agenda of federal government and continued to lobby for changes after his presidency. In 2003, the US Food and Drug Administration (FDA) mandated barcoding on unit doses and in the same year, the World Health Organisation (WHO) published a report recognising the scale of the counterfeit medicine challenge stating that 10% of medication worldwide was counterfeit. A step change took place in serialisation around 2005 and a number of countries began to set deadlines for implementation. However, after making some strides towards securing the supply chain, the challenge became less of a priority during the financial crisis in 2008. As the global economy has improved, slowly the momentum has shifted. Turkey introduced serialisation requirements in 2010 and other markets such as China, South Korea and India have regulations in place. With the EU Falsified Medicines Directive (FMD) coming into effect in February 2019 and the US introducing legislation in November 2017, as part of the Drug Supply Chain Security Act (DSCSA), it’s expected that more than 75% of global medicines will be covered by some form of track and trace regulations by 2019.

Look to the future

An ageing population is also placing new pressures on global healthcare systems, requiring more efficiency throughout the supply chain to meet demand and reduce costs. Patient empowerment is another interesting trend that will affect the way that medicines are delivered. Patients of the future are likely to demand more control over their medications, requiring the ability to self-verify their origin and genuineness using mobile technology. Mobile applications can also in the short-term assist medical personnel, allowing them to get a faster and better response for their patients. While we are beginning to witness the use of artificial intelligence in the automotive industry in the form of self-driving cars, we must explore the use of this technology in improving the pharmaceutical supply chain. To operate safely, self-driving cars must assess a lot of data to make the right decision. Similarly, serialisation involves large volumes of data that must be securely stored and exchanged. With the advancement of cloud-based applications, data storage is no longer such a big challenge as it was in the past and won’t limit innovation in the future. Our ability to exchange and process data will also become more advanced. With the right technology, it has become entirely possible to digitally connect with all your partners in the supply chain through one simple click. This could also be applied to the end user. Soon, it will be entirely possible to imagine a hospital of the future where doctors sit behind screens and diagnose patients based on data from various remote locations.

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Standardisation should also be an aim for the future of serialisation and track and trace systems. Global standardisation initiatives often require political involvement, however in the case of satellite navigation systems and mobile networks, the benefits of breaking down global boundaries have been realised. The healthcare sector needs to push towards global standardisation as collaboration is the key to accelerating developments.

Final thought There is still some way to go until global alignment is achieved. However, the fact the EU has finally taken note of the problem of counterfeiting and made this issue a priority is a positive. The FMD means there is now much more clarity on the responsibility of stakeholders throughout the supply chain There is still in eliminating the problem of some way to falsified medicines. Being able to imagine how the pharmaceutical supply chain can be transformed and improved using technology requires a particular mindset. Today, a new generation that has grown up with smartphones is helping to drive a mindset shift and an acceptance that technology can bring major benefits to not only the pharmaceutical manufacturing process, but critically, the safety of patients across the world.

“

go until global alignment is achieved. However, the fact the EU has finally taken note of the problem of counterfeiting and made this issue a priority is a positive.

Other sectors such as the automotive industry have a much more transparent network supply chain, making use of artificial intelligence, the internet of things (IoT) and mobile applications. It’s expected that these trends will also impact the future of the pharmaceutical supply chain, helping to create a safer and more connected global network.

”

Eric Tjoa will be presenting at NEXUS 17, an annual forum, hosted by TraceLink, taking place on 7 and 8 June in Barcelona. 25

32nd International Exhibition for Fine and Speciality Chemicals

Known for its focused profile Chemspec Europe is the place to be for international experts of the fine and speciality chemicals industry. Purchasers and agents looking for highly specialised products and bespoke solutions will find leading companies from all over the world presenting a maximum range of fine and speciality chemicals. Benefit from excellent networking opportunities and be inspired by the latest results in research and development at top-class conferences.

Top-class conferences Agrochemical Outlook Conference Chemspec Careers Clinic Pharmaceutical Update Conference Pharma Outsourcing Best Practices Panel REACHReady Regulatory Services Conference RSC Symposium

Chemspec Europe 2017 – The driving force for tomorrow’s business! Exhibition Conference Networking

31 May – 1 June 2017 Munich Trade Fair Centre, Germany

www.chemspeceurope.com

Organisers:

PURIFICATION & FILTRATION

Rising to the challenge Mark Kelly, business development manager for the Separation and Purification Sciences division at 3M Ireland, reflects on some of the challenges facing the biotechnology industry, and explains how the science-based technology company is rising to them.

he biopharmaceutical industry is always striving to make process improvements, which come in many forms. Recent improvements in the upstream process have led to higher product concentrations, which are associated with higher cell densities.

