EPM October 2014 by EPM Magazine

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OCTOBER 2014

Volume 14 | Issue 07

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Contents

Features 18

October 2014 | Volume 14 Issue 7

Regulars

PACKAGING & BOTTLING

NEWS

Including expertise from Essentra, Curtec, Travtec and Nolato

NEWS PROFILE

GRANULATION

Romulo Leon, Mettler-Toledo PCE discusses the challenges of pharmaceutical regulation

GEA Pharma Systems looks at how the use of microwaves is more effective than gasstripping

REGULATORY AFFAIRS

OPINION

Conception :

• Pictures credits: IStockphoto, Shutterstock, Patrick Bogner.

COPA-DATA and Patheon air their views

CHEMICAL REACTION Jim Hardisty, Goplasticpallets.com in the spotlight

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head ofﬁce Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE. Tel. +44 (0) 1244 680222 Fax. +44 (0) 1244 671074 Web: www.epmmagazine.com

editorial group editor lu rahman, lu.rahman@rapidnews.com associate editor Dave gray, dave.g@rapidnews.com contributing editor aleksandra jones, ola@rapidnews.com publishers mark blezard, duncan wood

production art samantha hamlyn

PUMPS & VALVES

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From Merck and Edwards

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PACK EXPO PREVIEW

IMAGE ANALYSIS Malvern Instruments discusses automated image analysis in pharmaceutical manufacturing

FREEZE DRYING Ways of building quality into your lyophilisation cycle

LAB INNOVATIONS PREVIEW

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robert anderton rob@rapidnews.com jacqui priestley tel: 07907 361588, jacqui.priestley@rapidnews.com

subscriptions subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £115 outside qualifying criteria UK - £80, ROW - £115 please subscribe online at www.epmmagazine.com Address changes should be emailed to subscriptions@rapidnews.com. European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals. Volume 14 Issue 7 © October 2014. While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

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COMMENT

Broadening our view

As winter approaches so does the reminder that many of the population would be wise to have a flu vaccine. Add to this the on-going issues surrounding antibiotic resistance and the quest for a vaccine to counter the threat from the Ebola virus, and once again we are made aware of the importance of drug development and manufacture. With this in mind, it was interesting to read the comments of Mary Baker, past president of the European Brain Council, who believes that pharma companies are focusing too much on patient centricity and instead, should widen their gaze to include the whole of society. In order to solve the problems with our healthcare systems, as well as the patients, she says we need to look at the healthy that benefit from over the counter medicines and other members of society that are healthy at the moment but are “sleep walking into illness in the future”. According to Baker, patient centricity is a narrow viewpoint to take and it is far better to focus on a company’s role in the wider health system and society. “If pharma companies pursue that they’re solely patient-led, patient-focused, patient-centric, they won’t be able to deliver,” she says. What Baker is concerned about, is she says, society and while the experience of the patient is an incredibly important part of this, it should not be the sole focus. She believes that currently pharma companies aren’t intrinsically involved in Europe’s major healthcare systems but are peripheral. And what she sees as being the problem is that the pharma industry is working in ‘primitive tribes’ which are competing instead of collaborating with one another. According to Baker ‘Novartis should not consider Pfizer its competitor and vice versa; they should consider sources of unhealthiness as their greatest foes.’

It’s an interesting point of view. Of course collaboration and parterships within the sector do exist. A good example of this is the Dow and Colorcon alliance which was set up to utilise joint resources in order to speed up pharmaceutical product development and reach global markets. More recently Colorcon announced it would be ramping up production of fully formulated ready-to-use pharmaceutical coatings. In order to grow the portfolio, it plans to use BASF’s immediate release coating polymer, Kollicoat IR. Of course ultimately pharma companies are businesses and collaborations need to offer clear financial benefits for all parties involved. Baker though seems to have recognised an industry trend. According to a report by Frost & Sullivan, the global healthcare industry is shaping up to be patient-centric, driven by factors such as disruption in the traditional industry value-chain as well as transformation of the healthcare systems. This, it says, comes at a challenging time for the industry, which includes diminishing returns on healthcare spending, unviable disease management systems and chronic disease burdens across the major regions. How the industry deals with this patient-centric approach will be interesting. Will we continue to accept it and find ways to work within its boundaries as single companies or will we as Baker advises, ‘create a movement by bringing everyone together and believing in something’?

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Lu Rahman

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NEWS

Trade body says stop Chinese fake medicine entering EU

he international trade body representing the holography industry is urging China’s manufacturers and authorities to redouble efforts to stem the tide of counterfeiting in the light of new statistics which confirm the country remains the main source of fake goods. The International Hologram Manufacturers Association (IHMA) says reports from the EU, the Japan Patent Office (JPO) and US Department of Homeland Security (DHS) are all reminders of the ‘huge’ threat posed to consumer safety by unscrupulous criminals.

It’s also a sobering reminder that the war on counterfeiting continues goes on, says the IHMA, and is a timely call to those desperate to protect not only brands and profits from the criminals but also people who are at risk from products that do not comply with stringent international safety requirements. Indeed, the problem of counterfeiting is so rife in China that the IHMA has launched a new initiative to raise its profile there to promote the benefits of holography to brand owners – it is targeting manufacturers as well as secured document issuers and printers to explain the advantages of working with its member companies.

These reveal that while China is a leading supplier of goods to the world’s markets, it is also the primary source of supply for counterfeit items entering Europe, the USA and Japan. Of all counterfeits confiscated at the EU’s border in 2013, more than 79% had come from China. This amounted to almost 36 million items which, if they had been genuine, would have had a domestic retail value in excess of €768 billion. Fake pharmaceuticals are the third most popular item detained by the authorities.

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The JPO survey on enterprises that have suffered from losses caused by counterfeiting inside and outside Japan reveals that almost 68% of the companies that have been hurt by counterfeiting report that they

have suffered losses in China. The IHMA is backing calls from industry bodies for greater cooperation between authorities to help stem the tide and consumer

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“More must be done - and quickly - to deal with the problem and this might include increased integration of holograms as part of brand protection strategies.” Increasing adoption of holograms in places like China and other global counterfeiting hot-spots reinforces its position as a preeminent security feature in the global anti-counterfeiting fight. Security holograms will ensure quality and help inspectors to seize and destroy items not displaying security devices. “Holography has a key role as a highly effective, highly flexible weapon in the ongoing battle to thwart counterfeiters and fraudsters,” Lancaster said, adding that, “the eye-catching and attractive holographic image can be supported by covert optical features and track and trace codes to enhance the hologram’s functionality.”

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Ian Lancaster, the IHMA’s general secretary, said: “Thousands of brand owners, along with those authorities responsible for legislation, are sure to be alarmed at these figures.

“All involved in the supply chain - manufacturers, distributors, consumers, tax authorities - will be reassured by the presence of holograms on products and recognise the benefits they provide.

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The IHMA’s work in China will help them to improve authentication strategies and protect documents and branded goods such as medicines and pharmaceuticals.

NEWS

Need for targeted, sepsis-specific therapies, says analyst With bacterial resistance to antibiotics becoming more commonplace, and a rise in the number of difficult-to-treat sepsis patients likely to follow, there is a desperate need for the development of sepsis-specific therapies, according to an analyst with research and consulting firm GlobalData. Marc Hansel, GlobalData’s analyst covering infectious diseases, states that as more people die each year from sepsis than from either lung or bowel cancer, more needs to be done to fill the glaring voids in the sepsis treatment landscape. Hansel said: “The only treatment options currently available for sepsis patients are the timely administration of antimicrobials and supportive care, but these methods fall short of meeting the needs of seriously ill patients. “Key opinion leaders (KOLs) have indicated to GlobalData that therapies targeted at sepsis patients suffering from coagulopathy, endotoxemia, acute kidney injury (AKI), acute respiratory distress syndrome, and/or immunosuppression are desperately needed to help supplement antibiotics.”

focus their efforts on demonstrating efficacy in smaller, homogeneous patient populations, or they risk suffering the same fate as Xigris and its counterparts. “As they are targeting niche patient populations, pharmaceutical firms

may be able to command premiumpricing when commercializing sepsis-specific therapies, especially considering the immense cost sepsis care currently incurs to the healthcare system,” the analyst concluded.

