IAHJ - Volume 2 Issue 2

Volume 2 Issue 2

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PEER REVIEWED

Volume 2 Issue 2

Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

Exploring Human and Animal Microbiota inHealth and Disease

The Tipping Point inCompanion Vector-Borne Diseases

Extrusion Cooking of Aquatic FeedsThe Path Forward

Overview of the Dutch Veterinary Medicines SectorOne Health Approach?

Official Supporting Association - Sponsor Companies -

Volume 2 Issue 2II International Animal Health Journal

Chapter Title

Full Research and DevelopmentService including: Formulation Development Analytical Development Clinical Studies Regulatory Consulting

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International Animal Health Journal 1www.animalhealthmedia.com

Contents

06 FOREWORD

WATCH PAGES

08 The Future of Innovation in Animal Health Innovation is at the heart of growth for any industry, as it is for any company. However, most business leaders’ focus is on achieving financial targets for the short term. This makes committing internal resources for tomorrow a bargain that many are not fully comfortable with, and they then try to rationalise this decision by claiming that innovation can’t be planned and is best realised as a spontaneous occurrence. In this article, Dan Peizer at Catalent proves this argument is misguided.

10 Blowfly Strike – Appropriate Steps for Prevention and Treatment

Warmer days during spring and summer are not necessarily such a joyous observation. As the temperature increases, perfect conditions for blowflies are created. The ectoparasite well known by sheep-farmers affects the vast majority of herds. Rachel Mallet from Bimeda presents the blowflies’ lifecycle and how they infect sheep, and lists prevention methods to avoid mass infection.

12 Animal Welfare: The Business Case for CompassionThe importance of animal welfare in pharmaceutical development is very significant nowadays. Contract research organisations set a ‘high bar’ for animal welfare due to the potential for public scrutiny. Jonathan Hare from Kingfisher discusses those issues, also mentioning the role of an active and engaged animal care committee.

14 European Animal Health Industry Calls for Performant New Set of Rules to Improve Availability of Veterinary Medicines Across Europe and Encourage Innovation in Animal Disease Prevention and Control

Roxane Feller from IFAH summarises the current situation of veterinary medicines across Europe. Supported by relevant data, she compares the human and veterinary medicine sectors, describes the legal flaws, and gives some resolutions which could help improving today’s system.

REGULATORY & MARKETPLACE

16 Animal Health Market Forecasting in an Increasingly Complex, Competitive and Interconnected World

Consumer incomes in emerging and developing countries are growing at a faster rate than in advanced countries. Consequently, animal health markets are evolving faster than animal health companies can respond, leading to unmet needs and missed opportunities. Tim Evans, the managing director of Vetnosis, claims this new situation demands a more predictive, longer-term approach to strategic planning and forecasting than has traditionally been used.

20 Total Cost of Ownership – Calculations in the Light of Changing Overall Conditions

A comprehensive TCO analysis, in particular of the cost drivers, makes a lot of sense in the context of an investment decision. With an eye to the future, however, an attempt should be made to anticipate future requirements.

MANAGING DIRECTOR Martin Wright

PUBLISHERMark A. Barker

PROJECT DIRECTORClive Baigent, PhDEmail: [email protected]

EDITOR Orsolya Balogh

EDITORIAL MANAGEROlga HenschkeEmail: [email protected]

DESIGNER Fiona Cleland

BUSINESS DEVELOPMENTRobert HarrisEmai: [email protected]

ADMINISTRATOR Barbara Lasco

FRONT COVER © istockphoto

PUBLISHED BY Pharma PublicationsUnit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DGTel: +44 0207 237 2036Fax: +0014802475316Email: [email protected]

International Animal Health Journal – ISSN 1758-5678 is published quarterly by PHARMAPUBS.

The opinions and views expressed by the authors in thisJournal are not necessarily those of the Editor, Publisher or the Supporting Organisations which appear on the front cover. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright.Volume 2 Issue 2 May 2015PHARMA PUBLICATIONS


Volume 2 Issue 22 International Animal Health Journal

Contents

Christoph Hammer, of Dividella AG, discusses why flexible packaging and modular machine design help to ensure the necessary margin for manoeuvre for the future. Production sites which respond appropriately are better prepared for changes; they can hedge their investments and are more competitive in the long term.

24 Could Our Main Challenge with Emerging Diseases Be the Way We Look at Them? Or, Maybe Even the Way We Don’t Look at Them?

The history of agriculture includes many developments related to animal and plant health that have had a major impact on humans. At the same time, human activities have often driven the appearance of emerging issues. The overlapping drivers of human, animal and plant diseases and environmental changes point towards the concept of ”One Health”. Frank Berthe from EFSA offers a different perspective on the constant problem of emerging diseases.

28 Towards Sustainable Feed & Food – Working Together at International Level

In 2015, compound feed production will likely reach close to 1 billion tonnes worldwide, and the FAO estimates that by 2050 the demand for food will grow by 60%. This poses significant opportunities and challenges for the entire agri-food chain. Alexandra Althayde from IFIF believes that only by working together at international level and focusing on innovation and capacity-building can our sector provide sustainable, safe, nutritious and affordable food for a growing world population.

RESEARCH & DEVELOPMENT

32 Accurate Early Markers of Renal Damage for Veterinary and Research Use

The assessment of renal function in small animals is of interest both to veterinary practitioners and research organisations, especially those investigating the possible effects of drugs developed for humans or companion animals, which might be destructive for kidneys. For veterinarians, one primary concern is the early diagnosis of chronic kidney disease (CKD), defined as primary renal disease present for an extended period of time. Sam Williams and Ludovic Pelligand from Delta Dot study this casus, presenting clinical trials data and the importance of the earliest-possible identification.

36 Keeping Your Farm Water Safe and FreshWater quality is a major issue for all species – animals and plants can go for several days without food, but cannot last long without access to water. This makes water the number one nutrient in all diets – although it is frequently neglected and taken for granted. As such, the quality and safety of water is essential in maintaining animal health. Lucy Waldron of LWT Animal Nutrition Ltd discusses why using an effective disinfectant and water sanitiser on farm or with various animal enterprises is important in maintaining animal health, productivity and welfare.

40 Exploring Human and Animal Microbiota in Health and Disease

A growing body of evidence shows that our microbial population plays a role in health and disease. As sequencing methods are rapidly developing and improving, it is essential to have state-of-the-art bioinformatic platforms and expert knowledge that allow for comprehensive

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Contents

visualisation and biological interpretation of the massive datasets. Future studies focusing on microbiota interaction with the host, and effect on animal host physiology, leave room for exploration and new discoveries within this dynamic field of research. Dr Sabina Lukovac from NIZO shows how it will help to identify novel biomarkers and aid in development of new therapeutic strategies.

44 World-leading Research and Surveillance at The Pirbright Institute

The Pirbright Institute is a world-leading centre of excellence in research and surveillance of viral diseases of farm animals and viruses that spread from animals to humans. This article summarises the research taking place at the Institute, which is based upon a combination of fundamental and applied bioscience and which utilises unique biological and physical resources. Dr Emma Fishbourne details some of the virus diseases we are currently working on, including diagnosis, host-pathogen interaction and vaccine development, and highlights the impact of our science across the globe on animal and human health.

CLINICAL STUDIES

50 The Tipping Point in Companion Vector-Borne Diseases

Within the past year, organisations such as the World Health Organization and the Bill & Melinda Gates Foundation (in partnership with the International Federation on Animal Health--IFAH) have chosen to recognise vector-borne diseases as a leading global public health topic. As key takeaways, we’ve learned that vector-borne diseases are gaining scope in awareness, comprise a class of diseases which are entirely preventable to both animals and humans, and affect over one billion people globally. Here, Prof. Norbert Mencke and Dominick Kennerson from Bayer Animal Health provide a framework on recent “companion vector-borne diseases” (CVBD®) activities that may provide some insight into the CVBD landscape for the next several years.

54 The Role of Feed Enzymes in Poultry Gut HealthFirst introduced into the poultry industry in the 1980s, enzymes are now used in over 90% of all broiler diets. Feed enzyme application in diets for poultry is also one of the most researched fields in poultry science today, with over 2500 independent enzyme trials conducted with broilers alone. Much of this research has been focussed on phytase and its mode of action. The penetration of carbohydrase and protease enzymes into poultry feed has been slower, particularly in markets that rely less on ‘viscous’ wheat- and barley-based diets. Luis Romero from Dupont compares and analyses several enzymes and the effects they have on poultry population, and as a result – more efficient production.

60 The Influence of MOS on Sow and Piglet PerformanceMannanoligosaccharides (MOS) are complex carbohydrates derived from the cell wall of selected strains of the yeast Saccharomyces cerevisiae. All of the effects MOS has on the performance of animals result in improved performance, and the scientific literature has shown that both growth rate and feed efficiency have been improved when MOS

product was provided in the diets of piglets post-weaning and during the growing-finishing period. Dr Jules Taylor Pickard from Alltech reviews all available sow studies for the response to MOS product and suggests possible modes of action for any positive response obtained.

TECHNOLOGY

66 Comparison of Antibodies Detection Time with Rapid Plate Agglutination (RPA) Test and with Enzyme-linked Immunosorbent Assay (ELISA) in Mycoplasma gallisepticum (MG) Infections

Published studies show different results concerning antibody detection time with RPA and ELISA. Caroline Pommellet from Biovac designed and conducted an experiment, in which nine 11-week-old chickens were challenged at day 0 by intranasal route with MG and bled for serology every two to three days, starting from the challenge day until day 25. Sera were tested with RPA and ELISA tests. Subsequently, she shares the results and draws conclusions.

MANUFACTURING & PACKAGING

70 Extrusion Cooking of Aquatic Feeds - The Path ForwardRaw materials and formulations have been the area of major changes in the aquatic feed sector. As shortages of fishmeal developed, the use of alternate protein sources greatly increased. This, coupled with growth in aquaculture, has strained even some vegetable protein sources. Availability might still be of no concern, but what about the ingredient quality? Joseph Kerns from Wenger describes the whole process of aquatic feed preparation.

76 Identifying the Best Delivery for Your Beloved PatientPackaging plays an increasingly important role in achieving optimal animal health outcomes. Experts estimate $51 billion dollars were spent on companion animals in the United States alone in 2011, with 25% of that spent on veterinary care (including medicines) and another 20% on over-the-counter medicines and supplies. Justin Schroeder from PCI discusses the important role of packaging in the whole process of taking care of your pet.

COUNTRY FOCUS

80 Overview of the Dutch (veterinary) Medicines Sector. One Health Approach?

In this Country Focus, Bjorn Eussen from FIDIN describes his (Dutch) point of view on the veterinary medicines market, also referring to the human medicines sector. He mentions different criteria, such as economic factors and legislative procedures. Finally, after comparing the human and veterinary medicine sectors to each other, he gathers all the elements into a ‘One Health’ conclusion.

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Discuss and make proposals on how to:• Promote market control• Improve market access• Promote mutual recognition and the formation of regional organisations • Showcase Africa regional harmonisation initiatives and local opportunities

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Foreword

Editorial Advisory Board

German Graff - Project Manager Business Development at Triveritas

Fereshteh Barei - Health Economist & Strategy Advisor, Founder of BioNowin Santé Avenue Association

Carel du Marchie Sarvaas - Executive Director, IFAH International Federation of Animal Health

Kimberly H. Chappell - Senior Research Scientist & Companion Animal Product DevelopmentElanco Animal Health

Dr. Sam Al-Murrani - Chief Executive Officer Babylon Bioconsulting & Managing Director at Bimini LLC

Sven Buckingham Buckingham QA Consultancy Ltd.

Dan Peizer - Director Animal Health at Catalent Pharma Solutions

Dawn HowardChief Executive of the National Office of Animal Health (NOAH).

Jean Szkotnicki President of the Canadian Animal Health Institute (CAHI)

Dr Kevin Woodward - Managing DirectorKNW Animal Health Consulting

There is a wealth of information in the articles in the May issue of the IAHJ, covering a wide variety of topics from parasitism to medicines availability, and from animal welfare to manufacturing. There is something in this issue for every reader, whatever his or her interests or background. Below, I just take a quick look behind some of the articles chosen, for no other reason than they are of interest to me. In fact all of the articles are of interest, but I have chosen specific topics because of the issues they raise.

Parasites are truly ubiquitous. They affect both plants and animals and they take many forms. Some parasites even have parasites themselves. They cause a vast range of diseases in humans, animals and plants and in addition to causing major health problems they can result in major economic damage, particularly when the animals and plants affected are those farmed by humans. For sheep farmers, blowfly strike is one of the most enduring problems. Blowfly strike or myiasis is a form of parasitic infestation where the body of a live animal is occupied by fly larvae, maggots which develop internally by feeding on its tissues and fluids. Many animals can be affected by myiasis, including humans, but the most commonly affected globally is the sheep, particularly where

the animals live in warm and wet conditions. The flies responsible lay their eggs in areas of the body heavily contaminated with urine and faeces. Once hatched, the larvae bite through the skin and burrow into subcutaneous tissue, leaving open sores. These then become susceptible to secondary infections including septicaemia. If untreated, the condition may be fatal. There are effective measures available to prevent this disease, and in this issue Rachel Mallet discusses the disease and the measures that can be taken to mitigate the huge economic losses that can and do occur, while also assuring the welfare of the animals.

Animal welfare is not just a focus for farm and companion animals. Animals are widely used in pharmaceutical development for both human and veterinary medicinal products. They may be used as models for disease or for surrogates in preclinical safety testing. In recent years, concerns have been raised by the public, by scientists and by animal rights activists over the welfare of animals used experimentally in human and veterinary medicine development, as well as in other areas such as crop protection, biocides and food additives. The modern approach to animal welfare in these settings is now formalised by the 3Rs approach – reduction, refinement and replacement – as part of strategies addressing the need to find alternatives to animal testing. This means replacement, where possible, of live animals with other experimental systems, reductions in the numbers of animals used, and refinement of existing approaches to minimise pain or discomfort while maximising information obtained. This has become an important area for regulators and in the European Union, the Committee for Medicinal Products for Human Use (CHMP) and the Committee for Medicinal Products for Veterinary Use (CVMP) now have access to the advice of the Joint Committee for Medicinal Products for Veterinary Use/Committee for Medicinal Products for Human Use Ad hoc Expert Group on the Application of the 3Rs in Regulatory Testing of Medicinal Products (JEG 3Rs). The JEG 3Rs can provide input in a variety of 3Rs areas, including the elimination of repetitious and unnecessary testing. Jonathan Hare discusses some of the key issues involved, and the measures that can be adopted to ensure this topic remains to the fore in a research environment.

So let us go back to animal diseases. Vector-borne diseases are another group of diseases that have health and economic consequences for animals and humans. Perhaps the best-known vector-borne disease is malaria, a parasitic protozoan (Plasmodium) disease where the vector is the Anopheles mosquito. In 2010, the WHO estimated that there were 219 million cases of malaria which led to 660,000 deaths. The economic and human welfare burden of this is enormous. Humans are not the only species affected by Plasmodium and Plasmodium is not the only vector-borne parasite – it is but one of many. For example, river blindness or onchocerciasis is spread in humans by the Simulium black fly. It is estimated that 17 to 25 million people are infected, with around 0.8 million having some loss of vision. In dogs and other mammals (but rarely humans), heartworm is another parasitic disease where the vector is a mosquito. In this disease, the worms may spread to the right heart and great vessels, resulting in cardiac insufficiency and ultimately congestive heart failure. Both diseases are treatable and one of the major drugs used in both diseases is ivermectin, a drug initially developed for use in veterinary medicine. Both diseases have one major ‘insult’ left for the unfortunate patients. In infected humans treated with ivermectin or other drugs, a reaction characterised by hypotension, fever, adenitis and pruritus occurs. This is the Mazzotti reaction; its intensity depends on a number of factors, including the intensity of the infection, and the release of factors from the dying parasites. A counterpart occurs in dogs treated for heartworm. Interestingly, the worms responsible for onchocerciasis and heartworm have an intracellular bacterium, Wohlbachia, and part of the reaction to treatment in both diseases may be mediated, in part, by its release from dying parasites. So, it is timely that Prof. Norbert Mencke and Dominick Kennerson examine some of the developments in vector-borne diseases in this issue of the Journal.

I hope that you too find these and the other articles in this edition interesting. Once again, I wish you happy reading.

Dr Kevin Woodward Managing Director at KNW Animal Health Consulting


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The Future of Innovation in Animal Health

Innovation is at the heart of growth for any industry, as it is for any company. Most business leaders are likely have it on their “top five” list of key growth initiatives, but don’t have a clear idea of what it looks like or how to achieve it. Their focus is on the “now”: achieving financial targets for the short term, making The Street, The Board, Head Office - all the various masters of key performance indices - happy with today. This makes committing internal resources for tomorrow a bargain that many are not fully comfortable with, and they then try to rationalise this decision by claiming that innovation can’t be planned and is best realised as a spontaneous occurrence. This argument is misguided. Innovation as a lucky accident cannot be considered a strategy for growth. Innovation can, and should, be planned and resourced to be properly fostered.

Consider the numerous game-changing innovations witnessed in animal health that have had substantial impact. Taking agrochemical pesticides and formulating them into safe, low-volume topical treatments for flea and tick control created blockbuster products that ostensibly moved dogs and cats from backyard to living room. Understanding that animals won’t voluntarily consume medication has seen the advent of soft-chews and other dose forms, bridging the space between treats and pills. More recently we have seen an air-gun converted to deliver doses of topical parasite control products to livestock – an ingenious innovation which not only minimises the labour involved in treating a herd, but reduces stress on the animals. All these innovations had the goal of making the treatment, or the prevention of diseases in animals, less labour-intensive and stressful, resulting in a positive impact on therapeutic outcomes for animals and the propensity for caregivers to stay compliant with therapy.

Animal health has long been a proving-ground for the expression “necessity is the mother of invention” and all manner of solutions for housing, transporting, feeding, grooming, and even entertaining animals have been devised, often through inefficient trial and error, resulting in an industry which today exceeds $100+ billion in global revenues. Innovation will continue to be a major growth driver for the animal health industry, particularly in segments such as veterinary medicine. Historically, however, the resources applied to research and innovation in animal health pale in comparison to human pharma. How, then, can animal health companies focus their innovation efforts to succeed in an ever more crowded and competitive market?

One path is to build an internal innovation function, with the purpose of establishing a creative environment and process, involving all critical business functions, which maps out the future for product development, with each function contributing their part in collaboration with the others. Marketing provides product trends and research to create a wish list of products with desired profiles, R&D assesses internal capabilities to achieve the target products, Legal ensures no patents are infringed upon and that new ideas

and products can be protected, Regulatory Affairs ensures products can be registered and claims can be supported, and so on. Ideally, innovation would be given the prioritisation and resources required to carry out the ambitious path outlined above, but the reality is many innovation roles tend to be staffed by one or two individuals provided with limited resources who become lone crusaders for the cause, working to cajole their colleagues in business functions to attend to innovation when all they want to do is focus on the day-to-day demands of the organisation. Obviously, this is not a path to achieving meaningful innovation, but there is hope. Enter the external development partner.

As small biotechs and virtual pharma organisations have emerged, and as larger pharma organisations have rationalised their internal development and supply networks, contract developers have emerged to serve the industry with an amazing array of technologies, expertise, and offerings. Eager to undertake the challenges of new product development, these developers are often able to provide innovation bandwidth to organisations looking to develop new products. Everything from molecule screening technologies, particle sizing, bioavailability enhancement, and a variety of new and interesting drug delivery technologies, are available through collaboration with external development partners, some of whom are even able to ultimately supply successfully developed products. Those focused on animal health understand how these technologies and offerings are best applied to products designed for animals, and can help achieve sometimes elusive target product profiles in ways that internally focused innovation processes may not.

One thing is for certain – innovation will continue to play a central role in the success of animal health products. Fortunately there are new resources for animal health companies to avail themselves of, and the future holds great promise for the emergence of exciting new products to benefit the health of animals and those that care for them.

Dan Peizer, Director, Global Sales & Marketing, Animal Health, Catalent Pharma Solutions, is an animal health business executive with over 17 years of experience which spans professional, retail, and business to business environments. Mr. Peizer is a graduate of Cornell University where he earned a degree in Animal Science. He has held positions in both sales and marketing throughout his career, which has included roles at Burns Veterinary

Supply (now Henry Schein), Bayer Animal Health, and his current role as the commercial head of the animal health business at Catalent Pharma Solutions.Email: [email protected]

Veterinary Contract Research OrganizationGLP Target Animal Safety ∙ Bioequivalence ∙ GCP Efficacy

Quality – Communication – Compassion www.kingfisherint.com – [email protected]


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Blowfly Strike – Appropriate Steps for Prevention & TreatmentAs spring quickly approaches the problem of blowfly strike once again looms. Many will be apprehensive following last year’s particularly warm summer which resulted in a severe fly challenge.

Blowflies are the most common ectoparasite of lambs and surveys suggest that every year 80% of farmers will encounter strike.

Blowfly strike is a devastating disease which impacts welfare as well as costing both time and money to counteract, so it’s important that we anticipate it and protect against it.

Once the soil temperature increases above 10oC and the air temperature is more than 17oC, the flies hatch from their pupae which survive in the soil over winter. This means the first wave of flies emerge around mid-April, although it could be earlier in a particularly mild year. One adult fly can lay up to 3000 eggs in its 28-day lifetime!

Blowfly strike occurs when the female fly is able to land on the sheep or lamb and lay eggs. The flies are attracted to moist, soiled fleeces and wounds. Once laid, the eggs secrete an odour which attracts other flies and rapidly exacerbates the problem.

These eggs quickly hatch into maggots and the maggots feed on the dead skin cells and secretions. As they feed, they ‘burrow’ deeper into the skin, creating wounds, which ‘kills the skin’, providing the maggots with more food and gradually creating bigger and bigger wounds.

If left to worsen, the wounds will increase in size, become infected and ooze. This will cause the sheep to enter a state of shock and perish. This further complicates the situation as an undetected carcass would be an excellent host for more larvae to develop and exponentially increases the number of flies in the area.

Animals Most Susceptible: • Sheep/lambs with faecal staining of the wool (parasite-

induced or dietary)• Sheep/lambs with open wounds (footrot or shearing

injuries)• Sheep/lambs with fleece rot.

TreatmentClipping of the affected area is vital to see how far the wounds extend, to clean, and to ensure that all debris which the maggots can feed on has been removed. Treatment with a licensed larvicidal product such as a cypermethrin pour-on is then required. The wounds may be serious and infected, causing the sheep to be systemically ill, in which case veterinary intervention is vital to ensure the best outcome.

PreventionPrevention is necessary to reduce the risk – good management and planning are vital, alongside preventative products, to minimise the risk of blowfly strike as far as possible.

1. Sheep, even after receiving preventative treatment, should be checked regularly and at least daily in periods of high risk where possible. The majority of strikes occur around the breech, where there is faecal or urine contamination of the fleece, with the remainder on the shoulders and the back.

2. Reduce the incidence of soiling by avoiding nutritional upsets which may cause scouring, and have a sound worm control strategy.

3. Dock lambs’ tails.

A UK study (by French et al in 1994) showed that the incidence of blowfly strike was approximately five times greater in undocked lambs. (Tail-docking must be carried out only in strict accordance with the following guidelines. It must be performed by a competent, trained operator and with the use of a rubber ring, or other device, to restrict the flow of blood to the tail. It is only permitted without an anaesthetic if the device is applied during the first week of life.)

4. Dispose of carcases quickly to avoid them acting as a source of blowflies.

5. Reduce the incidence of footrot.


Watch Pages

Footrot acts as a source of blowfly problems as well as causing serious welfare and production problems. Isolate and promptly treat any lame sheep. Consider zinc supplementation if lameness due to zinc deficiency is suspected and talk to your vet about vaccination in problem flocks.

6. Yearly shearing of ewes: Critical to prevention of strike in ewes.

7. Regular dagging of the fleece.It’s not enough for farmers to ensure that sheep are clean on application of the preventative product – farmers must ensure that lambs are kept clean in the weeks following treatment as faecal contamination will reduce the efficacy of all plunge and spray-on products.

8. Open wounds should be treated and monitored until resolved.

9. Pour-on/dip (e.g. cypermethrin pour-ons, dicyclanil pour-ons, organophosphate dips). Most farms now rely on pharmaceutical products to minimise the strike-affected sheep on their farm. It is important to note that products have to be correctly applied as per the pack instructions and that they have to be used in conjunction with the other management practices as outlined here.

Which Product is Best for my Flock? We all know there is a thin line between profit and loss when rearing lamb so it’s vital we make economical choices when selecting which products we use for protection. Pyrethroid pour-ons (high-cis cypermethrins) can give up to eight weeks’ blowfly protection. Insect growth regulators (IGRs) such as dicyclanil are suitable only for blowfly prevention and are not suitable for other ectoparasites or for blowfly treatment.

The withdrawal period and duration of action is very important as lambs may be going for sale in a matter of weeks and this will be a key factor in deciding what treatment is appropriate. Shorter-acting cypermethrins are much more cost-effective than longer-acting IGRs, and have the advantage of treating lice, ticks and blowfly strike in addition to prevention accompanied with a shorter withdrawal.

Rachel Mallet, BVM&S MRCVS, is a qualified veterinary surgeon, who now works as a Territory Manager for Bimeda, covering accounts in Scotland and the North of England. Rachel is passionate about animal health and about promoting best practice amongst farmers and animal owners.Email: [email protected]


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Animal Welfare: The Business Case for Compassion

As modern animal researchers, we all understand that the welfare of the animals we are privileged to work with has a direct impact on their physical and mental health. Likewise, ensuring animals are healthy and content means that the studies we perform are of the highest possible quality and involve the smallest number of subjects. Only the most egregiously backward scientist would fail to adopt this basic tenet.

But ensuring animal welfare in science, particularly in those studies that are destined for public scrutiny, is important for other, business-related reasons, as well.

Sponsors Demand Animal Welfare Many sponsors now conduct animal welfare audits prior to placing work externally. Their reasons for this are not entirely altruistic; publicly traded companies answer to their shareholders. How these companies conduct animal research is part of their commitment to social responsibility and they can be held to account by activist elements within their shareholders. On a more personal level, many of the sponsor representatives who place preclinical or animal health laboratory studies are veterinarians or animal researchers in their own right. They look for places that they are proud to work with.

As researchers, we believe our studies are conducted with the utmost attention to confidentiality and security. Nevertheless, we are only one social media posting away from a public relations nightmare and an awkward conversation with a sponsor representative who has been directed to pull their studies. Even legitimate research publications and regulatory freedom of information summaries can lay bare less than ideal research practices and poorly designed studies. So, like Caesar’s wife, we must comport ourselves with the utmost integrity. Maintaining strict standards for animal welfare is key to our ability to engage with the public, and defend the importance of our work while satisfying our sponsors that our animal care standards are exemplary.

We have to challenge ourselves to treat our animals in a manner that passes the “red face test”. In other words, if a lay person were to walk into the middle of a procedure, how would they react? Would they feel confident that the animals were being handled humanely and professionally by caring people, or would they be disquieted by what they saw? We need to make sure that the highest standards of animal care are applied in our studies. We need to ensure that veterinarians and veterinary technicians are performing procedures commensurate with their training and experience. Finally, we need to make certain that our equipment is modern and our drugs and materials are appropriate and well-selected.

A Strong and Engaged Institutional Animal Care and Use Committee (IACUC) is an Asset to Quality Research The business model of a contract research organisation (CRO) demands that study work be ongoing and that colony animals are used effectively. Empty cages and surplus animals quickly (and literally!) eat up the massive overhead that CROs carry. The management of a CRO is motivated to keep studies moving through the system with attention to the bottom line. At times, this can come into conflict with good science and animal welfare. The IACUC represents an effective check against this.


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The IACUC should be sufficiently empowered to allow free and open discourse on issues of animal welfare. They should not be just another rubber stamp. While organisations like the American Association for the Advancement of Laboratory Animal Care (AAALAC) and the Canadian Council on Animal Care (CCAC) have basic membership recommendations for the IACUC, consideration should be given to exceeding these. Soliciting input from additional community members, veterinarians, and technicians with different points of view can be beneficial. Debate should be lively and consensus should be solid. The IACUC is the moral centre of the animal research facility. They have the power to request changes and even stop studies. Interestingly, they can be an excellent ally of the study director and investigator in helping them stand up to a sponsor who is over-reaching on a project. Furthermore, they should never allow money, or lack of it, to be the reason for taking a short cut if there is any possibility that the welfare of the animal will be in jeopardy.

Better Animal Welfare Increases Colony Value and Longevity and Enhances Adoption RatesLaboratory animal research models can be difficult to develop and expensive to maintain. Instrumented animals, expensive and hard to maintain species, and genetically modified strains can all require specialised housing and care. Retaining them for a useful lifespan requires that they be maintained with the utmost care. Prematurely terminating these animals due to preventable disease or behavioural issues is a waste of resource.

Facilities with adoption policies will want to ensure that candidates are physically and behaviourally pristine. Adoption allows the adoptee, their family and their social network a surrogate glimpse at the quality of life the animal has received in a research setting. The aim for such a programme is to “adopt out” surplus animals, not to have the public thinking they have “rescued” their pet from a life of misery. Adoption of quality animals can be an excellent public relations strategy for an animal research laboratory, but only if there is due regard for welfare.

Attention to Animal Welfare Attracts and Retains Quality StaffCaring and committed staff are the bedrock upon which quality studies are conducted. Attracting and retaining these people is vitally important. In a modern animal research facility there is considerable training and up-front investment required before these people can be effective team members. Finding top-notch animal care attendants, veterinary technicians, and veterinarians is the start. Allowing them to develop by providing the resources for training, continuing education and a supportive environment that hears and respects their opinions is critical. These people chose their respective fields because of a calling to do right by animals. They want to be proud of the work that they do. Unless we pay attention to that fundamental basis of their career choice, they will no doubt seek employment elsewhere and all the time and resource spent training and developing them will be wasted.

Signs of their commitment are generally obvious: the animals get named and staff can identify them by their individual behaviours; people’s duties are quietly shuffled on post-mortem days; staff keep pictures of their “favourite” animals; adoption boards spring up in the lunchroom. There’s obviously a fine line between callous disrespect (the animal is just a “data point”) and having too much emotional investment in our subjects. But a healthy attitude is one that recognises the importance of the work that is done and the fact that, while these animals are with us, they will receive the best care possible in a manner consistent with their physical, emotional, and behavioural needs.

