EPM Mar/April 2017 by EPM Magazine

FORWARD THINKERS: GEA LOOKS AHEAD AT THE FUTURE OF SMALL-SCALE CONTINUOUS MANUFACTURING

MARCH/APRIL 2017

PLUS: • GETTING SERIALISED • INTERPHEX 2017

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Contents March/April 2017 | Volume 17 Issue 2

Regulars

Features

EDITOR’S DESK

WASTE MANAGEMENT

Real-life stories of re-use and recycling in pharma manufacturing

ANALYSIS

20 ON THE COVER GEA talks continuous manufacturing and the future of pharma

50 LAB DIARY Common headaches for those in the lab

In conversation with Videojet on serialisation challenges

FORMULATION Meet the parenterals

REGULATORY AFFAIRS

OPINION

Q&A

22 24

49 INTERPHEX EPM is heading stateside

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editor’s desk

Taking Things Seriously MR is back in the news (is it ever out?) and with good reason. The World Health Organisation has published a list of drug-resistant bacteria thought to pose the biggest threat to human health.

Forgive me the terrible corporate speak, but the phrase ‘joined up thinking’ seems to be coming up a lot in the serialisation discussion, particularly where machinery OEMs are concerned.

The list will be discussed at the G20 Summit this summer, and once again we’ll see the usual flurry of media attention as AMR comes back into the public consciousness. But the publicity is important, after all, it’s not a problem that’s going anywhere fast, and the more hands to the pump, the better.

In the case of pharmaceutical manufacturers that don’t currently have any serialisation solution that meets the necessary requirements, it’s probable that changes will need to be made company-wide, rather than just on the factory floor. Torben Vogt of Videojet Technologies goes into detail on this in his interview in this issue.

When the G20 last discussed AMR, back in September last year, it tasked the World Health Organisation with highlighting potential solutions to the problem, and report back in 2017.

Despite the inherent challenges associated with serialisation, we also should remember the significant opportunities available to pharma sector companies – particularly those who take steps to go beyond the minimum requirements.

Drawing up a list may not seem like such a significant leap – after all, it’s already well known which infections cause the most concern for the healthcare sector. But perhaps by formalising the problem, and applying some structure of sorts, WHO has taken an important step in getting AMR onto more governmental agendas worldwide – which is the stated aim of publishing the list. It’s a sign that the international community is taking the so called ‘antiobiotic apocalypse’ more seriously. In other news, serialisation continues to be a race to the finish. In fact, if I were to theme every issue, I’d have to name this one the Serialisation Edition. We’ve had some fantastic contributions on the subject, and it’s clear that the challenges and hurdles haven’t yet gone away – but that the end result will make for a safer industry. By 2020, the majority of the pharma universe will be fully ‘serialised’ so to speak, and hopefully without any casualties. But inevitably this coming period of change will prove more challenging for some suppliers than others. Fortunately there seems to be an abundance of expert guidance available.

As a branding exercise, those who take serialisation more seriously could stand to benefit in a marketplace that increasingly favours diligence and rigorous standards. If you’re a believer in the Big Data dream, you’ll also probably see tremendous potential in the power of serialisation to provide full transparency over supply chains, perhaps improving efficiencies and oiling the gears in the process. Indeed, serialisation may well hit quite a few birds with one stone. And of course, let’s not forget the real beneficiary: the patient. Last month a Canadian teenager died after overdosing on the illegal drug fentanyl, with reports now surfacing that she believed she was taking prescription Percocet. The sooner we live in an age of genuine transparency, the better. Dave Gray

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ANALYSIS

Advancing clinical trials with EHR data In the pharmaceutical industry there is a growing need for a new approach to clinical trial design that will increase the speed that drugs get to market. NorthWest EHealth (NWEH) writes.

EHR-enabled clinical trials In recent years, the implementation of electronic health records (EHRs) has increased significantly as countries worldwide work towards more efficient healthcare systems. There is profound interest in the use of EHRs to enhance randomised clinical trials (RCTs) through extracting real-world data. The adoption of EHR-enabled clinical trials and improved digital infrastructure could allow for more efficient and effective research processes for clinical studies. By accelerating timelines and reducing drug development costs, this would ultimately improve patient outcomes. Technology must play a key role in connecting EHRs across primary and secondary care in order for patient health records to be used effectively for clinical trials. NorthWest EHealth (NWEH) has recently developed Linked Database System (LDS) technology to support the collection of real-world evidence. The LDS links consenting patients across all of their everyday interactions with doctors, pharmacists and hospitals. The software has the ability to link primary and secondary care data, with 24-hour download intervals to a secure National Health Service (NHS) server, to provide an integrated EHR linked by the patientâ&#x20AC;&#x2122;s NHS number.

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LDS technology has been designed to monitor patient safety in near real time. Every time a patient comes into contact with a healthcare professional, this leaves an electronic footprint (e.g. note entry, prescription, or blood results) and this is recorded by the LDS. The LDS is linked to a fully validated electronic Case Report Form (eCRF) that ensures prompt safety monitoring and reporting of adverse events to end users (healthcare providers or researchers). The near real-time safety monitoring capabilities of the LDS creates an opportunity for study designs that could not be delivered using standard RCTs.

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Patients can live their regular lives throughout the trial, with no intervention from trial staff

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RCTs are usually conducted following strict inclusion criteria such as excluding patients with comorbidities. Using LDS technology for RCTs means that studies could be carried out to include those patients that would normally be excluded from traditional RCTs, increasing patient recruitment. Ultimately, this approach could change the way that future clinical trials are conducted, allowing studies to be designed that include a broad and inclusive population of patients, producing data that more closely reflects everyday clinical practice. This real-world patient data could provide evidence for effective targeting of drugs to stratified patients groups, enabling the potential development of precision medicines. Accessing existing EHR data through technology such as LDS allows studies to be designed so that patients can live their regular lives throughout the trial, with no intervention from trial staff. Patients can be closely monitored using LDS software, but with minimal intrusion. This means that the possible ‘Hawthorne effect’, often experienced in RCTs, can be largely reduced.

Salford lung study NWEH’s LDS technology was recently used to deliver the world’s first digitally enhanced RCT in the Salford Lung Study (SLS). The study examined the safety and effectiveness of a new treatment for chronic obstructive pulmonary disease (COPD). The LDS software collected healthcare information quickly and efficiently from a network of hospitals, doctors and pharmacies, accumulating data on the effectiveness of the new treatment in everyday clinical practice. It’s been estimated that traditional RCTs, which have strict inclusion criteria, would only allow 7% of COPD patients to take part in such a trial. However, the SLS was designed to include all patients over 40 years old who have experienced exacerbation in the previous three years. This meant the trial data would be far more relevant to everyday clinical practice and representative of a much larger proportion of patients. It also allowed observation of the effects and interactions of the new treatment with patients’ other medications that they may be taking for their secondary conditions.

Conclusion The adoption of EHR-enabled clinical trials will be essential for pharmaceutical companies to demonstrate the effectiveness of their new treatments in the real world. NWEH’s LDS technology connects EHRs across primary and secondary care, and enables rapid patient recruitment, reduced clinical trial development time and costs. It also increases responsiveness to patient safety through near real-time monitoring. This technology could be applied to any established health economy across the globe. This has the potential to change the way that clinical trials are conducted in the future by ensuring drugs get to market faster and therefore improving patient outcomes.

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ANALYSIS

Capital idea A new start-up established with the aim of transforming the traditional transfer of knowledge between pharmaceutical companies and pharmacies, has raised a total of €1,020,000 in series A capital funding. “We are excited to receive the new capital from our investors,” said Tomaž Erjavec, founder and managing partner of the new firm, which is called Doctrina. “Our goal is to make Doctrina an indispensable part of pharmacists’ workdays with the mission to optimize the transfer of knowledge and patient safety.” Doctrina helps pharmacists to access knowledge about new pharmaceutical products and other professional novelties on one independent platform. Due to the amount of products each pharmacy offers, it’s impossible for the employees of the pharmacies to keep track of all changes and innovations. Based on the fact that 87% of healthcare professionals conclude contact with a pharmaceutical sales rep in less than two minutes and that sales reps spend 50% of their working time in their cars, Doctrina has developed a signature technology that enables pharmaceutical companies to achieve greater reach, faster knowledge delivery with real-time feedback, and more efficient two-way communication. The method used to further train the pharmacists has been developed with the latest e-learning trends and is available in a video micro-learning format. This helps pharmacists and pharmaceutical technicians to access knowledge about products and all content in one place, anytime and on any device.

A substantial portion of investment will be used to execute the company’s growth plans, which are focused on Poland and the UK, as well as some other smaller markets, but will also focus on further product development, and the expansion of the international team. “Our platform is already used by 55,000 pharmacists from Poland, Russia, Slovenia, Romania and Croatia. The plan is to now bring

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our technology to other countries in Europe and enable pharmaceutical companies and pharmacists to increase the flow of effective knowledge transfer. We are also focusing on finding digital health enthusiasts to join our international team working on multiple markets” commented Jure Pucko, CEO and founder of Doctrina. “Our vision is to make Doctrina an indispensable daily source of product news and other professional information.”

ANALYSIS

The new normal Jean-Marie Aulnette, VP EMEA sales, TraceLink, discusses the three influencers shaping the new norm in serialisation

Regulations

Compliance

he pharmaceutical industry now has the power to stamp out counterfeit drugs from entering the global supply chain, an initiative that is collaboratively supported by drug manufacturers, distributors, dispensers, and governments around the world. Track and trace provides full transparency as medicines move from manufacturer to dispenser to patient. It eliminates medicines unfit for distribution and ensures patient safety. But without the right strategy and mindset, it also

Supply Partners

creates the type of challenges that can sink a company doing business in global markets. By the year 2020, drug serialisation and traceability regulations will cover more than 80 percent of the global drug supply across more than 50 countries. Before long, track and trace will be baked into the DNA of every successful company producing, distributing, or dispensing prescription medicines. Companies who look at track and trace as just another project to tick

Building a track and trace roadmap for success requires looking at three critical influencers: the constant evolution of global regulations, standards, and business processes; supply chain compliance as “business-as-usual;” and strong collaboration among supply partners. Let’s take a look at each one.

Regulations: Continuous evolution

Supply partners: collaboration is the key

Expect ongoing developments in global track and trace regulations to be the norm over the next decade. In the last year alone, the EU, the US, China, Brazil, and every other market that has embarked on track and trace to date have implemented changes to their regulatory requirements. To be successful, you’ve got to incorporate agility into your company’s operational infrastructure. Preparing for change starts with deploying a solution that is purpose-built for pharmaceutical supply chain compliance, and provides built-in flexibility when changes occur. If your solution can’t easily adapt to change, you’ll face unpredictable customization and IT services costs, and a much higher total cost of ownership. With a track and trace architecture that accommodates ever-evolving laws, you can buffer your enterprise from continual churn and high cost.

Pharmaceutical businesses across the supply chain depend on one other. The 2016 Global Drug Supply, Safety and Traceability Report revealed that in addition to achieving their own individual goals, companies often have demands that they expect trade partners to meet. More than 50 percent of those surveyed about lot-level requirements for the US Drug Supply Chain & Security Act (DSCSA) noted that they wanted suppliers and customers to make system changes suited to their company’s needs. Any company preparing for serialisation must consider how the lack of standards around data formats and exchange will open the door for customers and suppliers to make demands. Without a collaborative solution in place, accommodating these requests will magnify the burden of achieving compliance.