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Hansel noted that while there are some promising products being investigated, such as AM-Pharma’s recombinant human alkaline phosphatase (recAP) for sepsis patients with AKI, most of these are years away from regulatory approval. GlobalData’s analyst added that companies must avoid several pitfalls that have stymied the development of novel sepsis therapeutics in the past. The lack of a universal clinical phenotype represents a particularly formidable clinical and commercial barrier to improving treatment options. Hansel explained: “Recent highprofile failures, such as Eli Lilly’s once-marketed drug Xigris, Eisai’s Eritoran, AstraZeneca and BTG’s Cytofab, and Agennix’s talactoferrin alfa, highlight the need for a paradigm shift in how latestage sepsis clinical studies are conducted.” KOLs interviewed by GlobalData stressed that companies seeking to enter the sepsis marketplace must

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NEWS PROFILE

ccording to pharmaceutical industry experts, IMS Health, in 2011, the global pharmaceutical market was worth $880 billion, growing at 5-7% per year. Accountants Pricewaterhousecoopers (PWC) forecast a golden era for the global pharmaceutical industry, expecting it to be worth nearly $1.6 trillion by 2020.1 Currently, the US tops the list of global pharmaceutical markets with industry experts predicting 33% growth to $476 billion in the same period, thanks to the Affordable Care Act.2 However, emerging markets, including China and Brazil, are taking great strides forward and now boast the 3rd and 6th largest pharmaceutical markets in the world.3 Amid a wave of expiring patents on some of the industry’s most successful branded drugs and medicines and growing competition from cheaper generic drugs, pharmaceutical manufacturers are likely to see “minimal growth in their branded products up to 2016”, according to IMS health. The global generic drug market is worth US$225 billion and will continue to grow at 10% Compound Annual Growth Rate (CAGR) to US$358 billion in the next five years,

Challenges of pharmaceutical regulation By Romulo Leon, head of global sales, Mettler-Toledo PCE

according to according to a BCC Research report.4 However, this strong growth in the generic drugs market is threatened potentially from counterfeit medicine. The counterfeit drug market is growing rapidly and accountants Deloitte currently value it between $75 billion to $200 billion.5 The World Health Organisation (WHO) believes that over 25% of medicines available in developing countries and 50% of products ordered online are counterfeit6. The institute estimates that 100,000 people in Africa lose their lives each year due to counterfeit medication.7 In response, governments across the globe are beginning to tighten up pharmaceutical regulations, making traceability an obligation for the industry.

However, in the absence of a single international regulatory body, the pharmaceutical industry is finding it difficult to curb the counterfeiting menace. Recognising this problem, the US and Europe are leading global efforts to establish a comprehensive drug traceability framework. France, Italy, Greece, Belgium and Turkey have already adopted traceability regulations and other European governments are expected to produce similar legislation. Advanced product inspection technology, including track and trace systems, checkweighers, metal detectors and x-ray equipment, is being seen in the industry as the answer to enhancing the traceability of pharmaceutical products through the supply chain and to optimising product

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This complicated supply chain has only increased the importance of track and trace technology on pharmaceutical processing lines to enable manufacturers to demonstrate compliance with relevant safety regulations throughout its operations.

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quality and safety. The use of such technology can help protect the consumer from substandard medicines and guarantee the reputation of the pharmaceutical brand.

Keeping track of your line Globalisation has made the pharmaceutical industry procurement and supply chain more complex than ever before. Today, raw materials are often sourced in one country, processed in another, with the finished product being sold in a third. This complicated supply chain has only increased the importance of track and trace technology on pharmaceutical processing lines to enable manufacturers to demonstrate compliance with relevant safety regulations throughout its operations. The European Union (EU) Directive on Falsified Medicines, which will come into effect in 2015, will require pharmaceutical manufacturers to introduce advanced serialisation technology on their lines. The Directive aims to facilitate traceability of pharmaceutical products and protect consumers from the entry of counterfeit drugs on the market. Turkey has led the world in this area so far, introducing the Ilac Takip Sistemi (ITS) drug tracking system as early as 2010 to combat a drug counterfeiting epidemic in the country. France, Italy, Greece, and Belgium have since adopted their own traceability regulations ahead of the EU Directive and it is likely that concerns about drug safety among consumers in the region may push other EU nations to adopt similar frameworks. Developed and emerging economies elsewhere in the world are expected to follow the

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NEWS PROFILE same route in the near future. Advanced serialisation and vision inspection systems allow manufacturers to track their products through the production line from individual cartons to bundling to palletisation through to delivery. It is even possible to track individual pills as they progress through the production line. Such technology is also capable of examining packaging for the correct product identification (ID) number and bar code. As barcoding can be susceptible to print faults, immediate and reliable detection of faulty codes for fast moving pharmaceutical production lines is imperative to minimise the risk of product recalls due to non-compliant labelling, protecting profits and upholding brand reputation.

Safety first Pharmaceutical safety is not just about the active ingredient. There are additional issues that must be addressed to safeguard consumers, such as ensuring that products are free from foreign body contamination. The principal contaminant threat on a pharmaceutical production line is from broken sieve wire, which can enter the product flow during the processing of the raw ingredients that make up the final caplets or tablets. Metal detectors able to identify contamination from ferrous, nonferrous and non-magnetic stainless steel fragments are ideal for inspecting pharmaceutical products. Thanks to the advancements in technology, metal detectors are more sensitive than ever before and are now capable of overcoming the “orientation effect” – the phenomenon whereby metal fragments are easier to identify in one orientation relative to the metal detector search head than another. Pharmaceutical metal detectors can be used to inspect tablets, capsules and pharmaceutical powders, helping to ensure compliance with regulatory requirements.

Question of quality Other product quality parameters are also key to ensuring safety for consumers. Pharmaceutical manufacturers must inspect their products for seal integrity to ensure product sterility and minimize the risk of product tampering. They must examine their packaged products for broken vials and missing caplets and ensure the presence of Patient Information

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With advancements in technology, inspection systems have become more compact, simpler to use and easier to integrate with other systems on the production line than ever before.

Leaflets (PILs), which in many countries are a legal requirement. Manufacturers should monitor the fill-level of their packs as well. This can help minimise the instance of wasteful product giveaway, enhancing production line efficiency. X-ray inspection systems can identify contamination from foreign bodies including metal and glass fragments, high-density plastics and rubber. The technology can easily examine products for seal integrity, identify broken and missing components, measure product mass and check fill levels. Checkweighing systems are capable of inspecting fill level of bottles and vials for portion control, boosting efficiency of lines manufacturing single-use products, reducing product waste for manufacturers and safeguarding consumers against inaccurate dosages.

Extending your reach With the largest pharmaceutical companies operating in multiple locations worldwide, many are producing their products locally to ensure that they comply with the relevant local regulations. To reduce production costs, while upholding product quality and safety, manufacturers can harmonize their processing systems by sourcing the product inspection technology used on all of their manufacturing lines from the same supplier. Connecting

product inspection equipment across multiple production lines to a single data collection network can facilitate monitoring of performance records, giving manufacturers greater control over global product quality for the demonstration of due diligence. There are many options available for product inspection systems in the market but sourcing them from global manufacturers ensures the same standard and quality technology is used on every production line. With advancements in technology, inspection systems have become more compact, simpler to use and easier to integrate with other systems on the production line than ever before. Innovative product inspection software enables every machine to connect to a data collection network, allowing all product inspection records to be stored in one central location, facilitating tracking of product batches for manufacturers and, in the event of product recall, streamlining the

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identification of problem batches and corrective procedures.

Staying ahead of the pack In the next few years, in light of changes in the regulatory landscape and the globalisation of pharmaceutical production, more and more pharmaceutical manufacturers will turn to product inspection solutions to automate their inspection processes. Not only can the use of such technology enable manufacturers to uphold product quality, but it can also help in significantly reducing manufacturing costs. It is important the pharmaceutical manufacturers work in partnership with product inspection system suppliers to select the product inspection equipment best suited to the needs of their product and their production line. In this way, manufacturers will be able to face up to industry changes in regulation well into the future.

http://www.pwc.com/gx/en/pharma-life-sciences/pharma2020/market-opportunities-andoutlook.jhtml 2 http://www.forbes.com/sites/brucejapsen/2013/05/25/obamacare-will-bring-drug-industry35-billion-in-profits/ 3 http://www.pmlive.com/intelligence/country_reports/building_brics 4 http://www.bccresearch.com/market-research/pharmaceuticals/generic-drugs-globalmarket-phm009f.html 5 http://www.economist.com/node/16943895 6 http://www.who.int/bulletin/volumes/88/4/10-020410/en/ 7 http://www.un.org/africarenewal/magazine/may-2013/counterfeit-drugs-raiseafrica%E2%80%99s-temperature 1

Russia and CIS – navigating a fast-changing regulatory landscape Inna Demodova, head of regulatory affairs for Russia and CIS at ELC Group, looks at the upcoming regulatory requirements facing pharmaceutical companies looking to enter, expand or build momentum in what is currently the world’s fastest growing market

he continued dynamic growth of the Russian healthcare market makes it a compelling opportunity for the pharmaceutical industry. In 2013 the market notched up an impressive 14% year-on-year growth to RUB 1.045 trillion ($28.91 billion), with foreign producers dominating the top 10 listing of manufacturers operating in the market. Achieving market access is becoming increasingly complex and challenging following a host of new laws and regulations designed to boost domestic manufacturing. In 2012 the Russian government announced plans to increase the volume of domestic production of medicines on the country’s Essential Drugs List (EDL) to 90% by 2018 and launched its Pharma 2020 strategy, which is designed to increase the total share of domestically produced pharmaceutical and medical products consumed in the country to 48% by 2020. As a result, a number of multi-national organisations have already taken the decision to locate their manufacturing within Russia itself. From a regulatory perspective, the process of harmonising Russian and international pharmaceutical standards remains a ‘work in progress’ and international pharma companies need to be well orientated with the national legislation, rules and restrictions operating in

Russia and CIS – and prepared to manage uncertainties and risk in what is a fast changing political environment.

What’s changing, and why In 2010 the Ministry of Health of the Russian Federation issued Federal Law #61. The law changed the registration process for drugs, introducing the requirement for a local clinical or bioequivalence study for every submitted drug – a costly new step for international drug firms. There is just one exception to this requirement; if a molecule has been marketed for more than 20 years in Russia then this obligation can be avoided. The law also set out the regulatory framework for the Essential Drugs List (EDL) and the pricing of drugs included on the EDL. To restrict the importation of essential drugs, regulations relating to the Pharma 2020 programme, which are designed to enforce the localisation of the full cycle production of international pharma companies, are now coming into force. From January 2014 all local manufacturers had to certify with the GMP, as a consequence of which many big pharma names took the decision to initiate local manufacturing relationships in Russia.