This compassion is a good thing because it begets animal welfare, environmental enrichment, and early identification of physical and behavioural issues. Staff who are invested in the wellbeing of their charges will also resent practices that are less than ideal. Occasionally, investigators, juggling tight budgets, even tighter timelines and pressure from upper management, will have “scope creep” in studies with ever more procedures piled on. Animal care staff that recognise when too much is being asked of their charges, and are not afraid to speak up in their defence, are an important asset in maintaining a high standard of animal welfare and ensuring quality science.

Conclusion There is a case to be made that attention to animal welfare is a business imperative for research labs and CROs:

• Ensuring research passes the “red face test” gives sponsors peace of mind that their studies will pass public scrutiny;

• A commitment to compassion ensures the best possible public image of an endeavour that evokes an emotional response in many people;

• A corporate commitment to animal welfare and a strong IACUC provide credibility during study design;

• Quality staff with a strong knowledge of colony animals results in healthy animals with a longer useful lifespan that may have adoption as their eventual end goal;

• An environment of compassion enhances job satisfaction for those with direct contact with animals, making attracting and retaining quality employees easier.

To ignore or merely pay lip service to animal welfare in the 21st century is bad business.

Jonathan Hare, DVM, PhD is Vice President, Research at Kingfisher International Inc (KFI). KFI is a veterinary contract research organisation specialising in laboratory studies in dogs and cats. KFI staff have adopted out over 30 animals in the past year. Email: [email protected]


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European Animal Health Industry Calls for Performant New Set of Rules to Improve Availability of Veterinary Medicines Across Europe and Encourage Innovation in Animal Disease Prevention and Control

The European institutions are now in the throes of reshaping the regulatory environment for veterinary medicines and medicated feed with the revised legislation currently on the agenda of the European Parliament.

Moments such as these only occur once a decade, sometimes even longer, so now is the time to be bold in our policy-making. We need to seize this moment to make the rules governing our products more efficient by cutting red tape, simplifying rules, and ensuring a true single market to encourage innovation, while maintaining high levels of safety and quality.

There is a need for a major reduction in administrative tasks and full implementation of the single market. As a proportion of turnover, the administrative burden on the veterinary medicines sector stands at 13% versus just 6% for the human medicines sector. According to the European Commission this amounts to a massive EUR 538 million per year.

Europe has one of the world’s most stringent licensing systems for controlling medicines with an unusually high administrative burden associated with the licensing of veterinary medicines. The disproportionate costs of product maintenance and insufficient data protection, coupled with increasing data requirements, have had a direct impact on innovation with companies in Europe having fewer new products in the pipeline.

Overall the industry is encouraged by the current discussions but there is room for improvement in a number of key areas to further harmonise rules that would ultimately allow for increased innovation to develop much-needed medicines that safeguard not only animal, but also human, health.

One such improvement is a reduction of the administrative tasks associated with the marketing authorisation. The Commission has made several proposals, such as opening up the ‘centralised’ procedure to any product (currently restricted to innovative and ‘biotech’ products). A centralised procedure that would result in a single marketing authorisation for Europe is much more efficient than a multiple member state system such as the current mutual recognition procedure which, unsurprisingly, results in multiple national authorisations.

A risk-based approach to the variations procedure is another improvement that should be considered. The variations system should keep all the necessary paperwork well up to date. In conjunction with this, if we can continually monitor the safety of the product in the marketplace with an efficient pharmacovigilance system, then there is no need to follow a

fixed five-year time-point to review the benefit:risk of the product.

Reducing the red tape goes hand-in-hand with the need for an improved legal framework for periods of protection of technical documentation that will encourage investments to meet the demand for new and innovative medicines to protect both people and animals from future disease outbreaks and combat emerging animal diseases. If there is no data protection there is little or no incentive to make the significant investments needed into R&D. This also seriously hampers the competitiveness and indeed the future for all players in an already relatively small medicines market.

Roxane Feller is Managing Director of IFAH-Europe, the representative body of manufacturers of veterinary medicines, vaccines and other animal health products in Europe. With membership covering 90% of the European Market, it is a resilient and innovative sector with strong investments in Europe. IFAH-Europe’s member companies invest over €400 million in research and development each year. The sector employs

some 50,000 people in Europe.

IFAH-Europe promotes a single market in veterinary medicines across the EU ensuring the availability of medicines to protect the health and welfare of animals. More information on www.ifaheurope.org, on Twitter as @IFAHEurope, and on Facebook: www.facebook.com/WeCare.petsEurope.


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Animal Health Market Forecasting in an Increasingly Complex, Competitive and Interconnected WorldThe animal health industry operates within an increasingly complex, dynamic and competitive external environment. This is especially true within food animal markets where animal agriculture is undergoing a period of rapid change driven by unprecedented increases in consumer demand for animal protein across the globe; increasing requirements for food safety and quality; volatility in production input costs; evolving animal disease situations; and globalising animal protein trade. Consumer incomes in emerging and developing countries are growing at a faster rate than advanced countries, and income-driven changes to dietary preferences are having a profound effect on animal protein consumption patterns. Consequently, animal health markets are evolving faster than animal health companies can respond, leading to unmet needs and missed opportunities. This new situation demands a more predictive, longer-term approach to strategic planning and forecasting than has traditionally been used.

Why are medium- to long-range forecasts needed?Medium- to long-range forecasting and strategic planning are vital skills and processes that can determine success or failure of an organisation in an increasingly complex, dynamic and competitive global animal health market.While strategic planning and forecasting are amongst the greatest challenges for animal health executives today, Henri Poincaré’s adage from a century ago is still relevant today: “It is far better to foresee even without certainty than not to foresee at all.”

Medium- to long-range forecasts are critical support tools for research and development and corporate development which rely on a longer-term understanding of market dynamics and longer-term trends.

Budgeting, Operational and Strategic PlanningAll companies undertake an annual budgeting cycle to determine short-term financial objectives and sales targets that typically extrapolate trends and account for recent news and events. Many companies also use this process to undertake operational planning for up to three years, which typically includes anticipated new products and technologies. However, operational planning is predominantly focused on internal dependencies with less regard for external influences and longer-term trends.Medium- to long-range forecasting is increasingly important, given that product development timelines are lengthening, costs and risks are increasing, and being first to market is an increasingly important success factor and point of differentiation for company portfolios that are increasingly undifferentiated due to the widespread availability of branded generics.

Key challenges for medium- to long-range forecasting include:

• The collation of multiple, isolated forecasts submitted by each subsidiary can be fundamentally flawed due to increasing globalisation of animal protein production and trade;

• Local managers, who are focused on excellence in operational execution and delivering financial targets, cannot effectively monitor the complexities of animal protein supply and demand outside their local geographic responsibilities;

• Companies are focusing ever more resources on short-term operational execution at the expense of external monitoring and long-range forecasting;

• Emerging market potential needs to be quantified based on fundamental market drivers;

Fig 1. Typical Planning Cycle


• Large variations in health spend per animal accentuates the impact of globalising animal protein production;

• Will animal protein demand in emerging markets be satisfied with domestic production or increased imports from developed markets?

Animal Protein Demand ForecastingIncome growth will continue to drive increased consumption of animal protein in emerging and developing countries, whilst in advanced countries consumers are demanding ever more stringent standards of animal welfare and food safety, which in turn is influencing retailer and processor standards and specifications. Interestingly, animal protein consumption and production is already growing almost twice as fast in non-OECD countries as OECD countries, and this trend will continue.

Animal protein demand forecasting on a country-by-country basis is a combination of long-range per capita consumption and human population trends overlaid with short-term volatility caused by numerous factors.

Per capita animal protein consumption is driven by evolving preferences and eating habits, disposable incomes, new products, and access to and availability of animal proteins. While these factors are complex, studies have demonstrated a relationship between income and animal protein consumption for individual country markets and these demand elasticities can be used as a backbone for animal protein demand forecasting.

Medium- to long-range animal protein consumption data are critical in developing demand-driven production forecasts.

Production ForecastingAnimal protein production is ultimately governed by animal protein consumption, however, varying production life-cycles, government policies, volatile relative commodity prices, and trade and disease issues can affect the transmission and response to these market signals.

Animal agriculture is amongst the most regulated industries and is subject to intense political, regulatory and environmental scrutiny, as well as changes in consumer, processor and retailer attitudes and behaviours, which can influence supply and demand dynamics.

In addition, animal protein production is beholden to external factors beyond the producer’s control, such as disease outbreaks, weather events and climate change, natural disasters, trade disputes and policy issues, which can materialise as short-term disruptions to supply and demand.

TradeThe rapid expansion of the global trade in animal protein has fundamentally altered global agriculture by disconnecting local supply and demand constraints and barriers.

Global trade in animal protein is governed by highly complex regulations and standards required to maintain compliance, however, disputes can arise which take a long time to resolve.

In addition, trade can be temporarily disrupted by relative price movements, changes in feed costs, exchange rates and disease outbreaks, which makes short-term forecasting challenging but medium- to long-range trends prevail.

Bilateral trade agreements are being developed, e.g. TTIP, EU-Mercosur, TPP and these usually involve animal agriculture products. These free trade agreements will eventually open up more protected agricultural markets to increased competition, which is often a key source of contention.

Linking animal protein demand and supply through trade is a key determinant of production forecasting accuracy and demands complex tools and forecasting models.

Building models that simulate global animal protein trade over time allows for external factors to be accounted for while maintaining long-range fundamental trends in global trade flows, barriers and drivers.

ProductivityIn recent decades, advancements in conventional technologies, such as nutrition and genetics, have contributed significantly to improvements in animal agriculture productivity, which could soon be joined by further advancements in biotechnology and information technology to accelerate productivity gains.

Forecasting ModelsDespite all the complexities of global animal agriculture and animal health markets, the development of bottom-up market models can support the formation of robust medium- to long-range forecasts, which are critical success factors for animal health companies today.

The use of interconnected models for animal protein consumption, production and trade allows commodity balance sheets to be developed that account for the complexities of competing animal proteins within a country and also competition between countries for growing international animal protein demand.

However, animal protein production volumes alone

are unsuitable for animal health market forecasting, as the fundamental driver of animal health market demand is animal numbers. To forecast the number of animals




requires productivity improvements in each country and each species sector to be accounted for, as it directly influences the relationship between production and animal numbers.

Animal numbers must also be adjusted for “medicalisation rates”, which relates to the proportion of a population with access to animal health interventions. This is more important in emerging and developing countries where access to animal health and product inputs are increasing rapidly, while in advanced countries the vast majority of animals already have access to healthcare.

The output from a series of interconnected animal agriculture consumption, production, trade and live animal models are medium- to long-range forecasts for the number of “medicalised animals” by species in more than 230 countries.

Animal Health Market ForecastingDistilling simplicity out of complexity is the key to successful forecasting. Market fundamentals are the number of medicalised animals and the value of healthcare inputs each animal consumes, which is the next stage of a forecasting process.

This requires extensive knowledge of historical animal health market values and trends by species and product group to identify and quantify underlying trends in demand. Unlike human healthcare where this data is readily available and easily accessible, independent historical animal health market data is challenging to source.

Using medicalised animals and total animal health market size by species and product group it is possible to

derive an animal health “spend per medicalised treatable unit” segmented by product group. This is the second market fundamental input for medium- to long-range animal health market forecasting.

An intimate knowledge and understanding of the animal health market can then be applied to identify and model these market drivers over the medium to long-term. The impact of new technologies, generics, regulation and pricing all need to be considered.

By developing a series of models that connect animal agriculture and animal health together with the application of skill and experience, it is possible to build robust medium- to long-range animal health market forecasts.

Companion Animal Market FundamentalsWhile there are different market drivers for food and companion animal healthcare, the fundamentals are the same; how many animals are medicalised and the average animal health spend per medicalised animal.

However, companion animal market forecasting is even more dependent on evaluating the trends in advancing medical and surgical technologies, willingness and ability to pay, diagnosis rates and product pricing.

ConclusionsWhile medium- to long-range forecasting is challenging, it is critical for animal health companies to plan strategies to survive and thrive in an increasingly complex and competitive market.

The availability of independent forecasts allows animal health companies to challenge their own internal assumptions and improve the quality and effectiveness of their internal strategic planning processes.

Tim Evans is Managing Director of Vetnosis. He leads its global market analysis and forecasting research and has more than 20 years’ animal health market experience, including commercial and strategy roles in industry and as an independent analyst and consultant. He holds a first class B.Sc. (Hons) in Biochemistry and a Diploma in Marketing, and is a Certified Chartered Accountant.Email: [email protected]

Fig 2. Inter-connected animal protein consumption, production and trade models and animal health forecasts

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TCO Calculations in the Light of Changing Overall ConditionsThe TCO (Total Cost of Ownership) calculation has its origin in the IT industry. This method can be used to calculate the costs of an investment including operating costs. TCO calculations are therefore a good analytical basis for investment decisions. In this context, it is important to recognise any cost drivers and hidden costs and to quantify them, as far as possible.

Definition of TCO: “The Total Cost of Ownership is a method which is used to support investment decisions. In this method, the costs throughout the entire life cycle of a configuration item are calculated (from acquisition to disposal).” 1

The following explanations refer to a fictitious project to acquire a secondary packaging machine. They do not go into all blocks of costs in depth, only the most relevant.

1. The investment costsIn terms of investment costs, the following cost blocks are essentially of relevance: • The packaging machine(s) are likely to constitute the

largest block with regard to investment costs. • The installation and commissioning costs for the

machines.• The costs of qualification of the machines including

all documentation, creation of SOPs, etc. • Training costs for personnel. • Tools, spare parts, etc.

Experience shows that a cleanly-structured specification is an important prerequisite for obtaining meaningful quotations which can also be compared with each other. However, specifications are frequently too unclear and unstructured, and this makes even the first step of the TCO calculation considerably more difficult. Given a structured specification and correspondingly structured quotations, however, this first step is relatively easy. Therefore this is not considered in any greater detail.

2. The operating costsSome of the most essential blocks of costs are listed below.

2.1 Personnel costs (operator costs)The layout of the corresponding packaging installation can be used as a basis for the calculation of personnel costs. All necessary personnel interventions are then entered in a table. Essentially, on a packaging machine these involve the filling of magazines, e.g. for the folding box blanks, pack inserts, rolls of labels or other components not automatically fed to the machine. For the individual intervention points, the autonomy of the magazines, rolls, etc. concerned is entered. Then, in the

next column, the time needed by an operator to refill the corresponding intervention points is entered. It is now possible to calculate what percentage of operator time is required for each intervention point. The sum of all the percentages gives an approximate picture of the number of people required for the operation of the machine.

2.2 The infrastructure costs (space requirements) It is well known that the costs for a conditioned space in the pharmaceutical industry are very high. Accordingly, it is important to occupy as little of this expensive space as possible. On the other hand, it must be ensured that a reasonable flow of materials and short distances for the personnel are achieved. Consequently a good machine layout, tailored to local conditions, is of great importance.

2.3 Packaging material costsIn principle, the development of the packaging solution should take place right at the beginning of the decision-making process. The choice of a suitable packaging solution has a considerable impact on very many TCO points. Special attention must therefore be paid to the packaging solution, because it may undoubtedly be one of the dominant cost drivers.

A simple practical example will explain this:A pharmaceutical producer wants to safely package three syringes and a pack insert. The choice is between a classic blister pack in a side-loading folding box or a 100% cardboard solution consisting of a folding box with a glued corrugated flute, which can be produced on a toploader.

The table below shows how the material costs differ:

Table 1: Packaging material costs

For an annual quantity of, say, 2.5 million packs, there are recurrent savings of US$350,000 per year.

Of course, in addition to the pure material costs, other criteria have to be borne in mind, although these are difficult to represent as costs. These include, for example, ease of use for the user, simplicity of manufacture and, not least, the ecological benefits resulting from the substitution of plastic by cardboard.

TCO Christoph Hammer CTO Dividella AG page 1 of 1

Blister pack NeoTOP Folding box 0.10 US$ 0.08 US$

Plastic tray/cardboard flute 0.09 US$ 0.02 US$ Aluminium lidding foil 0.05 US$ -

TOTAL 0.24 US$ 0.10 US$ Table 1: Packaging material costs Packs per

container Costs per pack

Cost for 2 500 000 packs per year

Toploading 20’833 0.24 US $ 600 000 US $

Blister pack 12’315 0.406 US $ 1 015 000 US $

Table 3: Logistics costs



Figure 2: Above, a 100% cardboard pack (NeoTOP) and on the right a blister pack in a side-load cardboard box.

2.4 Logistics costsIn the particular case of products which have to be transported in the cold chain, the volume of the packing is of great importance.

In the above example the difference in volume is a factor of about 2. This big difference occurs because the toploading box is optimised for volume and in addition the edge of the blister for sealing with the lidding foil is eliminated.

By land, the costs for a 9 m3 container over 3000 km amount to approximately US$5000.


This simple example shows that it is precisely when products have to be transported refrigerated that the packaging assumes great importance. The difference in cost is even more dramatic if the products have to be air-freighted and can easily reach millions.

2.5 Energy costsThe energy costs for a packaging installation can be determined fairly easily from manufacturers’ information. Because of the high heat expenditure for the film forming and sealing process, a thermoforming machine (for blisters) will certainly come out worse than, for example, a toploader for monomaterial packaging (cardboard) which is only glued.

Basically, however, energy costs are not expected to have too much of an effect on the TCO calculation.

2.6 Maintenance costsWith regard to maintenance costs, most companies

are likely to have values obtained from experience at their disposal or they can obtain them relatively easily from industry organisations. In the case of a standard packaging machine from a good-quality manufacturer, it can be assumed that the maintenance costs too will have no relevant impact on the TCO calculation.

2.7 OEE (Overall Equipment Effectiveness)The OEE of an installation hangs like a pall of smog over the operating cost account, because it has an effect on many of the aforementioned cost blocks. If the OEE is low, personnel costs, energy costs, etc. increase automatically, because the processing of orders takes longer. It is important here to make a clear distinction between factors which are affected by the packaging machine or the packaging solution and those which have more to do with organisational matters and the periphery of the installation.

In this context, format changes are a classic and highly topical example. The OEE can be influenced massively by lot sizes, which are becoming smaller and smaller. In an integral approach, therefore, the packaging solution and the machine should be given equal consideration. This means that in the initial stage attention should be given primarily to harmonising packaging. If it is possible to unify the pack dimensions of different products, the cost and effort involved in switching between orders is automatically reduced. However, conflicts of aims may also arise. For example, with harmonised packaging the cost of change-overs falls, but may rise again due to a non-optimal packaging volume (see Logistics Costs). Therefore, the harmonised solution will be advantageous for small quantities, but this advantage diminishes as quantities increase and eventually becomes a disadvantage.

In a second stage the packaging machine must be considered. If format changes are unavoidable, then they should at least be able to be carried out easily, quickly and accurately. This means that a few, robust, small and light-weight format parts are beneficial. In addition, digital displays (setpoint/actual value), for example, assist the operator during a format change; the format change is completed more quickly and fewer mistakes occur.

Figure 4: Digital displays for fast, accurate format changes

TCO Christoph Hammer CTO Dividella AG page 1 of 1

Blister pack NeoTOP Folding box 0.10 US$ 0.08 US$

Plastic tray/cardboard flute 0.09 US$ 0.02 US$ Aluminium lidding foil 0.05 US$ -

TOTAL 0.24 US$ 0.10 US$ Table 1: Packaging material costs Packs per

container Costs per pack

Cost for 2 500 000 packs per year

Toploading 20’833 0.24 US $ 600 000 US $

Blister pack 12’315 0.406 US $ 1 015 000 US $




Line clearance is also part of a switch from one order to another. Here too, there is a great difference between different machine concepts. It is crucial that the machine has an idling mode, is of GMP-compliant construction and has no hidden “crannies” for objects. In addition, for example, easy access, ideally from both sides of the machine, is crucial for quick and easy cleaning.

These examples show how complex the topic of OEE is and that it has a major effect on the TCO calculation.

3. Changing overall conditionsIf it is assumed that a comprehensive TCO analysis has been carried out and an investment decision has been made on that basis, the result may still lead in completely the wrong direction, if key overall conditions change.

In today’s pharma world, for example, market trends, such as simpler forms of administration, improved compliance or environmental aspects (less waste or avoidance of plastics) can impose completely new requirements on the packing solution. Corporate mergers or reorganisations can change overnight the production environment and the product portfolio which is to be manufactured. This may mean that a site suddenly has to take over products from a different site, or an originally planned product has to be discarded. Amended regulations may mean that the packaging has to be modified, e.g. by adding to or increasing the size of a pack insert.

Ideally such changes to production goals can be accommodated without major investment in machinery. However, this is only possible if the packaging and packaging machine concept which was originally chosen allows for such adaptations. A flexible packaging concept and packaging machines of modular construction greatly increase the chances of being able to meet future requirements. It is therefore well worth taking this aspect into account in the decision and, where applicable, taking certain precautions. For example, space can deliberately be kept free on the packaging machine for additional

future functionality. This approach allows a certain degree of investment security (or “asset protection”).

4. ConclusionA comprehensive TCO analysis, in particular of the cost drivers, makes a lot of sense in the context of an investment decision. With an eye to the future, however, an attempt should be made to anticipate future requirements. Changing conditions can quickly transform the original TCO results into so much waste paper.

In this context, flexible packaging and modular machine design help to ensure the necessary margin for manoeuvre for the future. Production sites which respond appropriately are better prepared for changes; they can hedge their investments and are more competitive in the long term.

References 1. Dugmore, Lacey: A Managers Guide to Service

Management, 2nd ed., BSI Standards, 2006

Christoph Hammer has held the position of Chief Technical Officer and Deputy CEO at Dividella in Grabs for the past 16 years. He has a lot of experience in the food and pharmaceutical packaging industry in the fields of engineering and consulting. His expertise covers the capital equipment industry, and through extensive sales activities he has an excellent knowledge of international markets. Christoph was educated

as an electrical engineer with additional degrees in business and production technology.Email: [email protected]

Figure 5: Changed overall conditions



Could Our Main Challenge with Emerging Diseases be the Way we Look at Them? Or Maybe Even the Way we Don’t Look at Them?

The history of agriculture and animal production has known many emerging and re-emerging diseases. Some of these diseases of animals have had a major impact on humans. At the moment, there seems to be a trend of (re-)emerging diseases.

A Changing LandscapeTaking a European perspective, several unexpected outbreaks of vector-borne diseases have oc-curred in EU member states in recent years. Diseases such as West Nile fever have moved up the list of public health issues, with outbreaks in humans in Greece, Bulgaria and Croatia. In 2006, the bluetongue virus, serotype 8, was detected well outside its known geographical range. Since then, with incursions of a number of serotypes of bluetongue virus and the spread of serotype 8 to most EU member states, bluetongue has evolved from an ‘exotic disease’ to a more complex dis-ease situation with the potential of becoming endemic in certain previously free areas. While the situation has significantly improved in many areas over the last few years, due to efficient control measures, bluetongue remains an animal health threat to Europe.

In 2011, another vector-borne disease caused by the Schmallenberg virus emerged in ruminant animal populations and rapidly spread across Europe. More recently, Lumpy Skin Disease was re-ported from Cyprus. But also, non-vector-borne diseases have occurred in unexpected circum-stances, for example, the spill-over of Q-fever from animals to humans in the Netherlands between 2007 and 2010, with over 4000 human cases, raised serious public concerns and questions about factors contributing to the development of this outbreak.

Many reviews of infectious diseases at the human-animal interface show that more outbreaks, both new and already known, are to be expected in the future. In some of these reviews, Europe has been characterised by authors as a hot-spot for emergence, mainly as a result of socio-economic practices and changing climate patterns, since we Europeans live in a changing landscape. The contention, however, would apply well beyond European boundaries and it is high time to look at emerging diseases’ mergence as an “expected unexpected”.

The year of 2014 and the beginning of 2015 have been branded by the Ebola virus. The outbreak of the Ebola virus disease, which has been affecting several countries in Western Africa since December 2013, is by far the largest ever documented, with reported cases and deaths that have exceeded previous historical outbreaks; it is also the largest outbreak in terms of geographical spread. The outbreak is generally considered to have

happened after a single spillover event, with the index case believed to be a very young child living in a village of Guinea’s southeastern forest region. It has spread to the neighbouring countries, Liberia and Sierra Leone. Scientists usually consider that transmissions of the Ebola virus to humans occur by contact with dead or living infected animals. There is, however, uncertainty around all modes of transmission of the virus. Hunting, scavenging and butchering infected animals certainly leads to intimate contact with infected organs, body secretions and other fluids. Such contacts are a potential source of infection in humans. Although we believe we understand the mechanisms of the spill-over, the question remains why the Ebola virus turned active in West Africa, that far from its usual territory in Central Africa? As some have put it in simpler terms: why there and why now?

A better understanding of environmental, epidemiological and social factors that could lead to an outbreak such as the one of Ebola virus disease in Western Africa, and a better understanding of the spatial and temporal interconnections of these factors across the affected region and beyond, may help to prevent future outbreaks. Looking in the mirror, the lack of understanding of these drivers may simply hamper our capacity to prevent similar outbreaks in the future. A shortsighted view is probably to concentrate on hunting activities and use of bushmeat as a resource for food. Indeed, Africa is another changing landscape and our efforts should be to better understand the sequences of events which have gradually make such a spillover possible. Some of these sequences have their roots miles away and years ago.

This reminds us about the urgent need to explicitly take into account socioeconomic and environmental aspects along with epidemiological aspects of emerging diseases. It reminds also of the need to consider the interactions between factors belonging to such different aspects of reality.

Powerful DriversWe know that human activities are often the ones driving the appearance of emerging diseases, either directly or indirectly, sometimes even remotely. We increasingly use the concept of drivers: drivers have been defined as issues shaping the development of a society, organisation, industry, research area, technology, etc. They can be classified in categories such as social, technological, economic, environmental, and political. An important characteristic of drivers is that they can modify the onset of emerging diseases. They can either amplify or attenuate the magnitude or frequency of risks arising from various sources. A large body of literature is available on drivers


in different fields, including economy, social sciences, technology, health and environmental sciences. Drivers are very helpful to retrospectively analyse outbreaks; they similarly have potential for horizon scanning.

Just recently I attended a conference on the bluetongue virus, and found myself citing Jacqueline de Romilly on ancient Greek philosopher Thucydides: ‘…The future will always be unpredictable to us, but the continuities and analogies in history can serve to alert us to understand better what may well happen. So it is not about predicting the future, nor even about any practical utility, but rather about understanding events once they have happened on the base of an exact knowledge of the past. In a way, the use of drivers in emerging risk walks the same thin line between past and future.

The more humans expand the footprint of the global population, encroach onto natural habitats, alter these habitats to extract resources, intensify food production, and move animals, people and commodities and the pathogens they carry, the greater the potential for emerging or reemerging pathogens. Producing food plays a major role in this since food production is a human activity which has the largest impact on our planet. As an example to illustrate this, it is estimated that food production uses twice the amount of water compared to all other human activities combined. The risk of emergence and spread of existing and new pathogens has also increased as a consequence of global changes in the way food is produced, transformed, transported and consumed, as well as many other factors that characterise the Anthropocene. This is probably both a long-standing and a long-term trend if we consider that by 2050 the global population is expected to be over 9 billion. Not only is the global population expected to grow dramatically, but a substantial part of this population’s income is expected to be nearly three times what it is today with expected changes in food habits, such as an increased demand for meat, for example. The shifting demand will result in an increase in food production, which is likely to place a greater burden on the resources of the planet.

Of course, food production is far from being the only sector providing effective drivers for emerging diseases. For example, climate change is likely to provide newly suitable environmental conditions for species to broaden their geographical distribution. This concerns not only invasive species but also a number of pests and pathogens. Climate change will also increase pressure on the availability of food because of reduced reliability on seasons, and extreme climatic events such as droughts or heavy rains. Climate change is a strong source of drivers for emerging diseases. At the same time, population displacements due to multiple and overlapping political and humanitarian crises which have occurred over the last few years and continue to occur in several parts of the globe will be a feature of our future and will also represent a potential for emerging infections and spread of pathogens.

As a matter of fact, trying to list potential drivers for emerging diseases in a world of change inevitably results in a long list of items, most of which are related to each other. Many such lists have been prepared here and there in the context of preparedness or in desperate attempts at forecast. One should admit though that the question remains to know how to put these drivers into play.

One Health of Course, and BeyondIt is usually estimated that about two-thirds or three-quarters of infectious diseases in humans have their origin in animals. However, the connections between human and animal health are going well beyond this. The link between public and veterinary health is also recognised in the area of non-communicable diseases, such as, for example, asthma among farmers or occupational cancer among meat workers. Emerging diseases are not only a threat to animals, or the environment, but may have direct and indirect consequences on public health, either because of food shortage or because of the zoonotic impact such as new pathogens to humans or antimicrobial resistance. Indeed, those knitted implications, as well as the existence of overlapping drivers of emerging diseases and environmental changes do point towards the concept of ‘One Health’, an integrated view and approach to human, animal and environmental health. The One Health concept has gained momentum over the past years and an increasing number of initiatives have engaged in fostering synergies and bringing together public and animal health, development, ecology, economics, and other sectors to investigate connections between health and environmental change to generate science and policy outputs.

We would easily agree that long-term planning should take into consideration the unique nature of diseases at the human-animal interface and their emergence must involve the entire relevant scientific community. Looking at the drivers for emergence, this entire scientific community seems to grow dramatically and embraces the entire field of biological and social sciences.

Yet, we often miss the social sciences part. In the case of the Nipah virus disease and its emergence in Malaysia in the late 1990s, most of us have in mind a series of drivers such as forest fire of unprecedented magnitude, massive displacement of bat populations, encroachment of orchards and pig farming. However, less is often known about farmers belonging to ethnic minorities in some parts of the country, or farmer response to outbreak management measures put in place by the central authority.

Working on drivers opens a new dimension to the One Health concept because drivers drive for many different outcomes - animal and public health, ecosystem integrity, plant health, etc. and drivers belong to any category featuring the reality of the changing world. Working on drivers simply forces us to forget for a moment about our scientific disciplines and take a fresh look at the reality.




The challenge remains to understand the influence of human activities and behaviours, and to in-corporate this understanding into our approach to emerging diseases because human activities are often the drivers of emerging diseases.