Compliance: Business as usual Plan to integrate serialisation into and across your organisation. Track and trace will revolutionize standard operating procedures, affecting business areas that may never have been linked in the past. Your company needs to be track and trace enabled in obvious areas, like IT and Manufacturing, but also in Supply Planning and Customer Service. With compliance as a critical component of your operational strategy, assess how prepared you are to overhaul your traditional operating procedures for complete track and trace implementation. Where will a track and trace program live within your organization? How will track and trace become an efficient and effective component of product delivery, and an enabler to your long-term success? Find out the answers now, before it’s too late.

off, or choose a compliance solution merely for expediency sake, won’t adequately evolve their DNA and put their business at risk.

Now is the time to ask: How will my company adapt in an environment of continuous change, and are we prepared to handle evolving laws and business requirements? Do we have enough in-house expertise and resources to manage these changes, or should we partner with a provider that specializes solely in track and trace compliance for the life sciences? As we forecast our budget for track and trace, will our costs be predictable annually, or should we expect there to be hidden costs for customization and change orders if we have to make modifications? How do we work effectively with our trading partners to ensure uninterrupted product flow? Those who understand the complexities of today’s supply chain, embrace interoperability, and proactively evolve their DNA in an environment of continuous change will set themselves up for success. Those who do not are likely to miss regulatory deadlines and delay the flow of critical medicines to key markets, putting both business performance and patients’ lives at unnecessary risk.

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ANALYSIS

Trials and tribulations The pharmaceutical industry relies on innovation to develop new medical treatments, but bringing a product to market is high risk and high cost. It can take decades to develop a new medicine and cost hundreds of millions. What role will IP management play in protecting pharmaceutical companies in the future? Casey Fowler, VP of IP Search, CPA Global writes.

Protecting the process IP rights protect the extensive investment in research and clinical testing that must take place before a new product can enter the market. It can take 10–15 years to develop a new medicine - from the earliest stages of compound discovery until its approval for use by the public. The cost of developing a new medicine is also expensive - $2,558 million according to analysis conducted by the Tufts Centre for the Study of Drug Development. Capital invested in the pharmaceutical industry is almost all directed to clinical research and drug trials, rather than the manufacture of the final product. Copycats can replicate the manufacturing process for a new drug at a fraction of the cost. The threat of plummeting sales at the end of a long product lifecycle can be enough to discourage pharmaceutical companies from investing in R&D in the future. The pharmaceutical industry relies on innovation to develop new medical treatments. By patenting IP, pharmaceutical companies can protect against low-cost reproduction of clinical research that undermines the work of IP owners and the substantial contributions of investors.

Finding a place in the market Patents help pharmaceutical companies secure market exclusivity and create more opportunities for return on investment. However, the fight for market exclusivity has led to a number of patent challenges. In 2015 global pharmaceutical company Novartis AG lost a patent fight with Torrent Pharmaceuticals over its blockbuster multiple sclerosis drug Gilenya. With $2.5 billion annual sales in 2014, Gilenya is the

highest revenue generating drug for Novartis worldwide and contributes significant value to its IP portfolio. However, the US Patent and Trademark Office (USPTO) concluded that certain claims made by Novartis were “obvious” and did not merit patent protection. The first series of Gilenya patents will begin to expire in the US in 2019, leaving the market open for competitors and cheaper drugs. Patent disputes following copycat activity is an active threat and pharmaceutical companies aim to obtain patents for the entire lifecycle of a drug including methods of manufacture and active ingredients, to minimise the likelihood of disputes.

The unique challenges with pharmaceutical patents Patent protection for pharmaceutical companies is different from IP protection in other industries. Many technology-based inventions can be kept secret until they reach market, when products can utilise the full term of patent protection - 20 years. The high cost involved in research and development (R&D) means the majority of pharmaceutical companies apply for patent protection during research stages and before clinical trials. The average effective patent life for medicines is just 11.5 years. Early patenting not only reduces the patent life of a product when it reaches the market, but shortens the time available for marketing a new drug. Pharmaceutical companies should consider obtaining patents for the broadest possible scope during the R&D process. ‘Methods of use’ and ‘Formulation’ patents can be filed later – at the clinical trial stage of drug development and when the products use is properly defined. The issue of reduced patent life has been addressed in legislation in the United States, where patent applicants can now apply for a term

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Trade secrets are becoming an increasingly useful tool for pharma

extension. However, the time periods permitted for such extensions do not always equal the time lost. In the United States, patents can only extended for half the time period that was consumed by the regulatory approval process and for a maximum effective patent term of fourteen years. Trade secrets are becoming an increasingly useful tool for pharma, particularly in the US where recent changes to guidelines for examination at the US Patent and Trademark Office have applied severe limitations on the patentability of natural products and methods using laws of nature. While patent protection in many territories is limited to 20 years from the date of filing, the period of protection conferred by a trade secret can be indefinite. Trade secrets entail significant risk but can speed up the process of drug development.

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Kenya, South Africa, and South Korea. These nations are at varying points of economic development, but each is considered an “innovating developing country” in pharmaceuticals. If a pharmaceutical company cannot secure private investment, it may be forced to develop a new product in the public arena, making it harder to protect its ideas. Alternatively, it would need to resort to protection via trade secrets. The combination of poor patent protection and a lack of experience licensing IP to the private sector, means the development of commercial enterprises is much more difficult. Generic ‘copycat’ companies also have access to a company’s drug development process when it is forced to take place in public. With little chance of patents being an obstruction, companies can quickly reproduce drugs cheaply and in large volumes.

The great patent divide Drug development requires significant funding, but with a strong patent system and a market free of price controls, the American pharmaceutical industry is rarely short of investment. The private sector, which focuses heavily on R&D, is largely protected by patents. But the public sector is far more open. Until the Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement in 1994, many developing countries provided little opportunity for patent protection for pharmaceutical products. While the countries that joined the World Trade Organisation (WTO) committed to providing stronger patent protection, less developed countries were not required to meet this obligation until 2016.

To patent or not to patent? Generic companies such as Ranbaxy Laboratories are increasingly taking advantage of the tedious pharma patent lifecycle. Ranbaxy reportedly reaped $500 million in sales from its knockoff of Pfizer's ($PFE) cholesterol pill Lipitor during its first six months on the market. The competitive nature of the market makes patents a critical form of IP management and protection. It is important that pharma companies seek an intelligent intellectual property management solution to provide competitor insight, manage the lengthy protection process and fuel insightful research and development. Patents can significantly reduce the risk of revenue loss and safeguard the pharmaceutical industry’s development and innovation for the future.

Successful research and development in pharmaceuticals is occurring in developing countries such as Brazil, China, Cuba, Egypt, India,

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AL RI RT O VE AD

Harmonised Drug Delivery Device roadmap for efficiency, compliance and speed to market The use of electronic functional components is becoming a new crucial prerequisite to facilitate the patients’ drug administration, to ensure precise dosing quantity and timing, and predominantly to raise drug delivery to higher safety standards. The rise in complexity of a drug delivery device results in exponential growth of important factors which have to be considered when following the individual steps of the entire value-creation chain. Pharma companies need to look for partners who can help turn an idea into a successful complex drug delivery device, as well as coverage of a value proposition and a strategic platform. Further to provide turn-key manufacturing solutions for customers developing electro-mechanical drug delivery systems, correspondingly covering the regulatory requirements which have to be met e.g. for a connected health device, its validation procedures and particular constraints imposed by the responsible authorities in the countries concerned.

Bill Welch, CTO Phillips-Medisize and Morten Nielsen, CEO Medicom Innovation Partner, a Phillips-Medisize company, will discuss the importance of developping a connected health solution and device strategy to assure future success of connected health tools to improve outcomes for patients and reduce the total cost of care in the respiratory field. Initially the presenters will review how to develop a connected health solution from the perspective of understanding the market and patient needs in line with technical, regulatory and commercial conditions, inclusive of a robust device strategy. This workshop will also investigate data related aspects, such as: • what data will be gathered • by what data platform / interface, will it be shared and with whom? In addition, connected device development issues such as hardware and software, data management and security as well as manufacturing and regulatory pathways will be addressed. Outcome for Participants: The goal is for attendees to obtain an overall understanding of the key elements and challenges that go into successfully developing and realising the benefits of a connected health solution in the respiratory drug delivery arena.

During RDD Europe, Phillips-Medisize will discuss in it´s workhop about Realising the Benefits of Connected Health in Respiratory Drug Delivery.

WASTE MANAGEMENT

Waste not, want not Nick Carter of Mitie’s waste and environmental business explains resource recovery potential in the pharmaceutical industry and gives examples of strategies that have benefitted clients. Out of sight, out of mind

Resource from pharmaceutical waste – why do it?

Traditionally, pharmaceutical manufacturers have all had the same attitude towards waste. They rely on its scheduled removal by waste contractors, thereby removing the problem without seeing its potential for further value. Even after the material is in the hands of the waste industry, there is a tendency not to manage the waste in the most productive way possible. All the focus is on disposal, rather than investigating if it could be used as a resource.

The objectives of applying ‘resource not waste’ in pharmaceutical waste management are, increased sustainable practice, optimising efficiencies and the generation of new revenue streams. It is underpinned by the protection of the supply chain from the purchase of raw material, to reducing the production of hazardous waste at the end of the process. It really isn’t just about growing and supporting businesses, it’s about being responsible while doing it.

With the growth of sustainable practices and awareness, this type of waste (non) management wasn’t satisfying the corporate sustainability agenda, nor was it rewarding organisations when they looked into applying best practice to their waste process. This is what inspired us at Mitie to develop its contained waste outsourcing service.

Mitie does things a bit differently for its pharmaceutical clients by mobilising a significant pool of expertise, identifying opportunities and actual quantifiable innovations. In this way Mitie delivers a range of financial and environmental benefits throughout the life of the contract.

Mitie’s ethos is ‘resource, not waste’ which can be summarised by instead of considering materials as unavoidable waste and disposal of those as a cost, Mitie considers all materials as a resource. The first step in making this philosophy of ‘resource not waste’ work, is putting the customer at the heart of resource management and working as the organisation’s trusted partner. It’s a holistic method, involving corporate culture change and distancing from the ‘use and dispose cycle’, towards considering all possible resources to recoup. Then you work on extracting the value of all redundant materials, instead of relinquishing them to the waste industry. Share the gains so that waste reduction and changes in behaviour are incentivised.

Unlike other waste management contractors, Mitie is not under any pressure to fill its own waste disposal facilities, incinerator plants or funding the existence of expensive assets like fleets of vehicles and processing facilities. Instead Mitie creates a supply chain from existing suppliers that can execute all the necessary applications to streamline waste management performance. The intended outcome is to recoup as much resource from that waste for the benefit of the pharmaceutical manufacturing companies. Mitie uses its flexibility, know-how and connections to find the best and most effective services needed to achieve it. Even though Mitie offers a holistic service from office space to production, its biggest impact is in the streamlining of production wastes which have the most economic potential for resource recovery.