On 22 August 2014 it was announced that the Ministry of Industry and Trade and the Ministry of Health would jointly develop additional measures to support local pharmaceutical manufacturers. A draft directive, due to be submitted to the Russian government in mid-September, is expected to establish limits on the import of drugs if the country of origin is not a member of the Eurasian Customs Union (which currently includes Russia, Belarus and Kazakhstan – Armenia is ongoing). If two or more generics are already manufactured in CU countries, then an imported drug cannot be considered for participation in a tender or auction. The directive is also expected to incorporate incentives to support international pharmaceutical companies that invest in local manufacturing. In an evolving regulatory landscape, pharmaceutical companies need to consider their planned post-approval marketing activities when preparing their initial registration dossier and reflect carefully on their planned post-approval marketing activities. The potential for local production and the selection of local distributors will be important and should be given careful deliberation when evaluating the best market access strategy approach to take.

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OPINION Social listening in healthcare – is it responsible? There’s a quietly emerging niche in the healthcare industry: social listening for marketable data. But asks David Gray, is it moral? And is it safe?

nline firms are now popping up slowly but surely, selling packaged snippets of tweets, posts and comments from the health-conscious public at large. These bundles of ‘market data’ are already being sold to manufacturers, hospitals and healthcare providers, with the intention of informing anything from purchasing decisions, strategies, formulations and more. Social listening in the wider context is nothing new. It’s commonly used in targeted advertising online, and has sparked considerable controversy in recent years – and when we’re talking healthcare, for most a very personal thing, it becomes a morally grey area.

Morals qualms aside, I wonder if it’s responsible to sell data collected based on human patterns of online behaviour. Firms currently offering these services include Treato, Signals and PatientsLikeMe – which is a forum for the public to share symptoms and treatments, and the website explains “we take the information you entrust to us and sell it to the companies that can use that data to improve or understand products or the disease market”. These websites all use strict algorithms to filter through to the most valuable – and informative – core data. But, to be quite blunt, in comparison to algorithms, humans are illogical and emotionally-driven.

So online behaviour needs to be treated with caution, no matter how many filters and checks it goes through before it reaches the buyer. No doubt at some point in recent years, you’ve been caught offguard by an advert which has some significance to your personal life, but is promoting a product which is completely wrong for you. In digital marketing, this is a common problem – the algorithms for creating ‘targetted campaigns’ are not perfect – they often fail to feed the right products to the right people. And if you apply this to the pharma supply

chain, it gets really dangerous. So it all comes back to product marketing. It’s well-known that the pharma and healthcare industries still struggle with the weight of dominant forces and big budget campaigning for ‘fashionable’ treatments. If these are the only brands that filter back to the digitally conversing public, and the healthcare sector buys their opinion back as ‘data’, we run the risk of creating a very vicious cycle.

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IT’S GOOD TO TALK What are you looking forward to at Lab Innovations this year?

Innovation is at the heart of the show and with over half of exhibitors launching a new product, it is a real opportunity to see what’s new in the industry. I’m also excited to see our keynote speakers Robin Ince and Quentin Cooper. Such a unique chance to see these commentators in the industry!

Retsch UK is looking forward to promoting an entirely new type of high-energy ball mill – the Emax – a revolution in ultrafine grinding. The extremely high energy input in combination with the new liquid cooling system provides perfect conditions for mechanical alloying and colloidal milling down to the nanometer range.

Katy Morhen, event manager, Lab Innovations (Easyfairs)

We’re looking forward to meeting visitors and finding out more about their water needs. We’re also excited to introduce our innovative range of products, namely our Chorus range, which will give our customers even more choice. We want to discuss the complete package we offer including pre and post service support.

Jill Boyington, marketing and communications coordinator, Retsch UK

We’re looking forward to unveiling our new range of laboratory test sieving machines. The new additions are really targeted at the modern lab, so it should be the perfect event to demonstrate them. Our sales managers are looking forward to talking technical details at the show. Wayne Mar, sales manager, Endecotts

Steve Bradford, area sales manager Veolia Water Technologies

We can’t wait to show off our Biostat A. It’s a bioreactor/fermenter designed specifically as an entry-level model for fermentation and cell culture. The system’s control tower features easy-load peristaltic pumps, an aeration module and easy to access probe ports and supply connections. We’ll also be highlighting its compact design, which is a real space-saver. Matthew Samuels, marketing North Europe, Sartorius UK Ltd

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Q& A OPINION

Quick learners

Quick to Clinic is an initiative offered by Patheon. Anil Kane, executive director, global head of formulation sciences and Alan Lahaise, senior director, Europe business development, spoke to EPM about what’s behind the offering, how it can be of benefit and how this version of the program has been finely tuned for improvement

EPM: Tell us about Quick to Clinic - what is it and what sets it apart? AK: The Quick to Clinic offering includes a month of clinical trial stability studies, provides customers access to six flexible dosage forms and decreases the wait time from receipt of API for clinical trial materials for First in Human trials by one month. The updated program offers customers the ability to meet their unique scientific requirements with capabilities spanning from formulation development and manufacturing to clinical packaging and distribution. Patheon is now the only CDMO to offer customers an accelerated 12-week clinical trial material program with stability data with a variety of flexible dosage forms. Patheon applies phase appropriate analytical method qualification and verification and the use of disposable equipment for manufacture where feasible, which allows us to speedily manufacture clinical material. Patheon uses standard templates for documents such as ‘manufacturing batch record’ thus enhancing the readiness of clinical supply manufacture EPM: What prompted the move to update it? AL: We received feedback from the market and from our sales team that our previous Quick to Clinic offering of four months was not considered quick and didn’t offer sufficient dosage form or geographic options. We have addressed all these concerns in our new Quick to Clinic refresh.

EPM: How has Patheon ensured no loss of quality now the scheme has a shorter time frame? AL: Patheon has robust but flexible quality systems that allow us to manufacture GMP material for clinical supplies. We have an inventory of GMP released commonly used excipients that reduces the time required to make the material available for clinical batch manufacture. Use of trained operators, qualified equipment, pre-formatted documents and other quality systems ensures that quality is not compromised while bringing speed to the manufacture of clinical supplies. EPM: What does the company have planned for the rest of the year?

AK: Quick to Clinic is only one of the many offerings and services available to customers from Patheon and is focused on faster results in the development phase. As a leading provider of contract development and manufacturing services to the global pharmaceutical industry, Patheon is responding to the needs of all customers with unique services and has recently expanded its overall capabilities by adding small molecule API and biologic drug substance capabilities to the broad array of solid oral and sterile dosage form capabilities. Additional offerings and capabilities will be announced in the coming months to help customers simplify their outsourcing needs and achieve their goals faster.

New & improved: According to Anil Kane, Patheon, the updated Quick to Clinic program offers customers the ability to meet their unique scientific requirements

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OPINION

Taming the pharmaceutical validation dragon It takes an average of twelve years and over £200m to get a new drug from the laboratory onto the shelf. Here, Robert Harrison, pharmaceutical industry manager of COPA-DATA, explains how appropriate technologies can help, rather than hinder, essential regulatory compliance

ne of the main reasons why the pharmaceutical industry has been very profitable over the last decades is the existence of patent protected drugs. However, the sector is lagging behind in efficiency and sustainability. The patent cliff, rising competition, increasing material and manufacturing costs, and strict compliance of global regulations are additional challenges that pharmaceutical manufacturers face every day. Most chemical patents expire after 20 years from the date of filing, which is usually set as the start of clinical trials. Over the next five years, the annual estimated salesvalue of drugs with patents set to expire is over £150 billion. The companies that will survive are the ones that manage to make their quality management culture smarter and more malleable. There is no doubt that automating the manufacturing process plays a key role in making a company more efficient. But automation is of little use without a communication system that allows a smooth collaboration between research and development, shop floor production systems and the rest of the business. Industrial automation software can help enhance the control function

and data logging, processing and archiving of data within the SCADA system.

What’s stopping you? One of the most daunting aspects of new technology is the amount of time spent on implementation and training. The question most companies ask is ‘will it be worth it?’ What manufacturers often don’t realise is that the best cutting edge industrial automation software is extremely easy to implement, as well as very intuitive and ergonomic to use. When it is configurable, industrial software eliminates the complexity of writing program code for applications. Programmed code is a process which is not only very complex and time-consuming, but also needs significant validation and quality effort due to the high potential failure rate. Configurable systems are very efficient to validate. Parameterisation allows the designer to create use a function library that covers the engineering challenges faced by the pharmaceutical industry. Setting parameters instead of programming creates a well-defined process and limits the risks. Once installed, the software shouldn’t need further intervention or additional coding.

Another advantage of using best-in-class industrial automation software solutions is their native communication drivers. When the software provider is independent and has no links to specific hardware manufacturers, it means the software can connect directly to the process, regardless of platform and without stopping the production line.

