IVTIP Working.Indd

In Vitro Testing Industrial Platform

Review 2013 IVTIP Review 2013

IVTIP Board and Secretariat President Erwin Roggen | Novozymes A/S

The first point of contact is the IVTIP Secretariat: [email protected] IVTIP Review 2013

Letter from the President

By actively interacting with the European Commission and other regulatory authorities, we monitor research activities, industry needs and method validation requirements worldwide.

activities of the In Vitro Testing Industrial responsibility Welcome to the first annual review of the animal testing. Additionally, we endorse a meetingschemicals, have cosmetics, been attended consumer by productsdelegates fourth R, towards animals and pharmaceuticals industries. Our open activitiesPlatform (IVTIP).during the As pastthis is3 yearsour first to bringsuch to satisfy the growing demands of society - review, we provide information on our increasedwhile improving visibility methods as a result to assure of high- safety. peanfrom upCommission to 20 non-member and other organisations.regulatory impactSince public 2008, relationsIVTIP has activities substantially carried By actively interacting with the Euro you up to date with what promises to be industry needs and method validation re- an exciting 2014. - authorities, we monitor research activities, • IVTIP was established in December, out by our committed and driven Board, 1993, with the following aims: havealong organised with the enthusiasm annual open and discussion proac quirements worldwide. By these activities- onto advise industrial European requirements bodies (European for current forumstivity of alongside our members. our closed Additionally, meetings we and endorsing initiatives, such as the 21st andCommission, future research European projects Parliament) in in vitro to address issues that are critical for Century Toxicity Testing (Tox 21) strat testing egy, we aim to facilitate harmonisation, • to optimise the industrial value of standardisation, sharing and validation of European Union funded research test development, implementation and emerging alternative methods. projects acceptance. Finally, communicating our - • views and conclusions emerging from - validation and regulatory acceptance these discussions as peer-reviewed man ofto testsencourage based the on thisfurther research development, uscriptsA positive has by-producthelped grow of IVTIP’s our increased credi bility and visibility. - - tive forum for companies interested in in visibility has been that IVTIP has extend vitroIVTIP testing provides to replacean informal animal and regulatory interac ed beyond merely a European platform, and we now embrace companies and 30%organisations in the past in 5the years USA, to Brazil, more thanIsrael 40 and promotesafety and and efficacy disseminate testing informationin compound on Europe. Membership has increased by state-of-the-artdiscovery and development. technologies Werelated actively to the Erwin L Roggen full members, including test developers, 3Rs —replacing reducing and refining IVTIP President CRO’s and small and medium enterprises , up to large, international companies in the