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In the pharmaceutical industry there is, of course, a significant output of hazardous waste. It is vital to influence reduced production of such wastes, the knock-on effects of which extend right down the supply chain. This shifts the status of hazardous waste up the waste hierarchy by employing a closed loop approach. For example, toll recoveries allow solvents to be processed back into raw material for the manufacturer, instead of being resold elsewhere and thereby protecting the supply chain. Sustainability also plays a big part in applying ‘resource not waste’ as pharmaceutical companies tend to have strong Corporate Social Responsibility (CSR) targets. One of the main ways that Mitie recoups the most value for its clients, with the least negative environmental impact, is by shifting wastes from the costly use of high temperature incineration, to recovery or reuse routes.

Putting it into practice Pharmaceutical manufacturer No 1: A leading pharmaceutical company that specialises in the production of consumer drugs and medicines and that strongly believes in the waste hierarchy: prevention, minimisation, reuse, recycling and disposal in a responsible way. The strategy was changing the mindset of all stakeholders to see waste as a resource that must be recovered. The objectives of the project were: • divert 95% of all waste from landfill • recycle over 80% of the office waste • recover 90% of the aqueous solutions A joint project team was set up and together we began a full analysis of the waste process and identified areas that needed improving. Top of the list was to research potential new market routes and technological solutions for the non-aqueous waste not being recovered already. This included investigating different ways of treating the aqueous based solutions. Transport and recovery costs were also scrutinised to find ways of reducing them. One of the most important elements in any waste strategy It’s a holistic across all sectors is examining and implementing more method, involving efficient means of waste segregation and getting the employees’ buy-in on the new culture of waste awareness corporate culture and recycling practice.

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change

Apart from the financial and environmental benefits, the most significant improvement has been cultural by raising awareness that waste is actually a resource. Not only was education key to the project’s success but so was stakeholder engagement as their feedback proved invaluable. The pharmaceutical manufacturer has benefitted from a financial point of view, saving £150,000 over three years, while reducing its environmental impact. Pharmaceutical manufacturer No 2: Their waste management needs were diverse and through improving efficiencies in each area, significant savings were made. • Re-use of waste as secondary fuel was identified as a priority to meet corporate targets. Mitie identified waste hierarchy improvements which resulted in the diversion of approximately 170 tonnes of hazardous waste from incineration into substitute liquid fuel instead. This achieved cost saving of approximately £30,000 over one year.

• Tanker use improvement was a key issue as it became clear that they were significantly underutilised. The transport costs and the carbon footprint in terms of emissions was extremely poor as tankers were being sent out only partially full. This meant that costs were being expended for moving empty space and the carbon influence from transportation of waste was high. Once this situation had been rectified a saving of £51,000 per year was made.

• Managing bio-waste: the manufacturer needed a better solution for managing their egg waste resulting from the production of vaccine, whilst reducing their carbon footprint and costs. During an international pandemic, 26 tonnes per day of egg waste was contaminated with the virus for testing. Through some creative thinking, Mitie devised a solution that required separating the constituents of the egg in a centrifuge that was installed on-site for the purpose. The separated egg liquid was transported to an incinerator and the egg solids were sent for recycling at a local facility. A cost saving of 63% was achieved compared its original means of disposal. Furthermore, due to sustainable waste management practices, the reduction in transport emissions was 20 tonnes of CO2 per month.

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Together, Mitie and the manufacturer found new disposal routes for the previously unrecovered non-aqueous waste. This waste is now biologically treated and the solid cakes sold for aggregates. Mitie also found a distillation plant to recover the aqueous based solvents, during this process the water is evaporated and the solid cake left behind can be recycled as aggregate. One of the main changes on the site is the bulking of waste by type, which reduces the number of collections required. This results in a reduction of the recovery and transport cost as well as the carbon emissions involved in this process. Significant cost savings were made through various improvement projects: • re-negotiated prices with existing and new suppliers to maximise cost saving opportunities; • less than 5% of the waste from the client is going to landfill; • worked to eliminate the costs associated with off-site treatment of chemical waste streams; • optimised segregation and recycling opportunities for non-chemical waste streams; • increased landfill avoidance rates (9% across all non-water waste streams); • increased recycling rates from 20% in 2011 to 93% in 2013 across bulk waste streams.

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Production wastes have the most economic potential for resource recovery

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CONTINUOUS MANUFACTURING

To be continued… Stephen Closs, VP, Global Technical Operations, Patheon explains continuous manufacturing as an enabling technology for quality by design – and highlights five ways it adds value for the pharmaceutical industry.

ontinuous manufacturing holds great promise for the pharmaceutical industry, enabling much faster pharmaceutical production and more reliable products via an uninterrupted process. In some cases, manufacturing that takes a month by batch technology might only take a day using continuous manufacturing techniques, according to a recent FDA blog1. Similar approaches are already widely used by industries such as steel, petroleum, automobile and food, where they have lowered processing costs, improved quality and consistency, and boosted productivity. In the pharmaceutical industry, all continuous manufacturing processes – where material is allowed to flow from one unit operation to the next, not pausing to complete any one step2 – share two key attributes: • The definition of the batch size required to have consistent quality is not set by the scale of the manufacturing equipment • It is possible to devise real-time control strategies, which span across separate unit operations utilising data taken from the process in real time. Continuous manufacturing can improve reliability, while reducing waste and costs compared with the batch method.3 A feeder array dispenses materials into steadystate unit operations such as blending and compaction, making it much simpler to characterise a process, since these do not vary over time. This makes it easier to relate material attributes to process conditions and product attributes. As a consequence, Quality by Design (QbD) process understanding can be built on a scale more typically associated with pilot scale quantities than with manufacturing-scale production, requiring smaller investments in time and money. Continuous manufacturing offers value to the pharmaceutical industry in five major ways. First, there are monetary benefits. In traditional manufacturing, very large and expensive pieces of equipment – such as blenders and tab-

let presses – operate in batch mode. The standard approach to drug manufacture starts by producing batches in the 1kg to 10kg range, and then scales up by a factor of 10 for pilot scale experimentation, and another factor of 10 for commercial scale production, which typically involves 150kg to 800kg. At each step up the scale, multiple batches are manufactured over a relatively short period when compared to the full production lifecycle, often using active pharmaceutical ingredient (API) material that is still undergoing process changes. The product must be tested extensively at each step to ensure that it remains consistent. In contrast, the cost of development is much less for an API made using a continuous manufacturing process. In continuous manufacturing, an assembly line approach is used, with raw materials going in at one end, and product coming out at the other end, and no holding of intermediates. Unique sets of materials and process conditions can be tested in the time it takes for a change to move through the line. On current production scale manufacturing processes this consumes between 10kg and 60kg, which is on the same scale as batch pilot studies. It is not unrealistic for a company to save millions of dollars with continuous manufacturing based on the reduction in material costs from not needing to run multiple manufacturing-scale development batches during process development. The timeline to develop a continuously manufactured product is also shorter, driven by the fact that most development activities and preliminary process trials are carried out with the commercial manufacturing train. Under the traditional approval process, this may or may not affect the overall timeline. However, it does become critical in the event of a breakthrough therapy. Since the commercial scale process can be interrogated with pilot scale quantities, there is no need for additional costly scaleup. Overall API usage can be reduced by as much as a factor of 10. Efficiencies are gained by collocating all processes for a particular product in one area and not having to stop production. The resulting cost-of-goods savings bring benefits to both the patient and the manufacturer.

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Second, the time to market is accelerated due to the reduced development time, with no scale-up or pre-validation required for continuous manufacturing. Traditionally, clinical programs were dependent on the state of the development process, which often delayed filings. With continuous manufacturing, as soon as regulatory clinical trials are complete and in vivo data has been created, the company can move ahead with the filing. This has potential to improve pharmaceutical company revenues and alleviate drug shortages. Third, assurance of product quality is increased, a vital attribute for all healthcare stakeholders, including regulators, physicians and patients. Compared with batch production, continuous manufacturing involves a smaller operation, a unified assembly line, and a higher level of instrumentation, which generates large amounts of data on the process. Feedback and feed-forward control loops within this data-rich environment help ensure that the product meets quality targets at each step in the continuous process. This continually verifies the product based on quality markers at each process step, making alterations if needed to maintain the product quality within a defined range, and greatly reducing or even eliminating events where products fall out of spec (OOS). This ensures that product can be shipped directly without further testing once it comes off the line. Continuous manufacturing is the technological realisation of QbD – with quality built in rather than tested at the end – allowing true QbD programs to be executed from development through to commercialisation. Fourth, pharmaceutical engineers can do more with less, fitting five to 10-times higher capacity within a given manufacturing footprint, since continuous manufacturing uses smaller equipment for assembly-line production. In addition, compared with batch processing, continuous manufacturing operates more efficiently, resulting in a smaller carbon footprint due to reduced electricity and water requirements, and reduced waste production. Fifth, flexibility and supply chain optimisation is offered by construction of modular manufacturing trains, made possible by the smaller size of equipment and ability to integrate processes to make a continuous line. Today’s drug manufacturing landscape is filled with factories designed to produce blockbusters of the past. This model does not meet current requirements for flexible manufacturing, which often require multiple

supply solutions designed to fit a broad range of product volumes and patient populations. Tomorrow’s manufacturing operations will need to involve smaller, more flexible production plants, with more distributed local-to-market manufacturing options that can produce cost-effective and affordable treatments.5 A warehouse-like pharmaceutical workspace can be constructed that meets GMP requirements, and continuous manufacturing modules can be linked to manufacture a drug substance or drug product. These can then be taken apart, cleaned, and reassembled into different configurations, or combined with additional modules, to make a variety of products. Within a single workspace, manufacturing ‘pods’ can be created and integrated using advanced control systems to create novel manufacturing platforms or process trains to create virtually all products and dosage forms. These modular trains can also be transferred to other geographic locations. This offers more flexibility than many original equipment manufacturer (OEM) offerings, which are often permanently fixed within a plant. Looking ahead, in order to benefit from the many advantages of continuous manufacturing, drug companies will need to take responsibility for the whole manufacturing process, including process design. Continuous manufacturing can save substantial amounts of money, and enables companies to gather knowledge at each stage of the product lifecycle, from development to production, and feed this back into a single, risk-based control strategy. Through ongoing process improvements, manufacturers can reduce the need for testing of end-products – and even eliminate it over time – as the process becomes increasingly well understood, and controlled. On the rare occasions when a product falls OOS, adjustments can be made quickly, in real time, to minimise the amount of OOS product, saving time and money, and moving ever closer to the ideal quality standard.

References: 1

http://blogs.fda.gov/fdavoice/index.php/2016/04/continuous-manufacturing-has-a-strongimpact-on-drug-quality/

https://www.pharmaceuticalonline.com/doc/what-is-continuous-manufacturing-anywayagreeing-on-a-proper-definition-0001

http://www.patheon.com/en-us/Ideas-in-Action/Material-Details/84/Solving-the-OOSProblem-with-Continuous-Manufacturing

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ON THE COVER

Taking pharma further, faster The pharmaceutical industry is looking at continuous processing to improve production quality in an efficient and cost-effective way, and to comply with the increasingly stringent manufacturing acceptance criteria put in place by the regulatory authorities.

hen the US Food and Drug Administration (FDA) advised the pharmaceutical industry to get ready for the concept of continuous drug production, GEA was already there. While remaining true to its batch-based roots, the expanded GPSC in Wommelgem will enable the company to provide its customers with advanced technologies to develop, evaluate and optimise continuous processing techniques and help them to bring new products to market faster and cheaper. But that’s nothing new; GEA has been running a continuous line since 2007.