All of this is positive news. However, it also means higher levels of soluble impurities within the harvested cell culture fluid. As a result, this leads to challenges in the downstream process, particularly the primary capture and polishing steps.

Mammalian cell culture

Chromatographic clarification

Collaborative project

Mammalian cell culture is typically clarified in one of two main ways to enable further downstream purification.

The collaborative project involves two studies, each being performed independently by NIBRT at its global centre of excellence for training and research in bioprocessing in Dublin, Ireland.

The first is clarification based on density, methods of which include centrifugation, which employs centrifugal force to reduce the time taken for particles, such as cells and cellular debris, to settle out of the cell culture fluid. The second is tortuous path traversal, or depth filtration, which results in particles being retained within the filter media as they flow through a tortuous path.

The single-use chromatographic clarification product consists of a quaternary amine functional nonwoven, which provides a high anion exchange capacity, as well as a mechanical sieving of large debris, and a fine particle and bioburden reduction membrane. As a result, the hybrid purifier removes negativelycharged soluble impurities, such as host cell DNA and negatively-charged host cell proteins, early on in the purification process. This, in turn, can help address turbidity problems at various points in the downstream process.

Neither approach has much impact on reducing soluble impurities. Therefore, 3M developed an alternative technology, which uses charge to clarify the cell culture fluid, the 3M Emphaze AEX Hybrid Purifier.

Removing these soluble impurities at this stage in the process may also enhance the purification performance of the Protein A affinity chromatography step, which, in turn, may assist in the downsizing of anion exchange polishing steps.

The first study began in January and is on track for completion later this year, examining the effect of chromatographic clarification on host cell DNA and the specific type and quantity of host cell proteins removed prior to downstream processing. The second study will run later in 2017. It will investigate gains in performance from optimising the load conditions for the product. This research is aimed at qualifying and quantifying the impact that the 3M Emphaze AEX Hybrid Purifier will have on the downstream process, in terms of complexity and cost. The results are expected to be published early next year.

To further investigate the productâ&#x20AC;&#x2122;s potential, the National Institute for Bioprocessing Research and Training (NIBRT) was commissioned to conduct in-depth research into the hybrid purifier.

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NEC BIRMINGHAM, UK | 26-28 SEPTEMBER 2017

INJECTION MOULDING

EXTRUSION ROTATIONAL MOULDING

BLOW MOULDING

RECYCLING THERMOFORMING

MATERIALS VACUUM FORMING

DESIGN FILM EXTRUSION

RAW MATERIALS INSPECTION

A penny saved… Since its introduction a decade ago, portable Raman spectroscopy has become a vital technique for raw materials ID verification in pharma manufacturing. In this article, the benefits and issues surrounding through-container ID verification are examined and whether testing of incoming goods can save more money in raw materials ID testing.

he cost savings of Raman compared with traditional techniques are well known1 but can even more money be saved from incoming goods testing?

The largest costs in the incoming goods supply chain arise from the handling steps — quarantine storage of materials before and after testing, the logistics of moving pallets around, sampling the contents for testing, and so on. Sampling requires expensive containment facilities, safety measures and clean-up costs, as well as the difficulties of opening and sealing flexible containers. One consequence is that cost-constraints may govern a sampling strategy where only a small fraction of incoming containers are verified from a delivery, increasing the potential for bad containers to slip through. Avoiding these errors is one of the cornerstones of the PIC/S scheme,2 which is an internationally-agreed set of guidelines for improving the quality of pharmaceutical products. These guidelines have had a significant impact recently in Asia where several countries, including Japan and Korea, have signed up to them and implemented changes in their national forums.3 The problem with testing containers of incoming goods is that they are often not amenable to conventional Raman spectroscopy. Handheld Raman instruments are generally compatible with thin plastic bags and some glass containers, but are not useful when containers become opaque.