www.ivtip.org 1 IVTIP Review 2013

Past IVTIP meetings

Closed meetings IVTIP Autumn meeting Each year IVTIP holds closed meetings in vitro genotox- the possibilities for future regulatory use. November 7–8, 2013 for the membership and Board, but icity testing assays have been accepted By contrast, several Monte Carlo, Monaco some of the presentations go on to become important talking points in the remain about the high risk of false-posi- The topics covered in this meeting began by regulatory authorities,in vitrobut concerns tests are - open meetings. in vivo ity screening assays are hindered by false-positivetive results. As in positive vitro false-positivewith presentations results on and imaging. a preference Toxic for IVTIP Autumn meeting morefollowed animal by testing assays, might andbe being the rates done of short-term results for potently cytotoxic results can be high, November 14–15, 2012 - - - Brussels, Belgium tationthan necessary. on methods Phillipe to reduce Vanparys, the number ALTOX compounds. Toxic effects, however, fre This meeting was dedicated to Joan-Albert ICON, Antwerp, Belgium, gave a presen quently develop over the long term and, Vericat, former IVTIP President, who sadly - therefore, methods are required to assess had passed away earlier in the year. of false-positive results. In a separate broader toxicity potential. Peter James ofdiscussion, reconstructed Cyrille skin Krul, models TNO, Zeist,for testing Neth beO’Brien, used toUniversity improve Collegethe speed Dublin, and sensi Ireland,- erlands, presented information on the use tivitydiscussed of assessing how high-content human toxicity imaging poten may- and discussions on the regulatory status Such models have been developed to try ofThe alternative meeting began methods with in presentations several non-Eu - towith improve the micronucleus the relevance and of COMET exposure assays. conditions in in vitro genotoxicity assays demonstratedtial. In another the presentation technique onof enhancimaging,- ingYvon imaging Julé of Biocellvia,analysis as Marseille,discussed France, in the ropean countries, China, Russia, Brazil and the USA. The afternoon sessions testingfor dermally in case applied of in vitro compounds. positive effectsThis looked at specific techniques, including is a promising approach for follow-up - Southampton open meeting (see later). cell transformation assays, genotoxicity Skin sensitisation was addressed in testing,Cell transformation and an alternative assays micronucleus are current - in the standard genotoxicity tests. Ker several presentations. Erwin Roggen, from test. eggstin testReisinger, for micronucleus from Henkel, induction Düsseldorf, as an Novozymes, Bagsvaerd, Denmark, started off cosmetic and pharmaceutical industries alternativeGermany, discussed to the in vivothe use micronucleus of the hen’s test the session on new developments by putting- andly used academia in the chemical,to screen agrochemical,for and inves- to assess systemic availability and to be forward the current knowledge—and areas tigate basic mechanisms of carcinoge- - where knowledge is lacking—about sensitisation induction relevant for risk assessment. micronucleusused as a follow-up or chromosome tests in case aberration of clas onThis the was current followed regulatory by a round state up of from affairs An usingnicity. morphologicalConcerns about characteristics inter-laboratory and togenic effects in the mouse lymphoma, nette Mehling, BASF, Düsseldorf, Germany, unclearreproducibility, understanding the subjective of the molecular nature of in vitro assays mechanisms underlying transformation tests in mammalian cells. tofor assess skin sensitization hypersensitivity testing. to variousTwo product com- of TheEuropean remainder Union of Reference the meeting Labora was - presentations were given on torytaken for up Alternatives with updates to on Animal the activities Testing in vitro Harlanmean they Contract have notResearch been widely Services accepted Cy- pounds. Jim McKim from Ceetox, Kalamazoo, for regulatory purposes. Albrecht Poth, forMI, allergicUSA, presented contact dermatitisan update onthat an uses presented an update on current use and (EURL-ECVAM) (Valerie Zuang) and the three-dimensionalalternative based on reconstructed known mechanisms human totest Cell Research, Rossdorf, Germany, outcomes of an earlier meeting of ESTAF - (Cyrille Krul). anepidermis in vitro skinmodels. explant Shaheda assay Ahmed, that predicts Alcy adverseomics, Newcastle effects on upon the immune Tyne, UK, system discussed

Histopathological grading is used to distin- caused by chemicals and novel compounds.

guish between high and low potency and sensitiser and non-sensitiser compounds. Francois Busquet, the representative andof CAAT Claudius Europe, Griesinger also joined presented the meeting the to promote alternatives to animal testing,

update on EURL-ECVAM activities and the European Union Network of Laboratories for the Validation of Alternative Methods (NETVAL). 2 www.ivtip.org IVTIP Review 2013

Open meetings major issues that had been the driving Since 2008, IVTIP has been holding forces behind the development of alter- presented a novel bioengineered skin Stratatech Corporation, Madison, WI, USA, regular meetings that are open to its by a presentation from Bart De Wever human skin tissue that is being developed members and non-members. Mem- native methods. This talk was followed model, which is a full-thickness model of ber companies also have the chance to host meetings and showcase their and Constantin Turchina, founders of- the for therapeutic and testing purposes. - technologies and facilities. Alternatives à l’Expérimentation Animale Third, Samuel Constant, Epithelix, Sàrl, projectdans la Rechercheaimed at stimulating Appliquée research (ALEX and maintainsGeneva, Switzerland, all morphological described and a function fully dif- In vitro reconstructed human developmentANDRA) Association, of alternative on the methods launch of by a ferentiatedal characteristics airway of epithelium native tissue model for at that tissue models as alternatives least 1 year and can be used to replace in - vivo to animal testing: providing financial support to researchers and entrepreneurs worldwide. Additional testing in animals. applicability and limitations ly, they set out the mission and action plan InstituteThe meeting for In Vitrocontinued Sciences with in registered Gaith- April 26–28, 2011 byof thispresentations association. on three different tissue participants only. Rodger Curren from the The introductory talks were followed discussing the issues surrounding buying Monte Carlo, Monaco ersburg, MD, USA, began this section by models: eye, skin and airway tissues. First, open to registered and unregistered assessedPhilippe Vanparysto improve discussed the measurement a new laser- of commercial reconstructed tissue models, The first afternoon of the meeting was - opacitylight-based in the opacitometer bovine cornea that opacity was being and such as how model integrity, shipping and- ingredients might affect research results. attendees, and was opened by Alan Gold Albrecht Poth highlighted how three-di berg of CAAT USA. He introduced the permeability assay. Next, Lynn Hoffman of mensional culture models fit into hazard www.ivtip.org 3 IVTIP Review 2013