The ability to establish smaller, cost-effective and resource-efficient plants increases the chance that local manufacturing sites can be established to meet regional needs and so reduce global transport requirements. GEA now has more than 47 full continuous OSD manufacturing installations operational worldwide.

With decades of experience in pharmaceutical processing technologies and engineering, GEA has invested a significant amount of time and energy into the development of advanced continuous manufacturing (CM) technologies and pioneered the world’s first continuous wet granulation line to produce OSD formulations.

In 2015, demonstrating the ongoing implementation of continuous processing, Vertex Pharmaceuticals became the first pharmaceutical company to receive FDA approval for a therapeutic that was both developed and commercially manufactured using a GEA CM platform. In addition, GEA’s ConsiGma 25 unit forms the basis of a groundbreaking, award-winning collaboration between Pfizer, G-CON, GEA and, more recently, GSK, to develop the next generation of Portable, Continuous, Miniature and Modular (PCMM) solutions for pharmaceutical production. These on-demand mini-factories can be set up to manufacture medicines, at any production scale, just about anywhere in the world where basic utilities are available. Once production is no longer needed, they can be dismantled, transported and relocated elsewhere.

The implementation of CM represents a paradigm shift in the pharmaceutical industry, enabling a more efficient way of making drugs and moving away from stepwise and time-consuming batch processing to a fully integrated and closely controlled process that gives excellent product consistency by intrinsic design. The highly versatile ConsiGma manufacturing platform, for example, combines multiple technologies that convert powdered raw materials into coated finished drug products in one single, closed unit. The platforms take up 70% less space than batch plants, so can be built more quickly and with much lower capital expenditure. Individual ConsiGma units can be designed, deployed and approved for commercial-scale manufacture within a year, compared with two to three years for traditional plants. Furthermore, whereas some batchbased operations take weeks to produce tablets, the same products can be manufactured within minutes with a continuous system. 20

An industry first

GEA’s H. McCoy Knight, VP North America, APC Pharma, said: “Using a Quality by Design (QbD) approach, drug manufacturing cycle times — from API to product release — can now be measured in hours rather than weeks. The clear benefits demonstrated by the use of ConsiGma technology are facilitating the switch to continuous manufacturing and helping the pharmaceutical industry to produce higher quality products, enhance drug safety, reduce its industrial footprint and decrease waste, which provides significant advantages to governments, companies and patients alike.”

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Real-time quality assurance The benefits of continuous manufacturing for the pharmaceutical sector are manifold. Real-time quality assurance is enabled by the application of inline PAT systems that continually monitor processing conditions and product quality, and are linked to the automated adjustment of processing parameters. This facilitates real-time product release against a backdrop of less invasive regulatory oversight, as well as the reduced use of resources and energy, lower product losses and waste production, and minimised downtime. The ability to run CM plants for extended periods also decreases product wastage associated with each plant start-up and shutdown, while the high degree of automation minimises the need for manual intervention. A single continuous manufacturing line can be used to process any volume of product, from small quantities for formulation development and design of experiments (DoE), through to clinical trials and the full-scale manufacture of new chemical entities and high volume generics without the need for investment in costly new equipment or dedicated plant. Product output is rapid, scalable and can be adjusted according to need, such as in the event of major disease outbreaks.

you’re working with batch-based or continuous processes, the GPSC delivers a wider range of innovative solutions for our customers and partners, highlighting our ongoing support for the current and future pharmaceutical industry.” “With our unparalleled history of expertise in processing OSDs, from pills to pellets to MUPS, and our tried and tested technologies, I am convinced that we can continue to help our customers to get their products to market faster in a cost-effective way,” stated Marcus Michel, Head of APC Pharma: “This is an exciting time for the pharmaceutical manufacturing industry.” “The new center offers a wealth of opportunity for us and for our clients. From cost assurance and process optimisation to real-life simulations and test and loan machines, we provide a unique range of services that are designed to enhance production and expedite time to market. Our clients’ needs are critical and individual; our worldwide test centers have been created to meet those needs,” he added. GEA will officially open the GPSC with a ribbon-cutting ceremony in May. To celebrate the event, the company is inviting valued customers, pharma industry stakeholders and key partners to visit and tour the new facility during Interpack.

Committed to OSD

Conclusion

GEA has recently announced the grand opening of its new, state-ofthe-art Global Pharma Solids Center (GPSC) in Wommelgem. With a total footprint of 1100 m2, including 200 m2 of technical space, GEA’s multimillion Euro investment in the Belgian facility represents the cutting edge in solid dosage form testing, development and optimisation. Now almost tripled in size, the GPSC offers a full range of process technologies (both batch and continuous) to produce pharmaceutical solid dosage forms.

GEA believes that the development of small-scale, CM systems will be one of the most significant changes in the pharmaceutical industry in the next 10 years. Flexible development options will facilitate the commercial manufacturing process and enable greater process understanding to be achieved with smaller quantities of material.

“The expanded facility represents our continued commitment to the global pharmaceutical market and our investment in oral solid dosage (OSD) form technology,” says Frans Maas, VP Pharma Solids. “Whether

As a trusted innovator of manufacturing concepts, analytical technologies and processing equipment, GEA has the capability and will continue to play a major role in the global drive to develop continuous OSD manufacturing solutions that improve the quality, efficiency and costeffectiveness of pharmaceutical production for the ultimate benefit of patient health.

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REGULATORY AFFAIRS

Making it in America Diego Ingrassia, senior business development & licensing manager, ELC Group, talks post-authorisation challenges for local pharmaceutical companies.

any pharmaceutical companies in unregulated markets which are sufficiently large will eventually expand internationally, especially to the United States and European Union. The US and EU remain two of the most lucrative markets for pharmaceutical products, and dossiers approved in these territories are highly sought after due to their high quality compared to dossiers from unregulated markets. A marketing authorisation (MA) approval from the US/ EU can also boost confidence in the products of the companies involved.

US/EU-GMP certification, and to start manufacturing and supply to the EU/US. Partnerships can be established with local companies with interest in high quality dossiers and capabilities to manufacture for the local market, and where local authorities may require local bioequivalence study or local manufacturing. These products can then be marketed as branded generics due to their high quality, and can command a higher price than common generics. In non-regulated markets where counterfeit medicine prevails, there is a high demand of branded generics by consumers.

However, MA approval is just the first step. There are many steps post-authorisation that require due diligence in order to market the products and maintain the marketing authorisations. To Licensing is an art in itself, and requires a huge network of contacts, succeed in these highly regulated markets, it is very important to negotiation skills and market intelligence. work with experienced US/EU-based A brief process of out-licensing regulatory and market intelligence includes: 1) Selection of potential partners who can advise and It is very important to work with distributors or Marketing Companies implement strategies to yield real profit post-authorisation, including experienced US/EU-based regulatory (Licensee) interested in establish a long partnership for the commercialisation – but not limited to – pricing and and market intelligence partners of the Product in the Territory, on the reimbursement, formation of basis of product (Rx, OTC, Biosimilar), a network of local distributors, therapeutic indication and target determination of license and supply fee, pharmacovigilance, EU-QC central laboratory management, market (EU, US, Russia, China); 2) Introduction of the product to the qualified person (QP) release for each batch, and global life potential Licensees (scientific, clinical and marketing skill) highlighting the business case of the product in the territory; 3) Receipt of sales cycle management. forecast from Licensee, prepare market sales projection for the There are many inactive marketing authorisations (MAs) which are Territory, collect information from the markets (Intelligence activity), available in the market due to a number of factors, including the lack and define regulatory strategy. of competitive supply price by the current manufacturer, duplicate products in a company’s product portfolio due to merger and Bridging the US/EU versus non-regulated market gap requires acquisition, and so on. These MAs can be sold to partners outside navigation around many barriers including regulatory requirements, the EU/US who can provide a competitive supply price. The use of language, culture, and so on, but it can ultimately prove rewarding US/EU-approved market authorisations is also a quick method for where both parties can come to a win-win agreement for what would triggering inspections in non-US/EU manufacturing sites to achieve otherwise be an underutilised dossier/MA.

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Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP contract manufacturing

www.nemera.net information@nemera.net â&#x20AC;˘ Phone: +33 (0)4 74 94 06 54

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OPINION

The good, the bad and the unresolved GP and pharmaceuticals lawyer Dr Sam Samaratunga on the proposed changes to the UK market access for medicines.

At present medicines appraised by NICE and which have a costeffectiveness ratio of £20,000-£30,000 per quality adjusted life year (QALY) are usually recommended for adoption by the NHS, but the final decision is made by NHS England. It is important to note that these decisions relate to whether funding would be made available to the various organisations within the NHS in order to use the health technologies and they are not intended to fetter the clinical discretion of doctors to use the most appropriate treatment to care for their patients.

Introduction In October 2016, the National institute for Health and Care Excellence (NICE) and National Health Service England (NHS England) launched a 12 week consultation on proposed changes to the arrangements for evaluating and funding drugs and other health technologies appraised through NICE’s Technology Appraisal (TA) and Highly Specialised Technologies (HST) programmes. The consultation closed on 13 January 2017 and it indicated that, in general, the proposed changes will apply to all NICE technology appraisal topics considered after 1 April 2017.

Current situation relating to funding, NHS England and NICE At present in the UK, all medicines are required to meet the three key “pillars” of medicines regulations by demonstrating efficacy, safety and quality of a medicinal product, before a Marketing Authorisation (commonly referred to as a licence) is granted by the regulatory authorities. In order for a medicinal product to be successful, in a country where the majority of the healthcare is provided by a centralised state organisation - the NHS - it has become, in effect, necessary to overcome an additional hurdle relating to its funding and reimbursement. NHS England manages the budgets that enable care to be provided and has a statutory responsibility to ensure that its functions are exercised effectively, efficiently and economically within the funds provided to it by the Department of Health. NICE appraises the clinical and cost effectiveness of new health technologies (including medicines) and in doing so, it takes account of the fact the NHS has fixed resources available to it.

Background to the current consultation The importance of taking account of the financial impact when managing the introduction of new drugs and other technologies was highlighted by the Public Accounts Committee which recommended that “The Department of Health and NHS England should, in collaboration with NICE, ensure affordability is considered when making decisions that have an impact on specialised services. For example, building in consideration of how the cost of implementing NICE recommendations can be kept affordable within available commissioning budgets, and by using national bargaining power to get best prices for high-cost drugs”. The independent Accelerated Access Review has also identified the general issue of affordability, as well as emphasising the importance of developing a collaborative framework through which transformative technologies can be moved quickly through development, evaluation and adoption.

Aims of the consultation proposals NICE and NHS England say they intend to work together more closely to better manage access to new drugs and medical technologies (devices and diagnostics) by simplifying and speeding up some appraisals, and by making more clear the arrangements for funding others. The consultation sets out a number of ways in which NICE and NHS England say they can provide an environment that encourages the life sciences industry and the NHS to work together in the best interests of patients.