Through the container The difficulty with measuring through the container is that the containers themselves have very different optical and Raman properties. Some, like brown paper or bottles, are highly fluorescent, whereas plastic containers tend to have strong Raman signals and/or added pigments. As containers vary in their properties, detecting and identifying contents through all of these container-types is difficult and cannot be done using conventional Raman

—laser illumination and collection is at the same container location, with either a small or large spot illumination. Spatially offset Raman spectroscopy (SORS), a technique using off-axis measurements, has enabled a unique benefit in pharma testing — being able to routinely measure through containers. Raman measurements can be made through most common pharma containers for even relatively weak Raman scatterers. A commercially available unit — RapID, from Cobalt Light Systems — is suitable for routine use for incoming goods testing. Suppliers of raw materials use a wide variety of containers, which is a key variable in determining the cost benefit; to give some idea of this, a survey of pharma companies4 revealed that 56–81% of containers received are opaque, and therefore impossible for handheld instruments, and 19% are amber glass of various thicknesses, which conventional Raman can find challenging. SORS can measure through most containers — the most notable exception is cardboard/ fibre drums, which are optically impenetrable but make up almost 10% of containers on average. When the container doesn’t need to be opened the testing can be fast, safe and with minimal delay after receipt at the warehouse. An efficiency study, published by Astellas Pharma Tech in 2015,5 examined the cost-savings of through-container analysis versus sampled spectroscopy (in this case, IR spectroscopy). Astellas found that the confirmation test takes the greatest amount of time — though conventional Raman would be quicker than IR — but the additional 13.5 hours of sample-handling time avoided by measuring through the container is the same for any test that requires sampling. The same study confirmed that a wide range of common materials can be measured through paper or plastic sacks, including common sugars such as lactose and mannitol and ‘difficult’ oral solid dosage (OSD) excipients such as magnesium stearate, starches, hypromellose and crosscarmelose sodium.

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Other materials and containers Outside the high volumes of OSD excipients there are other applications that benefit from through-barrier verification. For highly-toxic active ingredients there are obvious benefits to being able to ID compounds with no risk of exposure. Similarly, for materials at risk of externally-derived contamination, avoiding exposure to any peripheral risk is achieved by not breaking the seal of any packaging. Liquids, such as sterile m-cresol, can work well with Raman, but 2.5 L amber glass can be too thick for conventional Raman, even at longer wavelengths. Polysorbates, which are often packed under nitrogen to avoid degradation by oxygen, are doubly-confounding because their innate Raman efficiency is low. These important liquids, usually supplied in small glass bottles, tend to be used in parenteral formulations where 100% ID is mandatory, which makes the QC burden correspondingly high. ID of m-cresol can be done in <5 seconds per bottle using RapID, whilst polysorbates take around 30 seconds. As batches of these liquid excipients can comprise hundreds of bottles the time saved is considerable.

Summary Through-container ID verification has significant benefits for incoming goods testing. SORS is an effective technique that works reliably through the most common incoming containers in pharma manufacturing. It is particularly compelling in those environments where there is high throughput testing, parenterals manufacture or safety concerns.

References: 1. http://www.americanpharmaceuticalreview.com/1504-White-PapersApplication-Notes/129832-Cost-Benefits-of-Handheld-Raman-forQuality-Control-Testing-of-Incoming-Raw-Materials-in-the-Pharmaceutical-Supply-Chain/ 2. https://www.picscheme.org/ 3. https://picscheme.org/useruploads/files/press_release_rome_2014.pdf 4. 2016 Global survey of Pharmaceutical QC users. Cobalt Light Systems. 5. Kawakubo, S., et al., Pharm. Tech. Japan, 2015;31(12):71–80.

FORMULATION

Not for profit

We talk to Dr Nik Marchetti, product manager of Lhasa Limited, a not-for-profit organisation and educational charity, about products, developments and innovations driving the company forwards. Q. Could you give a brief overview of Lhasa?

Q. How do you comply with regulatory guidance?

Established in 1983, Lhasa is a not-for-profit organisation and educational charity, which creates in silico prediction and database systems for use in metabolism, toxicology and related sciences.

The data within the Vitic Excipients database lends itself to the REACH initiative, allowing members to retrieve relevant information quickly, while potentially avoiding the need for costly experiments.

Today, the company has 140 employees across sites in the UK, USA and Poland. There are more than 350 consortium members from global companies, covering pharmaceutical, consumer products, universities and academics, regulatory bodies, government organisations and charities.