The Power of RepresentationIn our attempt for a holistic approach accounting for relations between drivers, potentially belonging to different families, the linear and causal relation between risk factor and disease emergence is no longer applicable. On the contrary, the aim is to examine the multidimensional links between a broad range of ecological, biological and socio-economic factors. Back to the example of Nipah virus disease, there was a network of interactions between several events which created favourable conditions for the emergence in 1997. Such events encompass deforestation, war, or migration of bat population, and some authors have proposed the use of spidergrams as a methodological tool based on a visual network representation. The spidergram also includes conditions such as poverty or level of containment of pigs. Working on similar representations, we came to realise that spidergrams were often interpreted as causality networks, where indeed interactions between drivers do not necessarily belong to this category, leaving space for other types of relations such as conjunction, correlation and even coincidence. This requires manoeuvring in a complex tissue of relations which constitutes another conceptual challenge that we only discovered while working on drivers for emerging diseases.

Many drivers can contribute to the emergence of infectious diseases and drivers of an emergence rarely act single-handed. Several authors have proposed conceptual frameworks for the holistic and interdisciplinary investigation of disease emergence and the underlying drivers. Most of these frameworks combine perspectives from both natural and social sciences, linked to public health, land use and conservation. However, the figurative representations they propose of zoonotic diseases are very often focused on the spillover event, demonstrating a strong influence of biology in those representations. Multi-disciplinarity - where experts from a variety of disciplines work together but keep separate questions, conclusions, and even disseminate in different journals - is therefore not enough any more. Trans-disciplinarity is defined as a collaboration process in which the exchange alters discipline-specific approaches, and integrating disciplines achieves a common scientific goal. Typically, a trans-disciplinary project brings experts to work entirely outside their own discipline, at least for some time. Trans-disciplinarity makes it possible to transcend the disciplines to capture complexity, and create new intellectual spaces. Let’s face it, inter- and multi-disciplinarity have gained traction, but there are still very few, too few, trans-disciplinarity approaches to animal health.

Working with drivers for emerging diseases has brought us to the importance of visualisation. The way we represent systems and the way we display our conceptual models both tell a lot about the way we see and represent the world. They are cosmograms, i.e. formal representations of the world. Looking at the representations made of recent events of emerging diseases show that our mental maps are still mainly driven by biology. What we may have learned from the exercise is that a main challenge of emerging diseases is the way we look at them. We should also recognise that what applies to emerging diseases, probably applies equally well to any disease.

Dr Franck Berthe is Head of the Animal and Plant Health Unit at the European Food Safety Authority (EFSA), at its headquarters in Parma, Italy. Within the Department for Risk Assessment and Scientific Assistance, the core activity of his group is to assess animal and plant production systems and practices with respect to primary production, ecosystem and public health. Dr Berthe provides scientific advice to the European

Union risk managers and decision makers on a wide range of risks at the human-animal-ecosystem interface.

Prior to coming to Italy in 2007, Dr Berthe was Associate Professor at the Atlantic Veterinary College (UPEI) and Canada Research Chair in Aquatic Health Sciences. His multi-disciplinary program aimed at exploring host pathogens relations in their environment. From 1994 to 2004, Dr Franck Berthe has led active research in aquatic animal health at the French institute for the exploitation of the sea (IFREMER) in France and overseas territories.

Dr Franck Berthe is President of the Aquatic Animal Health Standards Commission of the World Organisation for Animal Health (OIE). He has served on this Commission since 1996.

A native of France, Dr Berthe received his doctorate of veterinary medicine degree from the Veterinary School of Maisons-Alfort, and a PhD degree in molecular parasitology from the University Blaise Pascal, Clermont Ferrand. He has a diploma in bacteriology (molecular taxonomy and epidemiology) from the Pasteur Institute, Paris.

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Towards Sustainable Feed & Food – Working Together at International Level Synopsis: In 2015 compound feed production will likely reach close to 1 billion tonnes worldwide and the FAO estimates that by 2050 the demand for food will grow by 60%. This poses significant opportunities and challenges for the entire agri-food chain and International Feed Industry Federation (IFIF) believes that only by working together at international level and focusing on innovation and capacity-building can our sector provide sustainable, safe, nutritious and affordable food for a growing world population.

In 2015 compound feed production will likely reach close to 1 billion tonnes worldwide. This numerical milestone is a marker, not only for the achievements of our industry, but also for the opportunities as well as for the challenges we all face in the future.

The United Nations Food and Agriculture Organization (FAO) estimates that by 2050 the demand for food will grow by 60% and that between 2010 and 2050 production of animal proteins is expected to grow by around 1.7% per year, with meat production projected to rise by nearly 58%, aquaculture by 90% and dairy by 55%. This already marks a growth factor of almost two, however if we were to extrapolate the growth rates of the last forty years forward to 2050, this would in theory quadruple the needs.

This should be good news for the feed industry and our partners along the agri-food chain. However such growth comes with significant challenges and it is vital that our sector, as well as the wider agricultural chain, can meet these demands in a sustainable, safe and affordable manner, while maintaining consumer trust and confidence in the food supply chain.

This challenge is a global one and (International Feed Industry Federation) IFIF is a global organisation. Our members are made up of national and regional feed associations, feed-related organisations and corporations, which represent over 80% of worldwide animal compound feed production. IFIF’s vision is to provide a unified voice and leadership to represent and promote the global feed industry as an essential participant in the food chain that provides sustainable, safe, nutritious and affordable food for a growing world population.

However the challenge is also a common one, and we cannot meet the higher demand for animal proteins like beef, poultry and fish on our own. The Animal Health industry is a vital component and partner along the chain, and IFIF believes that only by working together with all stakeholders in the feed and food chain can we meet these future demands safely and sustainably. This includes engagement with governments, international

organisations such as the FAO, the World Organisation for Animal Health (OIE) and the Codex Alimentarius Commission, as well as close cooperation with the private sector and non-governmental groups, such as the International Federation for Animal Health (IFAH), the International Dairy Federation (IDF), the International Egg Commission (IEC), the International Meat Secretariat (IMS), and the International Poultry Council (IPC)

To support our industry on the road to the future, IFIF’s work is centred on three strategic pillars, including sustainability, regulatory matters and international standards, and supporting education and sharing of best practices.

One key part of IFIF’s mission is to continue to support and encourage the sustainable development of animal production. To this end we work with our members and chain partners to measure and improve the environmental performance of the livestock production chain.

The Specialty Feed Ingredients Sustainability Project (SFIS)IFIF, together with the EU Association of Specialty Feed Ingredients and their Mixtures (FEFANA) and a consortium of international companies and associations, launched the Specialty Feed Ingredients Sustainability Project (SFIS) to measure and establish the role of specialty feed ingredients (SFIs) on the environmental impact of livestock production. The study undertook a life cycle assessment (LCA) in conformity with the ISO 14040/44 standards in order to analyse the cradle-to-farm gate environmental performance of pig and broiler production with and without specialty feed ingredients supplementation and to provide credible scientific evidence for informed decision-making in areas related to the environmental impact of specialty feed ingredients.

The SFIS analysis examined the use of low-protein diets (nitrogen) and phytase (P) in pigs and poultry. The overall results of the study demonstrate that the use of SFIs in animal diets reduces the consumption of basic feed ingredients. Furthermore the study demonstrates that the use of SFIs results in clear reductions of the Global Warming Potential (GWP), as well as the eutrophication and acidification potential during livestock production.

It became clear that the use of SFIs in animal nutrition provides concrete benefits to the environmental impact of animal production, for example reducing the excretion of certain nutrients, such as nitrogen and phosphorus, improving the performance of the animals, and reducing the feed consumption or allowing the use of locally-based or unusual feed materials.



The results of the study were validated by an independent scientific council made up of global experts in the fields of LCA methodology and animal nutrition to ensure scientifically robust inputs in the analysis and prepare the ground for a future peer-reviewed publication of the project. This study should have a direct positive impact on the future environmental footprint of the feed and food chain. In addition to the positive results, the study also points towards future developments, such as improved feed conversion driven by advancing technologies in animal feeding through using SFIs.

LEAP and the Development of Global Feed LCA Guidelines IFIF, together with the American Feed Industry Association (AFIA) and the European Compound Feed Manufacturers’ Federation (FEFAC), is a founding member of the FAO-led Livestock Environmental Assessment and Performance Partnership (LEAP), which aims to improve how the environmental impacts of the livestock industry are measured and assessed, an important step to reduce the impact of livestock products on the environment. In less than two years, the LEAP partners were able to develop a methodology that will introduce a harmonised, science-based, practical and international approach to the assessment of the environmental performance of feed supply chains, while taking into account the specificity of the diverse production systems that exist globally. These ground-breaking global LCA Guidelines, published in April 2015, are an essential step to help reduce the impact of livestock products on the environment.

The LEAP/FAO Feed LCA Guidelines reflect a common vision among partners, including the FAO, national governments, private sector organisations, and NGOs. The Guidelines carry an international scientific consensus based on the input of twenty international experts in the drafting process and a thorough international public review, which took place ahead of their official release.

The Guidelines represent a significant milestone for the global feed industry and will enable consistent and credible environmental assessments with a view to reducing the environmental footprint of livestock products. Based on this, IFIF will continue to work with partners on the agri-feed chain to develop practical tools for feed and livestock producers to assist them in further reducing the environmental footprint of their activities.

The Global Agenda for Sustainable Livestock IFIF is a founding partner of the FAO-led Global Agenda for Sustainable Livestock, a partnership of livestock sector stakeholders supported by the FAO and committed to the sustainable development of the sector. Together the partners develop and implement initiatives to support growth, which contributes to socially desirable objectives. The Global Agenda brings together the public and private sector, producers, researchers and academia, civil society, NGOs, and inter-governmental organisations.

IFIF is a Member of the Guiding Group of the Global Agenda, and has signed the Global Agenda Consensus and actively inputs in the work of the Agenda. IFIF has supported the development of the initiative since its beginnings in 2010 and is working with other Agenda partners on ‘closing the efficiency gap’, in order to stimulate the application of existing, but not widely used, technologies and to transfer and adapt resource-efficient technologies.

Supporting Standards and Facilitating Trade Another key part of IFIF’s mission is to support worldwide trade and ensure that future demands for feed and food can be met efficiently. IFIF works to promote a balanced regulatory framework to support a fair global playing field to facilitate market access and support the competitiveness of the feed and livestock industries.

Engagement with international institutions is vital for this and IFIF collaborates with the FAO, the World Organisation for Animal Health (OIE), the Codex Alimentarius Commission and other international bodies to help set international regulatory standards for the whole feed chain, and to support fair trade.

IFIF has a strong collaborative relationship with the FAO dating back many years, and IFIF and the FAO Animal Production and Health Division organise the annual International Feed Regulators Meeting (IFRM). The IFRM continues as a successful joint effort to bring together government officers, intergovernmental organisations, academia and feed and food companies and organisations from around the world to discuss key issues of relevance, including mutual recognition and global feed safety standards. This important meeting also provides an opportunity for professionals belonging to feed public and private sectors from across the globe to exchange their thoughts and discuss concrete ideas for providing safe and affordable feed and food around the world.

As animal health is also a vital component of the feed chain, IFIF holds a cooperation agreement with the World Organisation for Animal Health (OIE). The two organisations work together with regard to the prevention and management of infectious diseases, including zoonotic disease, as well as the support for the development, updating and implementation of OIE standards and guidelines.

Finally, feed safety is relevant to Codex Alimentarius work as it impacts on the safety of food. IFIF is a Codex Alimentarius-recognised NGO and was actively involved in the development of the Codex Code of Practice of Good Animal Feeding, as well as a member of the ad hoc Codex Intergovernmental Task Force on Animal Feeding (TF AF). Codex work on animal feed continues in individual committees (within their mandate) and the participation of IFIF feed experts in Codex work contributes to keeping feed safety on the Codex agenda.



Facilitating Dialogue and Supporting Capacity-building To further strengthen the sustainability of the feed and food chain, IFIF supports producers and regulators around the world with a good practices manual and training workshops.

Recognising that feed safety cannot be attained by one single action or by an individual player and in response to several low-income countries’ request for capacity development, IFIF works to deliver capacity development workshops at regional level. IFIF also encourages countries, particularly in the developing world, to use the IFIF FAO ‘Manual of Good Practices for the Feed Industry’ as a guidance document to increase safety and feed quality at the production level, both for industrial production and on-farm mixing. Its overall objective is to develop the capacities of the relevant stakeholders to ensure the production and supply of safe feed. IFIF, together with the FAO, developed and published the feed manual based on the Codex Code of Practice on Good Animal Feeding. Supported by the Standards and Trade and Development Facility (STDF) of the World Trade Organization (WTO), the feed manual is available in Arabic, Chinese, English, French and Spanish.

Finally, IFIF aims to facilitate meaningful dialogue around the issues of policy, education and technology as our industry participates in the production of a safe, nutritious, sustainable and affordable global food supply. To this end, IFIF promotes science-based solutions and information-sharing for the feed industry by facilitating global forums, such as the Global Feed & Food Congress (GFFC).

The GFFC is a major milestone in the IFIF FAO collaboration and brings together leading representatives from the whole feed and food chain, including from industry, government, academia and civil society to discuss critical issues facing the feed and food chain. Sustainability will be one of the key issues at the upcoming 5th Global Feed & Food Congress, which will be held in Antalya, Turkey on 18-20 April 2016.

The 5th GFFC theme ‘Equity and Prosperity for All’ links to the global challenge to provide safe, affordable and sustainable animal protein sources to feed 9 billion people by 2050. Over 1,200 delegates from around the world will join sessions covering the whole feed manufacturing and food processing value chain including Sustainability, Markets & Trade, Feed & Food Safety, Regulations & Standards, Animal Nutrition and Innovation and R&D. I invite you to already mark the 5th GFFC in your calendar and hope you will all be able to join us for this important event.

Looking Ahead – The Agri-chain Must Act For the past years our industry and the wider agri-food chain has discussed the challenges of 2050. Much has been achieved through a focus on efficiency, increased production and sustainability and we must continue

to do more. Already there are seven billion people on the planet and in the future we need to produce more food with fewer resources. This requires technology and a platform for cooperation. More than that, more food must be affordable and available to the one billion who today do not have enough.

The global food industry, which includes the feed industry, is a large segmented chain: from agriculture and animal genetics, to seeds, fertilisers, agrochemicals, animal health, feed additives, pre-mixers, compound feeds, on-farm mixers, coops, all the way to aquaculture farming, poultry and swine integrators to the pet food industry.

We should work together and speak with one voice to consumers and to governments, who also influence our value chains with factors such as trade controls and subsidies. In particular, the importance of undertaking efforts on environmental performance is highlighted by the ongoing international negotiations on climate change reductions, which will culminate at the upcoming 21st Conference of the Parties of the United Nations Framework Convention on Climate Change in December 2015 in Paris.

In meeting these challenges and addressing these future demands, I believe sustainability and animal welfare are not optional, and I know this reflects many consumers’ concerns and wishes. At the same time, we have to be open towards innovation and technology, which will be the basis of producing more and better food over the next 40 years.

I invite you to visit our website www.ifif.org for more information about IFIF, and I look forward to working with many of you in the vital animal health sector in the next years. I know that together we can contribute to the sustainable supply of safe, healthy feed and, therefore, food of animal origin.

Alexandra de Athayde is Executive Director of the International Feed Industry Federation (IFIF), a post she has held since her appointment in April 2011.

Ms de Athayde has extensive agriculture and international experience representing the industry with governments and businesses. She previously held positions within the Monsanto Company Corporate Affairs Department in

Brazil, the US and Europe. She has also worked for the Brazilian Government as Adviser to the Deputy Minister of Agriculture and as Adviser to the Foreign Trade Secretary.

Ms de Athayde holds an International Executive M.B.A. from the University of Pittsburgh, USA and a B.A. degree in International Relations from York University in Canada. She is based in Wiehl, Germany.Email: [email protected]



Research & Development

Accurate Early Markers of Renal Damage for Veterinary and Research UseThe assessment of renal function in small animals is of interest both to veterinary practitioners and research organisations, especially those investigating the possible nephrotoxic effects of drugs developed for humans or companion animals. For veterinarians, one primary concern is the early diagnosis of chronic kidney disease (CKD), defined as primary renal disease present for an extended period of time, especially in cats. Studies suggest that 10% of cats over 10 years and nearly 50% of cats over 15 years old will suffer from the disease, with a proportion of cats progressing to end-stage renal disease. In dogs, CKD is less common but progresses more rapidly, with survival times after diagnosis often less than a year. There is also a clinical benefit in earlier detection of acute kidney injury (AKI) as implementing early administration of supportive care can lead towards a more favourable outcome than for a later diagnosis.

For research organisations, safety studies for development compounds conducted by the human pharma industry commonly require that a drug be tested in two mammalian species. The dog is generally viewed to be a sensitive second species (to complement the rat) and provides a valuable non-rodent species for decision-making. Classically, these are terminal studies and the kidney histology is investigated for signs of drug-induced damage. Efforts for identifying a good safety biomarker are motivated by (i) the pressures to reduce the number of animals sacrificed in scientific experiments, imposed both by regulators and public opinion, (ii) the need for an assessment of the rate of damage and evaluation of functional alterations which are not possible with histological endpoint only. The use of different tests during a study may also enable the location and type of pathological changes to be identified, and provide information on the sequence in which such pathological changes occur. Finally, tests which are used in animal experiments on living animals may be of further use in early human clinical investigations, where it is not possible to obtain the same histological information.

In research and in veterinary practice then, there is a need for an accurate and sensitive way to assess renal function in the living animal, such that small changes in function can be detected, whether due to the effects of drugs or the onset of CKD. Much of the research into such tests has focused on their use as a diagnostic tool in veterinary practice or as a research tool, but there is no reason why a technique used for one may not also be useful for the other.

Several methods for evaluating the kidney function in the living animal are currently used or have been proposed, some of which are detailed below.

Circulating Markers of Renal Function Measured from Blood

The relationship between plasma creatinine and glomerular filtration rate (GFR)In veterinary practice, the classic way to identify CKD is to measure plasma creatinine concentration. Due to the variation in normal serum creatinine concentration and the inverse exponential relationship of serum creatinine to glomerular filtration rate, serum creatinine increases only a small degree for a relatively large decrease in renal function in the early stages of CKD. This makes single measurements insensitive in detecting early kidney disease. Serial measurement may increase the sensitivity but the largest rises in serum creatinine occur in the later stages of CKD. As a result, the use of creatinine concentrations is really limited to assessing the extent of the damage in later stages of CKD. Similarly, in drug toxicity tests, a significant amount of damage (loss of 75% of nephrons, the functional units of the kidney) will have already occurred before any changes in creatinine concentration are observed (Figure 1A). Besides, creatinine levels are also affected by several non-renal factors, such as muscle mass, diet and medication, making it a less reliable marker of renal status.

Direct measurement of GFR is considered the gold standard test of kidney function. Decreases in GFR indicate that kidney damage is occurring. Urinary clearance of inulin is accepted as the best measure of GFR, but the test is difficult to carry out. Other measures of GFR have been developed for cats and dogs, including clearance of filtrated markers such as exogenous creatinine and iohexol. These tests require repeated blood samples over a few hours to calculate the rate of disappearance of the marker which is equivalent to its rate of appearance in urine (equal to GFR). Although these techniques have been fully validated, they have not been widely used, due to historically a high number of blood samples being

Figure 1 A: inverse exponential relationship between plasma creatinine and glomerular filtration rate. Renal function of dog A and B cannot be differentiated based on the plasma creatinine measurement alone.

A



required and a lack of commercial service to calculate clearance of the marker. An iohexol clearance assay of GFR requiring only three blood samples (2, 3 and 4h after injection of the bolus, see Figure 1B) is now available for veterinarians in Europe (deltaDot/Royal Veterinary College, UK) as well as in the USA (Michigan State University). It is anticipated that this will become more commonly used in the future. As a marker of renal damage in research animals, GFR may be more sensitive than alternatives; in an individual animal, GFR seems to vary naturally by about 10-20%, so changes greater than this would indicate renal damage.

New circulating markers that could predict GFR better than plasma creatinineCystatin C (CysC) - CysC is a 13 kilodalton (kDa) protein and proteinase inhibitor involved in intracellular protein catabolism that is produced at a constant rate. It is not bound to plasma proteins and is freely filtered by the glomerulus. It is not secreted by the proximal tubules, and although it is reabsorbed at this site, the reabsorbed fraction is subsequently catabolised. These features would seem to make it a good candidate marker for GFR. In addition, it has been reported that urinary CysC concentrations are much lower in healthy individuals compared with individuals with renal tubular damage, meaning that it can be used as a marker of proximal tubular damage. Some studies have found that dogs with CKD had significantly higher serum concentrations of CysC than healthy dogs or dogs with non-renal disease1. However, other studies have found an overlap in the range seen, which may cause problems with using CysC as a marker of kidney damage2. A further problem is that there is no current veterinary assay commercially available, so assays developed for use in humans must be used instead with a resulting loss of accuracy. Furthermore, higher CysC levels have been reported to be associated with greater height, weight and lean muscle mass, the same interferences seen with creatinine3.

Symmetric dimethylarginine (SDMA) – Recent research has shown that serum concentrations of SDMA may have some advantages over creatinine as a surrogate marker of renal function. Both are well correlated with glomerular filtration rate in later-stage CKD, increasing as GFR falls. However, one study has found that SDMA is more

sensitive as a marker of renal damage than creatinine, allowing CKD to be detected with only 40% loss of kidney function, as opposed to the 75% required for creatinine to be used. It has been claimed that use of SDMA concentrations enabled the onset of kidney disease to be detected in cats on average 17 months earlier, and in one case four years earlier, than was possible using creatinine concentration measurement alone4. Furthermore, unlike creatinine, SDMA concentrations are not affected by lean muscle mass, which declines in older cats. This can cause creatinine concentrations to fall, whereas SDMA concentrations continue to rise as GFR decreases. An assay of SDMA has recently been launched by IDEXX.

T i m e a f t e r i n j e c t i o n o f i o h e x o l ( m i n )

ioh

ex

ol

co

nc

en

tra

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(mg

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)

0 6 0 1 2 0 1 8 0 2 4 0 3 0 0

0 . 1

1

1 0

D o g A ( G F R 1 . 4 m g / k g / m in )

D o g B ( G F R 2 . 4 m g / k g / m in )

Figure 1B: plasma concentration time curve for iohexol after injection of a iohexol bolus (647mg/kg) for dog A and B. The steeper slope for dog B illustrates the higher iohexol clearance (ie higher GFR) of this dog. Ioxexol concentrations were measured by capillary electrophoresis by deltaDot / RVC.

B



Histopathology:For chronic toxicology studies in dogs, serial renal biopsies under ultrasound guidance would be perfectly feasible to undertake alongside GFR measurements if cumulative renal toxicity was a real concern. Clinically, renal biopsies may be carried out when cancer or other infiltrative disease is suspected. Although they could lead to an accurate diagnosis of early-stage CKD, the need for an anaesthetic and the potential complications related to the procedure (intra-renal haemorrhage) mean that the risks of the procedure need to be balanced against the value of the information obtained. In cats with small, shrunken kidneys in particular, the information obtained from a renal biopsy is unlikely to suggest a specific treatment of the cause of the kidney disease, since all that is detected is chronic interstitial nephritis and the underlying cause that has initiated this process is not evident.

Markers of Renal Function Excreted and Measurable in Urine:Urinalysis:Urine specific gravity can help identify early-stage renal damage. The normally concentrated urine in healthy animals has a urinary specific gravity (USG) higher than 1.030 in dogs and 1.035 in cats. USGs greater than

those cut-off values indicate that a significant amount of glomerular filtrate is being reabsorbed by the renal tubules. In the case of loss of 60% or more of the functional nephrons, urine become isosthenuric (1.008 < USG < 1.012). Conversely, if USG is less than 1.008, it indicates that the kidneys are capable of producing hypotonic urine and therefore partially functional, although they may be insensitive to vasopressin (diabetes insipidus) or demonstrate tubular impermeability to water.

Proteinuria, or the presence of protein in the urine, is also an indicator of kidney disease, although other diseases can also have the same effect. A recent review of the value of screening for proteinuria concluded that “Persistent proteinuria, in the absence of lower urinary tract disease or reproductive tract disease, is usually an indication of renal damage or dysfunction”5. Proteinuria is a result of one of two mechanisms being impaired; either a breakdown in the selectivity of glomerular filtration, resulting in an increased amount of protein in the filtrate, or the failure of the tubules to reabsorb the protein after filtration. Tests for proteinuria generally measure the albumin concentration of urine, but the most used methods for testing, the dipstick colourmetric test and the sulfosalicylic acid (SSA) turbidimetric test,

Figure 2: new markers of renal of renal function or toxicity at the interface between veterinary and human pharma and preclinical and clinical studies.


are not particularly sensitive or specific. Higher quality ELISAs are available which can provide more accurate results.

New urinary biomarkers: A number of urine protein markers have been identified from the urinary proteome excreted in preclinical models of toxicity in the rat. In humans, some of them are used clinically for the identification of renal damage, either from acute kidney injury or chronic kidney disease. The translation of these markers to dogs for safety studies in experimental animals or to detect early changes in renal function (AKI onset or CKD progression) is in its infancy.

These new markers include:• Neutrophil Gelatinase-associated Lipocalin (NGAL) is

potentially useful for the diagnosis of both acute and chronic renal disease in human and dog. Urinary and serum NGAL levels have been reported to be raised in several different kidney diseases, including IgA nephropathy, autosomal polycystic kidney disease, and diabetic nephropathy.

• Kidney Injury Molecule-1 (KIM-1). Sustained KIM-1 expression has been proposed to promote kidney fibrosis and provide a way in which acute and recurrent injury could be linked with progressive chronic kidney disease. In a recent study of human patients with type-1 diabetes and proteinuria, serum KIM-1 level at the start of the study accurately predicted the rate of estimated GFR loss of the next 5-15 years6. KIM-1 has been approved by the Food and Drug Administration and European Medicines Agency as a urinary biomarker for monitoring preclinical nephrotoxicity in rats. However, more research needs to be done if it is to be used in studies involving dogs.

• Liver-type Fatty Acid–Binding Protein (L-FABP). In a study of 50 patients with CKD, the urinary concentration of L-FABP was well correlated with the extent of tubulointerstitial damage and urinary protein excretion7.

Although these markers may prove useful in animal studies as well in the future, more experimental evidence is still needed to demonstrate their suitability for identifying renal damage in studies involving rodents and dogs and to develop them as commercially available assays.

ConclusionThere is a need for both veterinary practices and research organisations to be able to measure kidney damage in living small animals, both for diagnosis of disease and to obtain information on the toxicity of drugs being tested in pre-clinical trials. In the past, the crude measurement of plasma creatinine was the standard, but this marker is not very sensitive and may be affected by non-renal factors (muscle mass, diet). Newer tests, including serum SDMA concentration and direct measurements of GFR, are more sensitive, enabling earlier detection of kidney damage. They also have the advantage of being

applicable in humans, allowing the same tests to be used in clinical trials when the nephrotoxicity of a drug needs to be monitored. Other biomarkers of renal disease have been proposed and some seem promising, but more work is still needed to demonstrate their effectiveness. The future development of a multiplex ELISA for measuring several urinary biomarkers at the same time in companion animals, associated with increased acceptance of GFR testing, could greatly improve functional renal explorations in research animals or clinical patients.

References

1. Almy FS, Christopher MM, King DP et al. Evaluation of cystatin C as an

endogenous marker of glomerular filtration rate in dogs. J Vet Intern

Med 16, 45–51 (2002)

2. Braun JP, Perxachs A, Péchereau D et al. Plasma cystatin C in the dog:

Reference values and variations with renal failure. Comp Clin Pathol 11,

44–49 (2002)

3. Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan

GC et al. Factors influencing serum cystatin C levels other than renal

function and the impact on renal function measurement. Kidney Int.

65(4), 1416-21 (2004)

4. Hall JA, Yerramilli M, Obare E, Yerramilli M, Jewell DE. Comparison of

serum concentrations of symmetric dimethylarginine and creatinine as

kidney function biomarkers in cats with chronic kidney disease. J Vet

Intern Med 28(6), 1676–1683 (2014)

5. Harley, Leyenda, and Cathy Langston. “Proteinuria in Dogs and Cats.”

The Canadian Veterinary Journal 53(6), 631–638 (2012)

6. Sabbisetti VS, Waikar SS, Antoine DJ et al. Blood kidney injury molecule-1

is a biomarker of acute and chronic kidney injury and predicts progression

to ESRD in type I diabetes. J Am Soc Nephrol. 25(10), 2177–2186 (2014)

7. Kamijo A, Sugaya T, Hikawa A et al. Urinary excretion of fatty acid-

binding protein reflects stress overload on the proximal tubules. Am J

Pathol 165, 1243–1255 (2004)


Dr Ludovic Pelligand: Graduated from the École Nationale Vétérinaire d’Alfort (Paris, France) in 2001, where he completed a two-year small animal internal medicine internship. He then completed a three-year anaesthesia residency at the Royal Veterinary College where he gained his European Diploma of Veterinary Anaesthesia and Anaesthesia in 2006. Has been employed as a clinical pharmacology research fellow and is now a

lecturer in clinical pharmacology and anaesthesia.Email: [email protected]

Dr Sam Williams: Analytical biochemist, his PhD was on the detection of recombinant erythropoietin (EPO) in anti-doping samples. Currently working on a collaboration between the Royal Veterinary College, London and deltaDOT, looking at drug metabolism in veterinary applications and their transfer to humans, and the development of veterinary therapeutic drug monitoring applications. Recently launched an on-demand assay of

glomerular filtration rate for cats and dogsEmail: [email protected]



Keeping your Farm Water Safe and Fresh

IntroductionIn many parts of the world, farmers do not have access to clean, sanitised water. Although town water supplies are treated at chlorination plants before being piped onto properties, many rural districts have to rely on ground/borehole, river water supplies or roof water collection tanks. This is the case in most parts of rural New Zealand, for example, and back in the 1990s it was estimated that around 70% of the population of NZ relied on water supplies that were not subject to standardised sanitising treatment. More recent surveys have shown that stored tank water can harbour a wide range of pathogenic organisms including bacteria, viruses and toxic blue-green algae. Such pathogens produce toxins which cause a range of problems from gastro-enteritis to neuro-toxicity. In addition, water storage on farms via ponds and dams is highly susceptible to contamination due to faecal material or farm run-off entering the water. In many parts of the world, environmental legislation is now in place to try to control water contamination, however there is still much ignorance regarding the relevance of water quality to animal health and productivity.