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It suggests this would be achieved by facilitating collaboration and providing opportunities for early dialogue between innovators and the NHS, and by speeding up appraisal and adoption processes, which would enable the development of arrangements that deliver the right outcomes for both patients and the life sciences industry. The consultation suggests the proposed changes will benefit: • Patients - by providing timely access to the most effective and costeffective new treatments more quickly and by providing greater clarity for patients about the point at which treatments for very rare conditions that are appraised by NICE will automatically qualify for funding from routine commissioning budgets; • The life sciences industry - by increasing the opportunities for companies to help manage the introduction of their new technologies into the NHS by providing more flexibility in the adoption of costeffective, high budget impact technologies into the NHS. It also says there will be greater clarity for companies about the point at which treatments for very rare conditions that are appraised by NICE will automatically qualify for funding from routine commissioning budgets; • The NHS - to meet the challenges relating to financial sustainability.

The consultation proposals In summary, the proposals in the consultation document are: • The introduction of a new ‘fast track’ NICE technology appraisal process for the most promising new technologies, which fall below an incremental cost-effectiveness ratio of £10,000 per QALY, to enable these treatments to be evaluated and if successful, to reach patients more quickly. • To operate a “budget impact threshold” of £20 million, set by NHS England, to signal the need for an early dialogue with companies to agree special arrangements to better manage the introduction of new technologies recommended by NICE. The “budget impact threshold” scenario is said to apply to a small number of technologies that, once determined as cost effective by NICE, would have a significant impact on the NHS budget. • To vary the timescale for the funding requirement (from the standard 3-month period of deferred funding) when the budget impact threshold is reached or exceeded, and there is therefore a compelling case that the introduction of the new technology would risk disruption to the funding of other health services.

Conclusions It appears that NHS England and NICE have worked together to develop what they perceive is the optimal approach to implementing these proposals. The consultation sets out how both organisations propose to develop and coordinate their processes and are said to have been agreed by both organisations, subject to the outcome of consultation. There are potentially some encouraging proposals in the consultation. The introduction of the NICE fast track technology appraisal process (probably replacing the abbreviated process) should be well received. The automatic funding from routine commissioning projects for very rare diseases up to £100,000 per QALY represents the first time that NICE will formally appraise treatments for very rare diseases. Although the term "very rare" is not defined in the consultation document nor in European medicines legislation, it is likely that previous NICE guidance indicating a prevalence of 1 in 50,000 will be the critical level used for defining "very rare". The other point to note is that a "budget impact threshold" of £20 million per annum (suggested by NHS England and applying to all other NICE appraisals) does not apply in these specific circumstances. Whilst this is good news for very rare diseases, as acknowledged by NICE itself, it is likely to be applicable only to a very small number of treatments. On the other hand, the proposed changes may generate responses from key industry stakeholders as it introduces the concept of “budget impact threshold” of £20 million per annum as proposed by NHS England. This is significant because even if a treatment is likely to be approved for use by NICE, if the budget impact assessment (which is conducted early in the appraisal process) is thought likely to exceed the £20 million per annum threshold, NICE can pause the appraisal process and request the company to engage with NHS England in order to discuss and agree commercial terms before proceeding with the assessment process. This may impact the likelihood of companies willing to take up opportunities to develop treatments for rare diseases. The consultation and the proposals do not address the funding issues associated with treatments for rare diseases which often have a QALY figure over £100,000 nor the longstanding debate over whether a QALY based approach is the best way of determining the cost effectiveness of treatments for rare diseases. This is likely to continue to limit the ability of UK patients to access innovative and effective treatments for rare and neglected diseases.

• To automatically fund from routine commissioning budgets, treatments for very rare conditions up to £100,000 per QALY (5 times greater than the lower end of NICE’s standard threshold range) which have been assessed via NICE’s HST programme. The consultation also provides the opportunity for HSTs above the £100,000 per QALY range to be considered through NHS England’s annual specialised commissioning prioritisation process.

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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

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Organisers:

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n nsformatio a r t l a it ig D gs ferent thin means dif nt people to differe

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As an industry , pharma need s to get better at thre e things – trust, transp arency and governan ce

OPINION

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Redefining pharma through collaboration Jean-Paul France, EMEA managing director for life sciences, Dell EMC writes.

f I were to choose a buzzword to sum up the sector lately, it would be digital transformation. We have seen some incredibly inspiring and innovative projects taking place across job titles, business units and industries such as banking and retail. There is one industry however that is not as prominent in the digital transformation debate and that is pharmaceutical. It doesn’t appear to be from a lack of interest; in fact, almost every conversation that I have with pharmaceutical companies focuses on the role that technology and digital capabilities could play in helping the industry overcome some of its biggest challenges.

companies to acquire, anonymise and sell on for big money, the industry is in dire need of investing in and nurturing a culture that is based on collaboration. What is needed is a change in mindset.

Digital transformation means different things to different people. To me, it’s the ability to use technology to communicate any asset or piece of information in a simplified manner. Pharma is an information industry and the people in it spend a huge amount of their time trying to access, manage and extract information from the huge amount of data that they have at their fingertips.

Access to data: the most valuable data to pharma companies is structured treatment information that can be accessed in real time; currently extremely hard to come by and only for extortionate prices. By putting in place a federated collaboration between pharma companies and hospitals, this barrier is significantly reduced or even removed altogether.

Unfortunately, information management is a huge challenge for the industry and a big part of that is down to no integration or data flow internally within different business units or externally between organisations. Although the technology to facilitate is easily accessible, data still exists within silos, providing insight only to the people that have access to it. That could be one organisation or even one business unit within an organisation such as R&D or marketing.

Clinical trials: the costs associated with the traditional large clinical trial model have become unwieldy and unrealistic. A huge proportion of the cost of clinical trials goes towards the manual task of sifting through data pools. Pre-competitive information exchange could significantly lower this cost. The good news is that the industry is going in the right direction with the recent introduction of the new clinical trials transparency initiative which provides much needed transparency around clinical data.

As an industry, pharma needs to get better at three things – trust, transparency and governance. With the skyrocketing cost of clinical trials and health data available for

There is still too much anxiety that sharing information amongst companies will result in a loss of profit. In fact, sharing information could significantly reduce overheads and costs. The use of pre-competitive information (and agreeing on what information each are prepared and happy to share) could also accelerate the journey to successful outcomes.

Improved outcomes: being able to use other people’s data will help to take the guesswork out of product development

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and allow pharma companies to better understand the value of their medicine compared to competitors. It will also give pharma companies a better shot at getting it right first time. By collaborating on research, companies could have access to an easilysearchable database of information relating to preclinical “probes”, current pipeline candidates and “deprioritised” clinical-stage drugs. It would also open up the genome process and molecular libraries, providing an overview of broader compound sets. For example, many are looking to ‘re-engineer’ already profitable and licensed products to create new therapy types. They do this by redeveloping the raw materials with a view to treating different conditions with the same basic drug, either delivered or composed in a different way. R&D teams are driving the use of big data and IoT to prove this approach. The key is to take an already profitable production line back through early stage trials with the raw composition almost ‘paying for itself’, with the R&D process taking a significant amount of cost out of the process. I’ve recently spoken to several R&D directors who are looking to achieve this. They believe internal collaboration of R&D data and processes is key to executing this successfully. Changing a culture is no mean feat. However, we are already seeing some fantastic examples of best practice where collaboration between companies has delivered inspiring results. Companies need to start from the inside and work their way out; changing their internal culture by breaking down existing silos. The technology is there to make it happen, if they’re willing to embrace change.

SPOTLIGHT ON INNOVATION

Pushing the barrier

< Figure 1

For coated elastomeric closures, barrier properties alone are no longer enough to meet the needs of biologic drug packaging. Dr Susan Dounce, senior manager, business development and innovation, injection systems, Datwyler Sealing Solutions writes.

educing or eliminating silicone oil is being recognised as a means to mitigate risks and reduce time-to-market. Datwylerâ&#x20AC;&#x2122;s Omni Flex fluoropolymer coating technology provides numerous advantages and benefits in prefilled syringes beyond barrier properties, especially regarding stability, quality and end user experience. In the conservative, data-driven industry of parenteral packaging, market trends indicate a growing demand for fluoropolymer coated elastomeric closures, primarily to mitigate risks related to drug stability and compatibility. Rubber components are of high importance, particularly in the segment of liquid pharmaceuticals. Here, the drugs are in constant contact with the rubber component, e.g. the plunger of a pre-filled syringe or the closure of a vial. To meet the evolving needs of the biologics industry, the Omni Flex fluoropolymer coating is the first coating to both provide barrier properties and to eliminate the closure as a source of silicone oilbased subvisible particles (SbVPs) at the same time. This is particularly

critical with protein-based biologics, as a reaction to silicone leachable can cause the proteins to aggregate and eventually diminish the drugâ&#x20AC;&#x2122;s efficacy. As a consequence of the coatingâ&#x20AC;&#x2122;s chemical composition and method of application, Omni Flex Coated Plungers (Omni FlexCP) not only have barrier properties that result in superior chemical compatibility, but also have the added benefits of a significant reduction in SbVP levels and highly consistent delivery forces. This allows a safe and consistent administration of the drug even after a longer time of storage. Studies show that the plungers also have a highly consistent glide force with aging. The temperature and humidity at which aging studies are performed (refrigeration, room temperature, accelerated aging) have a negligible influence on glide forces for Omni Flex Coated Plungers. Omni Flex CP was launched in 2009. Today, it is the best performing fluoropolymer-coated plunger technology addressing the compatibility and performance challenges of the biologics industry and beyond.

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Figure 2.

Omni Flex fluoropolymer coatings are applied to several product classes, including Omni Flex CP (syringe plungers), Omni Flex Plus and Omni Flex 3G (vial stoppers). Omni Flex CP is developed in a two-step process. In the first step, the proprietary fluoropolymer film is applied by a tumble spray coating. The second step consists of a posttreatment process that provides sufficient thermal energy to bond the coating covalently to the Bromobutyl substrate and to form a smooth, continuous fluoropolymer film. Due to the line-of-sight nature of the spray coating, the entire plunger surface is covered, with the exception of the interior of the plunger-rod cavity. The total coverage by the Omni Flex coating stands in contrast with the partial coverage of most film coatings and therefore offers the benefit of providing a complete barrier. The total coverage of the fixed lubricious coating also eliminates the need for siliconisation of the plunger rills. This eliminates the largest source of subvisible particles and allows Omni FlexCP particle levels to be some of the lowest in the industry (Figure 1). And, in combination with the optimised product design, the elimination of siliconisation results in glide forces for Omni Flex CP which are highly consistent down the length of the barrel and from plunger to plunger (Figure 2). Furthermore, the spray-coating process easily lends itself to coating custom designs for innovative drug delivery devices.