However, the changing regulatory guidance has led to the need to build knowledge of elemental impurities in excipients. ICH Q3D establishes permitted daily exposures (PDEs) for elemental impurities of toxicological concern in drug products. The Vitic Elemental Impurities database can be used as part of the overall ICH Q3D risk assessment process as a support tool.

Q. The lead product, Derek Nexus, has recently won an award, could you tell us more? We’re thrilled with the success of Derek Nexus, which contributed to the company receiving its first Queen’s Award for Enterprise in Innovation in 2016, and more recently, the Yorkshire Business Masters Innovation Award. Derek Nexus is a knowledge-based software that provides accurate toxicity predictions. Using this tool to conduct in silico toxicity tests, enables the potential identification of toxic chemicals. Ultimately, aiding experts in rejecting any unsuitable drug candidates. Whether you’re in academia, or involved in an industry, Derek Nexus can be used to evaluate the potential toxicity of existing or prospective chemicals. The software allows users to make decisions about which chemicals are likely to have ‘more favourable’ toxic profiles when not all the experimental information is readily available. Q. How can Lhasa help pharma manufacturers ensure drug formulation is optimised? We’re involved in many pre-competitive datasharing initiatives, which often result in the development of databases. These include Vitic Excipients, which allows the anonymous sharing of excipient vehicle toxicity data, and Vitic Elemental Impurities, which is designed to share analytical data on the levels of trace metals within batches of excipients used in the formulation of pharmaceutical drug products. Our role in these projects is to facilitate datasharing, develop the database schema using the Vitic Nexus platform, and curate and input the data. Users of these databases have the opportunity to access existing information that has not previously been in the public domain, and by sharing the information, we can reduce duplication across different companies. As well as ensuring thorough cross-referencing, information that is found in the database can be used to inform testing strategies, meaning efficient use of laboratory resources.

Q. What other products does Lhasa offer? We’ve also got Zeneth, which is an actively maintained system for the prediction of degradation. As an expert-rule based system, the software is comprised of a knowledge base of transformations implemented by Lhasa’s scientific experts. Zeneth is a solution for scientists who need to understand the forced degradation pathways of organic compounds. The software shows predicted transformation and degradant information graphically, while assisting in the selection of appropriate excipients and highlighting the potentially problematic ones. It is also able to act as a training or learning tool In addition, is Sarah Nexus — a statistical-based system for the prediction of mutagenicity. The software allows identification of potentially toxic chemicals. The predictions are represented by positive and negative results, including confidence figures for the overall prediction and the fragments on which it is based. The predictions facilitate a thorough review by experts, giving a simple understanding on why your chemical is or isn’t predicted to be mutagenic. Sarah Nexus provides a confidence score as well as a structural explanation for each prediction. Q. Is it possible to integrate these products with other offerings? Vitic, Derek, Sarah and Meteor all sit within the Nexus platform. After a prediction, the Nexus results window provides all the information that you need as part of your decision support system for your overall risk strategy. Predicted structures from one Lhasa programme can also be submitted for processing in another within the same interface. Within Nexus, both Derek and Sarah are integrated in an ICH M7 workflow to allow fully compliant two-system predictions for use within ICH M7 submission portfolios. The products can also be outsourced to help other pieces of software achieve results. For example, StarDrop by Optibrium has a Derek Nexus module, which helps to guide in hit-to-lead and lead optimisation.

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FREEZE DRYING

Lyophilisation is crucial in the creation of pharmaceutical ingredients with an extended shelf life, however, current methods can still be costly and time consuming. Hosokawa Micron reveals its new method of contained active freeze drying as a potential solution

n the pharmaceutical industry the necessity of freeze drying (lyophilisation) is well known. Through removal of water, a product’s shelf life can be extended, with the added benefit of making storage and shipping easier. Additionally, in the case of active pharmaceutical ingredients (APIs), lyophilisation can ensure chemical stability at room temperature. In these instances, freeze drying is performed using trays.1,2 However, as a process this can be costly, complex and labour-intensive, which has led to a drive in the industry to adapt methods to streamline lyophilisation. In light of this, Hokosawa Micron has developed a method using a single sterilisable, closed vessel to deliver lump free, fine powder product.