Water quality is a major issue for all species – animals and plants can go for several days without food, but cannot last long without access to water. This makes water the number one nutrient in all diets – although it is frequently neglected and taken for granted. As such, the quality and safety of water are essential in maintaining animal health. Every summer in temperate and hotter regions, there are reports of toxic blue-green bacteria (which produce neurotoxins) posing a risk to people and animals from contamination and overgrowth in dams and rivers.

Modern Water SanitisersModern water sanitisers, such as Credence (Kiotech Agil, UK Ltd), rely on stabilised chorine technology that offers not only a fast kill rate, but also persistence in water to keep it clear for longer. The active triclosene sodium in Credence, alongside its slow-release technology, means it is effective and easy to use on farm. With each tablet containing 8.68 g triclosene sodium, this is sufficient to remove pathogens for 1000 litres of drinking water, or, at higher concentrations, be used for cleaning facilities and equipment or as biosecurity in foot and wheel baths. Credence has been trialled in many rural situations, including troughs, dams, boreholes and in feed and milk containers.

Research on Sanitisers in Drinking WaterResearch conducted in 2010 investigated the contamination of farm water troughs and dams by blue-green algae, and how these can be controlled by adding

a water sanitiser product. Samples were taken from concrete water troughs on dairy farms in the Manawatu and were shown to contain toxic blue-green algae growth. After addition of the water sanitiser Credence™, these harmful species were effectively negated after 24 hours. In addition, unlike commonly-used copper sulphate treatments, no over-production of toxins (the ‘toxin burst’) occurs during the kill-off of the algae, and the sanitiser had no issues regarding overloading individual minerals to the animals via the water system (Table 1).

Table 1. Efficacy of Credence water sanitiser on controlling pathogens in farm water troughs

Such findings are important, especially on dairy farms where pasture rotation can leave water troughs unused for several weeks, allowing stagnation and algal overgrowth. Other farming systems have different problems. Animals reared indoors rely on piped water supplies, which may contain water from unsanitised sources. Joints in pipework and around drinkers readily build up biofilms, which provide a haven for the colonisation and multiplication of toxic micro-organisms. Credence has been shown to kill off commonly-found pathogens in drinking water systems used on pig and poultry farms, including coliforms and Aeromonas, the latter of which causes gastroenteritis in young animals, and is linked to antibiotic-resistant necrotising fasciitis in wounds and organs.

Table 2. Efficacy of Credence in water pipes on farm

Trials on pig farms have shown that ingested coliforms from drinking water can end up causing contamination on meat – posing a human health problem. Using Credence in water systems reduces the exposure, both from intake

The Global Alliance for Livestock Veterinary Medicines (GALVmed) works through partners to make livestock vaccines, medicines and diagnostics accessible and affordable to the millions of whom livestock is a lifeline in Africa and South Asia.

Our approach addresses the entire value chain to ensure livestock health product sustainability. We achieve this by forming partnerships (e.g. distributors, manufacturers, vets, governments, policy makers, NGOs) while stimulating interactions, facilitating and supporting new and current ones.

Product developmentMuch of our work, which focuses on 12 livestock diseases, is at various stages of product development. We work with research institutes, pharmaceutical companies and universities to develop livestock health products and technologies.

Product deliveryWe work with manufacturing and distributing partners to produce and enable access to livestock health products with the small-scale farmer in mind. We also provide accredited training and development for vaccinators on the products.

Policy and advocacyTo ensure farmers access livestock health products, we support an enabling policy and advocating environment.

Our livestock disease focusWe currently focus on 12 livestock diseases that are the most detrimental to poor livestock keepers in Africa and South Asia.

They are: African Swine Fever, Classical Swine Fever, Contagious Bovine Pleuropneumonia, Contagious Caprine Pleuropneumonia, East Coast Fever, Hemorrhagic Septicaemia, Newcastle Disease, Peste des Petits Ruminants, Porcine Cysticercosis, Rift Valley Fever, Sheep and Goat Pox and Trypanosomosis.

Product delivery projects in Africa GALVmed works with various manufacturing and distributing partners, bespoke to each country, to provide safe and affordable vaccines to farmers so that they can protect their investments - livestock.

East Coast Fever kills two cows a minute in 12 East African countries. GALVmed supports the one-shot-for-life Muguga Cocktail East Coast Fever vaccine, which is produced and distributed by our partners.

Newcastle disease is a deadly and contagious disease killing up to 90% of poultry. We are at the forefront of the Newcastle Disease vaccine development and work to make the new I-2 Newcastle Disease vaccine accessible to livestock keepers.

For more information on the vaccines, email our Africa office at [email protected].

»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»»Contact uswww.galvmed.org [email protected] @GALVmed www.facebook.com/GALVmed

Africa office: Galana Plaza, 4th Floor, Wing C, Suite B, Galana Road, Kilimani, Nairobi, Kenya Ph. +254 (020) 5288627

GALVmed company profile for IAHJ May 2015 publication final draft.indd 1 14/05/2015 16:25:19



and in the environment, of pigs to contaminants which can result in meat contamination. Trials have shown that, when Credence was used in water systems on pig farms, Salmonella contamination of carcasses was reduced from 97% of carcasses down to 25%.

Biosecurity on FarmCredence has the added advantage of its flexibility for on-farm use. By increasing the concentration, Credence can be used as an effective biosecurity and sanitiser product, cleaning floors, animal facilities, equipment such as buckets and calfeterias, and for disinfecting porous surfaces. The product has been routinely used on specialist calf-rearing facilities as a sanitising agent as well as for biosecurity (wheel and foot baths). In these circumstances it is very useful as it requires minimal rinsing only, as the product in a dilute form is safe for drinking. Calves are highly susceptible to gastric disorders, especially under the age of three weeks. The complicated design of feeding equipment for calves makes them a potential vector for disease transmission, especially as busy calf-rearers may use the same feeding bottles or calfeterias between different calves. Trials whereby a dilution of Credence was externally sprayed onto the teats of individual bottles between individual calf milk feeding showed that Credence reduced the number of bacterial colony forming units (CFU) down to a negligible (0.4) amount from swabs, whereas water rinsing actually concentrated bacteria (66 CFU) in the tips of the rubber teats, increasing CFU levels compared to the unrinsed control (38.4 CFU). Keeping bacterial levels under control is important in preventing transfer of disease between animals, and applying Credence as a simple spray to maintain cleanliness between feeding individual calves is crucial to maintaining the health status of the animals during milk intake.

For buildings, it is important to maintain hygiene standards to prevent promotion or transfer of disease. This is especially important where young, old or breeding animals (e.g. kennels) are involved. Swabs taken from animal pens and concrete-floored buildings have shown that up to 75% of swabs analysed via microbiological methods were classified as highly contaminated. In fact,

following basic washdown procedures, no swabs were clear of microbial contamination. However, with Credence used in washdown, around 50% of the swabs were clear of any contamination, vastly reducing the potential for exposure of animals to pathogens. Likewise, in feed and water containers, contamination, even in rinsed vessels, can still be high, with up to 70% of swabs showing a high degree of CFU. When rinsed with Credence, only around 10% of swabs showed any bacterial contamination.

Viruses are a major problem, as they are much more difficult to treat in affected animals. Suitable biosecurity and cleaning regimens are essential to prevent the development of disease. For example, rotavirus is a major disease problem in young animals, especially calves, and parvovirus is a dangerous problem in young dogs in vet clinics and kennels. Controlled laboratory trials on the control of viruses by Credence have been carried out, and demonstrate that it provides good control against both of these viruses, reducing viable viral counts to zero.

ConclusionsUsing an effective disinfectant and water sanitiser on farm or with various animal enterprises is important in maintaining animal health, productivity and welfare. However, most products are either for only drinking water or sanitation or biosecurity. Credence has the flexibility and safety to be used in different concentrations to satisfy a variety of purposes in animal production and rearing. From keeping concrete yards clear of slippery algae, to preventing toxic pathogenic growth in drinking water and for hygienically cleaning down facilities and equipment – Credence is adaptable and easy to use in all these situations. In addition, it is typically much more cost-effective compared to alternatives in the market, and requires less rinsing or concerns regarding toxicity to animals for any remaining active compound.

Dr Lucy Waldron has a PhD in Animal Nutrition and, since 1995, has worked in the animal feed industry in all species, mainly in the development of feeds and speciality ingredients to improve feeding efficiency, welfare and reduce the dependency on chemical and drug prophylactics, including antibiotics and hormones. Within this work she has been involved in research work, new product development, regulatory affairs,

method development and running laboratories, technical support and marketing. In 2005 she moved to New Zealand providing scientific and technical services to the feed and allied industries worldwide, including research projects, student supervision and examinations, data analysis to training, writing and editing services. Dr Waldron is Editor in Chief for two scientific journals (World’s Poultry science Journal and Journal of Applied Animal Nutrition), and is a Registered Nutritionist in the UK and NZ. Dr Waldron has successfully supervised many postgraduate students, has been involved in 48 peer reviewed and conference publications and has written or edited ten scientific books relating to animal nutrition. Email: [email protected]


Corporate Profile

Advancing Animal Health

BRIEF HISTORYMoredun Scientific is a contract research organisation with over 25 years of experience in conducting efficacy and safety studies in livestock for the global animal health industry to GLP/VICH-GCP standards.

Our company is the commercial arm of the Moredun Group supported by world leading scientists at the Moredun Research Institute who have a research focus on the prevention and control of infectious diseases of livestock.

SERVICES OFFEREDOur range of services includes:

Efficacy StudiesWe offer an extensive portfolio of experimental and field infectious disease models for use in client studies, Table 1 details our areas of expertise. We also develop new models and protocols as required to meet the needs of our clients.

We can deliver short- and long-term studies (e.g.onset of immunity, dose determination, dose confirmation, duration of immunity, foetal

protection) and work with a broad range of product types including vaccines, antimicrobials, anthelmintics, and anti-inflammatories.Studies are conducted in our GLP accredited laboratories and in our extensive, flexible animal facilities. Our integrated complex incorporates purpose built farm animal accommodation, an operating theatre and a post mortem suite. A high containment facility is also available that provides optimal controlled environmental conditions for large and small animal species and facilitates research on specified pathogens up to Category 3.

Safety StudiesWe conduct safety and tolerance studies in compliance with relevant international guidelines for pharmaceuticals, biologicals and feed additives.

These include:

• Reproductive performance.• Spread of vaccine strain.• Local and systemic tolerance following single, repeat and

overdose administrations.• Dissemination in the vaccinated animals• Reversion to virulence• Potency and safety of vaccines for batch release.• Environmental safety, especially grazing studies.• Biosafety testing including adventitious agent testing,

biodistribution, etc

Field TrialsWe offer field trials to veterinary good clinical practice (VICH-GCP) to animal health companies requiring UK field trial data from cattle or sheep studies.

Our offering ranges from complete management and delivery of studies to provision of specific elements to meet client requirements including:

• Study design and set up• Protocol development• Site selection• Study monitoring• Study close out

Biological MaterialsCustom preparation of a range of biological materials including antisera, viruses, bacteria and other material for research or commercial use.

Quality AssuranceOur quality systems are a key element of the service we offer to our clients. Our independent quality assurance department has expertise in GMP, GLP and VICH-GCP. We are a member of the UK GLP compliance programme and are accredited for GMP (Testing).We are regularly audited and inspected by both our clients and regulatory bodies to ensure ongoing compliance.

CONTACT DETAILSFind out more about how we can support you:Moredun ScientificPentlands Science ParkBush Loan, Penicuik,EH26 0PZ , UKTel: +44 131 445 6206Email: [email protected]

Respiratory Diseases

Mammary Gland Diseases

Reproductive Diseases

Diseases of the Gut

Parasitic Diseases

Systemic Diseases

Bovine Virus Diarrhoea Virus (BVDV)Bovine Herpesvirus-Type 1 (BHV-1)Parainfluenza Virus Type 3 (PI3)Bovine Respiratory Syncytial Virus (BRSV)Mannhaemia (Pasteurella) haemolytica (Bovine,ovine)Pasteurella multocida (bovine)Mycoplasma bovisActinobacillus pleuropneumoniae (porcine)

Staphylococcus aureus mastitis (bovine)Streptococcus uberis mastitis (bovine)

Bovine Virus Diarrhoea Virus (BVDV)Porcine Reproductive & Respiratory Syndrome Virus (PRRSV)Neospora caninum (bovine)Chlamydophila abortus (ovine)Toxoplasma gondii (ovine)

Escherichia coli (bovine, ovine)Rotavirus G6 & G10 (bovine)Coronavirus (bovine)Salmonella spp. (porcine)

Endo and ecto Parasitic Disease (Bovine, ovine, equine, avian, natural and experimental infections)

Pasteurella trehalosi (ovine)Streptococcus suis (porcine)

Table 1: Disease models & areas of expertise



Exploring Human and Animal Microbiota in Health and Disease

SynopsisRecent progress in next generation sequencing techniques enables characterisation and identification of the microbial populations in several niches of the human and animal body. A growing body of evidence shows that our microbiota plays a role in health and disease. As the sequencing methods are rapidly developing and improving, it is essential to have state-of-the-art bio-informatic platforms and expert knowledge that allow for comprehensive visualisation and biological interpretation of the massive datasets. Future studies, focusing on microbiota interaction with the host and effect on animal host physiology, leave room for exploration and new discoveries within this dynamic field of research. This will help identify novel biomarkers and aid in development of new therapeutic strategies.

BackgroundThe human and animal body contain ten times more microbial cells than their own cells, colonising the intestines, skin, oral and nasal cavities, respiratory tract, encoding 100 times more unique genes than the host cells do. There is a continuous interaction between microbiota, their metabolites and the host, affecting host signalling pathways and physiology. Our knowledge of the important role of microbiota in human and animal health and disease is growing, supported by scientific evidence on regulation of host immune response by intestinal microbiota. This first became evident in studies with germ-free mice (Smith et al., 2007) and antibiotic treatment-studies (Hill et al., 2010). More recently, changes in microbiota have been associated with our mood and behaviour (Diaz Heijtz et al., 2011), as well as the pathophysiology of specific skin and metabolic diseases, such as diabetes, obesity, psoriasis, and atopic dermatitis (Cho et al., 2012). The list of conditions involving changes in microbiota composition is growing, however, the majority of the data published so far mainly demonstrates the associations and not causative relations between microbiota and the host physiology. In order to test the potential of microbiota as promising therapeutic or dietary intervention target, it is important to increase our knowledge and understanding of microbiota profiles in healthy and diseased state, as well as their direct effect on host physiology.

Microbiota Analysis Quantitative PCR Quantitative polymerase chain reaction (Q PCR) is a powerful analysis tool used for quantification of gene expression. Q PCR measures amplification during the PCR as it occurs, thus in ‘real time’, allowing for determination of the total concentration of nucleic acids present in a PCR reaction, which in turn corresponds to the expression of genes analysed. For microbiota analysis, Q PCR can be used specifically

targeting the 16S rRNA gene, allowing for quantification of total microbial population in a sample. In addition, Q PCR primers specifically targeting different microbial species can be designed in order to analyse specific microbial species. However, for each microorganism of interest, specific gene(s) need to be targeted using specific Q PCR primers. Q PCR does not allow for broad profiling of microbiota (16S Illumina sequencing is a better method for profiling, as discussed below). The higher the number of targeted genes required for analysis/quantification by Q PCR, the higher the costs of the analysis. Recently, an alternative method for absolute quantification was developed, namely the digital PCR. This is a new approach for quantification and detection of DNA, which estimates absolute numbers of molecules using statistical methods. The major advantage of digital PCR over traditional Q PCR is that unlike Q PCR, digital PCR does not require references or standards. Digital PCR provides an accurate technology and high reproducibility. In addition, digital PCR is less sensitive to PCR inhibitors which normally cause problems in regular Q PCR reactions, causing lower PCR efficiencies. Thus, for quantification purposes Q PCR or digital PCR are the most appropriate tools at the moment that can be used when specific genes of interest need to be analysed and quantified.

Table 1 16S rRNA Illumina Sequencing Analysis of microbial communities in and on the human and animal body has been performed for a long time, aiming to understand the role of microorganisms in health and disease. Conventional microbiology techniques have been applied previously for microbiota profiling including isolation, culturing and typing of microbial communities, which were often time- and labour-consuming. Moreover, only a limited number of microorganisms were being identified and large-scale profiling of microbial communities was not possible. Nowadays, next generation sequencing (NGS) provides faster and high-throughput profiling of microbial communities, which cannot be achieved by conventional microbiology techniques or Q PCR. NGS has three main pillars of novel state-of-the-art techniques, namely 16S rRNA metagenomic sequencing for microbiota profiling (based on bacteria-specific 16S rRNA gene), shotgun metagenomic sequencing (based on DNA sequencing for profiling of all genes and



organisms in microbial samples), and metatranscriptomics (based on RNA sequencing which allows for gene expression profile and thus functional analysis of microbial communities). For general microbiota profiling, Illumina 16S rRNA-based sequencing is most commonly used. Currently the technique incorporates barcoding of the samples prior to Illumina sequencing, which means that individual ‘barcode sequences’ are added to each sample prior to sequencing, while samples can be distinguished later during the analysis by their specific ‘barcode’. This allows pooling of the samples, thereby increasing the number of samples that can be sequenced during one sequencing run, which in turn decreases the sequencing costs and time. Sequencing is followed by complex analysis of microbiota composition and diversity using bio-informatics pipelines. Shortly, using this technique specific bacterial genes (16S RNA genes) are amplified by polymerase chain reaction (PCR), allowing for generation of many copies of the desired piece of DNA (DNA template) and subsequently analysed by high-throughput Illumina sequencing. Due to the attachment of the specific barcode sequences to unique samples, applying this approach allows for analysis of hundreds of samples simultaneously, thereby using the barcodes to differentiate the sequenced reads from each sample. This provides a large amount of information on microbiota composition and relative abundance up to the genus level. However, massive data output of the technology requires advanced bio-informatic tools and extended analysis methods for comprehensive and clear biological interpretation. Often, multidisciplinary teams of bio-informaticians and microbiologists work together to analyse and interpret outcomes of the Illumina sequencing data. State-of-the-art microbiota profiling and quantification at NIZO food research is one example of where these kind of complex analyses and biological interpretations are performed in collaboration with academic groups (Zeeuwen et al., 2012; Jaeggi et al., 2014). A schematic overview of the microbiota profiling analysis by 16S barcoded Illumina sequencing is illustrated in Figure 1. Sequencing data representing microbiota composition of human or animal samples such as skin or stool samples can be analysed.

Microbiota Analysis: From Massive Data to Comprehensive ResultsThe massive data output of the technology requires advanced interpretation strategies, to extract information from the data in a comprehensive manner. With the use of adequate bio-informatic tools, initial analysis of microbiota composition can provide relevant information visualised in a comprehensive manner, such as indicated by the Sundquist visualisation of jejunal microbiota composition in weaning and post-weaning pigs (Figure 2), making it possible for immediate discrimination between microbiota profile of the two groups, and for detection of pathogenic microorganisms at a glance. However, often plain analysis of microbiota profile is not sufficient. Often, we want to know whether the differences in profiles are statistically significant and whether the relative abundance of specific taxa increases

or decreases. Complex statistical methods can be applied, but the challenge is to visualise these statistical differences and microbiota shifts in a comprehensive manner, such as indicated in Figure 3, where significant differences between male and female microbiota composition are indicated at different taxonomic levels (Figure 3).

In order to explain differences in microbiota composition between groups and link them to health or a specific diseased state, it is important to analyse the microbiota in combination with other relevant parameters such as gender, body weight, age, or specific disease parameters. In addition to that, it is possible to analyse the function of microbial communities present in a sample (metatranscriptomics or metabolomics analysis), which can also be linked to the other outcomes (16S rRNA sequencing and metadata). We have developed methods to not only visualise the composition in a comprehensive manner, but to statistically compare the differences between different groups and link those outcomes to a broad range

Figure 1. Schematic overview of the microbiota profiling analysis by

16S barcoded Illumina sequencing. Sequencing data representing

microbiota composition of human or animal samples (eg. skin or

faeces) can be analysed in combination with other parameters such as

gender or body weight, and age, in order to link microbiota to health

or diseased status, and to interpret the biology behind the changes in

microbiota composition or diversity.

Figure 2. Visual representation of the microbiota composition of a

single or a group of samples from jejunum of weaning (A) and post-

weaning (B) pigs. Starting from the left, the microbial composition is

represented from the least (domain) to most specific taxonomic level

(species). The height of the horizontal bars represents the percentage

of reads that can be confidently placed at that level in the phylogeny

(except for classification at species level, which is only indicative). The

figure illustrates higher microbial diversity in weaning pigs compared

to post-weaning pigs. In addition, infection with Streptococcus suis

in (a number of) weaning piglets is detected (zoomed in part of

the image). The figure is generated applying software previously

published by Sundquist et al. (Sundquist et al. BMC Microbiol. 2007

Nov 30;7:108).


of metadata, indicating health or diseased status of the subjects. This requires complex and extended multivariate statistical analyses and in-depth biological interpretation by multidisciplinary scientific experts. The end result is biological relevance of translated massive amounts of sequencing data, explaining the shifts in microbial composition and its link to health and disease.

ChallengesThe expenses of NGS are decreasing, due to fast and remarkable development and improvements in sequencing technologies, as well as data-production pipelines, allowing for analysis of hundreds of samples in parallel. In vitro models mimicking natural microbial environment and composition of, for example, the gastrointestinal tract or the skin might aid in pre-screening of relevant leads and better selection of products for further in vivo testing. Although the majority of the microbiota research has focused on analysis of stool samples from both human and animals, mimicking this compartment in vitro remains challenging, due to the complex composition and high diversity of the microbial community in the gut. Another challenge is the profiling of the microbiota along different compartments of the gastrointestinal tract. So far, stool samples have increased our knowledge of microbiota and its role in health and disease, however, from animal studies we know that these samples do not represent the microbial communities of different gastrointestinal segments. Currently, novel methodologies are being developed and validated for in vivo sampling of gastrointestinal microbiota. The small intestine, for example, plays a crucial role in food absorption and digestion, as well

as in immunity of the host. Sampling microbiota from the small intestine in a non-invasive manner will help us to gain better understanding of the role and mechanisms of microbiota effects on gut health. At the moment, these methods are being tested and validated in both humans and animals, holding promising tools for future studies.

References1. Hill DA et al. Metagenomic analyses reveal antibiotic-

induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010;3:148–58.

2. Smith K et al. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol. 2007;19:59–69.

3. Diaz Heijtz R et al. Normal gut microbiota modulates brain development and behavior. P Natl Acad Sci USA 2011;108:3047–3052

4. Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012;13:260-270.

5. Deng P, Swanson S. Gut microbiota of humans, dogs and cats: current knowledge and future opportunities and challenges. Br J Nutr 2015;113 Suppl:6-17.

6. Zeeuwen PLJM et al. Microbiome dynamics of human epidermis following skin barrier disruption. Genome Biol. 2012;13(11):R101.

7. Jaeggi T et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015;64(5):731-42.


Sabina Lukovac PhD – Project leader/Scientist Microbiota Department of Health, NIZO food research, obtained her PhD in Gastroenterology. Her work involves studying physiological and molecular mechanisms of human and animal gastrointestinal tract. As project leader and scientist at NIZO food research she is currently working with a team of experts specialized in

host-microbe interactions studying the role of microbiota in health and disease. Email: [email protected]

Figure 3. Visual representation of all taxa significantly different

between two sample groups (comparative). The comparison in

differences between two groups based on relative abundance of taxa

is determined using rank statistics. Different levels of information are

provided in this figure: nodes represent taxa, edges (connecting lines)

link the different taxonomic levels, difference in abundance between

sample groups is indicated by node colour (on a scale from dark red

– white – dark blue), the average abundance of a taxon is indicated

by node size, and the significance of the difference is indicated by the

border width. This specific example indicates significant difference in

microbiota between male and female faecal samples. Red nodes with

wide edges indicate taxa mainly predominant in female samples, while

blue nodes with wide edges indicate taxa significantly predominant in

male faecal samples.

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World-leading Research and Surveillance at The Pirbright InstituteThis article summarises the research taking place at the Institute which is based upon a combination of fundamental and applied bioscience and which utilises unique biological and physical resources. It details some of the virus diseases we are currently working on including diagnosis, host-pathogen interaction and vaccine development, and highlights the impact of our science across the globe on animal and human health.

The Pirbright Institute is a world-leading centre of excellence in research and surveillance of viral diseases of farm animals and viruses that spread from animals to humans. Based in the UK and receiving strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), the Institute works to enhance capability to contain, control and eliminate economically and medically important diseases. This is achieved through fundamental, strategic and applied research in a number of overlapping disciplines, including entomology, epidemiology, genetics, genomics, immunology, mathematical biology, molecular and structural biology, proteomics and virology, utilising unique biological and physical resources. Our research directly contributes to global food security and improves quality of life for animals and people.

In addition to our fundamental and strategic research, the Institute has a surveillance role, providing expertise and capacity for laboratory investigations to monitor livestock for high consequence viral diseases around the world. This is achieved through the Institute’s Reference Laboratories which represent nine viral diseases of livestock and one poultry virus. The surveillance work carried out by the scientists working in these laboratories plays an important role in underpinning global disease control efforts.

Reference Laboratories have skilled and expert personnel, validated diagnostic tests, essential reagents and archive materials (viruses, antisera), and in our case, facilities for experiments in animals, to respond to outbreaks in a timely manner. Our Non-Vesicular Disease Reference Laboratory Group brings together all the Reference Laboratories working on non-vesicular diseases, including bluetongue (BT), African horse sickness (AHS), African swine fever (ASF), morbilliviruses (peste des petits ruminants (PPR) and rinderpest (RPV)) and capripox viruses (lumpy skin disease and sheep and goat pox). The Vesicular Reference Laboratory covers vesicular diseases including foot-and-mouth disease (FMD), swine vesicular disease (SVD), vesicular stomatitis (VS) and vesicular exanthema of swine (VE). The Institute also hosts the Marek’s Disease Reference Laboratory, a viral disease which causes tumours in chickens and turkeys.

Between them these Reference Laboratories provide an essential diagnostic and advice service to the UK Government (Defra), United Nations Food and

Agriculture Organisation (FAO), European Union (EU) and the World Organisation for Animal Health (OIE).

For some of the viruses we work on, our research and the impact on global animal and human health are summarised below. Peste des petits ruminants and foot-and-mouth are two very important diseases which currently have a major global impact on animal health. Whilst these viral diseases are spread through contact and airborne transmission, the Institute also works on many viruses which are transmitted by arthropod vectors. These viruses are able to grow inside vectors such as midges, mosquitoes and ticks, and are then transmitted to animals and humans whilst taking a blood meal. This significantly increases the ability of these viruses to travel great distances in a very short period of time and, consequently, complicates our capacity to defend against them. Our ability to do this requires expertise in diagnosis, entomology, epidemiology, genetics, immunology, mathematical modelling, molecular biology and virology along with essential meteorological input from our collaboration with the UK Met Office, a collaboration which helped us correctly predict that bluetongue would enter the UK in 2007.

Peste des Petits Ruminants Peste des petits ruminants (PPR) is an economically important viral disease of goats and sheep that has spread through large parts of the developing world. It is widespread throughout Africa, Asia and the Middle East and has been endemic in Turkey since 2000, and is now common in North African countries bordering the Mediterranean.

PPR is primarily spread by animal movement and attacks the immune system causing long-term immunosuppression. Clinical signs of disease include pyrexia, ocular and nasal discharges, necrotic stomatitis, diarrhoea and apathy. Mortality rates vary but can reach over 70% and appear to be worse in goats compared to sheep. Live attenuated vaccines are available which provide protection against subsequent infection, but improved vaccines and diagnostics are being developed at The Pirbright Institute to assist in control and eradication (Herbert et al., 2014; Baron et al., 2014). PPR may well become only the second animal disease to be eradicated, being the focus of a global control programme currently being developed by the OIE and FAO.

PPR is related to a similar disease which was seen in large ruminants, Rinderpest, the first animal disease to be globally eradicated in May 2012. The Pirbright Institute was the world reference laboratory for Rinderpest and played an important role in the control and eventual elimination of this very important disease of cattle and buffalo. This was achieved through the development of diagnostic tests and a major global training programme to train scientists around the world how to use the test.



Foot-and-mouth DiseaseFoot-and-mouth disease (FMD) constitutes a major threat to the global livestock industry and is considered one of the most important diseases of livestock animals (Sumption et al., 2012). The disease affects all cloven-hoofed animals and is caused by a highly contagious virus that has seven different serotypes: A, O, C, SAT1, SAT2, SAT3 and Asia 1.

The morbidity rate in susceptible animals can rapidly approach 100% with some strains limited in their infectivity to a particular species. FMD has animal welfare and economic implications, causing distress to affected animals, reduced milk yields up to 25%, reduced growth rates, loss of draught power with working livestock, reduced fertility, and death of young animals. Disruption to farming practices is another major impact of the disease with loss of income and loss of breeding animals, and it can also have an impact on the availability of animal products with countries having to import products. The loss of exports due to trade embargoes can have huge economic consequences and there are additional costs incurred with eradication and control policies (Doel, 2003).

Clinical signs of foot-and-mouth include pyrexia, vesicle formation in the mouth, feet and teats with lethargy and inappetence, as well as excessive salivation and lameness. The virus is present in many secretions and excretions and can be transmitted through a number of routes, including

respiratory aerosols, direct animal-to-animal contact and indirectly via fomites. The virus can survive for long periods of time in the environment, e.g. in slurry for about six months, and has a small infectious dose.

There are several research groups at Pirbright that work on FMD. Our research includes developing and evaluating molecular diagnostic methods, using gene sequencing data to trace the movement of the virus; understanding at a molecular level those parts of the virus that induce immune responses, including protective immunity; understanding the mechanisms of cell entry, penetration of the endosomal membrane by the virus; and induction of virus-induced vesicle formation. We are also working on vaccines and were part of a collaboration that developed a new synthetic vaccine which mimics the outer shell of the virus to initiate an immune response. As live infectious virus is not used to make the vaccine, it can be produced safely and has also been engineered to be more stable in warmer climates were FMD is endemic. Work is continuing to develop a vaccine that will provide cross-protection against multiple serotypes.