FDA 21 CFR Part 11 The FDA 21 CFR Part 11 regulation defines the criteria under which electronic records and signatures are considered trustworthy, reliable and equivalent to paper records. Often seen as an overcomplicated procedure by drug manufacturers, the regulation can be easily embraced by using the correct industrial automation software. In the case of paper batch records, mistakes can usually be traced back to missing entries or incorrect records. Industrial automation software can simplify the process of logging, archiving and reporting on information from a variety of sources including mobile devices, especially where the audit trail is concerned. Modifications and events at any stage are automatically logged, which ensures

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secure traceability of all process and operator actions. Process flexibility and validation efficiency come when using a product that can provide all ‘Part 11’ compliance needs in one software installation, with audit-trail, alarm management, historian, user administration, SQL and reporting. High end functionality, ergonomics, smart data processing and reporting functions are only a few of the ways in which industrial automation software can help pharmaceutical companies become more efficient and competitive. Embracing new technologies doesn’t mean putting quality or safety aside. On the contrary, it’s one of the best ways to make engineering more efficient, simplify the regulatory process, meet international regulations, and reduce quality violations. Industrial automation software can, in fact, be a pharmaceutical company’s most useful weapon in taming the validation dragon.

PACKAGING & BOTTLING

Perfectly packaged: One way to prevent counterfeit problems adopted by many pharmaceutical companies is to integrate security within the product packaging, says Essentra

Package control

invisible and only detectable with a special reading device. As with other covert technologies, taggants can only be identified by the brand owner or people they equip with the appropriate knowledge and technology, to provide conclusive verification.

Product protection now means so much more than simply ensuring it reaches its destination without damage â&#x20AC;&#x201C; it also has to take into account tamper-evidence and anti-counterfeiting. So what can be done to help protect pharmaceutical goods, asks Essentra Packaging?

Tamper-evidence

Integrated Design So how can companies maximise security? It is important to use both overt and covert design features which complement each other and are jointly used on packaging, integrated into the design of the carton, label or tear tapes and providing multi-layered functionality.

Tamper-evidence can be integrated into security solutions alongside providing a means of authentication - protecting against tampering, refilling, counterfeiting and diversion and assist in meeting the requirements of The Falsified Medicines Directive (FMD).

Packaging companiesâ&#x20AC;&#x2122; design studios can provide design capability for customers, adding value and delivering customised design concepts and artwork creation for packaging, building in security as part of the overall pack design.

Covert technologies such as infrared (IR) and ultra-violet (UV) inks, microtext and microscopic tagging are invisible and difficult to detect and replicate without specialist detection equipment. Forensic solutions include molecular markers, and biological tracers offer another level of authentication, but these features can only be identified using laboratory equipment.

Tampering can often render products unsafe, dangerous or in some cases even fatal. Tamperevident seals, materials or integrated packaging design provide a clear indication that tampering has occurred and can protect your customers and brands from potentially harmful interference.

With the use of increasingly sophisticated counterfeit methods, drug counterfeit criminals continue to advance and profit at the cost of public safety and company revenue. It is essential to implement security technologies to ensure that criminals are unable to re-use, copy or misappropriate pharmaceutical drugs or drug packaging.

Overt technologies

Images printed with UV inks are only visible under a UV light. UV inks are available in different frequencies, so depending on the formulation of the ink, the investigators will need to use either a long-wave or short-wave UV light in order for the printed images or text to become visible.

Overt features enable instant authentication of packaging through visual inspection by the user without requiring expert knowledge. Optically variable features such as

In addition to this, covert technologies such as taggants can also be placed on to packaging, with the most effective being completely

Tear tape is an ideal medium to incorporate easy-opening, tamperevidence and security into product packaging efficiently and costeffectively. Ten colour gravure printing and sophisticated slitting lines ensure tape products meet exacting print and quality standards and can be applied to a wide range of packs, from flexible overwraps and sleeves to cartons, boxes and even hermetically sealed packs.

t is estimated that counterfeit drugs are currently worth over $75 billion in global trade and criminals are becoming increasingly competent in packaging their products. One way to prevent counterfeit problems adopted by many pharmaceutical companies is to integrate security within the product packaging. In the healthcare market this can include a variety of technologies which can be integrated into the product packaging â&#x20AC;&#x201C; be it a carton, label, overwrap or specialised tear tape. Bespoke packaging solutions can carry a variety of sophisticated brand protection devices including layering overt and covert authentication and tamper-evidence technologies alongside the brand design features.

holographic devices, and colourshift inks, are some of the most common and effective overt security features, enabling packaging to be validated both quickly and easily.

Covert Technologies

Tear tape

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Anti-theft, tamper-evidence and authentication solutions enable inferior and potentially harmful counterfeit products to be reliably intercepted and stolen genuine products recovered. By implementing the new packaging security techniques, robust and reliable protection from tampering, copying and brand infringement is enabled and counterfeiting will become a less profitable and more challenging process.

PACKAGING & BOTTLING Got it bottled Getting your arms around the bottle â&#x20AC;&#x201C; implementing serialisation for high speed integrated bottling operations, by Ian Parsonage, PCI

elatively cheap and logistically effective, bottles have steadily become the standard for drug delivery. Bottles come in a variety of sizes and shapes, and the economics of bottles make them attractive for delivering a month or three monthsâ&#x20AC;&#x2122; worth of medication cost effectively. Companies tasked with packaging opt for high speed â&#x20AC;&#x201C; high volume bottling lines that are predicated on efficiency. That efficiency is what makes the prospect of integrating product serialisation such a daunting task for most drug companies.

unsightly. One solution to these aesthetic objections is to apply an ultraviolet (UV) code, imperceptible to the human eye. Commonly, a more significant obstacle to applying codes to the top of the bottle is that the majority of these plastic closures contain raised lettering for opening instructions, and this uneven area creates a substantial challenge for applying and verifying barcodes. The first option to address this is potentially applying codes to the insert should it be adhered to the top of the bottle. Similar to what was described above this can be achieved through an overt barcode, or more subtly, applied with UV ink.

Identity parade: serialisation requirements dictate the application of a unique identifier on the primary unit-of-sale

With speeds reaching multiple hundreds of bottles per minute, a typical bottling line is the integration of many parts, each providing vital services to the overall delivery and each a lynchpin for the overall line efficiency. Bottles may be packed in trays, cartons, or bundled into groups by a shrinkwrapping prior to placement into shippers for palletisation. Adding supplemental stations for serialisation creates reasonable concerns for companies trying to achieve every percentage point of OEE.

Evolving international requirements around serialisation and track and trace are a patchwork of varying standards. Many developed countries have aligned with GS1 standards, while other developing countries have requirements that vary. In the US and Europe legislation has been pushed to 2017, whereas markets such as South Korea, China, and Turkey have more immediate requirements. This creates a burden in serving international markets. When implementing serialisation, these developing requirements add to the complexity of product changeovers, which can impact one of the key elements of achieving favourable OEE and profitability. Serialisation requirements dictate the application of a unique identifier on the primary unit-of-sale. For bottling operations, this ushers new equipment into the line. Additional complexity is added when the

individual unit-of-sale is then married up to its tray, bundle, or shipper. When applying serialised codes to individual bottles, codes are typically applied to the bottle label, readable on the body of the bottle. When bottles are accumulated for the bundling operation these individual codes are then obscured when unitised into bundles. This concern over line-of-sight creates operational challenges for in-process electronic verification. One of the principles of aggregation is the inspection step, verifying what is contained in the grouping. This data must be vetted to ensure the integrity of the aggregation process. Individual bottle codes need to be verified and then aggregated to the bundle and its own code, with electronic verification. The challenge is introduced as individual bottle codes visible on the label are obscured when bundled into larger units. This aggregation cascades through subsequent logistical operations at downstream trade partners in the supply chain. The simple solution is to apply a redundant second barcode to the cap. This enables a vertical inspection of the bottles. The challenge, however, is negotiating the addition of this extra barcode with Marketing personnel who may view its presence as

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Alternatively, in situations where the insert may not be applied to the top, manufacturers may be forced to look to applying codes on the bottom. Depending on the size, shape, and orientation of the bottle this may also introduce substantial complexities. Aggregation of bottles-to-bundles is then mirrored as bundles are packed to shippers again with their own serialised code. These shippers are aggregated to the pallet. Each step is electronically captured and verified to ensure a structured and robust hierarchy of codes, critical to the logistical integrity of the supply chain. In bottling, speed and efficiency is of the essence. Carefully consider proposing new equipment and new systems are installed and validated as the consequences can be substantial on overall cost. At PCI we spent over 24 months carefully reviewing technologies and service providers before settling on a global serialisation solution for our 16 sites. Our experience, and that of our clients, has been that the investment in time and consideration was well spent in maintaining efficiencies and supply continuity.

In 2013, IMA’s net revenues grew by 15.8% and the total area of its production facilities by 12.1%. Despite this increase, water consumption only went up by 1.1%. A more sustainable economy is one of our goals, because a Group the size of IMA has to pay attention to both the local and the global environment.

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Laser Focus Introducing the LIS-250 UV Laser Imprinting System for Tablets, Softgels and Capsules Why Laser?