A closed process In active freeze drying, the initial step is freezing of the product, which is done within a specially designed chamber. The material to be dried can be a liquid, solid or paste as a result of the agitation freezing process employed by the chamber. Once frozen, sublimation begins, which is applied through the vessel jacket and distributed throughout the product by the stirrer. The frozen material sublimes, creating a loose powder that is then transferred to the collection filter.

“Every production step is completed within a single, sterile closed chamber,” explained Gerard Geurtsen, senior application engineer at Hosokawa Micron. “There is no dust to compromise operator safety. Nothing can enter the sealed system to contaminate the product within. Wet product is transferred from a reactor vessel, so no contamination risks associated with manual handling are introduced and aseptic operation enabled. When the vacuum is broken, on cycle completion, the finished dry powder is discharged directly into a container that was sterilised along with the full system internals before product entered the system (see figure 1). There is no requirement for additional containment equipment to protect operators or product for this pack-off stage.” Lump free: In tray drying procedures, the final product may require further crushing once collected. However, Hosokawa Micron state that using active freeze drying, this issue is removed and the resultant powder is often fine and uniform (see figure 2). “The product is very often porous and the easy dissolution facilitates for use in injections,” Guertsen said. “Without the need to introduce a milling stage the product is not damaged — we achieve ‘drying without harming’ of even the most sensitive, delicately structured products and living organisms.” Aseptic processing: As the system is fully contained it is suitable for aseptic processing. Cleaning of the system is performed by spray nozzles in the drying chamber, which commence on batch completion. Steam in place (SIP) is achieved using pressurised steam or hydrogen peroxide. Cost: “The Active Freeze Drying process is often faster and always less labour intensive than the traditional tray freeze drying process; producing lump free, free flowing powders in one step,” claimed Guertsen. “Consequently, handling times are shorter and simpler thereby saving time and money.”

Figure 2

References: 1. https://en.wikipedia.org/wiki/Freeze-drying 2. http://link.springer.com/chapter/10.1007/978-1-4939-6595-3_9

Figure 1

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QUEEN’S AWARD

The Queen’s Awards for Enterprise are prestigious awards given to companies for outstanding achievements in four categories. Here we briefly run through some of this year’s winners in the fields of innovation and international trade.

Assessing safety

Global success nisation (CRO), Clintec, has been Global service contract research orga the Queen’s Award for Enterprise for awarded for international trade in efforts to accelerate drug development the second time in recognition of its globally. Queen’s Award for Enterprise again “We are honoured to have received the success in clinical research,” said Dr as we celebrate 20 years of global of Clintec. “The people of Clintec are Rabinder Buttar, founder and CEO the business further and continue to very excited and energised to grow tions to our clients, several of whom deliver excellent clinical research solu s.” have partnered with us for many year

Continuous gro wth

Integrating expertise in drug discove ry Sygnature Discovery has been reco gnised with the Queen’s Award for Enterprise in international trade for its work in providing integrated drug discovery expertise. “Fundamentally, I believe that drug discovery research really matters,” explained Dr Simon Hirst, a medicina l chemist, founder and CEO of Sygnature Discovery. “It matters beca use there are so many untreatable or poorly treated diseases around. It matt ers because the chances are, one day, we will all be patients, needing care treat ment. Pharmaceutical research can deliver life changing medicines but it is a long-term goal and successes are rare and hard won.”

Specialist in molecular pathology for biopharmaceutical research and development, Propath, has received the award for international trade in recognition of its contribution to the UK’s life sciences sector. “Propath has invested consistently over many years to support the growth of its molecular pathology research servi ces for drug development. This award not only reflects our success in beco ming the UK’s centre of excellence for tissue cross-reactivity (TCR) studies, but also one of the few centres across Europe able to perform studies of this type,” said Dr Krish Soni, chief executive of Propath.

Watson-Marlow Fluid Technolo gy Group has Enterprise in inte won the Queen rnational trade, ’s Award for for recognition growth in overse of the company as sales over th ’s continuous e judging perio d. “We have clea rly demonstrat ed to the judg strategic decisio ing panel the n to move our success of our trading base in this part of our to internationa business now ac l trade. In fact, counts for 76.7 Whalen, presid % of total turnov ent of Watsoner,” said Jay Marlow Fluid Te powerful combi chnology Group nation of organi . “Through c growth, and a — including the series of strateg Hampshire-bas ic ac quisitions ed Bio Pure Tech grown our intern nology busines ational presence s — we have wh ile UK. Our strateg maintaining a str y to offer our gl ong profile with obal customers the fluid path techno a single source logies is clearly of complete working.”