African Swine Fever African Swine Fever (ASF) is an economically important haemorrhagic fever of domestic pigs which is caused by a large DNA virus (ASFV). ASFV is a cytoplasmic, icosahedral virus containing a double-stranded DNA genome of 170 to 193 kbp and is the only member of the virus family, the

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Asfarviridae (Dixon et al., 2000). Isolates of this virus vary in virulence, with the most virulent causing 100% mortality.In the wild the natural reservoir hosts of the virus are the warthog (Phacochoerus aethiopicus) and bush pig (Potamchoerus porcus), which show no clinical signs of disease, even when infected with the same highly virulent isolates of ASF that cause rapid, haemorrhagic death in domestic pigs (Oura, Powell et al., 1998). The virus persists in Africa in a natural cycle between the warthog, bush pig and soft tick of the Ornithodoros species (O. moubata and O. erraticus in southern Europe) (Oura, Powell et al., 1998).

The ability of the virus to persist in its hosts shows that it has mechanisms to evade host defence systems and this has been the focus of some of our research. The main target cells for virus replication in vivo are macrophages which have an important role to play in activating and orchestrating the innate and acquired immune responses of the host.

Other areas of our research include vaccine development and transmission studies. Currently there are no vaccines available for ASF but an improved understanding of which of the virus genes are involved in virulence and immune evasion has made the development of a rationally attenuated vaccine a realistic possibility.

African Horse Sickness African Horse Sickness (AHS) is a viral disease affecting equines, and in susceptible horse populations can cause mortality rates >90%, making it the most lethal of equidea infectious diseases (Mellor & Hamblin, 2004). AHSV is transmitted by certain Culicoides species (biting midges) and is endemic in many areas of sub-Saharan Africa, but disease outbreaks have occurred in India, Spain and Portugal.

AHS is characterised by clinical signs which develop as a result of damage to the circulatory and respiratory systems, giving rise to four different forms of the disease. Clinical signs include pyrexia, oedema of the supraorbital fossae, subcutaneous oedema of the head, neck and chest, congested conjunctivae, petechial haemorrhages in the eyes, colic, dysponea and death (Mellor & Hamblin, 2004).

Vaccines are available but current vaccines are live attenuated vaccines and are therefore considered unsuitable for use in non-endemic areas. There are also nine different serotypes and a vaccine against one serotype does not provide protection against others. Scientists at our Institute have generated a promising vaccine candidate for AHS based on a recombinant modified vaccinia ankara virus that expresses the main target of virus-neutralising antibodies, the outer capsid protein (VP2). This approach is being used to develop a vaccine that will protect across multiple serotypes and could be used to allow naturally-exposed animals to be differentiated from vaccinated animals, thereby freeing up trade restrictions that affect countries where the disease is endemic.

BluetongueBluetongue (BT) is an arthropod-borne virus, transmitted by the bites of certain Culicoides species (biting midges). The bluetongue virus (BTV) infects ruminants and camelids (Shaw et al., 2007), and is widely distributed around the world, particularly in warmer countries. There are at least 26 different serotypes of BTV and over recent years there have been a number of incursions of different serotypes into Europe, and the risk of further incursions remains. The significance of this is that infection/vaccination of an animal with one serotype does not confer immunity to any of the other serotypes and so some of our work is using molecular biological approaches to study the proteins and genes of bluetongue virus (BTV).

Knowing the serotype of BTV associated with a given outbreak is important in relation to the possibility that an appropriate BT vaccine might be available, and gives us clues as to the mechanism and route by which the virus had spread. The UK was in a great position to respond to the 2007 BTV-8 outbreak in Europe due to the work The Pirbright Institute carries out on the virus, and we were the only Northern European country that had circulation of the virus in 2007 but then none in 2008. Worldwide, BTV has been estimated to cause losses of $3 billion / year (Mellor & Wittmann, 2002) and since 1998, BTV outbreaks in Europe have resulted in the death of >1.8 million animals (Shaw et al., 2007).

Clinical signs are normally seen in sheep and some species of deer, but occasionally they are observed in cattle and goats, which occurred with the recent incursion of BTV 8 (Shaw et al., 2007; Darpel et al., 2007; Oura, 2011). Typical signs include pyrexia, hyperaemia and ulceration of the oral mucosa, subcutaneous oedema on the face and lips, and inflammation of the coronary bands which may result in lameness, muscle weakness and even death. Our scientists are currently looking at the pathogenicity and transmissibility of


re-assortment strains and looking at the immune responses of ruminants to the virus and to the vector saliva.

Zoonotic Viral DiseasesThe Pirbright Institute also conducts research on viruses that can spread from animals to humans, or zoonoses, including several viruses that cause arboviral encephalitis and arthralgia in mammals. Our research includes mosquito- and tick-transmitted viruses; in particular, the mosquito-transmitted alphaviruses Semliki Forest virus, chikungunya virus, and bunyaviruses including Rift Valley fever virus (RVFV). Our tick-borne virus research includes flaviviruses such as tick-borne encephalitis virus and its attenuated strain Langat virus. Some of our work focuses on the innate immune defence systems activated and antagonised by alphavirus and flavivirus infections in mosquito and tick cells and in mammalian cells, and looks at what proteins some of these viruses interact with and why macrophages are required for the clinical arthralgia and persistence of chikungunya virus. The importance of this research has been highlighted by the recent outbreaks of chikungunya, which have caused millions of cases of arthralgia in the islands of the Indian Ocean, the Indian subcontinent and SE Asia.

RVFV has caused severe periodic outbreaks of acute febrile (and often fatal) disease in both livestock and humans in sub-Saharan Africa and the Arabian peninsula, and is transmitted to susceptible hosts by a large number of mosquito species such as Aedes, Culex, Coquillettidia, Eretmapodite, Mansonia and Ochlerotatus (Chevallier et al., 2010). Virus epizootics are characterised by high mortality rates in young animals, especially sheep and goats, and large numbers of abortions in pregnant animals (Bird & Nichol, 2012). Human disease is usually a febrile self-limiting illness. However, a small proportion of infected individuals can develop severe complications such as encephalitis and haemorrhagic fever. Mortality rate in humans is usually below 1% and occurs mainly through contact with infected animals, but bites of infected mosquitoes can also transmit the virus (Chevalier et al., 2010). Currently there is no effective treatment for humans or animals and the current live attenuated animal vaccine, although effective, can be problematic. Scientists at Pirbright are working on modifying the virus that causes Rift Valley fever to see if it can prevent mosquito transmission. Other research projects will look at vector competence and vaccine development.

References1. Baron, J., Fishbourne, E., Couacy-Hyman, E., Abubakar,

M., Jones, B.A., Frost, L., Herbert, R., Chibssa, T.R., Van’t Klooster, G., Afzal, M., Ayebazibwe, C., Toye, P., Bashiruddin, J., Baron, M.D. (2014). Development and testing of a field diagnostic assay for peste des petits ruminants virus. Transboundary and Emerging Diseases Oct;61(5):390-6.

2. Bird, B.H., Nichol, S.T. (2012). Breaking the chain: Rift Valley fever virus control via livestock vaccination. Curr Opin Virol. 2012 Jun;2(3):315-23. Epub 2012 Mar 29.

3. Chevalier, V., Pepin, M., Plee, L. and Lancelot, R. (2010).

Rift Valley Fever – a threat for Europe? Euro Surveill 15 (11).

4. Darpel, K.E., Batten, C.A., Veronesi, E., Shaw, A.E., Anthony, S., Bachanek-Bankowska, K., Kgosana, L., bin-Tarif, A., Carpenter, S., Müller-Doblies, U., Mellor, P.S., Mertens, P.P.C., Oura, C.A.L. (2007). A study of British sheep and cattle infected with bluetongue virus serotype 8 from the 2006 outbreak in northern Europe. Veterinary Record, Aug 25; 161(8):253-61.

5. Dixon, L.K., Costa, J.V., Escribano, J.M., Rock, D.L., Vinuela, E. & Wilkinson, P.J. (2000). Asfarviridae. In Virus Taxonomy. Seventh Report of the Internaitonal Committee on Taxonomy of Viruses, pp. 159–165. Edited by M.H.V. van Regenmortel, C.M. Fauquet, D.H.L. Bishop, E.B. Carstens, M.K. Estes, S.M. Lemon, J. Maniloff, M.A. Mayo, D.J. McGeoch, C.R. Pringle, R.B. Wickner. London: Academic Press.

6. Doel, T.R. (2003). FMD vaccines. Virus Research. 91(1):81-99.

7. Herbert, R., Baron. J., Batten. C., Baron. M. and Taylor. G. (2014). Recombinant adenovirus expressing the haemagglutin of peste des petitis ruminants virus (PPRV) protects goats against challenge with pathogenic virus; a DIVA vaccine for PPR. Veterinary Research 45:24.

8. Mellor, P.S. & Hamblin, C. (2004). African Horse Sickness. Veterinary Research 35: 445 - 446

9. Mellor, P.S., Wittmann, E.J. (2002). Bluetongue virus in the Mediterranean basin 1998-2001. The Veterinary Journal 164: 20-37.

10. Oura, C.A.L., Powell, P.P. and Parkhouse, R.M.E. (1998). African swine fever: a disease characterised by apoptosis. Journal of General Virology 79: 1427-1438.

11. Oura, C.A.L. (2011). Bluetongue: new insights and lessons learnt. Veterinary Record 168:375-376.

12. Shaw, A., Monaghan, P., Alpar, H.O., Anthony, S., Darpel, K.E., Batten, C.A., Carpenter, S., Jones, H., Oura, C.A.L., King, D.P., Elliott, H., Mellor, P.S. & Mertens, P.P.C. (2007). Development and validation of a real-time RT-PCR assay to detect genome bluetongue virus segment 1. Journal of Virological Methods. Nov; 145(2):115-26.

13. Sumption, K., Domenech, J., Ferrari, G. (2012). Progressive control of FMD on a global scale. Veterinary Record 170(25), 637-639.


Dr Emma Fishbourne BSc (hons), BVSc, PhD, MRCVSAn experienced farm veterinary surgeon providing veterinary support to The Pirbright Institute’s Reference Laboratories, having worked on many of the diseases studied at Pirbright and completed a PhD investigating host immune responses to African Swine Fever Virus.


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Benchmark Holdings PLC Sets Sights

on Integrated Sea Lice Control

As highlighted in the interesting and well-considered article in last month’s publication, sea lice control in Atlantic salmon represents the number one challenge facing salmonid aquaculture, and Benchmark Holdings PLC have set their sights on an integrated, multifaceted control strategy involving all aspects of their business.

Benchmark’s core strategy is driving sustainability throughout the food chain and focusing on the role that good animal health and welfare has in ensuring efficiency and profitability. As Dr Roth outlined, the control of sea lice has become a limiting factor to the growth of the salmon farming industry and global costs to production are estimated at over $480 million.

It is Benchmark’s view that no one “silver bullet” will emerge for the control of this parasite and their unique position of influence at multiple key stages of salmon production will become of increasing benefit to the industry.

Fish Vet GroupEstablished in Inverness in 1995 and one of the founding companies of Benchmark Holidings, a key role for Fish Vet Group has been providing fish farmers with actionable advice towards sea lice control. They acknowledged the role of vets

and health advisors in developing appropriate treatment plans to avoid and delay the onset of resistance to products. Ensuring effective treatment methods and monitoring for resistant lice populations remains a core component of their consultancy work.

Fish Vet Group also worked to ensure that one of the key products against sea lice – Salmosan® – remained on the market. The acquisition of this essential medicine and its responsible distribution and use has led to Salmosan® becoming a market leading sea lice product in all salmon-producing regions.

Bolstered by the success of Fish Vet Group in Inverness, the group has since established sister companies serving in the world’s key salmon-producing regions of Norway, Chile and Atlantic Canada, as well as emerging aquaculture markets such as Asia and Latin America.

Benchmark Animal Health LtdThe need to invest in new and novel sea lice medicines is key to the business’s overall strategy. Benchmark Animal Health Ltd is the group’s product research and development division and currently has over 40 products in development, many of which are focused on sea lice control.

Working with in-house parasitologists, vaccine developers and environmental consultants, and in partnership with research institutions around the world, Benchmark Animal Health Ltd’s goal is to have effective and practical sea


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lice control products which have minimal effect on the environment in which they are deployed.

Biological ControlThe role of cleaner fish in sea lice control is of particular interest to the group’s sustainability science division and in particular their marine research facility – FAI Ardtoe on the west coast of Scotland.

Research undertaken at FAI Ardtoe is aimed at improving the welfare of cleaner fish in salmon farms, as well as focusing on the breeding cycle of the fish to enable them to be utilised without impacting wild fish stocks.

Juvenile Ballan wrasse and lumpfish are already being sold to the industry from FAI Ardtoe and their work alongside the RSPCA has ensured that their eventual use is both effective and welfare-friendly.

Training and EducationBenchmark’s technical publishing division focuses on the important role of education in disease control strategies. Their website thefishsite.com acts as a portal to a wealth of information from disease guides to live webinars. (Benchmark Animal Health Ltd’s leading parasitologist is delivering a free webinar on parasitic infections in Aquaculture on 11th June 2015.)

Through their partnership with The University of St Andrews, Benchmark also offers a range of online aquaculture qualifications from undergraduate certificates through to

MSc-level degrees. It is their belief that educating and informing the industry is pivotal to the control of disease in aquaculture, thereby improving sustainability and profitability.

Breeding and GeneticsBenchmark Holdings PLC is now also the world’s second largest Atlantic salmon egg producer and supply eggs 52 weeks a year from their advanced breeding facilities in Iceland and Norway.

An animal’s innate immunity towards disease challenges is largely driven by its genetic profile. By selecting generations of disease-resistant fish and directly identifying genomic sequences for resistance, the teams at Stofnfiskur in Iceland and Salmobreed in Norway have developed salmon eggs that grow into more robust fish.

This innate robustness has been applied towards sea lice and it is hoped that further generations of salmon can be developed which require fewer medicine treatments.

The breeding and genetics division are also investigating the role that genetic selection and genome marking can have on the survivability of lumpfish at sea. Being able to supply an innately robust cleaner fish population for salmon farms will improve the health and welfare of not only the cleaner fish themselves, but also the salmon with which they cohabit.

For more information on Benchmark Holdings PLC visit www.benchmarkplc.com


Clinical Studies

The Tipping Point in Companion Vector-Borne DiseasesWithin the past year, organisations such as the World Health Organization and the Bill & Melinda Gates Foundation (in partnership with the International Federation on Animal Health--IFAH), chose to recognise vector-borne diseases as a leading global public health topic, respectively. As key takeaways, we’ve learned that vector-borne diseases are gaining scope in awareness, comprise a class of diseases which are entirely preventable to both animals and humans, and affect over one billion people globally. At Bayer Animal Health, our decade-long scientific commitment to educating and informing audiences on what we term “Companion Vector-borne Diseases” (CVBD®) is clearly reaching a tipping-point, which provides an opportunity for veterinarians, human health practitioners, and patients to engage in new conversations, to raise awareness, while shaping policy in a new way. Here we provide a framework on recent CVBD activities that may provide some insight into the CVBD landscape for the next several years.

Describing the Global CVBD FrameworkWithin the past year, organisations such as the World Health Organization (WHO) and the Bill & Melinda Gates Foundation have provided new insights into the global importance and relevance of companion vector-borne diseases for veterinarians, human health practitioners, and the general public. For us at Bayer Animal Health, we’ve added “companion” to the VBD conversation (formerly ‘canine’) to better describe the way in which animals and humans interact in an ecosystem with the ability to share diseases.

Companion is defined, according to the Oxford Dictionaries as, “A person or animal with whom one spends a lot of time or with whom one travels1.” For us, this definition encompasses the fulcrum on which companion vector-borne disease conversations are understood and made plain for the general public to engage and take action: (a) companion vector-borne diseases affect animals and humans; (b) CVBDs may often have zoonotic consequences, where disease is transferred between humans and animals (or vice versa); and (c) humans and companion animals especially are spending more time together — we now live in a world where even our pets own passports and travel!

In this brave new world, pets and their human counterparts are interacting in new ways through global travel, are sharing tables at restaurants and eateries, and in many cases are considered to be family. In this new paradigm, veterinarians are primed to educate and inform pet owners, fellow veterinarians, and their human medicine cohort on the importance of parasite protection to recognise the incidence and prevalence of CVBDs in local ecosystems to advance public health.

Bayer’s Commitment to CVBDsAt Bayer Animal Health, for a decade, we’ve engaged on the

topic of companion vector-borne diseases through the CVBD World Forum — a global working group of leading experts in natural sciences, and veterinary and human medicine, from Europe, the Americas, Asia, Australia and South Africa. This group meets annually to lead a global CVBD conversation, via science, as a response to the increasing global threat of companion vector-borne diseases (CVBD).

As a programmatic addendum to the CVBD World Forum, in recent years, Bayer has also sponsored a web conference (www.cvbdwebconference.com) to share science outside of the CVBD World Forum circles to educate, inform, and engage a broader global audience. Much of this science is captured each year in the online accessible journal Parasites & Vectors. All CVBD articles, in what has become an annual series, have undergone the journal’s standard peer-review process and each article can also be found individually in hard-copy format and is made freely and permanently accessible online, without subscription charges or registration barriers.

Since the inception of the CVBD World Forum, we at Bayer Animal Health have been able to support: the publication of over 70 research articles and scientific reports, with over 350 author citations; and through the CVBD Web Conference format, we’ve been able to annually engage veterinarians in over 100+ countries. The value of this annual content is clearly in its readership, where approximately one-third of the publications to Parasites & Vectors are “highly accessed” — the designation provided for articles which have significant online traffic and relevance to a global scientific audience.

The CVBD Web Conference each year grows in scale and scope and may represent the largest online community of veterinarians worldwide. In 2014, we introduced the One Health concept into the CVBD conversation, while engaging with experts representing the Centers for Disease Control (United States), the National Center for Emerging and Zoonotic Infectious Diseases, and the World Small Animal Veterinary Association (WSAVA). We believe that by introducing the One Health concept and actively engaging physician audiences into the CVBD conversation, we were able to dramatically increase CVBD Web Conference participation (a year-over-year increase of +50%) — the 2014 CVBD Web Conference was viewed by over 12,000 online participants.

From a scope perspective, we have grown the CVBD Web Conference to include veterinarians, human health physicians (and allied health professionals), scientists, policy-makers and in many cases our materials are of interest to the lay public as well. As a first in 2015, the CVBD Web Conference now offers eight different languages: English, Spanish, French, Italian, Dutch, Russian, German, and for the very first time Chinese! By offering the CVBD Web Conference in different languages, we’re able to further develop the opportunity for global public health awareness in countries where Companion


Clinical Studies

Vector-Borne Diseases and their vector insect species reside. Through its online format, the CVBD Web Conference

connects with thousands of veterinarians, providing case studies, engaging roundtable discussions, and educational resources (i.e. media images). The 2015 CVBD Web Conference agenda is formatted for veterinarians, physicians, and the public, where users may, from anywhere in the world, choose their own interactive journey while learning about zoonotic CVBDs through interesting clinical case studies — either animal or human.

2015 CVBD Web Conference Programme:1. 3 Stories – where the moderator invites you to view

three stories where both pet owner and pet have health concerns or are already suffering from a companion vector-borne disease;

2. Clinical Cases – you will be invited to choose one clinical case out of seven (three human clinical cases and four animal clinical cases are available;

3. One Health Case Approach – once logged into the online clinical case study module, either a physician or veterinarian will ask you three questions about your case;

4. One Health Case Journey #2 – you will then have the opportunity to “journey” with a second clinical case;

5. Roundtable Discussion – following the two case studies, you will then be able to join the roundtable discussion — a One Health approach on CVBDs.

As an interactive value-add, CVBD Web Conference

participants are able to engage with experts by submitting questions online and upon completing the online modules receive a certificate of participation.

A Commitment to CVBD Awareness Creates Value At Bayer Animal Health, we believe the results of this decade-long initiative are reaping rewards in awareness while creating a platform where veterinarians, physicians, and scientists engage and learn. At the same time, we’re building a conversation of value to the general public and policy-makers to support better global disease surveillance for CVBDs, which must include public health systems to more accurately track incidence and prevalence data, is able to connect and transfer this data between physicians and veterinarians — information which may benefit the ability to better protect and treat patients, animal or human, against CVBDs.

As a promising indicator representing a true tipping-point in CVBD, One Health, and zoonotic awareness, on campuses worldwide, schools of veterinary medicine and human medical schools are partnering to further develop and implement the “One Health Curriculum”. As noted in the Journal of Veterinary Education (2013; 2), “most veterinarians are very interested in educational activities involving inter-disciplinary interactions with both human and ecosystem health professionals.” Historically, the issue has been meeting with physicians in tandem to advance the One Health conversation, though this is changing. As another flash-

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point adding to the scales representing the tipping-point in CVBD awareness, we also recognise the formation of the first ever One Health conference between the World Medical Association (WMA) and the World Veterinary Association (WVA). These two organisations, respectively, comprise, harness, and strategically implement topics, often within their respective countries, at thought-leadership levels that may have meaningful impact within patient and policy realms.

The WSAVA One Health Committee, established in 2010 “…with a mission of ensuring the prominence of the small companion animal-human interface in the global One Health agenda,” has diligently advanced awareness of CVBDs and One Health. In 2014, the WSAVA One Health Committee met at the renowned Duke Medical Center (Durham, North Carolina, USA) to engage with one of the world’s most influential medical communities directly.

These brief examples highlight the direct level of engagement taking place between veterinarians and human physicians on a topic that supports societies and can better protect humanity against disease.

A One Health Call-to-ActionWe see this tipping-point in companion vector-borne disease awareness as a call-to-action for veterinarians, especially to proactively connect with their human medicine cohort, to advance the One Health curriculum in faculties, and to inform and educate public health frameworks.

Our team at Bayer Animal Health has informed physicians and lay through Zoobiquity: The Astonishing Connection Between Human and Animal Health, by Barbara Natterson-Horowitz (a UCLA Medical Center cardiologist) and Kathryn Bowers (a UCLA professor and journalist), who vividly describe the often astounding and lesser-known connections between human and animal health. As a comprehensive introduction to the complexities and opportunities surrounding the connections between humans and animals, Zoobiquity accurately describes the landscape and begins the deeper conversation between physicians and veterinarians. For those outside of human and animal health industries, this book may also serve as the introduction to understand the fulfilment of a broader life sciences approach for firms, such as Bayer.

The broader acceptance and integration of the One Health curriculum on campuses worldwide provides an opportunity for the next generation of medical leaders to leverage the insights of a combined medical curriculum to advance science through new research topics that explore the human-animal bond from zoonotic, general health, and disease perspectives, respectively.

For those One Health and vector-borne disease specialists and experts, we regularly attend conferences where meaningful data is presented, but this data is often fragmented and/or locked inside a stand-alone database. Until this information is aggregated within a more open-source approach, public health systems will be unable to accurately respond to potential disease outbreaks and unable

to protect the population against the threat of companion vector-borne diseases.

For veterinarians, our role in the clinic, especially, provides us with a broad view of an animal and often their human counterpart. Through the clinic, we are often uniquely positioned to access the psychological, cultural, and health status of not only animal, but often their human companion as well. Through pet owner conversations, we generally better understand the needs of our patients, but how many of us know the steps to take if our patient has contracted a zoonotic vector-borne disease? Are we prepared, as a clinic or profession, to accurately respond or connect our patient’s owners to medical physicians and/or report the incidence of a zoonotic vector-borne disease to the local public health office? And would this public health office then know how to respond? Despite the responses to these questions, we veterinarians are standing on the front lines of public health disease surveillance, and uniquely aligned to communicate with physicians and the public.

References1. Oxford English Dictionaries accessed online at http://

www.oxforddictionaries.com/ on March 3, 20152. Journal of Veterinary Education http://www.ncbi.nlm.nih.

gov/pubmed/23475413

Prof. Norbert Mencke, DVM is the Head of Global Communications & Public Affairs at Bayer Animal Health. Dr. Mencke has been with Bayer Animal Health since 1989, in roles which have included Head of Global Veterinary Services and Head of the Target Animal Screening Laboratory at Bayer’s Institute for Parasitology.

Clinical Studies

Dominick Kennerson joined Bayer Animal Health Global Communications in 2013 and represents the firm’s companion animal communications. Dominick is a life sciences healthcare professional with deep experience in multi-national healthcare systems and companies.

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Clinical Studies

The Role of Feed Enzymes in Poultry Gut HealthThe Links Between Enzymes, Ingredient Variability and Gut Health

First introduced into the poultry industry in the 1980s, enzymes are now used in over 90% of all broiler diets. Feed enzyme application in diets for poultry is also one of the most researched fields in poultry science today, with over 2500 independent enzyme trials conducted with broilers alone (Rosen, 2010).

Much of this research has been focussed on phytase and as a result, its mode of action is comparatively well understood. The penetration of carbohydrase and protease enzymes into poultry feed has been slower, particularly in markets that rely less on ‘viscous’ wheat- and barley-based diets.

However, the tide is turning as producers try to maximise poultry output to cope with increasing demand and also minimise the impact of variability - in terms of feed cost and quality - on profitability. The use of cheaper, more fibrous but protein-rich feed ingredients, such as canola and sunflower meal, and dried distillers grains with solubles (DDGS), to bring down the cost of feed as raw material costs fluctuate unpredictably, has meant that feed quality is more variable. The drying process applied to DDGS can, for example, result in damaged proteins that greatly reduce the digestibility of certain amino acids such as lysine (Parsons et al., 2006). Also, the digestible amino acid profile of the diet will shift because a larger percentage of dietary protein comes from these fibrous ingredients, which generally have lower protein digestibility compared to more traditional protein sources. The increased presence of insoluble fibre leads to maintenance energy losses as the bird tries to deal with indirect effects of the anti-nutrients or extract energy from the substrates in this more complex feed. More undigested protein in the gastro-intestinal tract (GIT) may also be a predisposing factor for microbial challenges, as we will see later in this article. The impact of differing harvest and cultivation conditions on the nutritional quality of ingredients, even in simple, high-quality diets based on corn is starting to be better understood as companies offer easy-to-use services to compare samples regionally as well as on a per-country basis. It is clear from the results of this type of analysis that corn’s feed value is often variable, and sometimes just as variable as viscous grains such as wheat.

Dealing with substrates through exogenous enzyme application is not a new concept; since the early 1980s, xylanases and beta-glucanases have been successfully utilised to maximise nutrient digestibility and overcome the challenges posed by viscous cereal grains. Similarly, the first phytase enzymes to the market were launched around 20 years ago, although at that stage less was known about phytate as substrate. The difference today is that more is known about the structural complexity of substrates such as arabinoxylan, a key component of the non-starch polysaccharides (NSP) content of many raw materials. The

accumulation of soluble arabinoxylans in the alimentary tract results in water retention and increases the viscosity of digestive contents. It is well documented that high digesta viscosity has a negative effect on nutrient digestion and absorption of wheat-based diets (Choct & Annison, 1992a). Soluble arabinoxylan makes up around 30% of the total arabinoxylans in wheat and rye (Table 1) and is the reason for the ‘viscous’ nature of these grains when present in the gut. This viscosity effect, which is more detrimental in poultry than pigs, is known to negatively influence the gut micro-flora in terms of its content and composition.

Table 1 : Total arabinoxylan content of various feed raw materials and its solubility (%)

Another cause of variability that we have learnt more about in the past few years is phytate. Phytate is now seen as a potent anti-nutrient which can form complexes with minerals and peptides, reducing the bird’s utilisation of protein and energy. Research has also suggested that phytate is also responsible for increasing the endogenous losses of minerals and amino acids (Onyango et al., 2009). The combination of these factors and the fact that the bird cannot break down phytate sufficiently with its own enzymes often results in variable negative effects on performance when phytase is sub-optimally used, even when available phosphorus levels are sufficient.

As diets have become more complex and variable, levels of phytate have increased in some diets (see Figure 1), so the need to find more effective ways of tackling dietary phytic acid has increased. The latest Buttiauxella-based phytases offers additional benefits over E. coli equivalents, including much higher activity earlier in the digestive tract, minimising the anti-nutrient effects of phytate and maximising the time available for nutrient digestion and absorption. Contrary to the common paradigm, the risk for the producer is higher with the use of standard doses (300 FTU/kg for layers and 500 FTU/kg for broilers) than at higher doses of this type of advanced phytase (>1000 FTU/kg). This is because the impact of these highly bio-efficacious Buttiauxella phytases


Corporate Profile

Farma Research Animal Health is an independent Contract Research Organization that focuses on veterinary research. We have over 30 years of experience in projects concerning veterinary medicines and feed additives.

Farma Research Animal Health has a thorough knowledge of EU regulations and guidelines.

In collaboration with our partners ABL and Wil Research, we offer the following services:

• Consultancy• Animal Studies• Bio-analytics• Regulatory Affairs• Pharmacovigilance

Animal studiesWe conduct studies in companion animals and livestock, according to GLP and VICH-GCP standards. Studies are conducted in dog, cat, cattle, horse, swine, sheep, poultry, etc. The studies in dogs and cats are conducted in a GLP accredited laboratory. The studies in livestock are conducted, in compliance with GLP, at farms under normal zootechnical conditions.

Types of studies are:• Pharmacokinetic studies: bioequivalence,

bioavailability, pharmacokinetics• Target animal safety studies. Systemic tolerance, local

tolerance• Residue studies: tissues, milk, eggs• Palatability studies• Efficacy studies

We are very flexible concerning type of study, in numbers of animals, in housing, etc. Animals can be housed individually, in groups or on multiple farms.

Examples of non-standard studies performed are:• Parallel bioequivalence studies in 90 calves or 80 sheep• A tissue residue depletion study in 16 healthy milking

cows, to be subsequently included, just after calving• A 5-months explorative safety/efficacy study in more

than 80 healthy milking cows divided over 2 farms.• (Reproductive) safety studies with 20 pregnant sows

and more than 200 piglets• Long lasting safety and residue studies in chickens and

pigs (3-6 months)

Bio-analyticsFarma Research Animal Health has an extensive experience in bio-analysis of veterinary compounds in many matrices (muscle, kidney, fat, skin, liver, plasma, milk, eggs). Nowadays we collaborate with Analytical Biochemical Laboratory (ABL), located in the Netherlands too.