To see the LIS-250 demonstrated, visit Qualicaps at Pack Expo in Chicago, Illinois, USA Booth W-895

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Defects caused by ink (double print, ink spots, missing print, etc.) are eliminated

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CAD design allows for flexible imprinting options

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Eliminates the need for print rolls, ink and extra storage, reducing the run cost of imprinting

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No cleaning necessary due to the lack of ink

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Larger printable surface than ink printing

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Potential for the prevention of counterfeiting

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Non-thermal effects of UV laser allow marking without resulting in thermal denaturation on tablets

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PACKAGING & BOTTLING

Package deal P

harmaceuticals manufacturer Synthon started to use packaging made by CurTec some years ago. Derk Sanders, director of technology & GMP implementation, said it was extremely satisfied with the quality of a 20 litre wide neck container made by the company. “It had the right wall thickness, was sturdy and did not affect the stability of our tablets and capsules over the long term,” he said. Although Synthon was satisfied with the wide neck drum, the packaging proved to be too large for a number of applications. Synthon asked CurTec to develop a high quality alternative with a lower price. The container needed to be widely deployable and just as easy to recognise as the old packaging. Sanders said: “CurTec developed various prototypes for us. We eventually chose a nestable 20-litre container (Click Pack) which offered the most benefits to Synthon.”

Double vision Packaging line solutions specialist Travtec Group has expanded its operations with the opening of a second facility close to its headquarters in Leigh, Lancashire.

The new 150 m2 offices will house the company’s administrative support services, allowing its original building to increase its operational space by 200m2 . The investment is in response to continuing demand for Travtecdesigned systems, particularly for the pharmaceutical sector, where the company offers bespoke solutions to help meet current and forthcoming track and trace legislation, including the 2017 European Falsified Medicines Directive. The new facility has also enabled Travtec to further expand its product offering, with the introduction of the full range of Lixis inspection

Price point: Synthon asked CurTec to develop a high quality container which has helped contribute to lower supply chain costs “An important advantage of the Click Pack compared to the drum is that it allows PE liners to be easily emptied and removed. The nestable container does not have a neck but a large opening instead which means that there is no resistance to the bags. Another important advantage is the unique closing

point which is important for our contract manufacturers. There is only one way to close and open the container which provides clarity,” said Sanders.

equipment including a blister vision system and pinhole detector. Established in 1995, Travtec is a leading designer and manufacturer of specialist product handling systems for a wide range of industries with a large number of world leading companies among its customer base including GSK, AstraZeneca, Merck, Unilever, L’Oréal, Nestlé, Bristol-Myers Squibb and Johnson & Johnson.

those under development. Travtec’s subsidiary company Sunala is the UK and Eire distributor for the Wolke m600 thermal inkjet printer for the pharmaceutical sector.

The company’s product handling, coding and inspection systems are designed to complement inkjet printers, labellers, print and apply and thermal transfer equipment and it works in partnership with OEMs to develop innovative new applications for both existing products and

“The new facilities and additional space will help to ensure we continue to devise and bring to market quickly innovative solutions that help our customers increase efficiencies.”

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In addition to being easy to use, the new container also contributes towards lower supply chain costs.

“This is an important milestone in the continuing growth of Travtec, enabling us to keep pace with customer demands throughout Europe,” said Travtec Managing Director Harry Thomason.

PACKAGING & BOTTLING

Direct line: Nolato Medical Pharma Packaging can now print Braille directly onto plastic containers

Sound barrier Perlen Packaging says it is the first company to enter the ultra-high barrier segment with PVdC based blister films with its Perlalux - Ultra Protect.

Film star: Perlalux Ultra Protect films provide high transparency and can be processed on all standard blister lines

n 2006 Perlen Packaging launched of Perlalux - Tristar ultra, a PVdC based high barrier film and cost-effective alternative to PCTFE. The Swiss company’s latest offering is said to double the moisture and oxygen barrier again, using a multi-layer PVdC technology. “With Perlalux- Ultra Protect we can now provide the world’s first highly transparent PVdC film for the rapidly growing ultra-high barrier segment,” said Johannes Giessler, director sales & marketing at Perlen Packaging. “The advantage for pharmaceutical companies lies in higher product protection at improved processing and cost efficiency.”

The demands of the pharmaceutical industry on blister film barrier characteristics have increased substantially in recent years. The high barrier segment is growing at double digit percentages, driven by more complex molecular structures of new drugs, increased sales into tropical climate zones and the trend towards global distribution. Perlalux Ultra Protect films provide high transparency and can be processed on all standard blister lines with the same parameters as standard PVdC films, without the need of additional forming aids. The symmetrical structure can be sealed on both sides to the aluminium lid foil. The barrier layers in the middle give optimum protection and highest product safety.

Print perfect

olato Medical Pharma Packaging can now print Braille directly onto plastic containers. The process developed by Nolato Jaycare in the UK allows a lay down of UV cured ink with a thickness of up to 0.5mm, directly onto the surface of a plastic container. The screen printing facilities onsite were adapted to maintain an even and consistent print height, which is crucial for any Braille.

On reflection

lear packaging and films may be dream materials for pharmaceutical manufacturers but increasingly transparent and reflective packaging can pose nightmares for the production engineers tasked with detecting them accurately and reliably with optical sensors. Sick’s TranspaTect photoelectric distance sensor has been designed to provide advanced clear material detection without the need for a reflector. Its high optical performance and detection accuracy promise better production efficiency, cost-savings, and quick and easy commissioning for pharmaceutical packaging processes such as picking, placing, labelling and printing.

“Transparent and semi-transparent materials now pose no problem,” said Phil Dyas, Sick UK industrial sensor specialist. “The sensor is also quicker and easier to install. A key development was eliminating the need to mount a reflector on the conveyor to return the light beam. Operators no longer have the timeconsuming task of mounting the reflector and aligning the sensor to it. The push button teach-in process also facilitates rapid commissioning and set-up. “Instead of a reflector, the metallic surface of a convenient machine component is used a reference surface. This innovation also opens up extra design freedom for packaging machine builders.”

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The printing has been analysed by the Royal National Institute of Blind People (RNIB) in the UK and also meets the current EU directive for Braille on pharmaceutical packaging. The RNIB also commented on the fact that the Braille print offered superior definition when compared to some instances of Braille that has been embossed through pack or label.

Clear winner: Sick’s TranspaTect photoelectric distance sensor has been designed to provide advanced clear material detection without the need for a reflector

GRANULATION

Drying out The use of microwaves during high-shear wet granulation and drying in a single-pot processor is shown to be more effective and efficient than gas-stripping, says GEA Pharma Systems

Made to work: Diosna’s CGS is designed and optimised for the production of high potent granules.

ingle-pot processing is an established pharmaceutical technique for high-shear wet granulation and drying. Although several drying techniques can be used in single-pot processing, the basic principle relies on the application of a vacuum in the bowl, which lowers the evaporation temperature of the granulation liquid. The traditional heat source is the heated dryer walls, and heat transfer is directly related to the surface area of the walls and the volume of the product. To enhance the drying process and reduce drying times, additional drying techniques can be implemented. The efficiency of two of these techniques — microwave drying and gas-stripping — was examined. Gas-stripping enhances vacuum drying by injecting a small amount of gas through the product mass during the drying phase. Microwave drying relies on additional energy being supplied that’s preferentially absorbed by the solvents in the process to enhance evaporation.

Theoretical eﬃciency comparison To theoretically compare gasstripping and microwave drying, calculations were made — based on the specifications of a 75 L single-

pot processor (pilot-scale) — for the additional amount of water that could be absorbed/evaporated (in addition to the amount of water removed by vacuum drying alone) by the two drying techniques. Our calculations showed that microwave technology is capable of removing significantly more water from the process per time unit than gas-stripping: 0.9169 g/min for gasstripping, compared with 59.19 g/min for microwaves. Even if the air used for gas-stripping is heated to 60°C and a maximum flow rate of 100 L/min is used, the water absorption capacity remains significantly below that of microwaves (12.74 g/min compared with 59.19 g/min).

Experimental comparison To confirm the theoretical calculations, a small-scale trial was done using an UltimaPro 25 (25 L bowl capacity singlepot processor). Lactose monohydrate (8 kg) was manually loaded into the machine, purified water (1 kg) was sprayed onto the lactose using a pressure vessel at 2 bar and a flat beam spray nozzle (LX2, Delavan), and an impeller speed of 200 rpm was used to obtain a homogenous water/lactose mixture (without creating a granule).

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After wetting, mixing was continued for one minute before the drying phase was starting. The results confirmed the theoretical calculations, showing that microwaves have a much higher water removal capacity that gas-stripping. It was demonstrated that microwaves were capable of removing the water (approximately 1 kg) in 40 minutes, whereas gas-stripping took more than three hours to remove the same amount.

Conclusion Both the theoretical calculations and experimental data showed that vacuum drying is significantly improved when enhanced with microwaves compared with gas-stripping. Although gasstripping does improve the vacuum drying process, it cannot replace a microwave drying system without prolonging the drying time. However, process scale-up must also be considered: drying times will remain the same for both small- and large-scale applications when using microwaves, whereas the drying times will be longer for gas-assisted vacuum drying because of the impact of the volume:surface ratio when transferring from small- to large-scale.

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PUMPS & VALVES PRODUCT FOCUS

Pump it up UK

vacuum specialist Edwards took its range of dry vacuum pumps to the Spanish market at the beginning of October. During Expoquimia in Barcelona, the group displayed the CXS, a GXS and nXDS ranges, offering live demos and interactive sessions.