and risk ing regulatory acceptance of in vitro assessments and could improve the - ulatory acceptance of alternative meth- toxic effects. Blanca Suarez, Biomedicine odsmethods almost for necessarily testing of medicines. passes via Asthe reg inGroup, the toxicological Gaiker Technological evaluation Centre, of nano - results available with two-dimensional International Conference on Harmon- Bizkaia, Spain described new advances representativesmodels. The subject for the of eyecosmetics irritation indus - Nanomedicines offer opportunities to testing was taken up again by a group of of 3Rs alternatives into ICH guidelines materials. - isisation considered (ICH process), to be the implementation most promising stance by removing the need to use po- try, and presented by Pauline McNamee- lessen the risk of toxic effects, for in of Procter & Gamble, Egham, Surrey, hasUK. introducedThe European a programme Cosmetics Associato replace hasapproach been set to regulatoryup to further acceptance. improve theShe tentially harmful solvents in production. tion (Colipa, now Cosmetics Europe) applicationhighlighted ofthat the a 3Rsjoint in working the develop group- At the same time, side-effects, such as - been banned for assessment of cosmetic off-target toxic effects, might occur. Elias Draize rabbit eye testing, which has - aFattal, talk on from the the toxicological School of Pharmacy,evaluation Uni of in vitro assays can be ment of medicinal products. versity of Paris Sud, France, presented ingredients. Various projects are explor Safety assessment of ing how existing thenanomaterials. day addressed in vitro investigations refined and optimised. nanomaterials: current of Theresponses remaining to inhaled two presentations nanoparticles of Chantra Eskes (SeCAMet al Services & status and challenges ahead and skin exposure to metallic nanoparti- Consultation on Alternative Methods, Agno, Switzerland) . discussed the April 19, 2012 changes to classification and labelling Bilbao, Spain cles. The inhaled route of nanomedicines adopted in European legislation in 2008, Although the nanomaterials market re- can present specific problems, such- as which will introduce a new calculation mains dominated by materials that have pulmonary or systemic inflammation. ofmethod the European for classification Detergent of Association mixtures discussedTobias Stoeger, advances Institute and challengesof Lung Bi of in in 2015. They described a programme applications are being developed across vitroology investigations and Disease, Munich, to predict Germany, in vivo tox- of validated and adopted in vitro skin been in use for some time, many new icological responses to inhaled nanopar- and(AISE) eye to irritation/corrosion investigate the applicability methods to - multiple industries and, therefore, nano- ismaterials deemed have that beensome identified nanomaterials as a key might en potentialticles. Myriam of human Oron skin of AHAVA organ Deadculture as meet these requirements. Vera Rogiers - abling technology. In the European Union it anSea alternative Laboratories, to animal Israel, modelsdiscussed for the test - and Marleen Pauwels of the Centre for toPharmaceutical illustrate the importanceResearch, Brussels, of end point Bel be toxic and some might not, whether selectiongium, returned for skin to irritationskin irritation testing models in re- specific to the nanomaterial or the use and, ing the safety of metallic nanoparticles, thetherefore, Nanotechnology they require Industries risk assessment Associa- on which are widely used in products that model to predict rabbit skin irritation a case-by-case basis. Steffi Friedrichs from routinely come into contact with skin. constructed skin models. A stand-alone 2013: State of the art tion,As Brussels,some nanomaterials Belgium, discussed and/or existing ap- was found to have serious shortcomings regulatory issues. on alternatives from an upwhen by MTTthe Organisation colorimetric for testing Economic was used related to the available methods for industrial point of view: on hair dyes. These concerns were taken plications are new, several talks were ready for regulation? Co-operation and Development (OECD)- thetesting quality them. of Jeffreyassessments Card from in toxicity Intertek, May 15–16, 2013 and other analytical methods (eg, HPLC/ Cantox, Kanata, ON, Canada, looked at ther discussion of skin irritation and Southampton, UK UPLC) were suggested. Finally, in a fur in vitro experimentalstudies. Frieke methods Kuper from of testing TNO, Zeist,toxic corrosion testing, João Barroso, from effectsNetherlands, in vivo gave and ina presentation vitro on - EURL-ECVAM, explored whether - - lationMuch ofintroduced the focus byof the 7th2013 Amend open - methods adopted by the OECD were yet . - meeting was on the changes in regu able to replace fully animal testing, con Claus-Michael Lehr, Helmholtz-Insti became fully implemented across the cluding that none was yet a stand-alone biologicaltute for Pharmaceutical barriers to the Research safety and Saar ment of the Cosmetics Directive, which option. In his talk, Thomas Hartung of land, Saarbrücken, Germany, discussed the Johns Hopkins University, Bloomberg minor variations can make a difference harmonisationEuropean cosmetics and standardisation industry on March of toxicologySchool of Public approach Health, modelled Baltimore, on evi MD,- efficacy of testing nanomedicines. Even- 11, 2013. Another important theme was dence-basedUSA, explored medicine how an evidence-basedmight improve quality assurance of advanced alternative theto safety regulatory and efficacy, standards and for multiple nanomed fea- methods, and perspectives from other tures could be affected. Additionally, countries were presented to provoke onfurther the current discussion. perspectives on the approaches. The final presentation was icines are not yet clear. Manufacturers, The meeting opened with discussions made by Sonja Beken, Federal Agency for- therefore, are making efforts to find Medicines and Health Products, Brussels, effective and responsible ways to test 3Rs from key opinion leaders. Herman Belgium, who discussed issues surround biodistribution, targeting and immune Koëter, Orange House Partnership, 4 www.ivtip.org IVTIP Review 2013