Additionally, the reduction or elimination of silicone oils in rubber components and closures can reduce time-to-market. As recognised by the FDA, the interaction of proteins with silicone oil can present a risk to the safety and efficacy of therapeutic proteins. All Omni Flex coated products are produced aligned to our state-of-the-art First Line approach. Today, primary packaging component manufacturing is considered to be an extension of the drug manufacturing process itself. Therefore, all facilities implementing the First Line manufacturing approach are designed to meet the evolving standards of the parenteral industry. Apart from the Omni Flex coated plungers, we also manufacture needle guards and tip caps as well as closures for vials and for containers for liquid pharmaceuticals and biologics. The total coverage provided by the Omni Flex coatings can also easily be utilised in coating custom designs to fit the customersâ&#x20AC;&#x2122; specific needs. Datwyler has been an important player in the health care sector and has grown to a market share of over 20 percent in the market for pharmaceutical rubber components. This not only makes the company a leading global player in the industry, but also means every fifth syringe and pharmaceutical container worldwide is sealed with a Datwyler rubber component.

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Reducing or eliminating silicone oil is being recognised as a means to mitigate risks and reduce time-to-market

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FLEXIBLE MANUFACTURING SOLUTIONS

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Cracking the code

Torben Vogt, pharma director at Videojet Technologies, talks to EPM about implementing coding and marking systems for serialisation

How do you at Videojet view the regulatory challenge for the industry and how does Videojet support its clients in this endeavour?

A: Having clients in more than 130 countries around the world, we are approached by pharmaceutical clients on a daily basis, that look to us for guidance on how to address the complexity of coding regulations in their markets and for information on the capabilities of the latest technologies in coding solutions. In our Pharma and Medical practise we have people with many years of industry experience that can advise and guide our clients in this respect. This also covers key partnerships in the areas of vision, T&T integration and consulting, that we can bring into the picture to help customers understand the full picture and challenge of implementing serialisation.

How much planning is involved before Videojet starts work on-site? A: A signiﬁcant amount of planning is required to ensure that the client implements the right solution. First we spend time in understanding our client’s requirements in depth. This includes a variety of areas, both technical and business related. This enables us to help the client specify in detail to the machine manufacturer, the OEM, what coding solution is needed to integrate into the serialisation unit. When we sell our printers they are often shipped and installed at the machine manufacturer, so the installation is undertaken by the OEM. In terms of planning, from our perspective there is the time element of course – to ensure the systems are delivered on time to the machine manufacturer in order for them to keep to their schedules. Secondly, there is always the consideration in the pharma industry that installation of new systems and equipment will require a lot of testing, validation and qualiﬁcation. That needs to be factored into the planning process from the outset.

What key factors affect the timeline when it comes to implementation? A: There are a variety of factors that affect the timeline. One is of course that the process of implementing a serialisation solution requires the involvement of quite a large part of the organisation. It’s not just implementing a printer on the line – it’s implementing a set of equipment that needs to be working together, both from a hardware point of view and also in terms of how it’s integrated into the actual software applications. The process requires a lot of work in regard to integration, testing and validation and also what we sometimes refer to as change management - writing new procedures, training operators in new equipment, and when it comes to serialisation, training operators and supervisors in the new ways of working that this will require from an operational point of view. Being thorough and effective in handling the change management is key in minimising the negative effect on your OEE (Overall Equipment Efﬁciency). <continued overleaf>

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How does Videojet advise its clients on which products/solutions to select? As I mentioned before, we first need to understand the customer’s requirements in depth. Obviously the overall requirement is to comply with the regulations in a timely manner, but there are underlying technical requirements, such as line speed, type of print, type of carton material etc., that are critical when defining what the best solution to implement is. One area that is often overlooked is the environmental factor. This relates to the physical conditions the packages will be encountering from production to end use at the patient level. This information is required to help the client find the right combination of carton material and ink - when choosing ink-based printing technologies - or finding the right type of laser printer. We also help our clients by describing the business cases for different choices of printing technology. Some clients favour Thermal Ink Jet technology, as it has a lower initial investment when compared to Lasers. But then the consumables are significantly higher with Ink Jets than with Laser, which increases the operational costs over time.

Do you have to follow a strict plan with regard to compliance when implementing the solution? There is a well-deﬁned sequence of events in place when implementing a serialisation solution because of the requirements from the pharma industry with regard to testing, documentation and risk analysis - as well as following Good Automated Manufacturing Process (GAMP) 5 methodology.

There are many factors to consider when implementing a serialisation project such as this. Which three elements would you say are key to success? A: A clear strategy and plan from the start, that is endorsed and supported by the Executive Management team of the company, is a must. This is key to minimise the risk of roadblocks and delays and to understand and agree to the overall costs of the programme up-front. Another key success factor is strong attention to change management early on and involvement of all affected parts of the organisation. Here it is important to understand that the majority of the company’s functions will be more or less affected by serialisation, as this is signiﬁcantly more than a manufacturing and IT project. Finally I would suggest that focus on quality in both HW, SW and process is key to ensuring sustainable compliance and efﬁciency for the company.

How will serialisation benefit manufacturers? Serialisation enables manufacturers to track every pack manufactured throughout the supply chain. Historically, tracking only took place at batch level, whereas now we can break things down as far as a single saleable unit. This not only enables manufacturers to trace and recall products swiftly and efﬁciently if necessary, but also to follow the progress of each shipment to tackle issues such as diversion and counterfeiting.

Finally, are there any downtime issues? You cannot just plug these systems in and carry on production. You will have to cease production for a period of time. In some cases, if you are very fast, two to three weeks may be achievable, but in some cases it may be up to 2 months. If you take down manufacturing equipment that is running at 89-90 percent efﬁciency, for example, then you have to plan carefully to bring in safety stock to cover you while your production is down. If you are down for much more time than expected then you will run into supply problems with your product – therefore you must plan for this downtime well in advance.

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GRANULATION, MIXING AND BLENDING

Granular details L.B. Bohle recently made some major enhancements to its service centre. EPM learns more…

complete pharmaceutical production line is available at the group’s service centre in Ennigerloh, Germany, to develop and test machines and processes. This makes it possible to work under actual conditions at pilot plant scale. Various measuring, test and analysis equipment supplements the production line. New to the centre is the BFC TriPan, which can be operated with three pans. “As part of the test runs in the Service Centre, numerous customers have already expressed great satisfaction with the quality and productivity of our machines,” said CEO Lorenz Bohle. “Reliable tests with a focus on our customers’ needs is the best recipe for success,” Bohle continued. The BFC TriPan can be operated with three pans for batch sizes of seven to 75 litres. The coater drums can be changed in less than 30 minutes.

“

infrared product temperature sensor was also incorporated as a fixed component. It continuously measures the core bed temperature in addition to the supply and exhaust air temperature. The BFS 30 Bohle Uni Cone BUC, which has also been installed at the service centre, was extended by the GMA 70 high-shear granulator to form a system with a compact footprint. Therefore, all classic wet granulation processes are now available for test runs at the service centre. L.B. Bohle sees great potential in the fluid bed technology in particular. The Bohle Uni Cone BUC process, which was presented at Interpack back in 2014, offers numerous advantages compared to the conventional Wurster process.

Several patents have been achieved with the system

“The innovations of the BFC TriPan primarily concern the design. The nozzle arm was expanded to six nozzles in total,” said Andreas Altmeyer, head of the service centre. The nozzles themselves are fed independently (three peristaltic pump double heads for six nozzles) so that spray products that are difficult to process (e.g. methylacrylate) can be sprayed securely with every nozzle. Moreover, the angle of the spray nozzle and the distance between the spray nozzles and the tablet bed can be set automatically as a recipe parameter. When a trial is started, these important recipe parameters can be optimised without manual intervention. The

”

According to Andreas Altmeyer, head of the service centre: “Fluid bed systems are state of the art and offer various benefits. Compared to the classic top spray process, granulation/drying and pellet coating are performed in one system without requiring any changes or additional inserts. Several patents have been achieved with the system.”

Thanks to constant cooperation with universities or as part of customer trials, process analytical technologies (PAT) such as the Parsum probe for online particle size measurement or NIR/MW humidity sensors are used at the service centre as well. This ensures an optimum process flow for agglomeration by agitation or pellet coating (prevention of pellet agglomeration).

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FORMULATION

Meet the parenterals Dr Elham Blouet, global market manager, injectables and dialysis, from Roquette’s pharma and health unit, gives an expert view on preparations and challenges in parenteral formulations

arenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants (1). They are sterile preparations

This article will describe the main challenges encountered during the formulation of parenteral preparations, as well as Roquette’s solutions meeting the formulator’s needs.

intended to be administrated directly into the systemic circulation in human or animal body. They are required, like any pharmaceutical dosage forms, to meet the pharmaceutical quality standards as described in pharmacopeias and to be safe for the intended purpose of use (1, 2, 3).

They must meet the following minimum compendia criteria (1, 2, 3):

In addition to being sterile, parenteral preparations must be pyrogenfree. Sterility can be achieved by different processes of sterilisation that should be appropriate to the formulations, while the pyrogen-free aspect will require, if no depyrogenation process is used during the preparation of the sterile drug products, the use of pyrogen-free pharmaceutical ingredients; drug substances or API (active pharmaceutical ingredient) and excipients. They are usually supplied in single dose glass or plastic containers (PVC nowadays less recommended, or polyolefin) or more and more in pre-filled syringes or pens to facilitate the ease of use (1).

The parenteral preparations are intended to be administered through the human or animal body, either by direct injections (for example, bolus intravenous (IV), intramuscular (IM) or subcutaneous (SC)) or by infusion with a controlled infusion rate or by direct implantation.

• To be sterile and pyrogen-free • To be clear or practically exempt of visible particle and to be free from sub-visible particles as required by pharmacopeias EP, USP and JP • No evidence of phase separation for the emulsions, or aggregates formation for aqueous dispersion such injectable Mab (monoclonal antibody) preparations • In case of suspensions, the use of appropriate particle size and any sediment should be readily dispersed upon shaking to give stable formulations and ensure the correct dose to be withdrawn and injected.

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Parenteral preparations may require the use of excipients that should be biocompatible, be selected for the appropriate use and to be included at the minimum efficient concentration (3). The functionality of these excipients is as follows: • To make the preparations isotonic with respect to blood (glucose/ dextrose, mannitol, sodium chloride) • To adjust the pH to the physiological one (mineral or organic acids or salts) • To prevent the degradation of the drug substances • To ensure or increase the drug substance’s solubility • To provide adequate antimicrobial preservative property (only applicable to multidose preparations) It should be stressed that excipients should not adversely affect the intended medicinal action of the drug products, nor at the concentration used to cause toxicity or undue local irritation. The main challenge of all the different parenteral dosage forms is to achieve a good compatibility of the drug substances with the excipients (no formation of new impurities either by degradation of the drug substance or formation of new chemical entity between the drug substance and the excipients) as well as the compatibility of the preparations with the primary container (no leachable or adsorption to container) (3). With regards to solutions and emulsions, the drug substances should be soluble and remain soluble during the entire shelf-life of the drug products. When drug substances are not soluble, dissolution can be achieved by the use for instance either co-solvents, or surfactants, or a soluble pro-drug, or eventually the use of solubility enhancers such the cyclodextrins thanks to the formation of inclusion complex. The pH is one of the critical aspects of parenteral preparations which should have a pH close to the physiological one. However in certain cases, a compromise should be found between the pH ensuring stability of the drug substance (such for peptides requiring alkaline pH or proteins at pH close to the isoelectric point) and the physiological one. In all cases, large volumes preparations (LVP, i.e. more than 100 ml as defined in pharmacopeia) should not contain a pH buffer as the blood has already a buffer effect property that could enter into competition with the injected drug product.