The CXS is designed to improve reliability levels during pharmaceutical processes. The group states that users typically see a low cost of ownership and at the same time minimise their environmental impact. It’s design is in response to calls from various chemical industries for vacuum equipment to be more reliable, flexible and available on demand in a ‘plug and pump’ setup.

Two of the pumps displayed at the show were connected wirelessly to computers, with the group demonstrating the various control and monitoring features.

The nXDS dry scroll pump is suitable for use on vapour handling processes, and can handle corrosives and particulates, says the firm. It features an advanced scroll form and quiet operation levels.

The nXDS was shown in operation running together with a vacuum chamber, and Edwards’ application team performed live experiments throughout the show. “Our dry vacuum technology can provide real cost benefits and environmentally friendly solutions to the pharmaceutical and process industries”, said Dr. Don Collins, market development manager, Chemical Sector, Edwards.

Spanish eyes: During Expoquimia in Barcelona, Edwards displayed the CXS, a GXS and nXDS ranges, offering live demos and interactive sessions

Finally, the GXS range, which also made an appearance at the event, has been designed for robustness in harsher applications, and has long service intervals (up to 5 years), reducing maintenance levels.

Testing testing M

erck Millipore’s Steritest Symbio pumps have been designed to offer easier, safer and more reliable sterility testing of pharmaceutical products in laminar flow hoods, isolators and cleanrooms. The pumps were developed to address stringent pharmaceutical testing requirements. “The Steritest Symbio pumps are the newest addition to our comprehensive portfolio of innovative and reliable sterility testing products”, notes John Sweeney, Head of Lab Solutions, Merck Millipore. “Sterility testing is a critical aspect of pharmaceutical production and necessary for the release of sterile products to market. To help our customers through this process, we continue to leverage our strong legacy and expertise in sterility testing to offer cutting-edge solutions for pharmaceutical professionals.” The compact housing design of the Steritest Symbio pumps should allow easier access in laminar flow hoods and enables compatibility with vertical and horizontal air flows. The new design also frees working space and increases loading capacity in isolators, improving workflows and efficiency.

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New addition: The Steritest Symbio pumps are the newest addition to Merck Millipore’s portfolio of sterility testing products

PACK EXPO & PHARMA PACK

Leader of the Pack This year Pack Expo will take place in Chicago from 2-5 November. It will be co-located with new show, Pharma Expo

he last Pack Expo in Las Vegas hit new records for its organiser, the PMMI. This year’s event takes place on 2-5 November at Chicago’s McCormick Place.

Making a mark

Qualicaps will use Pack Expo to debut its LIS-250 laser imprinting machine in the USA. The system imprints on tablets, softgels and capsules at speeds of up to 250,000 per hour. As a method, laser imprinting is often preferable because of defects caused by ink. It can offer a flexible range printing options, as well as a larger printable surface than ink printing. Other benefits include the potential to help with counterfeiting, and the ability to print on tablets without causing thermal denaturation.

“Packaging and processing solutions providers know that Pack Expo is the show their customers attend, and our space sales to date prove it,” said Jim Pittas, vice president, trade shows, PMMI. PackExpo and Pharma Expo are expected to attract more than 50,000 attendees, including 5,000 international visitors from 130 countries.

Qualicaps, Stand W-895

Focus on pharmaceuticals As pharmaceutical manufacturers aim to combat counterfeiters and speed time to market, new package printing technologies are making it easier for them to overcome these hurdles without sacrificing the bottom line. Pharma Expo will serve as a resource for the latest innovations in marking, coding and package printing. The show, a joint venture of PMMI and the International Society for Pharmaceutical Engineering (ISPE), will help pharmaceutical manufacturers discover the solutions they need to significantly raise printing speeds, increase efficiency, decrease downtime and reduce operating costs. On show will be laser marking systems that allow pharmaceutical manufacturers to produce high quality marks on moderate-to high-speed production lines. Such technologies have virtually no font, code or graphic restrictions and are ideal for marking complex codes — offering complete marking flexibility and delivering many spot size variations to cater to a broad range of marking effects. With changing regulations and the prevalence of short batch label runs creating challenges for manufacturers in the pharmaceutical, chemical and industrial sectors, Pharma Expo will feature new labelling solutions that grant manufacturers the flexibility to scale up to production demands. Designed to deliver greater efficiency, productivity and cost savings for a higher volume of industrial and manufacturing applications, these technologies can dramatically elevate printing speed — enabling efficient and reliable production of high mix label requirements and variable printing demands. It’s a first: Qualicaps will use Pack Expo to debut its LIS-250 laser imprinting machine in the USA

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Doubling up The IMA booths at both Pack Expo and Pharma Expo 2014 will offer a cha nce to discover what the company has for the pha rmaceutical sector. The GIMA 590 capsule fi lling machine machine has been designed for low production volumes. It has the same technical solutions as the GIMA 595 and can handle both inje cted and thermoformed capsules of different dim ensions. Also on show will be an automatic tube filler, suitable for handling alu minium, polyethylene and laminate tubes. The C970 is an automatic tube filler marked by stu rdy stainless steel frame, 9-station turntable with dire ct drive and diving

nozzle with positive shu t-off valve. Innovative fea tures include a dosing pump that can be dismounted without tools, a quick and ergonomic changeover from aluminium to plastic tub es (and vice versa) and a smart HMI. It is also available for special applications (eg handling shapes such as unidosis and cannulas. IMA will also be exhibiting the Spine automatic inspection and sorting sys tem for tablets and capsul es. The machine has an erg onomic design and inspec ts the entire surface of tab lets and capsules - ie siz e, shape, cracks, colour dev iations etc. Memmert GmbH + Co. KG, Hall 1, Stand A77

IMA, Stand S-1721 W -890

Take the tube: On sho w will be an automatic tube filler, suitable for polyethylene and lamina handling aluminium te tube

Inspector gadget Seidenader will debut its new CS-60 high-speed inspection machine, which can be equipped with up to seven camera stations for the inspection of liquid or lyophilised parenterals.

AIM high

The machine can detect very small leaks, thanks to an HVLD SLIM module. This module can be retrofitted at a later time using a straightforward plug-and-play setup. Further modular options are available, says Seidenader. Ampules, cartridges and vials of up to 100 ml can be inspected for particles in the product and defects in the containers, with the machine reaching speeds of up to 36,000 containers per hour

neration of fully is the first of the new ge Take AIM: This machine pect up to 600 vials chines designed to ins automated inspection ma per minute, says Bosch hnology, a supplier , Bosch Packaging Tec At Pharma Expo 2014 ls a vial inspection ea rev ging technology, of process and packa is the first of the 8 series. This machine machine of the new AIM chines designed ma ated inspection tom au y full of ion rat ne new ge ct and cosmetic ls per minute for produ via 0 60 to up ct pe ins to id pharmaceuticals as particles inside liqu container defects, such series’ main module on the container. The or scratches and spots bbles in the liquid or bu e in table to reduc -sp pre a h wit d pe uip is eq tem ensures quick ns. A puck transport sys homogenize suspensio r handling. over and safe containe and easy size change

Seidenader, Stand W683

Bosch Stand W-603

Triple whammy Weiler Engineering’s focus is to provide advanced aseptic liquid processing technology, available through the application of customised Asep-Tech blow-fill-seal machinery and integrated services. Weiler’s Asep-Tech Systems are designed and built in a 140,000 ft² manufacturing plant, in Chicago. Asep-Tech blow-fill-seal machines from Weiler incorporate the three-step process of blow moulding, aseptic filling, and hermetic sealing of liquid products in one sequential operation on a compact machine frame. These machines have the flexibility to produce sterile, liquid filled, tamper-evident containers from 0.5ml up to 1000ml, in small runs or full-scale production.

Stand W-628

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IMAGE ANALYSIS

Detective work

Exploring the impact of agglomeration on particle morphology Agglomeration typically involves the adhesion or cohesion of small primary particles to form larger entities known as agglomerates. However, size alone is not always a reliable distinguishing feature. Relatively large primary particles may also be an intentional or inadvertent product of the manufacturing process. Often agglomerates are either less regularly shaped than primary particles and/or have a more convoluted perimeter. Combining both particle size and particle shape data can therefore be helpful when assessing agglomerates and differentiating them from primary particles.

Dr Deborah Huck-Jones, Malvern Instruments discusses using automated image analysis for the detection of agglomerates in pharmaceutical manufacturing

n pharmaceutical manufacturing, the agglomeration of particles has the potential to be either beneficial or detrimental depending on the process and the product. The larger particles that result from agglomeration may, for example, exhibit improved flowability and packing characteristics, making handling easier and more efficient. Conversely, their impact on the important in vivo characteristics of the product, such as dissolution rate, bioavailability and overall efficacy, means that uncontrolled agglomeration has implications for product performance and safety. Deploying robust analytical methods for agglomerate detection is therefore critical to optimising manufacturing processes and ensuring effective quality control (QC).