ABL works both for human and veterinary pharmaceutical companies and contract research organizations. For this work, ABL is able to claim GLP and/or GCP. Main techniques are chromatography and immunochemistry. ABL has experience with all possible human and animal biological matrices, including blood, plasma, serum, urine, faeces, tissues and milk.

Good Laboratory Practice (GLP)Most studies are performed in compliance with OECD Principles of Good Laboratory Practice.

Owners of Farma Research Animal Health have more than 20-years’ experience with GLP in veterinary studies. The organization is inspected by the Dutch GLP inspectorate on a regular base (once in 2 years). Additionally the organization is audited frequently by sponsors. In GLP multi-site studies we are your contact. Farma Research Animal Health acts as Test Facility, responsible for Lead Quality Assurance and Study Director. In these studies we are responsible for the total organization and we prepare the study report.

Studies performed by us have been used in registration dossiers submitted all over the world.

Regulatory affairs Farma Research Animal Health prepares complete or partial dossiers for the registration of your veterinary medicinal product, including all the Expert Reports required and provides ongoing assistance during the registration procedure.

Over the past years, Farma Research Animal Health has significantly contributed to successful (European) registrations of animal medicines.

PharmacovigilanceFarma Research Animal Health offers pharmacovigilance services.

Contact detailsIf you are interested in how we can support you:

Farma Research Animal Health

Toernooiveld 300-H6525 EC NijmegenThe Netherlands

Phone: +31 24 3505574Email: [email protected]: www.frah.nl


Clinical Studies

seems to be higher at low doses because of the steep slope of the initial response. Taking that view means that considerable opportunities for profitability through addition over standard doses are missed, particularly where the diet is particularly variable and the bird requires additional nutrients to achieve maximum performance. For example in laying hens, where 300 FTU/kg has been considered to be the optimum phytase dose, recent research using a Buttiauxella phytase in a wheat-based diet with alternative ingredients showed that the best return on investment to the producer occurs at a much higher range of 580 – 985 FTU/kg (Barnard et al., 2014, Figure 2).

Figure 1- Levels of phytate found in commonly-used feed raw materials. Number of samples used are provided in parentheses (Harvest data, Danisco Animal Nutrition, 2013).

Figure 2 - A value-based approach to determining the most profitable phytase dose for laying hens fed wheat-based diets with alternative ingredients (Barnard et al., 2014).

The Impact of Variability on Gut MicrobiotaDietary variability, in terms of the type, amount and availability of undigested nutrients or ‘substrates’ in certain sections of the gastro-intestinal tract, has been shown not only to impact digestibility and growth performance (Romero et al., 2013; 2014) but also to cumulatively impact the composition of the microflora and the populations of non-beneficial bacteria in the intestine. Both Dahiya et al. (2007) and Drew et al. (2004) have pointed to increases in undigested protein substrate as a predisposing factor for dysbacteriosis,

in particular relation to necrotic enteritis. Numerous scientists, including Choct (2009) and Hoerr (2010) have made the connection between achieving an optimal gut structure and digestive function through nutrition, and achieving maximum healthy growth potential and profitability.

Feed enzymes offer producers a measurable and standardised means to target and hydrolyse substrates in a format that can work in the animal intestine after pelleting. A better understanding of the mode of action of carbohydrase and protease enzymes in particular has led to the development of more bio-efficacious enzyme combinations that complement the animal’s endogenous enzymes, tackling specific substrates but in a synergistic manner.

We know that enzymes such as xylanase have a significant impact on the breakdown of insoluble arabinoxylans (hemicellose) in both corn- and wheat-based diets (Kiarie, Romero & Ravindran, 2014). Research has also demonstrated that protease improves the digestibility of fibre, possibly through the breakdown of structural proteins in the cell walls (Colombatto & Beauchemin, 2009). Recently, it has also been demonstrated that xylanase and protease work additively in combination to release pentosans and protein from corn-DDGS (Pedersen et al., unpublished). Olukolsi et al. (2012) demonstrated increments in the disappearance of xylose and arabinose in response to proteases in broiler chickens. Even though it is normally assumed that the effects of proteases are confined to protein digestion, it is now clear that they also have effects in the solubilisation of fibre, which can have nutritional implications, as well as effects in promoting a healthy microbiota in the intestine of chickens.

Recent research (Figure 3) has shown how combinations of xylanase, amylase and protease work together:

• Xylanases break down non-starch polysaccharides (NSPs), including soluble and insoluble arabinoxylans, in the fibre fraction of plant cell walls (Barletta, 2010), as well as reducing digesta viscosity and improving digestibility, nutrient release and feed passage rates (Choct, 2006; Mirzaie et al., 2012). This ‘door opening effect’ makes cell components more accessible by other enzymes (Cowieson, 2005).

• Amylases act on starch, increasing its hydrolysis and thereby improving its digestibility. Its actions complement the secretion of endogenous amylases by the bird, freeing up energy to fuel growth (Gracia et al., 2003; Barletta, 2010). Increasing starch digestibility also reduces the presence of glucose as a potential substrate for non-beneficial bacteria in the latter part of the GIT (Anguita et al., 2006).

• Proteases increase protein digestibility through hydrolysis of storage and structural proteins, and disrupts interactions of proteins with starch and fibre in the diet. Additionally, they target other anti-nutritional factors in the diet e.g. residual trypsin inhibitors and lectins in soybean meal and some other vegetable proteins, thereby improving nutrient digestibility (Yu et al.).


Clinical Studies

The synergistic impact achieved by using these enzymes in combination is due to the fact that the effects of the enzymes are not limited to their specific substrate. Xylanase, for example, disrupts fibrous fractions, increasing protein digestibility by making the protein substrates more accessible to other enzymes. This not only maximises growth performance but also means there are fewer undigested fractions that could act as a substrate for non-beneficial bacterial species. Its ability to reduce the viscosity of the digesta also enables other endogenous and exogenous enzymes to access previously unavailable substrates, which results in increased nutrient digestion (Satchithanandam et al., 1990).

Figure 3 – The impact of xylanase, amalyse and protease addition to 56 different corn samples included in broiler diets reduced the variation in performance measured as FCR (Romero et al., 2011).

Recent research focussed on the impact of a xylanase, amylase and protease combination on more complex and challenging diets has also demonstrated the positive effects of carbohydrase and protease enzymes in combination. Ileal digestible energy from starch, fat and protein in broilers fed corn- / soy-based diets with added DDGs and canola was incrementally improved, showing a greater enzyme response than in the simpler corn / soy diet. The results also demonstrated the additive effect of the protease enzyme on top of the xylanase and amylase enzymes (Romero et al., 2014, Figure 4).

Phytase offers a relatively cheap, affordable way to eliminate the anti-nutritive effect of phytate and also maximise nutrient uptake, and ileal protein and amino acid digestibility. It is clear from a wide body of research that phytase, carbohydrase and protease enzymes have the significant potential to improve energy and amino acid digestibility of broiler diets. It is also very apparent that these enzymes should not be given arbitrary fixed matrix values that are independent of the substrate levels and inherent digestibility of the diet to which they are added. When used at the correct levels to tackle the various substrates in the diet,

carbohydrase and protease combinations with a Buttiauxella-based phytase add even more value, resulting in radical feed quality and body weight/calorie conversion improvements which could save ~$80,000 - $100,000 per million birds produced through optimised nutrient availability (based on 2013 feed costs).

The potential absolute digestibility of a raw material is obviously impacted by a number of factors over and above raw material quality and the presence of anti-nutrients, such as the health status of the animal and its age, but generally the variation in the nutritional value of ingredients and bird performance will be reduced with the use of multi-enzyme combinations

Figure 4 - Contribution of protein, starch, and fat to the apparent ileal digestible energy of corn- and wheat-based broiler diets in response to exogenous xylanase and amylase without or with protease (Romero et al., 2014).

Healthy Enzyme Benefits Enzymes have been shown to work both in the foregut and hindgut of chickens. During the transit of digesta in the duodenum, jejunum and ileum, they remove fermentable substrates that could impact digestibility and impact gut microbiota balance. During the caecal phase, degradation products of hemicellulose, such as pentose oligomers, are fermented by caecal bacteria. Xylanase not only reduces digesta viscosity through the hydrolysis of soluble arabinoxylans in the small intestine but this process also generates arabino-xylo-oligosaccharides (AXOX) to be fermented, particularly in the caecal phase. These act as prebiotics, selectively stimulating the growth of beneficial bacteria. They also produce short chain fatty acids (SCFA) in the intestine, which in turn can be utilised as an energy source by the animal. Health-related effects of cereal-derived AXOS in humans are well documented. In chickens, they have also been shown to reduce Salmonella in the bird’s caeca, cloaca and spleen (Eeckhaut et al., 2008). Kiarie . (2014) have shown increments in caecal production of volatile fatty acids (VTAs) due to application of xylanase in wheat- and corn-based diets. Additional SCFA production has also been noted in the caeca of broilers fed wheat-based diets supplemented with xylanase from Trichoderma ressei and protease from B. subtilis (Choct et al., 2009). Fernandez et al. (2000) also demonstrated that xylanases have prebiotic effects in poultry and noted


Clinical Studies

that their application in wheat-based diets improved bird performance in a Campylobacter jejuni challenge model.

Undigested protein, which can be tackled through protease and protease and xylanase combinations, has also been suggested as a factor linked to the establishment of Clostridium perfringens, coccidiosis, and associated necrotic enteritis episodes in chickens (Williams, 2005).

In addition, Dahiya et al. (2007) discussed the role of undigested protein and starch as a predisposing factor for dysbacteriosis related to necrotic enteritis, while Peek et al. (2009) noted that protease addition improved the performance of chickens challenged with Eimeria spp. (one of the pre-disposing factors in necrotic enteritis). As well as the indirect effect that protease has on reducing undigested protein, some authors have suggested that a direct effect of these enzymes in stimulating the production of mucus could be associated with better responses of chickens in response to coccidial challenges (Peek et al., 2009), although this hypothesis remains to be confirmed.

Enzymes - Not the Only Tool for Supporting a Healthy Gut MicrobiotaTaking the concept of multi-enzymes supporting a healthy gut microbiota one step further, recent research has looked at the potential c o m p l e m e n t a r y modes-of-action of carbohydrase and protease enzymes and probiotics, not only in further improving digestibility but also improving liveability. In trials with non-challenged broilers fed a corn / soy diet containing some fibrous cereal by-products, Romero et al. (2013) observed significant incremental increases in nitrogen-corrected apparent metabolisable energy (AMEn) with additions of a three-strain Bacillus probiotic and xylanase, amylase and protease enzymes.

ab Values without a common superscript are significantly different (P<0.05)The next step was

to check whether the benefits could extend to a specific necrotic enteritis (NE) challenge model. The improvements in body weight corrected FCR in both experiments with the combination product gave net benefits of 14% in relative cost per kg live weight gain versus the challenged control at current feed prices, illustrating the strong economic value of this concept under experimental NE challenge conditions (Southern Poultry Research, Georgia, USA, 2013, Figures 5 and 6).

In another study containing phytase in addition to a xylanase, amylase, protease and Bacillus combination, a cost comparison with an antibiotic growth promoter (based on current price of live weight of chickens and feed cost) showed that the enzyme and probiotic combination resulted in 2.5% higher gross profit (DuPont internal data). Bans are already in place on the use of the antibiotics as growth promoters (AGPs) in the EU and South Korea, and it seems increasingly likely that market pressure for AGP removal in poultry production in places like the US will limit their use. The time is therefore right to identify an alternative means of improving liveability, as well as performance and profitability.

With pressure constantly on the poultry industry to reduce production costs without compromising bird performance or gut health, the use of multi-enzymes, with or without other additives such as probiotics, appears to offer good opportunities to unlock the potential nutritive value and healthy potential of feed, and offer associated cost savings.

References available on request from [email protected]

Luis Romero, Ph.D. Animal Nutrition, Global Innovation Lead, Danisco Animal Nutrition (part of DuPont Industrial Biosciences)Dr. Luis Romero has worked in the animal nutrition industry since 2000. Before starting his career, he studied Animal Sciences (with a focus on cytogenetics and agricultural marketing) at the National University of Colombia and then took a PhD focussing on the bio-economic links between broilers and

breeders at the University of Alberta. He also received training on production economics at the University of Alberta to complement his animal science studies. Dr Romero then worked for 5 years managing commercial poultry production operations, giving him an understanding of the challenges facing customers and possible solutions. He was employed at Danisco Animal Nutrition from 2008 to 2011, and then transitioned when Danisco became part of DuPont. During his time with Danisco/DuPont, he has managed worldwide teams, working on large research projects (from idea to prototype, internally and with external academic partners) and IP strategy. His strong knowledge of biotechnology applications, statistics and production economics, married with a highly tuned commercial focus, enables him to deliver revenue growth for customers.Publications, citations, articles authored/co-authored: >10 peer reviewed, >15 invited talks, > 35 conference abstracts, numerous trade press articles and 4 patentsAffiliations: Poultry Sciences Association (PSA), World Poultry Science Association (WPSA)

Figure 5

Figure 6

Figures 5 and 6 - Bodyweight gain and FCR in unchallenged birds compared with birds challenged with Clostridium perfringens on days 20-22 -/+ three-strain Bacillus probiotic and a xylanase/amylase/protease enzyme combination. Two experiments at Southern Poultry Research, Georgia, USA.


Chapter Title

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Clinical Studies

The Influence of MOS on Sow and Piglet Performance

Mannanoligosaccharides (MOS) are complex carbohydrates derived from the cell wall of selected strains of the yeast Saccharomyces cerevisiae. The primary effects of MOS on the performance of animals results from several clearly defined modes of action:

• Agglutination and attachment of certain pathogenic bacteria, such as E. coli and Salmonella, by MOS, thus improving the microbial status of the gastro-intestinal tract

• Modulation of the immune system • Improved intestinal function or gut health • Better nutrient provision and utilisation for production

purposes since less nutrients are needed for the activation of the immune system.

All of these effects result in improved performance, and extensive reviews of the scientific literature by Miguel et al. (2004) and Rosen (2006) have shown that both growth rate and feed efficiency have been improved when the MOS product Bio-Mos® (MOS; Alltech Inc.) was provided in the diets of piglets post-weaning and during the growing-finishing period.

The purpose of this paper is to review all available sow studies for the response to MOS and to suggest possible modes of action for any positive response obtained.

Description of TrialsA description of the trials carried out is presented in Table 1.

Table 1. MOS in sow diets: Description of studies and measurements

Key to trials:In total, 12 trials have been carried out: four studies have been conducted at universities / research stations, whereas the remainder were carried out as commercial trials, often under

the supervision of trained experimental technicians. Litter size was not recorded in Trial 1 and in Trial 6; only the number of piglets weaned was recorded. Trial 1 used only 24 sows and this is too few to support confidence in the data, especially in relation to litter size. The birth weight and weaning weight of the piglets were recorded in all trials with the exception of Trial 1, where only weaning weight was recorded. In four studies, colostrum samples were taken and analysed for their content of immunoglobulin: IgA, IgG and IgM.

Effects on Litter Size and Pre-weaning MortalityThe effects of MOS in sow diets on litter size are presented in Table 2. There was no significant (p>0.05) effect of the inclusion of MOS in the diet of the sow on the number of piglets born alive compared with the control animals: 11.24 (±1.33) vs 11.14 (±1.18), respectively.

The number of piglets weaned per litter was numerically higher when sows were fed MOS: 10.11 (±1.09) vs 9.67 (±0.74), respectively, but the overall difference was non-significant (p<0.05). The increase in the number of piglets weaned per litter when adjusted for differences in the number born alive was 0.32 (±0.34) (range 0.0 to 1.27).

The increase in the number of piglets weaned when sows were fed MOS resulted from a 21.0% decrease in pre-weaning mortality: 11.5 (±1.85) vs 9.13 (±1.67) %. The effect was cumulative and independent of litter size (Figure 1).

Figure 1. The effect of MOS on pre-weaning mortality1. Newman and Newman (2001)

2. O’Quinn et al. (2001)3. Maxwell et al. (2003)4. Barac et al. (2002)5. Spring et al. (2003)6. Fetcheverry and Soriano

(2003)

7. Medel et al. (2004)8. Babinsky (2005)9. Le Dividich et al. (2009)10. Le Dividich et al. (2009)11. Gomez and Landeau

(2009)12. 12) Czech et al. (2009)


Clinical Studies

Table 2. The effects of MOS on litter size and pre-weaning mortality Effect on Birth Weight and Weaning WeightThe effect of MOS in the diet of the sow on piglet birth weight and weaning weight is presented in Table 3.

The inclusion of MOS in the diet of the sow resulted in the mean birth weight increasing from 1.46 (±0.11) to 1.52 (±0.11) kg (p>0.05). Indeed, in several of the individual studies, this difference was significant (p<0.05). This increase in birth weight is noteworthy, and one interpretation may be that nutrient availability is increased in the MOS-fed sows, which results in greater foetal and tissue accretion and hence piglet birth weight.

Similar to birth weight, the inclusion of MOS resulted in an increase in mean weaning weight across all trials: 7.17 (±1.28) vs 6.87 (±1.25) kg (Figure 2); and again, for several of the trials, this difference was significant. When corrected for difference in birth weight, the increase in weaning weight was 0.26 (±0.23) kg per piglet.

Figure 2. The effect of MOS on the weaning weight of piglets

Table 3. The effect of MOS on piglet birth weight and weaning weight

Colostrum Quality and QuantityIt has been hypothesised that the improvement in the weaning weight, and hence growth rate, of the piglets from sows fed MOS may result from an improvement in colostrum quality. Colostrum samples were therefore taken within the first 24 hours of farrowing and the concentration of IgA, IgG and IgM analysed (Table 4). Indeed, in one study (Le Dividich et al., 2009), Study 9/10, the rate of colostrum production was also measured.

Within several of the studies there were significant increases (p<0.05) in individual Ig concentration. One study reported a significant increase in IgA and four studies indicated significant increases in IgG and IgM. Across all trials where colostrum composition was measured, there was a 5.8, 8.1 and 15.1% increase in the concentration of IgA,

A212 Alltech TheInfluence MOS FINAL (2)_May2015-GOOD TO PRINT 4

Table 2. The effects of BM on litter size and pre-weaning mortality

Trial No. Control BM

1 Total born Born alive Weaned Mortality (%)

2 Total born - - Born alive 9.96 9.78 Weaned 8.84 8.89 Mortality (%) 11.27 9.09*

3 Total born 12.47 12.13 Born alive 11.00 10.76 Weaned 9.34 9.39 Mortality (%) 15.10 12.70

4 Total born - - Born alive 10.53 10.08 Weaned 9.49 9.26 Mortality (%) 9.88 8.13


6 Total born - - Born alive - - Weaned 10.10 10.90 Mortality (%) 9.20 6.50






12

Total born - - Born alive 12.64 13.47 Weaned 11.20 12.38 Mortality (%) 11.39 8.09

Mean

Total born Born alive 11.14 (±1.18) 11.24 (±1.33) Weaned 9.67 (±0.76) 10.11 (±1.09) Mortality (%) 11.56 (±1.85) 9.13 (±1.67)

* Denotes statistical difference (p<0.05)

A212 Alltech TheInfluence MOS FINAL (2)_May2015-GOOD TO PRINT 5

Effect on Birth Weight and Weaning Weight The effect of BM in the diet of the sow on piglet birth weight and weaning weight is presented in Table 3. Table 3. The effect of BM on piglet birth weight and weaning weight

Study Control BM

1 Birth weight (kg)

Weaning weight (kg) 6.37 7.61*

2 Birth weight (kg) 1.66 1.70



Weaning weight (kg) 5.63 5.77





6 Birth weight (kg)












12a Birth weight (kg) 1.61 1.57


12b Birth weight (kg) 1.48 1.57


Mean Birth weight (kg) 1.46 (±0.11) 1.52 (±0.11)

Weaning weight (kg) 6.87 (±1.25) 7.17 (±1.25)

* Denotes statistical difference (p<0.05)


IgG and IgM, respectively, in the colostrum within the first 24 hours post-farrowing for sows fed MOS compared with control-fed sows.

One interesting feature of Trials 9 and 10 by Le Dividich

et al. (2009) was that in addition to collecting colostrum, the growth rate of the piglets within the first 24 hours post-birth was recorded, and since litter size was known, the production of colostrum was calculated (Table 5). Colostrum production was significantly increased (p<0.05) in the first 24 hours post-partum when MOS was included in the diet of the sows, by 16.6% and 13.1% in the French and Canadian trials, respectively. This significant increase in colostrum production resulted in a significant improvement in growth rate in the 24-h period post-birth. However, the improvement in growth rate may not solely be associated with the increase in colostral immunoglobulins, but also with the additional nutrient supply, as well as other metabolic stimulants at the higher colostrum intake. However, other nutrients present in colostrum were not analysed.

Table 5. The influence of the inclusion of MOS on colostrum production and piglet growth rate (Le Dividich et al., 2009) Other EffectsFew studies have measured the subsequent or long-term effects on reproduction. However, in the study of Quinn et al. (2001) there was a reduction in the weaning to oestrus interval from 7.27 to 5.20 days (p<0.01) when MOS was included in the diet during both gestation and lactation. In addition, on rejoining the breeding herd, 88% of the MOS-supplemented sows returned to oestrus compared with only 77.6% of the control sows. Maxwell et al. (2003) found a 0.5-day reduction in the wean-oestrus period from 6.41 to 5.96 days.

In terms of piglet performance, the benefits of MOS in the sow diet may extend beyond weaning. In the studies of Medel et al. (2004), MOS had a greater effect on the performance of the piglets post-weaning when MOS was added to the sow diet than when added to the weaner feed. In the post-weaning period (28-60 days of age), the growth rate of piglets from sows fed MOS was 363 g/day compared to 339 g/day for those from control sows. This 7.1% increase in growth rate of piglets post-weaning compares with a 4.2% increase reported by Miguel et al. (2004) for a review of the

extensive data available. Feed conversion efficiency was also enhanced from 1.50 to 1.39 g/g, respectively. This suggests a ‘carry-over’ effect into the period post-weaning for piglets from sows fed MOS.

Economic BenefitsBased on the mean responses from the 12 studies investigated and the various costs of production, as well as the cost of MOS, it has been possible to calculate the cost-effectiveness of its inclusion in sow rations.

A number of assumptions have been made which have been based on sound scientific principles.

1. Cost of MOS inclusionThe recommended MOS inclusion rate is 1 kg/ton during both lactation and gestation.• Sow consumes 1.2 t of feed per year. Therefore MOS

inclusion = 1.2 kg• Cost of MOS = $5.50/kg Total cost of inclusion =

$6.60/sow/year

2. Effect on litter size• Across all trials the improvement on litter size was 0.32

/ litter• If we assume 2.4 litters/sow/year, this equates to an

extra 0.77 piglet/sow/year• Value of piglet at weaning = $40. Therefore value of

extra piglets = $30.8/sow/year

3. Effect of enhanced piglet weaning weightIt is generally recognised that for each additional 0.1 kg in piglet weaning weight the animal takes 1 day less to slaughter (Wolter et al., 2001; Smith et al., 2007).• Across all trials the mean improvement in weaning

weight was 0.30 kg/pig.• Thus, piglets take 3 days less to achieve slaughter weight.• This represents 3 days less feed for maintenance;

equivalent to 1 kg of feed per day = 3 kg of feed @ $0.2/kg = $0.60 / pig

• If 20 piglets are sold per sow per year = $0.6x20 = $12/sow/year

Clinical Studies

* Denotes statistical significance (p<0.05)

Table 4. The effect of Bio-Mos on colostrum quality


4. Reduced overall costs• Pigs take 3 days less to slaughter and this represents 3

days less production costs @ $0.1/kg = $0.3/pig = $6/sow/year ($0.30x20)

5. Net return• The overall benefits of MOS in the sow diet = $30.8 + $12

+ $6 = $48.8/year• The cost of MOS inclusion in the sow diet is $6.6/sow/

year• Thus, the net return per sow per year is: $48.8 - $6.6 =

$42.2/sow/year• The calculated return over investment (ROI) = $48.8÷6.6

= 7.4 : 1

These calculations do not consider any additional benefits associated with a reduction in the period between weaning and oestrus.

Overall ConclusionsThe results of the review show that when MOS is included in the diet of the sow during gestation and lactation, the following responses were recorded:• An extra 0.32 piglets weaned per litter = 0.77 piglets/

sow/year• An improvement in piglet weaning weight of 0.30 kg• An increase in the concentration of immunoglobulin in

colostrum• An increase in colostrum production during the first 24

hours post-partum• Improved piglet growth rate in the first 24 hours of life• A ‘carry-over’ effect with higher performance of piglets

post-weaning• Reduced wean-oestrus period = fewer empty days = more

litters born• A very cost-effective response with an ROI of 7.4:1

These responses may be associated with several of the proposed modes of action:• Better microbial status of the gastro-intestinal tract• Better prevention of immuno-suppression associated

with infection • Better immune and health status of the sows and her

piglets• Better maintenance of gut integrity and function = better

gut environment• Reduced acute-phase protein production = more nutrients

available for production purposes (Che et al., 2009)• Better utilisation and accretion of nutrients• Improved birth weight = better piglet growth = better

subsequent performance• Enhanced immunoglobulin intake in early life = better

protection.

The responses to MOS in sow diets are therefore constant, with considerable advantages for both sow and piglet performance and hence profitability.

References1. Babinsky, L. (2005) Effect of Bio-Mos supplementation on sow performance. Research

Report, Faculty of Animal Sciences, University of Kaposvar, Kaposvar, Hungary.

2. Barac, I., Milic, D., Parker, J. and Fuchs, N. (2002) Udnak manan oligosaccharida in prehranc kamace na odlike prasadi. National Feed Conference. Opatia, Croatia, June 20-22.

3. Che, A. (2009) Influence of Mannanoligosaccharide supplementation of sow diets on colostral, sow and piglet plasma immunoglobulin content and piglet performance. Poster presentation at Alltech’s 25th International Symposium on Science and Technology in the Feed Industry, Lexington, Kentucky, USA.

4. Che, M. T., Johnson, R. W., Kelley K. W., and Pettigrew, J. E. (2008) Effects of Bio-Mos mannan oligosaccharide and manna-rich fraction of Saccharomyces cerevisiae on production of cytokines by alveolar macrophages. Journal of Animal Science 86(Suppl. 2): 347.

5. Che, M. T., Johnson, R. W., Kelley K. W., Van Alstine, W. G., Dawson, K. A., Moran, C. A., and Pettigrew, J. E. (2009) Effects of Bio-Mos® mannan oligosaccharide on immune response in weaned pigs experimentally infected with PRRS virus. Poster presentation at Alltech’s 25th International Symposium on Science and Technology in the Feed Industry, Lexington, Kentucky, USA.

6. Czech, A., Mokrzycka, A., Grela, E. and Pejsak, Z. (2009) Influence of Mannanoligosaccharide supplementation of sow diets on colostral, sow and piglet plasma immunoglobulin content and piglet performance. Poster presentation at Alltech’s 25th International Symposium on Science and Technology in the Feed Industry, Lexington, Kentucky, USA.

7. Czech, A., Mokrzycka, A., Grela, E. and Pejsak, Z. (2009) Influence of Mannanoligosaccharide supplementation of sow diets on blood parameters of sows and their piglets. Bull. Vet. Inst. Pulawg. 53: 89-95.

8. Fetcheverry and Soriano (2002) Effect of Bio-Mos on Sows. Report to Alltech Inc. Presentation of Results. Argentina Farm Trial.

9. Gomez, J. and Landeau, E. (2009) Effect of Bio-Mos on sow and piglet performance. Farm Trial Mexico. Presentation of results. Report to Alltech Inc.

10. Le Dividich, J., Martel-Kennes, Y. and Coupel, A. (2009) Bio-Mos in diets for sows: effects on piglet performance. Poster presentation at Alltech’s 25th International Symposium on Science and Technology in the Feed Industry, Lexington, Kentucky, USA.

11. Le Dividich, J., Martel-Kennes, Y. and Coupel, A. (2009). Effet d’une supplémentation de l’aliment de la truie reproductrice en mananne oligosaccharides (MOS) sur les performance des porcelets allaités. J. Recherche Porcine 41: 249-250.

12. Maxwell, C.V., Ferrell, K., Dvorak, R.A, Johnson, Z.B. and Davis, M.E. (2003) Effect of mannan oligosaccharide supplementation through late gestation and lactation on sow and litter performance. J. Animal Science 81 (Supplement 2): 69.

13. Medel, P., Pineiro, C. Kocher, A., Baucells, R. and Garcia, M.I. (2004) The effect of mannan oligosaccharides on reproductive performance in sows. J. Animal Science, 82 (Supplement 1): 332.

14. Miguel, J.C., Rodriguez-Zas, S.L. and Pettigrew, J.E. (2004) Efficacy of Bio-Mos for improving nursery pig performance. J. Swine Health Prod. 12: 296-307.

15. Newman, K.E. and Newman, M.C. (2001) Effect of Mannan Oligosaccharides on the microflora and immunoglobulin status of sows and piglet performance. J. Animal Science 79 (Supplement 1): 189.

16. O’Quinn, P.R., Funderburke, D.W. and Tibbetts, G.W. (2001) Effect of dietary supplementation of mannan oligosaccharides on sow and litter performance in a commercial production system. J. Animal Science 79 (Supplement 1): 212.

17. Pettigrew, J.E., Miguel, J.C. and Carter, S. (2004) Dietary MOS may improve sow performance. Feedstuffs 76: No. 53.

18. Rosen, G.D. (2006) Holo-analysis of the efficacy of Bio-Mos® in pig nutrition. Animal Science 62: 683-689.

19. Smith, A.L., Stadler, K.J., Serenjug, T.V., Bass, T.J. and Maby, J.W. (2007). Effect of piglet birth weight and weights at weaning and 42 days post weaning. J. Swine Health Prod. 15 (4): 213-210.

20. Spring, P. and Geliot, P. (2003) Effeto di diete contenenti mannanoligosaccaridi sulle prestazioni delle scrofe. Meeting Annuale della SIPAS. Salsomaggiore, Italy, March 27-28.