The efficiency of the selected sterilisation process should be demonstrated through validation studies, using the appropriate biological indicators, to ensure an ASL (assurance sterility level) of 10-6 (1). Roquette has developed a pyrogen-free range of products with high pharmaceutical standards and being biocompatible for the manufacture of parenteral preparations. Lycadex PF (dextrose/glucose monohydrate pyrogen-free) is used as a source of carbohydrates in large volume and small volume preparations (LVP and SVP) and in parenteral nutrition (TPN) as well as an osmotic agent for dialysis solutions. Pearlitol PF (mannitol pyrogen-free) is used in LVP and SVP as APIs and isotonic agent, as well as bulking agent for freezedried injectable powders. Neosorb PF (sorbitol pyrogen-free) is also used as source of carbohydrates in LVP and SVP as well as osmotic agent in sterile irrigating fluids. Kleptose HPB & HP parenteral grade (hydroxypropyl betacyclodextrin pyrogen-free) are widely used as solubility and stability enhancer of APIs as well as enhancer of clinical tolerance. Sodium Gluconate Pharma is usually used as source of biological organic salts and as pH regulator. All these pyrogen-free range of products are obtained from natural and renewable raw materials. Besides their compliance to pharmacopeias and other ICH quality requirements (for instance ICHQ3D for elemental impurities), all these pyrogen-free products, even when used as excipients, are manufactured in compliance to GMP, ICHQ7, and certified by competent authorities (ANSM the French Competent Authority and US FDA). Parenteral preparations are sterile and pyrogen-free preparations intended to be administered directly into the systemic circulation in human or animal body. They should meet the pharmaceutical quality standards as described in pharmacopeias and ICH guidelines and also ensure the clinical tolerance as well as to be safe for the intended purpose of use.

References: 1: EP, USP and JP Pharmacopeias 2: ICH Q6, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products 3: ICH Q8, Pharmaceutical development

The stability of the drug substance is another critical point that a formulator can face during the development of the formulation. Unstable drug substances will lead to the formation of new impurities jeopardising the safety of use of the preparations. When the use of a stabiliser is justified (for instance the use of mannitol as free-radical scavenger or cysteine in paracetamol solution for injection), it should be included at the minimum concentration demonstrated to be efficient at release and during the entire shelf-life (3). In the cases of powders for injection or infusion obtained through a freeze-drying process, the use of bulking agent (such as mannitol) and /or a cryoprotector will be needed when the dose of drug substance(s) cannot ensure solely the formation of acceptable “cake”. Finally the process of the sterilisation should be selected according to the characteristics of the parenteral preparations (for instance, heat steam sterilisation for aqueous solutions and dry heat for nonaqueous solutions) but in any case it can be justified by the nature of the primary containers.

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TIME IS SHORT – SERIALIZE NOW !

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HOW TO: CLEANROOMS

Cleaning up Compressed air is a very common, useful and non-disruptive power source for various types of process equipment, however the introduction of an external air source into a controlled environment is a potential source of contamination. Crowthorne Hi-Tec Services (CHTS) explains more

egular testing and validation of production environments is an accepted practice but, to date, similar testing of compressed air lines that run into clean rooms is not. Crowthorne Hi-Tec Services (CHTS) validates a large number of clean rooms that contain compressed air systems but is only scheduled to test compressed air in about 15% of these environments. If you introduce air into a controlled environment that is not of the same standard, then you have degraded the facility and therefore the quality of the environment. Apart from internal QA/QC practices there are a number of industry standards that set out parameters for the quality of compressed air. BS ISO 8573 ‘Compressed Air and Purity Classes’ is the foundation standard but users should note that compressed air standards are not rated in a comparable manner to that applicable for the background production environment; particle sizes and densities differ and this is an important factor. Other relevant standards are HSG 39 ‘Compressed Air Safety’ and BCAS (British Compressed Air Society) Guidance Note 102. In addition, the regular maintenance of compressed air equipment forms part of wider legislation covering a range of lab and production equipment.

• Quality integrity: In controlled production environments, compressed air may be viewed as a Critical Process Parameter which should be controlled as part of an overall quality regime. Compressed air can contain a number of contaminants. A basic test will look at: • Water vapour/ Dew point test • Hydrocarbons and oil mist • Particles • Bioburden Testing regimes can then be customised to take into account the risk of contaminants particular to a specific plant or process. Crowthorne customers who schedule the compressed air testing service, receive a five point plan to ensure that their compressed air utility provides pneumatic power and nothing

else into their controlled environments: • Basic testing to determine to what standard the compressed air is working to. • Assistance and guidance to determine the correct level at which the system needs to work to maintain environment integrity. • Identification of remedial action if necessary • Development of a maintenance programme and periodic testing accompanied by avalidation report. • Assistance and advice on extending and/ or amending the compressed air network All compressed air testing carried out by CHTS takes place using calibrated equipment that has been the subject of independent autoclave sterilisation before it is connected to a customer system, again with a view to retaining the integrity of the clean room environment.

As part of a controlled environment quality system, compressed air systems should be tested from a number of different perspectives: • Product safety: Loss of environment integrity could prejudice product safety; CHTS has come across a persistent bio-burden contamination issue arising from the use of organic thread sealant in a compressed air unions rather than PTFE tape. • Personnel safety: Ensuring that compressed air systems are clean and safe makes an important contribution to your labs health & safety compliance. Dampness or water vapour can cause particle agglomeration causing blocking of safety valves and pressurised oil or oil vapour can act as an incendiary risk.

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CASE STUDY

Universal Appeal

R-Pharm Germany is a CMO producing and packaging pharmaceuticals for customers in more than 150 countries. In order to supply pharmaceuticals to markets that demand serialisation or aggregation, the company uses tools such as the Case Aggregation Kit from Mettler Toledo PCE on a semi-automatic case packer from Christ Packing Systems. Serialisation from as early as 2017 Protection against falsified medicines has become the leading issue for the pharmaceutical industry in recent years. According to EU Regulation 2016/161, all pharmaceutical packaging must be serialised and fitted with an antitampering device from February 2019. The USA has also set a similar law in motion, the Drug Supply Chain Security Act (DSCSA), which requires serialisation to begin as early as 2017. Other major markets are already calling for measures to protect against product piracy. Those wishing to export goods to China, Korea, or Saudi Arabia,

for example, are already required to aggregate their pharmaceuticals. “If we are to serve these strategically important and high-volume markets, we need secure and flexible technical solutions for aggregating packaging,” said Michael Unbehaun, manager of engineering projects at R-Pharm. “Over the years, we have built up a firm partnership with Mettler Toledo PCE in the field of pharmaceutical serialisation and aggregation. Together we have been able to successfully implement a number of technological developments that focus on the production process. The first of 10 serialisation and aggregation lines was launched back in 2009 – this is why we recently opted for another semi-automatic aggregation solution from Mettler Toledo PCE.”

Customisation R-Pharm Germany has rounded out its service portfolio with the Case Aggregation Kit – a customised OEM kit from Mettler Toledo PCE that is designed to upgrade existing packaging lines – in combination with a compatible case packer platform from Christ Packing Systems. This means that the company can now execute manual, semi-manual and fully automatic serialisation and aggregation for folding boxes,

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bottles and wallets. The result is a needs-based service with a highly flexible structure, which enables the customer’s production requirements to be implemented in a cost-efficient manner at all levels of aggregation. It was with this end goal in mind that the company joined forces with Mettler Toledo PCE and case packer manufacturer Christ Packing Systems in 2014 to devise a new packing line that could aggregate ready-packed, serialised, and sealed individual packages in a centralised manner. The investment decision followed an external benchmarking process, in which technology from various providers, concept designs, and the potential outlay were analysed and compared. A semi-automatic case packer from Christ’s CaseTeq 100 product range forms the basis of the packing line. The Case Aggregation Kit from Mettler Toledo PCE – which consists of the software, cameras, control monitor, and cabinet – sits on top of this. In order to ensure that this solution would work efficiently in three-shift operation, the individual components of the apparatus first had to be precisely coordinated with one another. “The challenge lay in ensuring that the case packer and the aggregation software could communicate with each other without any problems,” said Achim Gombert, a sales engineer at Mettler Toledo PCE. “To make this possible, we used our PCE Line Manager software and adapted the workflow to fit the case packer.” Michael Meyer, product manager at Christ Packing Systems, said: “Thanks to our close and constructive collaboration with Mettler Toledo PCE, we were able to rapidly develop a solution that is perfectly tailored to the specific needs of R-Pharm Germany.”

Aggregation via camera For open orders, the employees at R-Pharm manually place the bundled pharmaceuticals on a conveyor belt. The semi-automatic case packer from Christ transports the bundle past a camera, which in this case identifies preprinted serial numbers on the individual packs layer by layer and forwards the data to the PCE Line Manager software. The system then places the bundle into a box in such a way that the serial numbers are visible on the top. Once the box is completely filled, an employee applies a self-adhesive shipping label that contains the aggregation code, including the serial number and other variable data. Once the code has been verified using a handheld scanner, the software is notified that this box is full and has been labeled. This prompts the software to assign to the box all the serial numbers recorded in it. The boxes are then transported to the sealing station, where they are closed up for transport. This enables R-Pharm to ensure that the compounds and serial numbers within a specific box can be determined at any time within the supply chain. “Aggregation of boxes is not just stipulated by regulations – it also lays the foundations for a high degree of transparency and thus for the potential to improve the logistics process for our customers. This guarantees that our digitisation solutions are viable in the long term and creates benefits for patients and companies,” said Unbehaun.

Statistics and line reporting During the ramp-up phase for this system solution, R-Pharm made use of the log and debug files in the Line Manager software from Mettler Toledo PCE to carry out statistical evaluation, enabling the company to identify and eliminate weaknesses within the packaging process. Audit trails also allow pharmaceutical manufacturers and packers to verify that the serialisation process has complied with the regulations at every single stage and has not been manipulated. Finally, once the packaging process is complete, the Site Manager software from Mettler Toledo PCE forwards the serial numbers processed for a specific order to external platforms, run by the customer or markets, via specially configured connectors and interfaces. The combination of the semi-automatic case packer and the Case Aggregation Kit from Mettler Toledo PCE supports R-Pharm in the efficient production of its orders. In bundle mode, 250 to 300 pharmaceutical packs per minute can be packaged and aggregated. The system is highly flexible and a single person can implement a format change in under one hour.

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STERILISATION

Need to know: a guide to sterilisation

With the increased amount of biological products coming to the market, new practices to provide greater assurance on pharmaceutical sterilisation processes are necessary. At the same time, however, changes in the types of materials and products are forcing changes in typical sterilisation methods.

Sterilisation technologies: A pharmaceutical product, based on the nature and the dosage form, can be sterilised using different methods and techniques.