- - For instance, sharing of Brussels, Belgium, opened the talks by Man) project, which involves the Dutch addressing what is meant by risk assess Government, companies, academic insti ment in the traditional sense (animal tutions and other partners. The partners ‘source code’ for in vitro all stakeholders to improve application testing of hazards and exposure) and- aim to encourage collaboration between whether it will mean the same with tissue models might andalternative practices methods have changed of testing. in theThom USA thatof 3R an approaches. open source Karsten approach Mewes could from as Hartung described how attitudes bringHenkel, innovation Düsseldorf, to theGermany, cosmetics proposed in- help to solve problems, rapidover the advances past few that years. are beingHe described made in in initiatives, such as Tox 21, and the vitrodustry tissue as it modelshas in the might IT industry. help to solve For - instance, sharing of ‘source code’ for extend usefulness areas of non-animal testing, such as and could possibly increase the likeli- high-throughput omics analysis, map problems, extend usefulness and so on, - ping of toxicity pathways, integration of- vative model to assess respiratory chem- and so on, and could new testing strategies and organotypic icalhood sensitisers of regulatory on a acceptance. three-dimensional An inno cultures. Coming back to Europe, Elisa - bet Berggren from Ispra, Italy, set out the - possibly increase the priorities of the EURL-ECVAM to achieve airway epithelium model made from hu consumersregulation of and chemicals supporting while alternative protecting man donor cells was described by Samu animals, manufacturers, workers and el Constant. Although not stand alone or likelihood of regulatory cheap, the model indicates what might - asmethods. a response Erwin to Roggenethical concernshighlighted about that be achievable. The next poster, presented- acceptance this organisation welcomes the changes by Yvon Julé demonstrated imaging soft that the tools available might not be as ware that enables discrimination of cel advancedanimal testing, as necessary but raised to ensureconcerns compli - lular components within tissue samples, Coalitionwhich is helpful to End inAnimal assessment Experiments/ of toxic The meeting moved on to approaches effects. Finally, Katy Taylor, European ance with the Directive. - BUAV, London, UK, discussed hindrances to product testing, with Marianna Gaça, to the validation process for new alterna British American Tobacco, Southampton,- facilitatedtive testing through methods the and actions suggested of authori ways- icalUK, startinganalytical off studies the session to research by describing into in which regulatory approval might be how the industry has moved from chem - ties and companies. plant sciences, human biology genomics Regulatory hurdles were discussed - changeand bioinformatics. for cosmetic Albrechtproducts Poth and hasdirect in the afternoon session of day 2. Vera- ly addressed how risk assessment must Rogiers, Scientific Commission of Con thesumer roles Safety of different (SCCS), stakeholdersEuropean Com in embraced moving toxicology towards safetymission, evaluations Brussels, Belgium,and offered explained advice on assessment of mode of action as well as understanding the complexity of Euro- (or rather than) outcomes of exposure. onDavid the Basketter,concept of DABMED safety in Consultancy,relation to in vitroBedford, UK, presented some thoughts pean legislation. A specific example of that a substance is or is not a hazard but a hurdle to toxicology testing and how tests, which frequently can identify it was overcome through pragmatism this might affect uptake of alternative was presented by Tzutzuy Ramirez of cannot always assess the risk, and how BASF, Ludwigshafen, Germany. The - meeting was rounded off with a talk by thetesting United methods. States Theprovided presentation useful details of Jos Bessems, National Institute for Pub Kate Willet from the Humane Society of thelic Health concept and of thetoxicokinetic Environment modelling (RIVM), Bilthoven, Netherlands. He put forwardin about adverse outcome pathways; the vitro doneOECD in provides vitro guidance on how the to reflect systemic effects in humans - study of pathways can be at least partly not yet. The completely approach replace tests dose in vivo responses animal . in human tissue models, although it can Day 2 of the meeting began with a display of posters, some of which were studies. The creation and databases of accompanied by presentations. Cyrille Krul previously published data to draw on introduced the SLIM (Sneller van Innovatie rather than making the animal tests first naar Mens, or Faster from Innovation to choice was supported. www.ivtip.org 5 IVTIP Review 2013