21. Wolter, B.E. and Ellis, M. (2001). The effect of weaning weight and rate of growth immediately after weaning on subsequent pig growth performance and carcass characteristics. Can. J. Anim. Sci. 81: 363-369.

Clinical Studies

Dr. Jules Taylor-Pickard, a nutritionist, obtained her PhD

specialising in piglet gut health, physiology and immunity. Taylor-

Pickard is currently the Solutions Deployment Team Manager

for Alltech Europe. Within this role, she directs the European

commercial research strategy, provides technical support to

the sales force, initiates, supports and interprets multi-species

research activities, specialising in providing natural solutions

to optimise animal performance and efficiency. Previous roles

held within Alltech include Global Mycosorb Manager and Pig

Technical Manager for Europe. Previously she worked with pharmaceutical applications

in the monogastric sector.

Email: [email protected]


Chapter Title


Technology

Comparison of Antibodies Detection Time with Rapid Plate Agglutination (RPA) Test and with Enzyme-linked Immunosorbent Assay (ELISA) in Mycoplasma gallisepticum (MG) InfectionsAvian mycoplasma is a cosmopolitan disease whose economic impact lies in the profit losses of infected herds. Mycoplasmas are the smallest free-living bacteria (between 0.3 and 0.8 μm in diameter) and are characterised by the lack of a cell wall. Clinical signs differ from one species to another: respiratory symptoms for Mycoplasma gallisepticum, infectious synovitis or subclinical infection of the upper respiratory tract for Mycoplasma synoviae, and specific immunosuppression in turkey for Mycoplasma meleagridis. Eggshell apex abnormalities are also induced by Mycoplasma synoviae.

An early detection of the infection of the flocks is a key point to putting in place corrective measures such as treatment, vaccination or disposal of the batch.

Mycoplasma gallisepticum can be diagnosed by different methods such as detection of specific antibodies with rapid plate agglutination, hemagglutination inhibition or enzyme linked immunosorbent assay (ELISA), by direct isolation or by detection of specific DNA by polymerase chain reaction (PCR). Culture of Mycoplasma gallisepticum is time-consuming. PCR, which is referred as a confirmation test (Asgharzade et al. 2013), can give negative results after an infection if an antibiotic treatment has been implemented during this period. Thus, the usual detection methods rely on both antibodies detection and PCR.

Rapid plate agglutination (RPA) tests are known to detect antibodies before ELISA as they detect IgM and IgY, whereas ELISA detects only IgY. In some studies, RPA shows a positive reactor 7 to 10 days after inoculation or vaccination (Asgharzade et al. 2013; Kleven 1975, 1998). In other studies (Pakpinyo et al. 2006) a positive result is only reported three weeks after inoculation, like ELISA.

The aim of this experiment is to assess the detection time of antibodies after MG experimental infection in chicken with these two methods.

Experimental ProcedureAnimals: Ten 11-week-old Mycoplasma gallisepticum and Mycoplasma synoviae-free chickens were raised in individual cages. Daily check-ups were performed to avoid unnecessary suffering (1 chicken was euthanised within 2 days after challenge).

Strain and challenge: All the animals were challenged at Day 0 by intranasal route with 100 μL of a solution containing a Mycoplasma gallisepticum strain at a concentration of 1.109 CFU.ml-1.

Serum collection: Chickens were bled aseptically from brachial vein, in sterile blood collection plain tubes, for serology, every 2 to 3 days, starting from the challenge day until the end of the experiment at day 25.

Tests: The serological tests were performed with Biovac’s RPA (Mycoplasma gallisepticum, Mycoplasma meleagridis, Mycoplasma synoviae, Salmonella Enteritidis, Salmonella Pullorum Gallinarum), Soleil’s RPA (Mycoplasma gallisepticum and Mycoplasma synoviae) and ELISA tests (Mycoplasma gallisepticum and Mycoplasma synoviae). All RPA tests were carried out in the Biovac laboratory. ELISA and other Biovac RPA tests were carried out in an RPA COFRAC-certified laboratory*.

Dilution: RPA tests in the Biovac laboratory were done using pure and diluted sera. Dilution rates were 1/2, 1/4 and 1/5. In the COFRAC laboratory, RPA tests followed the French mandatory procedure in which sera are tested non-diluted and with 1/5 dilution rate and heating.

Heating: All the sera were heated at 56°C during the 30 minutes before being diluted. Pure sera were not heated.

Methods:- Rapid plate agglutination tests - ELISA test commercially available.

ResultsRPA with Biovac tests performed at Biovac: Figure 1 shows the evolution of positive RPA reactors observed from D0 (challenge day) to D25.

Agglutinations, when using pure sera, appeared at day 6 and shot up to 80% at day 8. Positive results with dilutions to 1/5 reached a first plateau at 10% starting at day 8 and a higher one (33%) at day 20. In comparison, ELISA’s positive results started at day 25.

RPA with Biovac tests performed by the external laboratory (Figure 2): The general pattern was rather similar with a quick

Figure 1: Positive results at different days of age after challenge at D0 with Biovac MG RPA tests performed by Biovac and ELISA performed by an external laboratory


Technology

and strong reaction of the pure serum. Diluted sera curved on the lower end.

On closer inspection, the latter differed slightly with a first plateau at 20% of positive results and a peak at about 70% on day 22.

RPA with Soleil tests performed at Biovac (Figure 3) The product had a high sensitivity with a peak of 100% and 65% for ½ and ¼ dilutions respectively on day 20. The detection time was slightly increased compared to Biovac products but still one week before ELISA (from day 6 to day 18 for 1/5 dilution).

Statistical InterpretationConsidering the low number of animals challenged, the data did not follow a normal distribution. The Wilcoxon test was used to compare the mean day of detection of antibodies between each test with R data analysis software. There was a statistical difference between the two RPA tests using pure or ½ diluted sera, and ELISA (p<0.01).

At ¼ dilution, there was a statistical difference between Soleil test and ELISA (p<0.01) and at 1/5 dilution between Biovac test and ELISA (p <0.02).

Specificity (Table 1): The specificity of the RPA and ELISA products was assessed by testing the sera with Mycoplasma meleagridis, Mycoplasma synoviae, Salmonella Enteritidis and Salmonella Gallinarum Pullorum.

Out of the 846 additional RPA tests performed, only one turned out to be positive on pure serum alone (Soleil range MS on one chicken on day 11). On the other hand, the ELISA tests displayed positive results twice on day 15 and 20 for the MS assay (126 tests in total).

DiscussionIn this experiment, positive reactors in ELISA tests were detected 25 days after inoculation, which is slightly longer than in other experiments (Kleven 1998; Pakpinyo et al. 2006; Asgharzade et al. 2013). In the case of rapid plate agglutination, positive results with pure sera were observed less than a week after challenge and the 100% mark was reached within 11 to 18 days. Dilution to 1/2, 1/4 and 1/5 were performed to comply with all countries and/or laboratory regulations. As expected, the strength and the time to reaction decreased with the dilution ratio. It was however possible to observe a difference of at least 5 to 17 days between ELISA and RPA using 1/5 and pure dilutions respectively. These few days of difference can have important consequences in regularly tested flocks.

RPA results seemed to be quite erratic. Positive results decreased on days 20 and 22, just before positive reactors were observed with ELISA tests. A possible explanation relies on the presence of different types of antibodies produced by the immune system. IgM appears sooner compared to IgY and if ELISA only detects IgY, RPA reacts with both. The slight decrease described above could therefore be attributed to the transition between the two types of antibodies (point A on Figure 4).

RPA tests are prone to false positive reactions (Nassik et al. 2013). In this study, the sensitivity and specificity of all the tests were good. It should be noted that the chickens were not vaccinated before as it has been described that false positive results are associated with inactivated vaccines that contain oil emulsion or virus vaccines prepared in cell cultures supplemented with mammalian serum (Butcher 2012).

Figure 2: Positive results at different days of age after challenge at D0 with Biovac MG RPA. RPA test and ELISA are performed by an external laboratory

Figure 3: Positive results at different days of age after challenge at D0 with Soleil MG RPA done by Biovac and ELISA performed by an external laboratory

Table 1: Number of false positive results on tests other than Mycoplasma gallisepticum results throughout the entire experiment. Total number of tests: 972


Chapter Title

False positive results can also be associated with frozen sera which have been thawed before testing.

This is why before interpreting any erratic results, some points need to be carefully checked in the laboratory:

• Sera must be sampled at least 24 hours before testing, but not be more than 72 hours old;

• Positive and negative controls must be done before each series of tests;

• Antigens are gently but thoroughly and regularly shaken;

• The same volume of antigen and serum has to be used;

• All components are brought to room temperature, between 20 to 25 degrees Celsius, before use;

• Avoid any contact between sera and antigens before mixing;

• Shaking must last exactly 2 minutes for poultry sera and 3 minutes for turkey sera;

• Reading must be done within 30 seconds after shaking.

Conclusion In this experiment, chickens challenged with MG produced immune response detected by RPA 5 to 17 days before ELISA. Positive reactors were observed 6, 15 and 17 days after inoculation with respectively 1/2, 1/4 and 1/5 diluted sera in the case of Soleil RPA tests and 25 days for ELISA. Biovac tests were positive 6 days after challenge with ½, ¼ and 1/5 dilutions.

Serological tests are performed for a screening of the flock’s status, not for a diagnosis (Feberwee et al. 2005). Considering that detection programmes generally rely on monthly sampling, a few days of difference in detection can be of immense importance for biosecurity. In France, it is compulsory to perform detection programmes with RPA. Thanks to this method, Mycoplasma gallisepticum has dramatically decreased in France during these last few years. The most important issue in the use of this quick and inexpensive method is to follow the instructions very strictly.

References1. Asgharzade S, Zaeri S, Hasanzade M, Ahmadi M, Talebi

AR (2013) Detection of Mycoplasma gallisepticum in experimentally infected broiler chickens using Culture, SPA, ELISA, and PCR methods. Comp Clin Pathol 22:1051-1055

2. Butcher G.D. (2012) Factors to Consider in Serologic Testing for Mycoplasma gallisepticum (MG) and Mycoplasma synoviae (MS). Veterinary Medicine-Large Animal Clinical Sciences Department, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida.

3. Feberwee A, Mekkes DR, Jd W, Hatman E, Pijpers A (2005) Comparison of culture, PCR, and different serologic tests for detection of Mycoplasma gallisepticum and Mycoplasma synoviae infections. Avian Dis 49:260-268

4. Kleven SH (1975) Antibody response to avian mycoplasma. Am J Vet Res 36(4):563-565

5. Kleven SH (1998) Mycoplasmosis. In: Swayne DE, Glisson JR, Jackwood MW, Pearson JE, Reed WM (eds) A laboratory manual for the isolation and identification of avian pathogens, 4th edn. American Association of Avian Pathologists, Kennet Square, PA, pp 74-80

6. Nassik S, Rmili N, Rahmatallah N, El Rhaffouli H, Lahlou Amine I, Fassi Fihri O, El Houadfi M (2013) 18th WVPAC Congress 2013, Nantes, France.

7. Pakpinyo S, Pitayachamrat P, Saccavadit S, Santaswang T, Tawatsin T, Sasipreeyajan J (2006) Laboratory diagnosis of Mycoplasma gallisepticum (MG) infection in experimental layer chicken receiving MG vaccines and MG organisms. Thai J Vet Med 36:29-37

Technology

Caroline Pommellet is Director of the division of Reagents and Swine Autogenous Vaccines at Biovac Laboratories (France) since 2013. She works with the Research and Development department and is in charge of many trials in the field as well as in the animal house laboratory. Following her graduation from the Ecole nationale vétérinaire de Maisons-

Alfort in 1985 she was a field practioner in Brittany France, for 15 years. Since then she has worked with the agroindustry as General manager at Zootech laboratories, in the Even group (responsible for the medicated feed for the four feed plants) and the Merial group. She has been for several years a member of the French Scientific Committee for Feed industry. She has published numerous articles on her work in scientific journals. Email: [email protected]

• A

Figure 4: standard Ig G and Ig M kinetics after infection


Corporate Profile

“The Animal Health Company produce a leading range of supplements, hygiene and grooming products for Canines & Equines. This family run business was set up in 1990 by Nick Westcott. The company have expanded their range over the years and plans to keep going with exciting innovative products for this market. The company had grown from the humble beginnings with Nick, to now occupy 5 industrial units at their base in Halstead, Essex. The company remains in the family and is now run by Nicks son Paul Westcott.

The Animal Health Company pride themselves on creating ways in which animals receive the greatest benefits, in the highest quantities, from the herbal elements of their products. As a result they mastered the Therminfusex technique. This process is designed to manufacture liquid herbal products, as it is believed that herbs in liquid form are more easily digested and absorbed by the body. These are made without using alcohol, which can be found in some other liquid herbal products. No other company manufactures products of the same magnitude that could rival The Animal Health Company’s extensive and varied range. The NoBute range has become one of the market leaders in comparison to other products of its type.

The Animal Health Company has received a number of commendable awards for the innovative ways in which their products increase the well-being, comfort and health of animal consumers. For example in 1999 their noBute range won Your Horses Readers choice award, Hormonise was voted product of the year by a top U.S. magazine and in 2011 the company won the East Anglian Entrepreneur Business Award.

The companies ranges of products are made by them on site. These are mainly aimed at the canine and equestrian market, but have recently extended to domestic poultry too. Along with the aforementioned NoBute range, which is a devils claw based supplement, they also have, a hygiene range. This includes a DEFRA approved disinfectant called Defence 7 and the CVL tested Parvo-Virucide. They also have

an odor-Kill, a bed/rug wash, Supaclean and an antibacterial bedding powder. The Animal Health Range extends from replacement milk powders, rehydration powders to various vitamin and mineral supplements. The Health & Herbal range of supplements for joints and movement, stress, digestion and general wellbeing. The grooming range comprisies of unique shampoos & sprays including some new SLS free products. Finally they have a Tea Tree range of products under OzOil. These are creams, shampoo’s, ear cleaners, sheath cleaners and leave in conditioning sprays.

In the last two years the company has launched it’s own dog food brand “Westcotts”. This high end complete dog food is unique to the market as it contains their own Hyper Coat prime supplement, which has 87% Omega oils. These Omega oils help to attain and maintain a healthy skin and coat. “Westcotts” contains Glucosamine, Chondroitin Sulphate, methylsulfonylmethane & Omega 3 fatty acids to promote joint repair and mobility. To help aid digestion & keep a healthy gut it contains Pre-biotics & Pro-biotics. There is no added wheat, wheat gluten, soya, beef or pork.

The duration of the company’s existence has been invested in expansion, research and providing flagship products that mark a commendable contribution to the improvement of animal health and welfare. Which is reflected in the company moto “Committed to Animal Care”. For the further the company plans to continue it’s research and expansion into creating new and exciting products to improve the condition and wellbeing of pets and livestock.


Manufacturing & Packaging

Extrusion Cooking of Aquatic Feeds- The Path ForwardHistorically, extrusion cooking was at best an art requiring a well-informed operator to manage the system yielding a finished product. This individual controlled everything about the process: dry ingredient flow on a volumetric basis, liquid injections by hand controls, and temperatures by cracking the valve open. All would be duly noted for the next time the product was made. The extruder barrel was assembled, and the design and placement of parts greatly affected results. All of these played a major role in control of these devices, called extrusion cookers. Initially there was simplistic control at best, with seat-of-the-pants reactions to varying conditions and challenges coming from all directions, generally resulting in total chaos, and finally shutting down to clean and start all over again. The learning curve was long, interesting and very rewarding for all of those who were up to it. Let’s look at the current status of extrusion cooking and how things have changed.

Photo of TX-300 Twin Screw Extruder

There are many methods to conduct a review, but let’s do it on the basis of the generally accepted rules of extrusion, which are as follows:

1. Raw materials or formulation2. Mechanical setup of the equipment3. Operational parameters4. Final product characteristics.

Raw materials and formulations have been the area of major changes in the aquatic feed sector. This area has had impacts on the mechanical and operations areas of extrusion. Fat levels, reduced availability of fish meal and fish oil, increased use of vegetable proteins, novel ingredients, as well as demanded use of indigenous raw materials all affect the process. The goal is to move from 1 to 4 in the above rules. It can be as simple as obtaining soybean meal manufactured under different conditions. Is soybean meal all the same all of the time? As shortages of fishmeal developed, the use of alternate protein sources greatly increased. This, coupled with growth in aquaculture, has strained even some vegetable protein sources. Availability might still be of no concern, but what about the ingredient quality?

Extrusion systems yield a better finished product with quality functional ingredients and low temperature dried vegetable protein sources. Protein denatures at 60-700C and as protein denatures, it becomes insoluble or non-functional. A good analogy of non-functional ingredients, which do not bind together well, would be like trying to make a ball to throw from a pile of sand. The industry adjusted when years ago fishmeal inclusion increased in salmon diets and difficulties arose from high temperature produced fishmeal. Pellets did not have the final characteristic as desired, and had no strength of form. Formulation, configuration and operational factors were all addressed in that era. In the case of vegetable proteins, the Protein Dispersibility Index (AACC Official Methods 46-10, 46-23, 46-24, 1976) is a lab test that gives an indication of the functionality of soy ingredients. The more soluble in water, the better the ingredient. The following photo shows the difference in colour which relates to heat damage when a soybean product is dried after solvent extraction. The darker the product, the lower the PDI, and this also relates to lower solubility. Projections of this to other vegetable proteins show similar traits: higher heat damage and lower functionality.

Photo: Soybean Meal Colour and Solubility. Dark Colour, low solubility, Light Colour high solubility

Another major formulation factor in aquatic feeds is the starch level, and the rules might have to change. It was generally considered adequate if 10% starch was included for sinking feeds and 20% starch for floating feeds. This is on a total basis from the starch in ingredients, as well as possibly added starch. Extruders bind the materials together in a matrix as opposed to forcing the ingredients as in compounding feed technology. Soluble proteins aid in this matrix development. Low PDI ingredients need something to assist in the binding of the formula together, and it might be that additional starch or higher quality starches are required if lower quality ingredients are used.

Grinding is another critical factor in the raw material area. Good grinding is a plus for extrusion as well as compounding feeds. Grinding should be followed by sifting to get the desired particle size. As smaller and smaller aquatic feeds are desired by the industry, smaller die holes and thus finer ground materials are required.

Mechanical setup of the equipment is not just a topic for the extruder but for the entire plant design. Some examples of topics for discussions are the actual raw materials and bin

Manufacturing



designs for proper flow, pre-grinding or post-grinding, double mixing to avoid grinding vitamins and select ingredients, and plant design for sanitation. The above ingredients were discussed in general. One of the advantages of extrusion when compared to compounding feeds is that the starch level normally needed is reduced, opening up the formula for a wider range of good quality protein ingredients. Ingredients with lower total protein levels can be combined to achieve the proper amino acid mix as well as the desired level of total protein.

Using various levels of a wide variety of ingredients required improved preconditioning and elevated use of water and steam to overcome varieties of vegetable and terrestrial proteins and other fibrous ingredients. Conditioners now exist for added flexibility; try preconditioning a product with 50% fresh meat slurry (by product from terrestrial or aqua-based animals), 11.5% steam added and achieve 3.4 minutes retention time with 35% moisture and yield the desired free-flowing characteristics. Free-flowing material into the extruder barrel is needed for continuous operation without downtime due to flow blockage.

Photo of a High Intensity Preconditioner (HIP)

Ever-changing ingredients and the desire to understand the conditions needed or required for optimum extruder operation resulted in the development of a specialised piece of equipment, the phase transition analyser (PTA), to assist in understanding or predicting how extrusion equipment needs to be operated and configured for the desired end results. It has also been used to understand on a “what happened” basis. Individual ingredients or groups of ingredients are placed in a containment area where heat and pressure under varying moisture levels allow generation of points for curves to be graphed. In essence, the extrusion process is defined by glass transition and melt transition curves. Eventually understanding of the data allows for explanations as to why some pellets are different in terms of their structural final form.

Photo of graphed results from a PTA study: With these particular ingredients it can be seen that water content greatly affected the temperatures needed for compaction or flow movement in these cases.

Photo of table-top lab equipment. Phase transition analyser.

Modifying the extruder components yields various results, depending on the actual design. As noted, different ingredients and their quality require various levels of liquid and energy inputs. The configuration of the actual extruder barrel for increased or decreased residence time or changing of the cooking effect can be accomplished by a number of methods, but this greatly improves the ability of the system to handle varieties of formulations. Historically, the machine was stopped and the parts changed to achieve the required effect. Devices are available to manipulate the cooking effect in the barrel while running, yielding less downtime and predictable control adjustments almost on an instant basis.

Many extrusion systems require the operator to visually see what is going on and take corrective action to overcome any situations in making the final product, the last of the extrusion rules, and the characteristics of the finished product. While doing so it is usual to verify the other area of importance in an extrusion system, the dryer. Today’s high capacity system all require some form of drying for moisture removal. Not only is it a major area that determines operation profitability, but it is important to the downstream processes and results. Simply stated, different levels of water need to be removed based on product diameter and capacity or production rates into the dryer. Temperatures, belt speeds and air flows are


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adjustable and dependent on the product being made, and affect the final product quality. Evenness in drying gives the product the conditions for proper coating and qualities desired. A tight moisture variance will yield similar results in terms of oil variance after the coater.

Operational parameters or the running conditions of the process are also quite important, and a viable way to control the outcome. Variations of water and steam are essential for formulation variances as well as a key factor in floating or sinking products, let alone slow sinking. Accurate and proper inclusion in the conditioner and extruder barrel allow for the exacting but seemingly always changing levels needed based on formulation fluctuations over time.

The question is what has changed over the years in controls? In terms of operation, raw materials are metered in, water and steam and other liquids are added in the conditioner and extruder barrel, and product comes out the end. Manually this can be accomplished, but computer controls can do it faster and more accurately. The true answer is everything has changed, and nothing is exactly the same although it is similar. Starting with the dry feed system, most use a compensated loss-in-weight system ensuring the exact amount of dry material by weight is introduced into the extruder each and every moment. Liquid flows are slaved to the dry flow rate for exact inclusion via flow meters and motorised control valves. All of this is easily accomplished by a computer control system. How can you dry evenly if the material from the extruder is in a constant state of fluctuation? Let’s take it up a level to not only controlling liquid inputs, but also product qualities, out of the extruder.

Computer systems can accurately control all dry and liquid ingredients; couple this with density management for +/- 20% on a gram per litre basis and this starts to get interesting. The correct dies, getting you in the right range for control, and motorised flow restriction for increased pressure, shear and temperature mounted on the end of the extruder puts control at a new level. Add into the system an in-line sensor between the extruder and dryer for verification and control feedback. Detect and verify the density and send the information to the computer, allowing for adjustments in specific mechanical energy (SME) inputs to modify the density at the end of the extruder automatically, with no operator adjustments. SME is an important factor that can be related to product quality in terms of possible oil infusion after the dryer, exacting densities of the product and verification of the energy input for species where GDAS, gastric dilation air sacculitis, is a

factor.

Photo: Basic unit to collect bulk density and moistures ON line courtesy of Source Technology.

Dryers, as mentioned, are also an important aspect

of extrusion cooking. Water is required for extrusion and thus water removal is also critical to avoid shrinkage as well

as making the best product. Proper dryer designs allow for moisture variance out of the dryer at 0.5% variance across the dryer discharge bed. This is not taking moisture out of one common discharge point but from a cross-sectional location at the discharge for absolute verification of evenness in drying. In-line sensors or testing devices can verify after-dryer moisture results. Additional systems are available to control energy usage. Monitoring all of the discharge flows from a dryer gives insight on how to manage the dryer for effective energy usage.

Bringing it all together, predictability is the factor achieved in total control of the extrusion system. Control is placed in management’s hands with off-site access, trending of key parameters, defined bands of operation, maintenance alarms and system fault alarms, to mention a few. Improved extrusion from more accurate ingredient input control results in perfect product from the extruder. Sounds simple, but the total attention to all aspects of extrusion is what matters; no more balling up of ingredients in the down spout requiring downtime to clean, which gives a pure benefit from better preconditioning. Improved extrusion barrel components include density control devices, so we no longer need to stop the extruder to make a change, but can simply do it while running. Add computer control and on-line sample detection and the system can control itself on such aspects as density, moisture levels and energy inputs. An improvement of 2% efficiency in an 11-ton-per-hour plant is five additional tons per day, 24 hour operation.

Evenness in products from the extruder has allowed for the dryers to advance in areas of moisture variance and lower energy usage. Evolution of dryers was basically right behind extruders. This was not easy, not knowing until the extruders were up to speed. Extrusion of constant moisture, density, internal cell structure and product diameters were all factors in dryer advancements. Analysis of dryers has also advanced with design improvements, and commitments to sanitation in order to meet the industry needs.

The results are more even moisture out of the dryer at elevated levels for less shrinkage, constant conditions for evenness in oil and other liquid coating applications, and fewer returns and rework from a balanced system.

Extrusion has changed; it has moved from an art to a science. Technology has surrounded this field and it will be hard to back away as the results point to improved production quality and bottom line results from new designs and computer control capabilities.

Joseph P. Kearns, Vice President Aqua Feed Division for Wenger Manufacturing, has multiple patents on aquatic feeds and methods of production. He graduated from Kansas State University in engineering and has been with Wenger since. His involvement in the extrusion cooking field worldwide has resulted in an understanding of the needs for the

industry on many styles of feeds. He can be reached at [email protected].

At Kemin, our inspired molecular solutions are employed daily around the globe to improve the health of people and animals everywhere. As populations rise and environmental conditions shift, we are creating new ways to meet the demands of tomorrow. By 2050, an estimated 9 billion people will occupy the planet. They will require 70 percent more food than we have today. The growing demand for protein around the world provides opportunities for producers to continuously improve their operations and profitability. It is our mission and passion to do that with safe, nutritious food on a worldwide basis. The company’s six divisions share a unified vision of improving the quality of life by touching half the people of the world every day with its products and services. Connecting Globally to Apply Technology to Local Conditions For more than 53 years, we have built our reputation on providing customers with thorough research, sound science, and insights which build meaningful relationships. As an industry leader, we offer honest, open dialogues with our customers. We regularly bring customers together with regional experts throughout the world to learn what their conditions and needs are, now and in the future. This constant exchange of ideas drives Kemin innovation. It allows our scientific specialists to address customer concerns through new products that enhance animal nutrition, produce more food at lower cost, and improve the quality of life. Offering TOTAL NUTRITION™ Platform Kemin offers a range of feed ingredients to help you raise healthy animals that produce safe food for consumers. It is through this focus on animal nutrition and health that Kemin offers Total Nutrition™, a comprehensive program including three product platforms providing safe solutions, healthy solutions and efficient solutions. Expanding to Meet Future Needs The demand for high-quality products with nutrition and health benefits has never been stronger. Around the globe, Kemin has been expanding our laboratories and manufacturing facilities to service our customers better. In 2013, we opened our new $16.7 million Molecular Advancement Center. This collaborative space shared by 60 scientists helps us accelerate innovation and is a direct reflection of our expanding business around the globe. Last fall, we broke ground for a new $17 million encapsulation facility for amino acids at our headquarters in North America. The 16,000 square-foot manufacturing facility is scheduled to open in November 2015. Our animal nutrition and health customers look for feed ingredients that provide the most consistent and efficient ways to deliver nutrients to their animals. Our encapsulation technology protects and delivers these nutrients through targeted release in an animal’s intestinal tract.

Achieving a Perpetual Balance As part of our commitment to serve our customers and the environment, we use proprietary plants to develop some of our specialty ingredients that enhance nutrition and health for humans and animals. Our breakthrough approach combines science, agronomy, and profitability for the betterment of the planet’s resources and people. After stringent audits, 100% of our rosemary and spearmint crop production have been certified Sustainably Grown by SCS Global Services (SCS), a leader in third-party environmental and sustainability certification. Sustainably Grown is one of the most stringent certification standards, supporting long-term sustainable agricultural production by identifying crops grown in accordance with environmental and social responsibility as well as quality and safety requirements. The market demand for plant-based antioxidants, preservatives and flavorings is soaring in the petfood, food, health and personal care industries. Kemin remains steadfast in providing a long-term sustainable approach for our partners.

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Identifying the Best Delivery for Your Beloved PatientThe New Animal Health EconomyInvestment in the animal health industry is at an all-time high, with strong growth projections for the future. Spend on animal medicines and vaccines represents roughly 22% of the estimated 100 billion dollar animal health market1. Future growth projections look strong, with industry expectations set at compound annual growth rate of 5.7% for the market2. Consumer spending on companion animals is particularly bullish. Experts estimate 51 billion dollars were spent on companion animals in the United State alone in 2011, with 25% of that spent on veterinary care (including medicines) and another 20% on over-the-counter medicines and supplies3. This represents 62% of US households, or 73 million homes4. Spending on pets is expected to grow 3.3 per cent in the United States, but in emerging markets where per capita disposable income is on the rise, spending is expected to be much greater. By comparison, in Latin America growth is targeted at over 10%5. These trends, coupled with increasing pet ownership and longer life expectancy for companion animals, have created a substantial growing market for pet medications. Access to pet medications is increasing both in the retail sector and traditional veterinary-supplied medicines, and broader types of treatments are available as compared to just a decade ago.

All of these factors create a need to ensure effective ways to deliver medication to each beloved patient. While pet owners are increasingly choosing to spend discretionary income on their pets, they do expect value and effectiveness for the medication treatment. Similarly, for certain vaccines and other treatments for equine or livestock, for example, considerable amounts of money are invested in these therapies. Owners want to rest assured that their animal receives the maximum benefit of the medication, returning to and subsequently maintaining optimal health. For some treatments, this may involve maintenance therapies that may very well continue for the life of the animal.

The Importance of the Product DeliveryEnsuring effectiveness of the treatment can often be directly tied to the role of packaging. Packaging plays a role both in the protection of the medication and ensuring its efficacy, as well as the primary tool for delivering the medication properly. This is namely communicating how to administer the medication as well as providing for the physical application of the drug product.