Automated image analysis systems provide data on a range of particle parameters. Their advanced optics capture and record images of thousands of individual particles within a wet suspended or powder dispersion in a matter of minutes. Sophisticated software then builds particle size and shape distributions using the particle dimensions determined from these individual images. Parameters that are especially useful in agglomerate detection include:

Optical techniques for particle characterisation have much to offer in this regard and are effective in generating the morphological data that allow reliable discrimination and characterisation of agglomerate species. Microscopy is one of the techniques recommended by the pharmacopoeias for characterizing both oral solid dosage formulations and those for inhaled delivery [1]. Conventional manual microscopy techniques do, however, have some drawbacks, being both laborintensive and prone to operator subjectivity. Such challenges are overcome in today’s image analysis systems, which offer fully automated particle characterisation and deliver statistically significant morphological data in minutes. Here Dr Deborah Huck-Jones, Product Manager for Analytical Imaging at Malvern Instruments, presents efficient strategies for the use of automated image analysis to detect agglomerates. EPM 28 29 EPM 28

• Circular Equivalent Diameter (CED) – the diameter of a circle with the same area as an imaged particle.

• Convexity – a shape parameter that relates to the surface roughness of a particle. Convexity is calculated by dividing the convex hull perimeter of a particle (explained as the length of an elastic band put around the particle) by its actual perimeter producing values in the range 0 to 1. A smooth shape has convexity close to 1 while a spiky or irregular object has convexity much closer to 0 (see Figure 1). • Circularity – a shape parameter that quantifies how circular a particle’s cross-section is. It is calculated by dividing the perimeter of a circle with the same area as the particle by the perimeter of the actual particle. Again, values range from 0 to 1. Circular particles have a value of close to 1 while less regular, non-circular particles have much lower values. By employing morphological features that are determined using these and other size and shape characteristics, image analysis can easily classify, group, identify and quantify particle populations. This capability supports highly efficient agglomerate detection.

Detecting agglomerates on the basis of particle size and circularity Combining particle size and circularity data is often a successful way of distinguishing large primary particles, which tend to have high circularity, from agglomerates. Agglomerates are usually less regularly shaped and therefore have lower circularity.

Figure 1: Example particles showing how circularity and convexity can be used to identify different particle types. These parameters can aid in detecting different agglomerate forms.

Figure 4: The Raman spectrum for a particle collected from a pharmaceutical blend (black) shares chemical features with API 1 (red) and API 2 (blue) indicating it is a multi-component agglomerate.

Figure 2a and 2b: Plotting particle CED against circularity reveals large particles with low circularity (Figure 2a, left). Viewing images of these particles confirms they are agglomerates (Figure 2b, right).

Figure 2a shows automated imaging data (Sysmex FPIA-3000, Malvern Instruments) for a sample thought to contain agglomerates. The results are presented in the form of a scattergram, a plot of CED against circularity. The depth of color within the scattergram denotes particle concentration within each region of the plot. The results show that most particles in the sample are small and circular. However, there is also a population of relatively large particles with low circularity. Visual examination of the images of the larger, less regularly shaped particles that constitute this population confirms that they are agglomerates (Figure 2b). The example described above illustrates the value of circularity measurements in agglomerate detection. However, the most effective shape parameter will depend on the nature of the agglomerate. In certain systems, particularly in suspensions or emulsions where adhesive forces are very low, string- or fractal-like agglomerates may form. Here convexity rather than circularity measurements may be the most appropriate. In another study (data not shown), fractal agglomerates were robustly identified as particles with a CED of greater than 5 µm and convexity of less than 0.993.

in a single sample. Some of the primary particles are small and circular but issues in a manufacturing process have also resulted in misshapen primary particles that are out-ofspecification. At the same time, fractal-like agglomerates have also formed. In this case measuring both convexity and circularity, alongside size, enables secure identification of each of type of particle present, as set out in Figure 3.

Fig 3a

Fig 3b

Detecting agglomerates in systems with irregularly-shaped primary particles In the preceding example, primary particles in the system studied were highly regular, making it easier to identify agglomerates using just a single shape parameter. Primary particles are often relatively circular, but not always. Many systems have irregularly shaped primary particles and here classification on the basis of size and a single shape factor may be insufficient for robust detection of agglomerates. Figure 3 shows images of three different types of particle present

Fig 3c

Figure 3: Particles in a sample containing small regular primary particles, larger misshapen primary particles and agglomerates can be successfully differentiated using circularity and convexity data.

Where primary particles occur in a variety of shapes and sizes it may not be feasible to identify agglomerates even using multiple size and shape parameters. Such systems are most usually associated with a relatively broad size specification or, more commonly, a blend with multiple components. In these situations visual scrutiny of the images can be helpful in picking out the particles that are agglomerates. Sorting particles on the basis of size, and perhaps a single shape parameter, can help to make this visual identification more efficient. This is easily done using the sophisticated software that is an integral feature of modern imaging systems.

measured using MDRS (Morphologi G3-ID, Malvern Instruments). The particle was selected for Raman analysis because it had a particle size and shape suggestive of an agglomerate. A comparison with the library spectra for two pure active pharmaceutical ingredients (APIs) known to be present in the sample, API 1 (red) and API 2 (blue), indicates that the particle has spectral features relating to both APIs. This confirms it to be a multicomponent agglomerate (MCA).

Using automated image analysis in combination with Raman spectroscopy to elucidate agglomeration behavior An alternative approach to visual identification is to differentiate morphologically similar agglomerates through the combined application of image analysis and a chemical identification technique. Morphologically Directed Raman Spectroscopy (MDRS) is a technique based on the complementary application of automated imaging and Raman spectroscopy. It can be used to determine the composition of an agglomerate and discover whether it is composed of one type of particle or of different particles – an active and an excipient for example. Such information provides insight into the provenance of an agglomerate and the mechanisms associated with its formation.

In conclusion

Figure 4 shows the Raman spectrum (black) of a particle within a sample of pharmaceutical formulation

References United States Pharmacopoeia General Chapter <776>

The chemical information offered by MDRS can be used to classify particles within the formulation as each API only or as MCA agglomerates.

Controlling agglomeration is essential in order to achieve clinical efficacy targets and at the same time to optimize manufacturing efficiency. Automated image analysis measures morphological parameters that can be used to robustly identify and quantify agglomerates in a sample. The complementary application of Raman spectroscopy (MDRS) allows the chemical identification of chemically different components within an agglomerate, providing detailed insight into its origin and the mechanisms of formation. Together these techniques support reliable agglomerate detection and deliver information that helps in understanding agglomeration processes, which is essential for successful pharmaceutical manufacture. [1]

Table 1: Circularity and Convexity values selected for identification of agglomerates. Particle Type

Classiﬁcation

Primary Particle

Circularity > 0.96

Misshapen Primary Particle

Circularity ≥ 0.896 < 0.96

Agglomerate

Circularity < 0.896 Convexity < 0.873

EPM 29

Example Particle

FREEZE DRYING The Lyostat drying microscope from Biopharma Technology. Freeze drying microscopy carried out by an expert is the best way to determine the collapse temperature of a product

Quality counts How close are you to the edge? Katriona Scoffin discusses ways of building quality into your lyophilisation cycle

uality by design for lyophilisation is about building a robust process that proactively flags critical points and ensures delivery of the best quality product.

Freeze drying, or lyophilisation, is a common preservation method for pharmaceuticals. Because it removes solvent by sublimation under reduced pressure it avoids the high temperatures required by some drying methods that could cause product damage. Lyophilisation involves three main stages: freezing, primary drying and secondary drying. Each stage involves varying levels of temperature, pressure and time (Figure 1). These variables all affect the efficiency of the drying process and the quality of the dried product. A well dried product will have predictable behaviour throughout storage and reconstitution and, most importantly, the reconstituted product will have a consistent bio-efficacy.

Fig 1

The QbD family for freeze drying The critical quality attributes (CQAs) for freeze dried pharmaceuticals include: the appearance of the final product; the residual moisture left in the dried product; the behaviour under reconstitution; the preservation of biological activity; the stability of the dried product; and the sterility of the dried product. Each of these CQAs can be assigned a quality target product profile (QTPP), and linked to variables that affect the quality of the process. The following table outlines key CQAs, QTPPs and some of the controllable variables that can mitigate the risk of a poor quality outcome.

Critical Quality Attribute

Quality Target Product ProďŹ les

Risk mitigating controllable variables

Appearance

Type of Cake Uniformity Shrinkage Cohesiveness

Choice of excipients

Residual moisture

% moisture by Karl Fisher analysis

Primary and secondary drying conditions, type of structure, freezing rate, thermal profile, containment Choice of excipient

Reconstitution

Porosity Pre connectivity Crusting Crystallinity / amorphous structure

Excipient choice Glass transition testing Use of annealing to control crystal size

Preservation of activity

Customer assay and tolerance

Secondary drying temperature (for temperature sensitive products) Choice of excipient

Dried product stability

Stability length Storage conditions Sales stock cycles

Moisture content Tg (glass transition in dried state) Choice of excipient

Sterility

How the product will be transported and used Stress / strain resistance Product application

Production conditions Component controls

Figure 1: Each stage of the lyophilisation cycle involves varying levels of temperature, pressure and time, all of which affect the robustness of the cycle and the quality of the dried product.

The advantages of QbD for lyophilisation Quality by design (QbD) for lyophilisation is about building a robust process that proactively flags critical points and ensures delivery of the best quality product. QbD is important for regulatory compliance. The FDA and the MHRA both require details of the lyophilisation cycle for product registration. A well designed cycle also has economic benefits since the best quality cycles are the most efficient in terms of energy usage and in time. The difference of a few degrees in temperature during drying can result in a loss or gain of hours of manufacturing time.