Published papers

Toxicology in the 21st century – Working our way towards a visionary reality

A review article based on the November, 2009 meeting, calling for adoption of theCitation: US National Research Council vision and strategy for Tox 21. Toxicology In Vitro Berg N, De Wever B, Fuchs HW, Gaça M, Krul C, Roggen EL. Toxicology in the 21st century – working our way towards a visionary reality. 2011; 25: 874–881. Implementation challenges for designing Integrated In Vitro Testing Strategies (ITS) aiming at reducing and replacing animal experimentation

in vitro testing strategies might be implemented in Based on the follow-up meeting in 2010, this paper presents the key discussions on how differentCitation: industries.

In Vitro De Wever B, Fuchs HW, Gaça M, Krul C, Mikulowski S, Poth A, Roggen EL, Vilà MR.Toxicology Implementation In Vitro challenges26: for designing Integrated Testing Strategies (ITS) aiming at reducing and replacing animal experimentation. 2012; 526–534. State of the art on alternative methods to animal testing from an industrial point of view: ready for regulation?

This review, based on the open meeting in May 2013, addresses current legislation to protect experimental animals, and how companies might adapt toCitation: meet the requirements with alternative methods.

Ashton R, De Wever B, Fuchs HW, GaçaAltex M, Hill E, Krul C, Poth A, Roggen EL. State of the art on alternativealtex methods to animal testing from an industrial point of view: ready for regulation? 2014; published online May 4; http://dx.doi.org/10.14573/ 1403121.

6 www.ivtip.org IVTIP Review 2013 members and speakers talk freely about methods, achievements and difficulties