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Continuous printing Domino Printing Scien ces has been acknow ledged by the Queen’s Enterprise for it’s a-Seri Award for es i-Tech range of indust rial continuous ink jet printers. This range of printers have been designed to off er high-performance low consumption of coding, organic solvents, red uced service interven a range of ink formu tions and lations that comply wit h European and glo packaging guidelines. bal food “We are honoured an d proud to have been selected for a Queen’s Award for Inn ovation,” commented Nigel Bond, CEO of Domino Printi ng Sciences. “It is a fitting tribute to our skilled and tal ented team who have worked on the A-Series and i-Tech ink system, which is pro viding so popular with custome rs across the world.”

Bridging the gap

tablishing and for the use in es ge id br e nc ta 90) has seen t of a resis ture Scale (ITSCo-developmen ra pe m Te l na io ’s Award for e Internat d with the Queen disseminating th de ar aw be h) ec logy (IsoT Isothermal Techno of innovation. eld fi e th rology Enterprise in the National Mete is now in use in t uc od pr is th , ds, Called the microK e primary standar rldwide, alongsid wo Is) M (N tes tu Insti otech is delighted director said: “Is g in ag an ing m d an under ised that the exist John Tavener, fo success, I recogn l na tio s; nt na ne ter in po such lete com to have achieved d relied on obso an gy r lo tte no be ch te th old device, wi instruments used loped this new ve de we l so ro Met cooperating with older designs.” wer cost than the lo d an ce performan

Assessing mutagenicity Lhasa, an educational charity that crea tes in silico prediction and database systems for use in metabolism, toxicolog has received the award for innovatio y and related sciences, n for Sarah Nexus, a statistical-based software that predicts mutagenicity. “These awards are approved by Her Majesty The Queen and are the UK’s highest accolade for business success and innovation and we are naturally thrilled to have rece ived this honour and recognition of our work for the seco nd year running,” said Dr Chris Barber, CEO of Lhasa. “Sarah Nexus […] provides fast and accurate predictions of mutagenicity in an inexpensive way, identifying potentially toxic chem icals and therefore helping pharmac eutical companies in bringing drugs to market more quic kly.” This is the second Queen’s Award for Lhasa, which received one for innovatio n last year for Derek Nexus. “I’m proud of the valuable work we do here and the software we bring to market — something which has been reflected with two Queen’s Awards for Enterprise,” Barb er concluded.

Controlling temperatu re

In recogniti on of its inn ovation in th serving the e temperatu pharmaceu re controlle tical indust the Queen’ d packagin ry , Peli BioTh s Award fo g sector ermal has b r Enterprise een recogn . The award ised by specifically recognises Advance, the develop a range o ment of the f single-use advanced company’s shippers th insulation a Chronos at use n d phase ch temperature ange mate stability. rial for “This is a m omentus occ asion for th including e entire com the highly pany, skilled eng the design in eers involv of our Chro e d in nos Advan successfully ce system, set new sta which ndards with controlled in the temp packaging erature industry,” sa president o id David Willia f Peli BioTh ms, ermal.

To the point

, specifically the tion pen needles jec in in ts en pm ’s develo t of the Queen’s Owen Mumford ledged by receip ow kn ac en be s, have Unifine Pentips Plu vation. in the field of inno ise pr ter vice with Award for En an integrated de the company is m fro le oviding pr ed r ne he n ot needle and the The all-in-one pe n pe w ne e th ws users to fit e containing development allo two chambers, on is Th . al os sp di ber for interim e of the old one. a removal cham sponsibly dispos re d an se ea th age a new needle wi life and encour prove quality of im to Jarl ek d se te we en rk, ,” comm “Through our wo healthcare costs ce du re d an t atmen adherence to tre Mumford. director at Owen g in ag an m Severn,

The X factor! Mettler Toledo’s X-series of food and pharmaceutical X-ray systems have been recognised by the Queen’s Award of Enterprise for Innovation. The Safeline X-ray offers manufacturer s the ability to perform quality control functions as well as cont ainment detection, such as fill level inspection, mass measure ment and component counts. “We are delighted to have been hono ured with this award,” said Anthony Darraugh, product engi neering head at Mettler Toledo Safeline X-ray. “It is great recogniti on for all of the team at Safeline X-ray, who have been instr umental in creating and launching the highly successful X-Series product line up.”