The sterilisation market has dynamically improved from moist heat sterilisation (steam) to the progressive Ethylene Oxide (EtO), gamma radiation and low temperature gas plasma sterilisation, and finally to recent technologies like NO2-based sterilisation. Steam/moist heat sterilisation, despite being the oldest method, is still the most preferred in a healthcare setting due to its ease of use and low costs as compared to low temperature sterilisation. E-beam and low-temperature hydrogen peroxide gas plasma (LTHPGP) sterilisation techniques are gaining popularity over conventional methods due to various advantages conferred by them. continued overleaf >

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The role of sterilisation in medical packaging has been of crucial importance, especially of finished products like saline bottles, needles, syringes, etc. In life sciences applications like research laboratories, steam sterilisation (autoclaves) is widely practiced to avoid any decontamination of media, culture, equipment, and glassware. Hence, with a wide array of applications, the sterilisation market is expected to foresee a stable growth in the coming years.

Biologics lack viable options for sterilisation due to their very delicate and complex properties and hence cannot be terminally sterilised. This has helped the adoption of filtration technique in the industry. High potency drugs - which comprise small molecules, complex biologics and combinations of both - are growing at a faster pace than the industry average globally. Requirement of specialised containment facilities for high potent compounds is contributing to the growth of the outsourcing sterilisation market.

Major equipment/processes used for sterilisation: Several specialised equipment are used in different types of sterilisation technology:

Need of Contract Sterilisation Service Providers:

• Autoclaves for moist heat sterilisation

The sterilisation services industry has been growing at a healthy growth rate in the past decade. Rising incidences of infections and the need for state of the art containment facilities for handling drugs to avoid regulatory compliance issues, has led to the growth of both onsite as well as offsite sterilisation services. The offsite sterilisation market is growing faster than its predecessor. The improving healthcare infrastructure in many of the emerging Asian countries has also contributed to the growth of the industry.

• Dry heat sterilisers (e.g. an HEPA filter) and hot air ovens for dry heat sterilisation, • Steam sterilisers for the widely used steam sterilisation • UV chambers for non-ionizing radiation sterilisation • Sterilisation-In-Place (SIP) and Clean-In-Place(CIP) systems

Following reasons have led to the outsourcing of sterilisation activities to third-party agencies:

Market Info:

• Stringent sterilisation regulations imposed by healthcare authorities

The United States leads the global market with a share of 29% closely followed by Europe with 27%, during 2014-2020. Filtration, was the leading technology for sterilisation in 2014 with US$2.7 billion of the total $4.8 bn.

• Cost-containment strategies of many medical device manufacturers, pharmaceutical product manufacturers • Economic fluctuations • Increasing number of contract sterilisation service providers offering better services to clients • Specialised sterilisation services for complex and difficult to handle molecules Piramal Pharma Solutions, which supplied this guide, provides sterilisation services for sterile liquids, lyophilised parenterals and injectables, ADCs and High potent APIs through specialised containment facilities and suitable experience in various sterilisation technologies. References: High Potency APIs - Containment and Handling. /www.pharmtech.com Sterilisation Market / www.prnewswire.com Sterilisation Technologies - A global market overview / www.industry-experts.com

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STERILISATION

Find the cure A white paper that provides evidence of the positive effects of post-curing on the reduction of cyclosiloxane contamination in silicone tubing manufacture has been published by Watson-Marlow Fluid Technology Group (WMFTG). As a provider of single-use components including peristaltic pump and associated fluid path technologies, WMFTG says that the post-curing process significantly reduces the presence of cyclosiloxane contaminates in silicone tubing. Thereby, drug manufacturers opting to use post-cured tubing and tube assemblies, will benefit from improvements to the safety of the final drug product. The data and analysis published in WMFTG’s white paper contains the results of a study which makes comparisons between the semi-volatile extractables profile of post-cured and non post-cured samples of its own Pumpsil platinum-cured silicone tubing. This document offers essential reading for those involved in the manufacture of biopharmaceutical products; many of whom will be concerned about the sources of potential contamination from processing equipment.

“

leachables which may migrate in to the final product,” says Dr Mokuolu. At WMFTG, as part of the manufacturing of the Pumpsil silicone tubing, there is an additional post-curing step to the tubing production process. This additional step ensures more cross-linking that not only makes the tubing mechanically stronger, but reduces the semi-volatile compounds. This extra processing step may not be carried out by other manufacturers of platinum-cured silicone tubing, which means there is a very real risk of cyclosiloxanes migrating into fluids that come into contact with the tubing. This is a major safety concern and one that drug manufacturers must be aware of.

Manufacturers using post-cured tubing improve the safety of the final drug

According to the report’s author, Sade Mokuolu, Ph.D Group Product Compliance Manager at WMFTG, the scale of this problem is greater than many may assume: “It is interesting to note that 15% of the drug recalls reported by the FDA in the last six months have been due to contamination from processing equipment,” she says.

A primary area of concern is the direct contact of plastic processing materials that comprise single-use components with the drug product. It is widely known that this can result in the presence of compounds may affect the efficacy, safety or quality of the final drug. For manufacturers working on multi-million dollar drug trials and treatments, the implications of this from a product development and brand integrity perspective, are significant. “Focus must therefore be given to the process used to manufacture equipment and ancillaries. Specifically, the manner in which platinumcured silicone tubing is manufactured, must be given attention: the process used to manufacture this tubing has the potential to affect the types of

The study included in WMFTG’s paper reveals noteworthy results that affirm the need for drug manufacturers to adopt post-cured tubing as standard. The paper details that samples of WMFTG Pumpsil tubing (postcured and non post-cured) were extracted with a 50% ethanol: 50% water solution for 30 minutes at 25C and seven days at 40C. For the purposes of this paper, the extractables studied were the cyclosiloxanes (mixtures of cyclosiloxanes have been of particular interest due to concerns about their potential toxicity).

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The study demonstrated the presence of cyclosiloxanes was reduced by a minimum of 25% in the post-cured extracts, as compared with non post-cured extracts over a seven day extraction period, and by 50% over a 30 minute time point. Dr Mokuolu’s concluding advice to biopharmaceutical manufacturers is clear: “The drug industry must embrace the arguments for postcured silicone tubing; and this white paper presents some data to support this position. It offers proof that the post-curing of tubing can significantly reduce the amount of cyclosiloxanes that are present after manufacturing. At a commercial and reputational level, this will help the biopharm and drug industry have greater assurance of the efficacy, safety or quality of their final product.”

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New York, New York, so good they named it twice Interphex is back for 2017. From March 21–23, the global pharma community will once again descend on the Javits Center, New York City.

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ith a new administration and a heavily regulated industry investing in pipelines and infrastructure, a lot can happen very quickly: market shifts, new regulatory mandates, changes in development strategy, manufacturing processes, intricacies of manufacturing or delivering advanced drug candidates. Pressure on CoG and drug prices are also coming from many directions. 2017 will bear witness to continued pressure on not only research and development, but also manufacturing. As the industry looks to reduce costs, increase productivity and maximise efficiency, Interphex is set to address and deliver the solutions for these ongoing challenges by providing the latest in state-of-the-art technologies and access to industry expertise from subject matter experts. For 38 years, the show has been the place to “Learn It, Experience It, Procure It” through a unique combination of a free conference, Interphex Live, the Keynote Series, exhibits, demonstrations, new technology launches, networking, and opportunities to do business.

Things to see and do: Network with 90+ new exhibitors from a field of 625+ and new industry professionals. In 2016, 31% of attendees were new. Discover industry and technology trends within the technical conference developed by a panel of industry experts on the technical advisory board right on the Show Floor. • No cost technical conference: “Moving the industry forward and beyond: leveraging efficiency, quality and cost effectiveness” Session tracks: - Continuous manufacturing opportunities keep expanding - Leveraging quality systems & strategies in a heavily regulated environment - Implementing modularity and speed in facilities/facilities management - Enhancing processing & production utilizing innovation - Enabling technologies to streamline operations - Bringing your vision to your reality via the contract services solutions Reconnect with old friends and industry colleagues; 2016 brought 11,500+ from 48 States and 52 Countries Invest in your professional development through Interphex Live. Increase your knowledge, get exposed to new efficiencies, learn CoG strategies, and take back best practices and solutions to your team. Explore INTERPHEX for the many new technologies launching this year from industry leaders such as SKAN, AdvantaPure, Marchesini, Watson-Marlow, CapsCanada, JRS Pharma, Fluid Air, Parker Hannefin and many more Don’t miss the opportunity to see Germfree’s Mobile Adaptive Bioproduction Suite housed within a 53’ trailer Visit the India Pavilion, brought to us by FICCI, Federation of Indian Chambers of Commerce & Industry, offering many leading India-based equipment, technology and API providers for you to do business with Register today at: interphex.com/register

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O Diary entry

LAB DIARY

The latest note from R&D software provider IDBS looks at the challenges scientists face when working with the banality of starting routine procedures from scratch, the subtle, but integral, art of collaboration, and the love/ hate relationship between scientists and their equipment.

1. Process inefficiencies A common pain point for researchers is the need to regularly start processes from scratch every time, rather than using a standard operating procedure (SOP) template. The time spent writing out procedures could be used far more effectively. By using a comprehensive data management software system that has both the appropriate functionalities to complement scientific research and enough capacity to ensure all SOPs are searchable to maximise efficiency, procedures can be stored centrally, for ease of access, sharing and training. This is outlined further in The World Health Organization’s Good Laboratory Practice Handbook.

2. Collaboration concerns Collaboration is the new buzzword for the workplace outside STEM, and although science and research is already familiar with the concept, it doesn’t make it any easier for researchers to do. Certain co-workers can be difficult to work with, young residents often think they know everything, and even supervisors can add unwanted stress to daily activities. And that’s not yet considering macro-scale collaboration; globalisation has encouraged teams of scientists from all corners of the globe to work closely on specific projects. It’s very exciting - but challenging. Collaboration can add value to methodology and analysis, but poor communication can impact the integrity of any conclusions, often found out after it’s too late. Fortunately, certain digital solutions can ameliorate these pain points. In this feature on data informatics, Scientific Computing World (SCW) explores how the use of informatics software can increase data integrity in the lab. When working with external partners, unified platforms can overcome communication barriers by digitising workflows, allowing all parties access to the same data. Organisations such as Nutricia Research have benefited from this approach by implementing flexible platforms that holistically support their activity when working with different partners, whilst still securing their data and intellectual property (IP).

3. Equipment trust issues Lastly, every researcher enjoys a tenuous relationship with their equipment. Lab utensils are the driving forces of the scientific process, but even so, scientists have their favourites and some teams avoid some equipment altogether! Unreliable pH meters cause havoc with buffer reactions so you use your neighbouring labs meter instead, until you find out they are doing the same back with your own. Autoclaves break too often and take far too long; there are never enough Bunsen burners; and finding micropipettes and pipette-men have been thrown together happens more often than not. We’ve all been there. Especially when you find equipment that, wait for it, actually works perfectly and you have to find a secret location to store it away from everyone else. Unfortunately, though, not every lab pain point has a simple solution. Henderson Hasselback equations in pH experiments are only as good as the meter. Bunsen burners will always be popular – and no, propane torches are not a valid alternative – and someone will always mess with the equipment storage. Equipment rage is an accepted part of laboratory life. And it’s a reminder that not every problem can be solved by the seemingly omnipresent relief of digital and data innovation. 50

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