Similar to human health medications, animal health medications come in many delivery forms. These may include traditional oral solids such as tablets or capsules, more convenient chewable tablets or flavoured

soft chews being packaged in bottles and blister packs, liquids administered orally or topically via bottles or tubes, or perhaps injectibles and other parenterals including innovations such as transdermal delivery forms or other increasingly convenient methods of delivery. The need for product protection from the elements forces packagers to incorporate protective barrier materials, providing shelf-life stability to ensure both safety and efficacy until administration and after. Increasingly, products being commercialised have need for higher levels of protection from the detrimental effects of moisture and oxygen. The packaging materials industry has stepped up to provide more effective barrier materials, benefitting animal health product manufacturers. As suppliers continue to innovate, the performance of these materials continues to develop, allowing for extended shelf-life and faster commercialisation of medicines.

Product protection also comes in the form of better methods of delivery. Through effective package design, medicines can be delivered more safely and effectively. This ensures that care providers realise the maximum benefit for their investment, and the animal receives the maximum benefit of the therapy. Innovations in package design, such as unit-of-use blister packs with ease of administration, can significantly outperform outdated package styles or bulk containers. By virtue of these innovations, consumers realise value through both the product and the package itself. Incorporating innovative time-saving features can benefit the owner. Options for recloseability or resealability can extend the life of the product and extend the value for the animal owner.

Packaging as the Important CommunicatorPackaging can also deliver benefit through its ability to communicate to consumers. This may be reflected in many different ways. For example, consumers need clear and concise


communication regarding the proper methods of delivery or product application. When administering to animals, the method and technique of the application can often be pivotal to achieving the desired result and impact of the therapy. Without this vital instruction, or more specifically clear and concise instruction, the benefit of the medicine is not realised and the purchaser is certainly left frustrated. Likewise, the package plays a key role in educating the care giver about the potential side-effects or what to do in the case of adverse reaction. Conversely, packaging is often the primary method for identifying the key benefits of the medication and how it may be superior to a competitive product. Likewise, a particular product may feature several different strengths, and dosing dependent on the size of the animal. The packaging highlights the weight or breed considerations critical for effectiveness. Whereas human health products rely on pharmacists and physicians to supplement patient education about the medication, animal health products in retail or veterinary distribution do not share that luxury. This makes the packaging a frontline tool for educating the person administering the medication.

Packaging can play a key role in educating the pet owner about the disease state or affliction. Some medications may be a simple and relatively short course of treatment, whereas others may be maintenance therapies that could extend the life of the animal. Packaging also communicates what specifically the medication does or does not treat, an essential role for pet owners left to select the best course of treatment in a crowded retail environment full of colourful options.

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Package labelling is the primary communication tool for identifying critical safety considerations. In addition to potential adverse effects considerations for the animal receiving treatment, clear instruction is provided for inadvertent exposure to humans, particularly children. This often includes poison hotlines with vital contact information, as well as immediate treatment and considerations such as whether to induce vomiting for exposure. This role of packaging may also include key features to help protect children through the use of innovative child-resistant features. Packaging also plays a critical role in identifying how to effectively store the product to protect children while at the same time ensuring product safety, such as keeping the product out of sunlight or storing it in refrigeration. The role of packaging is multifaceted.

ConclusionAs rates of pet ownership increase globally, coupled with increases in discretionary income both in developed and developing countries, more investment is being focused on the treatment of animals and their course of therapy. These therapies include many traditional treatments, as well as therapies for afflictions once thought to be reserved only for

humans. As these products are commercialised, packaging is playing a pivotal role in the success of the product and extending the life of the animal by virtue of packaging’s ability to protect and house the medication, protect the owner from unintended exposure, and ultimately deliver the optimal effectiveness of the medication for the beloved patient. As the market continues to increase, so too will the impact of packaging in ensuring future success.

References1. http://www.zoetis.com/animal-health/growing-industry2. http://www.zoetis.com/animal-health/growing-industry3. h t t p : / / w w w . s p r i n g e r . c o m /c d a / c o n t e n t / d o c u m e n t / c d a _downloa ddoc u m ent /9781461444 3 8 1 - c1 .pdf?SGWID=0-0-45-1351111-p1745128574. h t t p : / / w w w . s p r i n g e r . c o m /c d a / c o n t e n t / d o c u m e n t / c d a _downloa ddoc u m ent /9781461444 3 8 1 - c1 .pdf?SGWID=0-0-45-1351111-p1745128575. http://www.zoetis.com/animal-health/companion-animal-health


Justin Schroeder is the Executive Director, Marketing, Business Development & Design at Packaging Coordinators Inc. (PCI). Mr Schroeder is responsible for new account development, global marketing, and creative package design with a focus on the development and commercialisation of unitdose and compliance-prompting packaging.

He holds a Bachelor of Science from the School of Packaging at Michigan State University, and a Master of Business Administration in Marketing from Northern Illinois University. Mr Schroeder has been at PCI/Anderson since 2000, holding positions including Process Development / Packaging Engineer, Customer Project Manager, Director of Project Management and Planning, and most recently Senior Director, Marketing & Development Services. Previously, Mr Schroeder held package engineering positions with Hershey Foods Corp and at the J.M. Smucker Co. (Smucker’s). Mr Schroeder is a Certified Packaging Professional from the Institute of Packaging Professionals (IoPP) and is the Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email: [email protected]

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Country Focus

Overview of the Dutch (Veterinary) Medicines Sector. One Health Approach?In order to keep the world’s population healthy and treat it for diseases, the world needs (veterinary) medicines. There are some similarities between the veterinary and human medicines sectors, but unfortunately these are hard to find. This holds true for the Netherlands. This article is meant to provide an overview specifically of the Dutch situation. There is a focus on economic parameters (labour force, turnover and expenditure), legislation procedures, the distribution situation and some social developments (worrying about antibiotic resistance; increasing specialisation).

The size of the Dutch human pharmaceutical market (4.3 billion euros in 20131) is about the same as the size of the European veterinary pharmaceutical market. The Dutch 2013 veterinary medicines turnover was approximately €250,000,0002, of which the livestock farming industry accounts for around 70%. By way of comparison, in the European market (4.5 billion euros in 20123) about 50% of the veterinary medicines were used in the livestock farming industry. Still, the Dutch turnover is only 6% of the total EU veterinary medicines turnover. The Dutch human healthcare sector is one of the biggest sectors in the Netherlands when it comes to employment. Over 1.1 million people work in the sector out of a total 11 million (potential labour force)4. The total expenses are 45 billion euros, of which 4.3 billion are for medicines1. The Netherlands is amongst the European countries with the highest expenditure as a percentage of GDP (643 billion in 20135). The most expensive healthcare is long-term care6; around 15% of the Dutch are over 65. Also, it is expected that these elderly people more often will live on their own7. This demographic development has a significant influence on the healthcare industry. The Dutch healthcare system is publicly organised, whereas the farming industry is private in nature. Therefore the use of veterinary medicines is, amongst other factors, related to a professionally organised livestock farming industry. This branch produces food, milk and eggs meant for consumption, and a large proportion of this is goods for export. In April 20128, the agricultural census stated 2.3 million cows of over one year old (of which 1.48 million were dairy cows). 1.4 million cows and 14.3 million pigs were slaughtered for the industry in that year; there were almost 400,000 goats and the sheep flock consisted of over one million. The poultry production industry counts approximately 29.6 million chickens and has a gross production of 810,000 tons. Smaller in size but nevertheless important is the group of companion animals, although the amount of companion animals has been decreasing for a few years, likely due to the economic crisis and the ongoing urbanisation. Nevertheless, 59% of families in the Netherlands have at least one companion animal, and the number of families with a companion animal is increasing. Companion animals are most likely to be cats (2.9 million), dogs (1.5 million), (song)birds (2 million) or aquarium fish (6.6 million). The Dutch spend 2.12 billion per year on the acquisition and care of these animals. The companion animal

sector provides 18,000 fte’s (education, research, trade, services) and is worth around 3 billion euros per year9.

LegislationRegistration of veterinary medicines has been harmonised based on European Regulation. This means that the same policies concerning the assessment needed to receive marketing authorisation apply to all EU member states. As is the case with veterinary medicines, medicines for human use also need marketing authorisation before they can be released onto the market. The competent authority is the Medicines Evaluation Board (College Beoordeling Geneesmiddelen, CBG). The CBG assesses whether or not the advantages of a medicine outweigh the disadvantages by closely examining the efficacy, risks and quality of the medicine10. In the Netherlands the Veterinary Department (Bureau Diergeneesmiddelen, BD), part of the CBG, coordinates the marketing authorisation for veterinary medicines11. The BD uses the test results and research from external institutes such as the National Institute for Public Health and the Environment (RIVM) and the Central Veterinary Institute (CVI). Particular to the assessment of veterinary medicines in comparison to medicines for humans is the additional ecotox assessment. DistributionIn general it is safe to say that a (veterinary or human) medicine is prescription-only when a physician or veterinarian is needed for a diagnosis. There are four situations in which a prescription is necessary:

• When there might be a direct or indirect danger when the medicine is used without medical supervision, e.g. antibiotics;

• When, due to using the medicine differently from stated in the SPC or due to using the medicine for food-producing animals, there might be a direct or indirect danger to one’s health;

• When a medicine is so new the efficacy or possible side-effects have to be investigated. As a rule of thumb, a medicine should have been used for at least five years as POM;

• When parenteral application is involved.

Most medicines for human use are only to be delivered by a pharmacist after prescription from a physician or other authorised healthcare professional. Some medicines, however, are for sale at local druggists or pharmacies12. This way there are two types of medicines: POM and non-POM. The criteria for POM are stated in article 71 from 2001/83/EC. This POM/non-POM distinction also applies to veterinary medicines. For veterinary medicines the Netherlands has created a combined policy consisting of both the European regulated prescription policies and the national distribution regulation, the so-called ‘canalisation policy’, which regulates whether

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Country Focus

or not a veterinarian’s prescription is needed for distribution of the veterinary medicine, who may deliver the medicine (veterinarian or pharmacist (human)), or the possibility of selling the medicine by a licensed merchandiser. The four types of canalisation are UDD (only to be delivered and administered by a vet), UDA (only to be delivered by a vet or a pharmacist (on prescription)), URA (only to be delivered by a vet, pharmacist or licensed merchant (on prescription), VRIJ (may be traded without prescription). At this moment pharmacists play no significant role in the Netherlands in the distribution of veterinary medicines. Furthermore, the healthcare inspectorate (IGZ) supervises the entire medicine distribution chain. In order to ensure the quality of medicines, manufacturers and wholesalers need to comply to strict regulation for good distribution practices. This is different from the veterinary market. The IGZ, in cooperation with BD, also carries out GMP inspections at manufacturers of veterinary medicines.

Antimicrobial ResistanceIn the Netherlands, antimicrobial resistance is relatively low. There are many countries in which resistance is a bigger problem. One factor explaining this is the fact that in the Netherlands antibiotics are only available after prescription. Also, healthcare organisations are on the alert. There has been considerable attention paid to the use of antibiotics in the livestock farming industry. The first reports to make a comparison between EU member states showed a relatively high use of antibiotics in the Netherlands. This is contrary to the human healthcare sector, where the Netherlands are amongst the lowest-ranked countries. This comparison led to a lot of political attention on the use of antibiotics, which in turn led to regulations to decrease their use, which in 2014 resulted in a 60% decrease compared to 200913. Now, the Netherlands are among the average users in Europe 14, which is, given the intensity of the industry, quite an achievement.

Human patients with antimicrobial resistance are treated separately and professionals follow strict hygiene measures. By doing so, professionals and organisations avoid new contaminations15. The Dutch Working Party on Antibiotic Policy (SWAB) formulates national legislation for the use of antibiotics. These are meant for adult patients and are used as a foundation for composing local and regional antibiotic formularies. The SWAB is also involved in surveillance of the use of antibiotics and the resistance in various micro-organisms. Over the past decade antibiotic use has increased by 15%, from 9.86 to 11.34 DDD/1000/day16. The increase we’ve seen between 2002 and 2009 seems to have been stabilising within Dutch hospitals since 201017. There are few cases with MDR or superbugs in the Netherlands. Infections with these types of bacteria are hard to treat, because these bacteria are also increasingly resistant to last-resort antibiotics. Based on data from 2007 it is estimated that seven people die each year from MRSA, and MRSA leads to 300 extra days in hospital, costing around €78,000 in total. E. coli, resistant to third-generation cephalosporin, causes 37 deaths per year and 1600 days, costing around €378,00018.

The need for reduction in the use of antibiotics in animals is related to possible public health risks. One consequence of increasing bacterial resistance is the impossibility of treating certain patients with antibiotics. The latest scientific insights reveal a rather small contribution to antimicrobial resistance from the livestock farming industry19; nevertheless it is necessary to restrict the use as much as possible, and also to control the resistance within animals and livestock. Therefore the use of fluoroquinolones and third- and fourth-generation cephalosporin has been restricted over the last years. As a result, Cefotaxime resistance in E. coli in poultry dropped from 20% in 2007 to 5.8% in 2012. In 2012, 37% of the E. coli in livestock animals was resistant to amoxicillin and 4.9% to ciprofloxacine20.

As a consequence of the increasing attention paid to antibiotic resistance on the one hand, and the veterinarian’s authorisation to distribute and deliver veterinary medicines on the other, there has been a great deal of attention on the interpretation of good veterinary practice. The veterinary professional organisation (the KNMvD) has implemented good veterinary practice by means of guidelines and formularies (also concerning antibiotics). The veterinary disciplinary tribune supervises the veterinarians. The public debate on the widespread use of antibiotics in the livestock farming industry has resulted in a large number of veterinarians appearing before the tribune. The Dutch approach to restricting the use of antibiotics has drawn a lot of attention from the European community due to the fact it was based on the sector’s self-regulation. The government determined reduction targets but left the concrete interpretation to the sectors. Consequently there was considerable foundation among those working in the livestock farming industry and progress has been made efficiently and quickly. The approach is known in Europe as The Dutch Approach.

SpecialisationAs a consequence of market forces, healthcare organisations are forced to specialise. Specialisation makes organisations more visible for healthcare seekers and health insurance companies21. The government stimulates this, aiming at improved quality and lower healthcare expenditure. There are three types of specialisation: specialisation based on efficiency, specialisation based on focus, and domain specialisation. When specialising based on efficiency, the keywords are standardisation and protocolisation. Specialisation based on focus leads to high-end care which distinguishes the organisation from other providers. Domain specialisation means covering a specific domain, such as cardiology21. In 2011, out of each thousand men, 168 were referred to a specialist; for women, this was 229 out of 100022. The care for companion animals is getting more and more specialised and veterinarians are forced to differentiate during their training. It is common practice for veterinarians to focus on one species only, and the number of European registered specialists (EBVS23) is increasing rapidly in the Netherlands. Nowadays there are 28 veterinary clinics with specialists24. Also there are 23 equine specialists working in veterinary clinics24.


Corporate Profile

Animal Food and Feed safety are under continuous scrutiny. Governments, consumers and the food industry itself all want to take control of what gets into our bodies via the food chain. Being a highly experienced analytical chemical research laboratory, DUCARES helps producers comply withthe wishes and requirements of both the government and consumer. This is achieved by providing chemical analyses and consultancy on residual undesired substances in the animal food and feed production chain.

DUCARES - Analytical Research Laboratory During their lives production animals are administered antibiotics amongst other things. Whilst this is unavoidable, the consumer should not consume unintended substances. DUCARES is specialized in detecting and identifying substances in animal food and feed. E.g. antibiotics, hormones and other (prohibited) substances in matrices like meat, blood and offals.

Safe and sustainable food and feed European legislation makes it mandatory for all actors within the production chain to ensure animal food and – feed products are free of undesirable substances. DUCARES contributes to the safe and sustainable production of animal food - and feed products by offering our expertise to a variety of private companies and governmental bodies, both at home and abroad. We do this by providing chemical residue – and contaminant analyses as well as proficiency testing services. The latter is as a proven means for laboratories to monitor, safeguard and improve the quality of their analyses.

Veterinary medicine researchWith 25 years of experience in detecting and identifying known and unknown veterinary drug molecules, DUCARES has broad knowledge on their dynamics and kinetics in animals and environmental behaviour. This expertise is of valuable use for veterinary pharmaceutical companies dealing with drug R&D - and/or regulatory issues.

ConsultancyBesides our chemical analytical laboratory services we provide consultancy on related subjects like setting up and managing surveillance programs for monitoring residues, - research studies on veterinary residues and advising on improvement changes as a result from proficiency testing participation. You

can benefit of our extensive knowledge networks within e.g. TNO, Utrecht - and Wageningen University and our regular participation in research projects.

QualityDUCARES has a wide range of ISO17025 accredited analytical methods available and holds an ISO17043 accreditation for the organisation of proficiency tests. A full overview of our accredited analyses and proficiency testing services is published on the www.rva.nl.

As an official laboratory appointed by Dutch law, DUCARES has an obligation to regularly benchmark the quality of its analyses. This is facilitated by our participation in proficiency tests which are conducted by European Union Reference Laboratories. In these, DUCARES consistently achieves top-of-class scores.

OwnershipDUCARES is a spin-off company of TNO, the largest Dutch Applied Research Organization. Since 2008, DUCARES is a privately held company, 100% owned by TNO Companies.

Further informationDUCARES – a TNO CompanyReactorweg 47A3542 AD Utrechtthe NetherlandsE: [email protected]: +31 (0)88 3822705www.ducares.nl


The significant increase in demand for specialised care requires the availability of (veterinary) medicines to develop likewise, that is, the supply of (veterinary) medicines should specialise as well. The veterinary medicines industry is trying to cope with this demand. Given the fact that there is a similar demand in the field of human healthcare, the veterinary medicines industry might benefit from that knowledge and expertise. An existing dilemma, which is not specific to the Netherlands, is the limited availability of medicines for the equine sector. Veterinarians seem to be obliged to use medicines not officially authorised for equine use (off-label). Human healthcare sometimes faces the same problem, for example in specialised hospitals. One Health Challenge

Based on the information and policies, we can draw a remarkable conclusion. Although there are common grounds in legislation and authorisation institutions, there is little, if any, cooperation between the veterinary and human fields. Some institutions involved, such as the CBG, are responsible for both ‘sides’, but maintain separate processes in fulfilling their roles. The crosslinks seem to be missing between the sector and even within institutions, resulting in unused potential.

Collaboration between human and veterinary healthcare professionals can be beneficial in controlling resistance more effectively. A striking example is the Dutch cooperation between Nethmap (resistance monitoring, human) and Maran (veterinary)25. By publishing the data simultaneously, trends can be analysed and recognised and moreover, there is improved coordination in the fight against antibiotic resistance. A similar cooperation can be found between SWAB and the Veterinary Medicine Authority (SDa)26. The private diagnostic laboratories possess a great deal of knowledge about the development of antibiotic resistance of the collected samples. However, due to privacy reasons or corporate interests, these data are not available for further research. Still, these are rare examples of cooperation. The cooperation between specialists and other healthcare professionals is limited and desirable. There is no significant exchange of relevant knowledge, and especially in primary care this would be useful to recognise and analyse infections at an earlier stage. Cooperation between human and veterinary healthcare professionals concerning antibiotic resistance could make a serious contribution to the constraint of the spread of resistant pathogens. There is a lot of knowledge and expertise available in both sectors not being used by one another. Reinventing the wheel should be replaced by symbiotic communication and cooperation.

The development of new medicines would probably also benefit from cooperation. In the past, most veterinary medicines were developed by companies which had already put on the market the active ingredient for human use. These days, pharmaceutical companies increasingly buy new molecules or dossiers for their own market purposes. Both industries, human and veterinary, develop their own molecules and products, instead of building on existing knowledge. This widens the gap between the veterinary division and human division. To be able to use existing knowledge and expertise from pharmaceutical companies operating in different

sectors it is imperative to share it. This increases the chances for development of new authorisation for medicines against certain indications. Umbrella associations could play an important role in facilitating this exchange of knowledge and expertise.

References1. GIP databank, Diemen, uitgaven zorg 2013, http://www.gipdatabank.nl/infoPagina.asp?naam=01%2Dactueel

2. FIDIN, The Hague, Feiten en cijfers 2013. www.fidin.nl

3. IFAH-Europe, Brussels, 21 January 2013, IFAH-Europe Annual Report 2012, www.ifaheurope.org

4. Nationaal Kompas, Bilthoven, arbeidsparticipatie 2013, http://www.nationaalkompas.nl/participatie/arbeidsparticipatie/omvang/

5. CBS, Heerlen, Bruto Binnenlands Product 2013, http://statline.cbs.nl/Statweb/publication/?VW=T&DM=SLNL&PA=82262NED&D1=0-4,9-17,20-21,88,91,94,97,130-132,135-136,139,142&D2=a&HD=141013-1643&HDR=G1&STB=T

6. Gezondheidsbalans, Bilthoven, uitgaven van de langdurige zorg 2012, http://www.gezondheidszorgbalans.nl/

7. KCWZ, Utrecht, demografische ontwikkelingen 2012, http://www.kcwz.nl/dossiers/feiten_en_cijfers/demografische_ontwikkelingen

8. Vee, Vlees en Eieren. Kengetallen in Nederland 2012. http://www.agriholland.nl/cijfers/PVE_Vee,%20Vlees%20en%20Eieren%20in%20Nederland%202012.pdf

9. Hogeschool HAS, Den Bosch, Feiten & Cijfers Gezelschapsdierensector 2011. 2nd edition. http://edepot.wur.nl/186568

10. EMA, London, marketing authorisation 2015 http://www.ema.europa.eu/ema/

11. CBG, Utrecht, homepage 2015 www.cbg-meb.nl

12. CBG, Utrecht, marketing authorisation 2015, www.cbg-meb.nl

13. SDa, Utrecht, http://autoriteitdiergeneesmiddelen.nl/nl/publicaties

14. EMA, London, European Surveillance of Veterinary Antimicrobial Consumption 2012, http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500175671

15. RIVM, Bilthoven, antibioticaresistentie 2015, http://www.rivm.nl/Onderwerpen/A/Antibioticaresistentie

16. WUR, Wageningen, Nethmap 2013, http://www.wageningenur.nl/upload_mm/7/8/9/52388c6c-858c-483c-b57d-227029fe778a_005738_Nethmap_2013%20def_web.pdf

17. Nationaal Kompas, Bilthoven, antibitoicaresistentie 2015, http://www.nationaalkompas.nl/gezondheid-en-ziekte/ziekten-en-aandoeningen/infectieziekten-en-parasitaire-ziekten/antimicrobiele-resistentie/trend/

18. Kraker, M.E.A., de, Wolkewitz, M., Davey, P.G., Koller, W., Berger, J., Nagler, J., et al. (2010). Burden of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay associated with bloodstream infections due to Escherichia coli resistant to third-generation cephalosporins. doi: 10.1093/jac/dkq412. Journal of Antimicrobial Chemotherapy.

19. One Health Congress, Amsterdam, Antibiotic resistance: from medical to One Health problem? Prof. Dr Dik Mevius, 2015

20. RIVM, Bilthoven, antibioticaresistentie in Nederland neemt toe 2013, http://www.rivm.nl/Documenten_en_publicaties/Algemeen_Actueel/Nieuwsberichten/2013/Antibioticaresistentie_in_Nederland_neemt_toe

21. Squarewise, Amsterdam, zorgspecialisatie 2012, http://www.squarewise.com/downloads/publicaties/HMR_142_KraaijHeinenBlok_Zorgspecialisatie.pdf

22. Nivel, Utrecht, specialist 2015, http://www.nivel.nl/specialist

23. EBVS, Thessaloniki, European Board for Veterinary Specialisation 2015, www.ebvs.org

24. KNMvD, Houten, GVS dienstenrooster 2015, https://www.knmvd.nl/groepen/GVS/item/10835679/GVS-dienstenrooster

25. WUR, Wageningen, MARAN 2014, http://www.wageningenur.nl/upload_mm/1/a/1/0704c512-5b42-4cef-8c1b-60e9e3fb2a62_NethMap-MARAN2014.pdf

26. SWAB, Nijmegen, Gezamenlijke Europese Antibioticumdag 2014, http://www.swab.nl/swab/cms3.nsf/uploads/363F89128521DED2C1257C270047DB01/$FILE/Gezamelijk%20nieuwsbericht%20Symposium%20Europese%20Antibioticadag%20DEF%20(2).pdf

Country Focus

Björn Eussen graduated in veterinary medicine from Utrecht University. He has worked as a veterinarian, for a veterinary pharmaceutical company, founded a veterinary software company and since 2007 he has been active as secretary of the trade organization for the veterinary medicines industry in the Netherlands (FIDIN). He recently received his

MBA from Nyenrode Business University and now works on a PhD on collaboration between veterinarians and physicians.Email: [email protected]


Advertorial

New Techniques to Control Mycoplasma synoviae

Awareness of the increasing clinical and economic relevance of Mycoplasma synoviae (M.s.) prompted the Dutch poultry industry to implement a mandatory control and eradication programme for M.s. in early 2013. Researcher and PhD student, Remco Dijkman, has been working since last year on various new molecular tests to type the M.s. strains more accurately. “It is very important to control M.s., as the financial damage is huge.”

GD Animal Health is developing various ‘new’ molecular tests that will help to increase our understanding on the spread and will help to better control M.s. GD employee Remco Dijkman, researcher and PhD student, has developed a new technique to further zoom into the genetic variation of the bacteria.

Diversity The key aim of Dijkman’s research is to type M.s. isolates in such a way that reliable genetic relationship and geographical origin can be demonstrated. Because there is a great deal of contact between poultry farms in many parts of Europe, such as in the Netherlands, the M.s. strains may show little variation. There are differences, but they are more difficult to find. “Older molecular techniques, such as AFLP and vlhA, are unable to detect these differences, as the strains are genetically very similar.” The new typing technique for M.s., Multilocus Sequence Typing (MLST), helps us to better characterise the genetic variation of the M.s. isolate, and the origin of the M.s. isolate can be established more accurately. “M.s. strains in the Netherlands, France, Germany and Italy are genetically more similar. In countries with less contact between poultry farms, such as the US and Australia, there is more genetic diversity of the strains. Therefore, the geographical origin of these are easier to trace.”

MLST TypingDue to the lack of genetic diversity of M.s. strains in parts of Europe, it was not possible to demonstrate geographical origin and epidemiological relationship using the old techniques. Therefore, Dijkman developed and validated the MLST technique for M.s. isolates. “First we fully sequenced a

number of M.s. strains. After comparing different DNA parts of the genome, we could identify five loci to type the isolates more reliably.”

The newly developed MLST for M.s. also has other advantages. “The MLST provides hard data, so labs are better able to compare their results now.” Typing refinement means that it is more easy to draw reliable conclusions about the presence of M.s. clones and the circulation of M.s. strains. With this new technique, advice can be given to poultry farms on whether they are facing a reinfection of the same strain or an infection of a new M.s. strain and what the possible origin of the new strain is. This information also provides new objective data for further research. Until now, the characterisation of 188 isolates using MLST has yielded to eleven main clonal divisions (see illustration). “There are of course many more, but we require more isolates to identify them. The intention is that – as for other bacteria – to create a platform on which people can post

MLST data of M.s. The MLST typing technique is a very valuable tool, as it provides hard sequence data.” And the more strains posted to the platform, the more extensive the genetic map becomes.

Clinical SignsScientifically interesting, and perhaps in the future also of practical use, is to study which genes of the M.s. genome are related to virulence and in causing less or more severe clinical signs. “There are M.s. strains that can infect chickens without causing any clinical problems. Furthermore, some M.s. strains are responsible for respiratory problems, and others for joint problems and eggshell deficiencies.” Which gene or genes make the difference in the clinical outcome is uncertain, but scientifically very interesting, according to Dijkman. “Why do some M.s. strains look the same, yet cause different clinical signs? There must be something we still haven’t identified.”

Practical ValueWith the introduction of the MLST technique we can trace M.s. strains. This will facilitate poultry cooperatives to identify problems during outbreaks. Identifying the strains


Advertorial

and studying their relationships helps us to understand how a strain has been transmitted and to identify the source of an outbreak. “Though this might be not too interesting for the individual chicken farmer, sequencing provides poultry cooperatives and integrations practical insights on the progress and distribution of strains during an outbreak. If for instance MLST data show that the M.s. infection has been introduced from multiple sources, then biosecurity should be reviewed thoroughly.” Discovering the relationship between strains and outbreaks is valuable information to control and prevent M.s. infections.

Vaccine Strain Versus Field StrainEarlier this year, researcher Dijkman developed a differentiating PCR to distinguish between M.s. field strains and the M.s. vaccine strain MSH. “A test to identify vaccine strains and differentiate them from field strains is important because we are dealing with living vaccines. The vaccine helps to mitigate clinical signs and protects the poultry against lesions, but does not prevent a M.s. field-strain infection. It can spread from vaccinated flocks to unvaccinated flocks within the same farm.” Experiments and field studies demonstrate that vaccinated poultry can still become infected with a field strain and thus form a risk for M.s.-free poultry flocks. Because it was not possible to distinguish between field and vaccine strains using the old PCR methods on trachea swabs, M.s.-vaccinated flocks that became infected remained undetected. The differentiating test developed by the research team is therefore essential for a sector-wide M.s. approach. “We want to reduce

M.s. in the same way we are controlling Mycoplasma gallisepticum. The economic impact of M.s. infections has increased to high levels. By better identifying the infection, we see more clearly what’s going on and what the sources are of the M.s. infection. Now we can make the correct steps towards prevention.”

Remco Dijkman studied biology and medical laboratory investigation at the Royal College IJselland in Deventer. He worked as a molecular biologist researcher in the department of dermatology of Leiden University Medical Center and joined the Dutch Food and Consumer Product Safety Authority in Zutphen in 2006, where he worked as a molecular

biologist in the department of virology and bacteriology. In 2010 he joined GD Animal Health, where he developed or made essential contributions for the development of various PCRs; amongst others for schmallenbergvirus, Mycoplasma bovis, Haemophilus parasuis, M. synoviae and Eimeria spp.

Anneke Feberwee became Doctor in Veterinary Medicine at Utrecht University in 1992. She finished her PhD thesis entitled: ‘Detection and epidemiology of Mycoplasma gallisepticum and M. synoviae’ in 2006. She has been employed at GD Animal Health in Deventer from 1996 until present dedicated to the diagnosis and control of poultry diseases including

Salmonellosis and Mycoplasmosis. In 2011 she received the Bart Rispens Memorial Award for the most outstanding scientific publication in Avian Pathology in 2009 and 2010.


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Exploring Human and Animal Microbiota inHealth and Disease

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