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O Diary entry #4

LAB DIARY

In the latest instalment of the lab diary, R&D software provider, IDBS, examines why pharma companies should be implementing cloud software. The pharmaceutical sector thrives off innovation and new developments, but these are rarely the result of one person or one organisation. Collaboration is the catalyst for innovation and cloud software is its fuel. Forward thinking pharmaceutical organisations are already adopting cloud software to manage data and projects both internally and externally, but there is still some apprehension about using cloud software. Here are three reasons why pharmaceutical organisations should embrace the cloud.

1) Saving time 69% of companies have said that using cloud software increased their employees’ productivity. This is a significant figure considering the approval process for a new drug can take up to 15 years. Time is a precious commodity and shaving just one week off the drug discovery timeline can save $6 million, according to a report by Nature Reviews Drug Discovery, ‘How to improve R&D productivity: the pharmaceutical industry’s grand challenge’.1 Additionally, in PwC’s 20th annual CEO survey,2 35% of pharmaceutical CEOs stated they want to strengthen innovation to capitalise on new opportunities and cloud software solutions can help with that as they are incredibly agile and easy to deploy.

2) Saving money According to research by the Journal of Health Economics, ‘Innovation in the pharmaceutical industry: New estimates of R&D cost’,3 $2.5 billion is the average cost for new drug and biologics development — a pretty substantial sum. Managing costs is a major priority for pharmaceutical organisations, and decision makers are continuously researching ways to reduce spending. Saving money and optimising systems is critical in bringing this average cost of a drug down. As reported in a recent article by Mckinsey4 “Senior business leaders from across the company saw more speed, less complexity, and lower costs” by moving computing workloads into the cloud. Cloud is a critical piece of the digital re-invention puzzle that needs to be considered.

3) Protecting IP and data The current nature of the pharmaceutical industry is heavily focused on collaboration, which revolves around sharing data. But how do organisations monitor, accredit and protect data and consequently IP? The report by The European Union of Intellectual Property Office estimated that legitimate industry loses approximately Ð10 billion of revenue annually due to the presence of counterfeit medicines.5 There are several data management solution providers available to help facilitate collaboration and protect IP, but there is a common misconception that cloud-based data management platforms are less secure than the on-premise counterparts. 62% of CEOs surveyed by PwC said they were “somewhat or extremely concerned about cyber threats”, but pharmaceutical organisations are more likely to have IP and data corrupted unintentionally as opposed to malicious cyberattacks. An example of the unintentional, but still extremely damaging, data and IP corruption is the Micro Therapeutic Research Labs data scandal that resulted in the European Medicines Agency (EMA) recommending the suspension of over 100 drugs in development.6 EMA stated the suspensions can be lifted once alternative data establishing bioequivalence are provided. Using a cloud-based data management platform would enable organisations to monitor all key aspects of data and IP generation, notifying sponsoring organisations in real-time of any operational misconduct. These are just some of the potential benefits of cloud software for pharmaceutical companies and why implementation should be the next logical step. Referenc es: 1. Paul, S. M., et

al., Nat. Re v. Drug D 2. https:// iscov., 20 10;9:203 www.pwc. –214. com/gx/en pharmaceu /ceo-age ticals-andnda/ceos life-scienc urvey/2017 es.html 3. DiMas /gx/indust i, J.A., et al ries/ ., J. Health Econ., 20 4. http://w 16;47:20 ww.mckin –33. sey.com/b mckinsey/ usiness-fu our-insight nctions/d s/healthca igitalfor-digita re-giant-s l-reinventio hares-pres n?cid=ot 1705&kui criptionher-soc-lk =ZiAmjA n-mip-mck Zbzlt3R3tV -othaRRmIQ 5. https:// euipo.euro pa.eu/oh infringem importal/ ent-pharm en/web/o aceutical-s bservatory ector /ipr6. http://w ww.ema.eu ro pa human/ref .eu/ema/ index.jsp?c errals/Mic url=page ro_Therape jsp&mid= s/medicin utic_Resea WC0b01ac es/ rch/human 05805c51 _referral_ 6f 000413.

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