Membership

- small companies come together and pres- ciation by submitting a letter of intent entIVTIP the is state a forum of the where art on large, relevant medium topics and your interest in joining the IVTIP asso membership will be formalised during - the next appropriate IVTIP business addressed to the IVTIP Chairman and - beingmeeting a full and member will be activeinclude once unrestricted the mem in an open atmosphere. A key advantage - scribeBoard, youremailed activities via the in IVTIP the area Secretariat of the bership fee has been paid. Benefits of - of IVTIP membership is that information ([email protected]). You should briefly de on different companies’ activities in alter - toaccess vote tofor the or IVTIPrun for internal membership web site, of thepar native testing are shared in an informal, imentation3Rs, how you for plan product to contribute assessment to the and ticipation in IVTIP meetings and the right non-competitive way during IVTIP closed stateIVTIP your mission expectations of replacing and animal anticipated exper meetings and business meetings. During Board or the Presidency. Additionally, you meetings, IVTIP members and speakers asked to nominate in that letter a repre- acquire the right to use the IVTIP logo on largetalk freely companies about methods,is that they achievements are kept up to benefits of IVTIP membership. You are your web site and on communications and difficulties. One of the benefits for relatedEvaluation to the criteria 3Rs. offered by test method developers and sentativeStep 2 as a contact person for IVTIP. date about new technologies and services- ing opportunities and the fact that mem- For full membership we will consider CROs. Other advantages are the network - On receipt of the letter of intent, your - associated members whose key activities representative will be invited by the - •include at least some of the followingin vitro test bership is not restricted to any specific sec IVTIP Board to attend the next appropri items: specialtors. Furthermore, topics and discussions many interesting by experts topics, plenumate IVTIP business meeting as an observ • activelybeing active driving in the the field implementation of such as regulatory issues, applications and er and to present your case to the IVTIP development (eg, test developers) Step 3 . - (eg, nanomaterials, three-dimensional - sion-makingand acceptance in productof 3Rs strategies, development with modelling, imaging etc) are discussed focus on replacement, for early deci toduring one placemeetings. and hear Besides all about this, IVTIP the latest func A formal acceptance or rejection (with - • sponsoring or funding of research tions as a market place. Members can come justification) of associate membership - and (regulatory) safety assessment. will be sent by e-mail within 1 month af technologies and information. ter the next business meeting. For accept reduction(with focus that on contributeapplied research) to the devel in the- IVTIP members ed associated members, the membership opmentarea of replacement, of replacement refinement strategies and Our members represent model and tech- beingwill become an associated active once member the membership include un- • - fee (see below) has been paid. Benefits of seminars and sessions aimed at the sponsoring or funding workshops, nology providers, biotechnology compa restricted access to the IVTIP internal web nies and CROs in the following sectors: Stepsite and 4 participation in IVTIP meetings. dissemination of knowledge and - chemicals, cosmetics, consumer products After 1 year as an associated member tributesexpertise to in the the development area of replacement, of re- Howand pharmaceuticals. to become a member of IVTIP placementrefinement strategies and reduction that con Step 1 • your fulfilment of the IVTIP aims and key activities will be evaluated by the IVTIP active participation in IVTIP As potential member, you should express members. If approved, acceptance of full activities. www.ivtip.org 7 IVTIP Review 2013

Collaborations and external meetings -

IVTIP has representatives in several bodies and is involved in host •ing various external meetings. These are the most recent.

In 2011, the European Society of Toxicology In Vitro (ESTIV), Center for Alternatives to Animal Testing Europe (CAAT-Europe) and IVITP formed a collaboration that remains strong. We thank • these organisations for supporting the fifth IVTIP open meeting in Southampton in May, 2013. • IVTIP is represented by Bart De Wever, IVTIP’s Executive- Officer, on the EURL-ECVAM Stakeholder Forum (ESTAF). The meeting “A joint Scientific roadmap for the future of ani • mal-free systemic toxicity testing” in Brussels, Belgium, on March 20-21, 2012 http://www.alttox.org/spotlight/063.html • A Joint Information Day on “High Content Imaging Technology in Safety Sciences” was held in Mainz, Germany, October 24, 2013 IVTIP •has ACuteTox also participated in multiple projects funded by the European Union Framework Programmes:

• Sens-it-ivForInviTox • ReProTect • ESNATS • Predict-IV

8 www.ivtip.org IVTIP Review 2013

IVTIP members 2013

Agenolab GmbH Germany AHAVA–Dead Sea Laboratories Israel Alcyomics Limited United Kingdom Beiersdorf AG Germany BioDetection Systems bv Netherlands BioMed-zet Life Science GmbH Austria Biopredic France Biopta Ltd United Kingdom BioTeSys GmbH Germany British American Tobacco United Kingdom BSL Bioservice Germany CeeTox USA CellSystems GmbH Germany CIT France Cyprotex /Apredica United Kingdom/USA Epithelix Switzerland Evocutis plc United Kingdom Fraunhofer Institute Germany Gaiker Spain Harlan Laboratories Ltd. United Kingdom Henkel Germany Huntingdon Life Sciences Ltd. United Kingdom IIVS –Institute for In Vitro Sciences USA InSphero AG Switzerland KaLy-Cell France Kallistem France Kirkstall Ltd. United Kingdom Leitat Spain Leopharma Denmark L’Oréal France MB Research Labs USA Medicyte GmbH Germany Natura France/Brazil Novozymes A/S Denmark Novo Nordisk A/S Denmark Philip Morris Products SA Switzerland Reinnervate United Kingdom Scantox Denmark Thor Personal Care SAS France TNO Quality of Life The Netherlands Tridskin Brazil Vitrocell Systems GmbH Germany