EPM 30 31 EPM 30

Risk mitigation: Select your excipients with drying in mind

Risk mitigation: Establish the critical temperatures

The choice and balance of excipients in a formulation has a significant bearing on its freeze drying process parameters. Various additives offer protection for different processing stresses, and formulation development aims to create a balance that results in the best possible final product. However, the exact constitution of a formulation is what defines the subsequent process parameters and for this reason formulation and cycle development should ideally be conducted together.

Scientific methods of determining the critical temperatures of a formulation make it possible to design a high quality cycle. The key technologies are freeze drying microscopy (FDM), differential thermal analysis (DTA) and impedance analysis. FDM involves the visual examination of the behaviour of a small sample of the product as it freezes. An expert operator can pinpoint the temperature of the critical events. FDM is used to determine the eutectic melt temperature and the collapse temperature.

Risk mitigation: Know your equipment

DTA allows the determination of significant endothermic and exothermic changes such as crystallisation, eutectic melt, and glass transition events. Impedance analysis detects changes in molecular mobility that thermal techniques may not pick up. This allows determination of events such as glass transition in more complex amorphous products, or changes in the frozen material that do not have an associated exothermic or endothermic signature.

The efficiency of your freeze drier can be maximised by following the manufacturerâ&#x20AC;&#x2122;s specifications when setting up shelf spacing, choosing vial fill depth and deciding on the product load. Equipment limitations can be determined by carrying out ice slab tests. These can be used to determine the trapping rate and the choke flow of your machine, in other words, the maximum rate of vapour that can be efficiently extracted. Another point to consider is the temperature gradient through the drier. Temperature may vary by height or across a shelf. Shelf mapping will locate any pockets of difference that may impact drying.

Building a design space A design space is a multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of product quality. A successful and detailed study into all the product and process variables makes it possible to establish a design space that provides repeatable, consistent and provable results. Figure 2 shows the process of building a lyophilisation design space.

Fig 2

Figure 2: The process of determining a safe design space for lyophilisation.

EPM 31 EPM 31

LAB INNOVATIONS

Fab lab Those working in the pharmaceutical industry will have plenty to see when Lab Innovations, the show dedicated to the latest laboratory technology and consumables, analytics and biotech equipment, returns to the Birmingham NEC on 5 and 6 November 2014

ig name exhibitors and smaller inventive suppliers will have a presence at the exhibition, with many taking the chance to launch new products to the UK market.

Chorus line Veolia will be showing its Purelab Chorus range of laboratory water purifiers. With specific technologies to remove impurities such as RNase, DNase and bacteria, as well as trace ions such as silica and boron to below detectable limits, Purelab Chorus can be customised to deliver water purity from Type III for general laboratory use to Type I or I+ for applications such as ICP-MS, ultra trace analysis and molecular biology techniques.

To the max Retsch is launching its Emax to the UK market - a new type of ball mill for high energy milling. The combination of high friction and impact results in extremely fine particles and thanks to a cooling system with water, the high energy input is effectively used for the grinding process without overheating the sample.

Select offering Purite which will be showcasing its Select Lab range that provides water purity to 18.2 MΩ.cm at rates of up to 48 l/hr. Purite will also be promoting its Swap Out scheme, offering replacement units of any brand to customers that take out a Purite service package.

It’s a gas JSB will be showcasing its multidimensional gas chromatography system, the GCXGC QTOF, which makes it possible to unravel complex matrices. It allows quantitative and qualitative data to be obtained, simplifies quantification and makes molecular characterisation of a complex matrix possible.

Safety first The Anton Paar stand will feature its compact MCP 100 benchtop polarimeter, offering convenience, safety and traceability as well as complying with all of the national and international pharmacopoeias. Its Peltier temperature control constantly ensures accurate sample temperature, which is wirelessly transferred to the instrument.

Analyse this Ash Scientific will be displaying its analytical instruments for chemical and biological detection and identification. The ranges will include its High Performance Ion Mobility Spectrometry (HPIMS) from Excellims Corporation, which offers simultaneous detection and separation so that molecular identification can be carried out in real time in solid, liquid or gas.

In control The Vacuu Control web-based remote control system will be featured on the Vacuubrand stand. This enables the monitoring and

control of vacuum pumping units via computers or mobile devices. Merck will be exhibiting its EZ-Fit filtration unit - a ready-touse, disposable filtration device for bioburden testing. Merck claims the system is faster and more efficient than traditional methods, resulting in increased reliability and streamlined workflows. Other highlights of the event include the Royal Society of Chemistry which will be hosting a full conference programme and Robin Ince, presenter on BBC Radio 4’s The Infinite Monkey Cage, will deliver his day one keynote address on Curiosity Kills No Cats! Quentin Cooper, presenter of Material World, will be headlining day two of the conference and will deliver his keynote address on the image of scientists. The conference will also feature Sustainable Labs, with a topical case study on the first carbon neutral lab in the UK, The Centre of Sustainability at the University of Nottingham, funded by GlaxoSmithKline. This unique centre acts as a hub to catalyse new collaborations within the industry, aiming for the highest ‘clean & green’ standards in a bid to minimise the impact on the environment and ensure new discoveries are sustainable.

EPM 32 33 EPM 32

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EPM 33

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CHEMICAL REACTION It’s important to keep on top of the latest services, companies and individuals. EPM’s Chemical Reaction highlights a technology, service or business we think would be worth keeping an eye on...

Cleaning up Jim Hardisty, managing director of Goplasticpallets.com, believes that the key to improving hygiene standards in the pharmaceutical sector is introducing plastic pallets and pallet boxes right at the start of the supply chain

EPM: Who are you and what do you do? JH: Goplasticpallets.com was set up in 2001 to facilitate the supply of plastic pallets and boxes to businesses in the UK. Thirteen years on, we’ve signed exclusive partnerships with a number of pallet and box manufacturers across Europe and today offer the most comprehensive range of 155 plastic pallets and 115 plastic containers, crates and trays available in the UK. Our dedicated sales team has more than 100 years’ combined experience in plastics, which is invaluable in giving our customers the best product advice and helping us continually meet and exceed our sales targets. EPM: What have you focussed on recently? JH: We’ve recently expanded our warehouse which has doubled the volume of products we hold in stock – currently 57,233 items – and means that we can fulfil approximately 90% of orders directly from stock and deliver many of them next day within the UK. Researching new pallet models and plastic technology and constantly updating our range is an ongoing focus. For instance, we introduced our first hygienic pallet to our range more than 10 years ago and since then we have been working closely with IPS (now CABKA-IPS) – for whom we’re sole distributor in the UK – to enhance the pallet to achieve optimum hygiene standards. Although other manufacturers have imitated our IPS Hygienic pallet, none have equalled its quality. EPM: What is you latest service/ innovation? JH: Our GoBox Hygienic pallet box was recently added to our range to help improve hygiene right at the start of the pharmaceutical supply chain. Made up from three plastic

components – a hygienic pallet base, a fully sealed 5mm sleeve centre, and a secure fitting lid – it’s ideal for transporting packaging components from the supplier to the production facility (bottle tops, foil trays, rubber closures, aluminium caps plastic bags etc). Exceptional environmental credentials also make our GoBox Hygienic an attractive proposition. Firstly, it removes the need for packaging components to be prepackaged, wrapped or bagged for transportation – removing up to five layers of additional packaging. Secondly, it folds flat when empty so it can be stacked 10-high in collapsed mode, saving space and fuel on return journey transportation back to the supplier for repeated use. In addition, all three components are recyclable, so at the end of their long working life the plastic can be reground to produce other plastic products.

CMY

My advice to drug companies is simple – put hygiene first and go plastic. I don’t just mean using plastic pallets in clean room environments, where the tiniest traces of dust and dirt on wooden pallets can contaminate medication. I mean by introducing plastic pallets right at the start of the supply chain. Jim Hardisty, Goplasticpallets.com

EPM: How can you beneﬁt the pharmaceutical sector? JH: A large number of pharmaceutical companies still use wooden pallets. However, in the last four years, a series of incidents where drug manufacturers were forced to recall products as a result of contamination issues – thought to have been caused by the timber pallets they were transported on – has put a big question mark over the safety of using wooden pallets in the pharmaceutical supply chain. My advice to drug companies is simple – put hygiene first and go plastic. I don’t just mean using plastic pallets in clean room environments, where the tiniest traces of dust and dirt on wooden pallets can contaminate medication. I mean by introducing plastic pallets right at the start of the supply chain. Pharmaceutical manufacturers take great care packaging products to ensure product safety and avoid external influence. However, it

Q & A

appears that less importance is given to choosing the type of pallets the products are distributed on. The Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03) provide only vague advice on the topic of delivering medicinal products to wholesalers. Under the heading ‘Deliveries to customer’, section 20 states: “Medicinal products should be transported in such a way that: they do not contaminate, and are not contaminated by, other products or materials.”

EPM 34

Product contamination issues could be prevented by offering manufacturers clearer guidance on the selection of pallets for transporting packaging components and medicines. EPM: Future plans? JH: We’ll continue working closely with plastic pallet and box manufacturers to further expand our range, as well as seeking new ways to educate pallet users about the advantages of plastic, especially the hygiene and environmental benefits.

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The Indian pharmaceutical market is currently valued at US$ 12.20 billion. Registering an accelerated 15-20% annual growth, the total Indian Pharma market is expected to reach a value of US$ 55bn by 2020.

CMY

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