Discover our citoxlab nonclinical services

Global expertise, Local response

Toxicology servicesGeneral toxicology:

- Rodents - Non-rodents: dogs, NHPs and minipigs

InfusionInhalationDermalOcularImmunotoxicologyReproductive toxicology including minipigs and NHPsCarcinogenicity studies also in rasH2 and p53+/- miceGenetic toxicology: ICH compliant packageIn vitro toxicology : BCOP, MUSST, DPRA, Photo 3T3, Episkin™Agrochemical / Chemical / REACHQSAR Physical chemistryEcotoxicology: wide range of test species

Safety pharmacologyCV telemetry / ECG / BPJacketed External Telemetry (JET) / ECG / BPRespiratory / plethysmography / JET telemetryCNS / EEGEarly safety pharmacology

DMPK and biomarkersRadiolabelled DMPK: in all speciesBioanalysis LC-MS/MS, GC-MS/MS, LC-ICP/MS, ELISA, RIAToxicogenomics, miRNA: Affymetrix™ / Accredited service providerImmunology: 10-color flow cytometer, Luminex, Mesoscale

Specialized expertisesJuvenile studies including minipigsFertility studies in rodents and NHPsRadiation safety and efficacy studiesTissue Cross Reactivity: human and animal tissue banksGene therapy vector biodistribution via qPCRES cell testing: devTOX™ and cardioTOX™ (with Stemina) Lead optimization and predictive toxicology services: Leadscreen™

CiToxLAB Group companies

CiToxLAB FrancePhone +33 (0)2 32 29 26 26 Email [email protected]

B.P. 563, 27005 Evreux cedex - France

CiToxLAB North AmericaPhone +1 888 353 2240Email [email protected]

445, Armand-Frappier Blvd,Laval, Quebec H7V 4B3 - Canada

CiToxLAB HungaryPhone +36 88 545-300Email [email protected]

Veszprém, Szabadságpuszta, 8200 - Hungary

CiToxLAB ScantoxPhone +45 56 86 15 00Email [email protected]

Hestehavevej 36A, EjbyDK-4623 Lille Skensved - Denmark

atlanbioPhone +33 (0)2 51 10 01 00Email [email protected] www.atlanbio.com

1 Rue Graham Bell - Z.I de Brais B.P 40309, 44605 Saint Nazaire Cedex - France

Also represented by

Media Services Ltd JapanPhone +81 3 3666 9915Email [email protected]

Fuji 16 Bldg 7F1-11-2 Nihonbashi Kayabacho, Chuo-ku,Tokyo 103-0025 - Japan

Croen Research Inc.Phone +82 31 888 9390Email [email protected]

Advanced Institutes of Convergence Technology - B-6th Fl., 864-1, lui-dong, Yeongtong-gu, Suwon-si - Gyeonggi-do, 443-270, Korea

Partner company

SteminaPhone +1 608 204 0104E-mail [email protected] www.stemina.com

504 South Rosa Road, Suite 150Madison, Wisconsin 53719

- Ju

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Media Services Ltd JapanCroen Research Inc.

CiToxLab Hungary

CiToxLab ScantoxCiToxLab France

atlanbio

SteminaCiToxLab North america

CiToxLAB, our newly established group, created through the merger of CiT and LAB Research, provides a comprehensive range of preclinical and specialty services from our facilities in France, Canada, Denmark and Hungary. With a combined capacity in excess of 800 employees, 27 000 rodents, 5 000 non-rodents, including 1 200 non-human primates on-site, and purpose built facilities of 60, 000 m2 (645, 000 ft2), the new group is a major global player in the preclinical outsourcing arena.

Our broad range of GPL and non GLP nonclinical services combined with our 40 years of experience are at the service of our customers to meet the demands of today’s complex global marketplace. We can provide you with accelerated product development, expansion into new markets, risk mitigation, reduced regulatory delays and improved quality.

Reports from our four facilities have been successfully used by our clients in support of marketing authorization and new product approval submissions around the world, including to the European (EMA, ECHA), US (FDA and EPA) and Japanese (MHLW and MAFF) regulatory authorities.

CiToxLAB is committed to the humane treatment of the research animals entrusted to our care. We guarantee they will be treated with the highest standards of respect and compassion, and particular attention is accorded to housing conditions, social interaction and enrichment of their environment.

CiToxLAB's ethics committees have established and rigorously enforce our ethics charter for Laboratory Animals. All employees must continuously demonstrate their commitment to animal welfare and are required to sign our ethics charter as a condition of initial and continuing employment.

Since 2004, our high ethical standards have been recognized by accreditation from the American Association of Laboratory Animal Care (AAALAC).

As a highly qualified service provider, we also strive to be flexible, accomodating and respond as quickly as possible to each of your individual needs.

Our objective can be summarized by our claim:

CiToxLAB: Global expertise, Local response.

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Ethical commitment CiToxLAB’s ethics committees have established and rigorously enforce our ethics charter for laboratory animals.All employees are encouraged to continually demonstrate their commitment to animal welfare and are asked to sign our ethics charter as a condition of initial and continuing employment.CiToxLAB employs independent attending veterinarians, dedicated to animal care. CiToxLAB is particularly committed to the 3Rs to minimize animal use, to enhance their well-being and to use alternative methods whenever possible. Laboratory animals are not exposed to unnecessary distress or pain. Endpoints for the removal of animals from a study are defined for all studies.

Housing and enrichmentCiToxLAB always complies with the highest standards of animal care and use. CiToxLAB has a well defined housing policy which was designed to ensure animal well-being in accordance with regulations and current scientific knowledge. Animals are group housed and kept under appropriate conditions to facilitate the expression of species behavior.

StaffCiToxLAB employs highly qualified and trained staff, who receives continuous training in order to reinforce their skills and provide updates on the latest techniques for animal well-being optimization. CiToxLAB employs trained veterinarians with relevant experience in laboratory animals, and who are committed to monitoring and improving the animal care and use program.

Our ethics committees include veterinarians and laypersons. They review all study protocols to ensure that CiToxLAB complies with its ethical commitments.

Our commitment to animal welfareCiToxLAB is committed to the humane treatment of the research animals entrusted to our care. We guarantee that animals will be treated with the highest standards of respect and compassion, and particular attention is accorded to housing conditions, social interaction and enrichment of their environment.

AAALAC recognition has been obtained for most of our sites.

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Study types Acute toxicology Subchronic toxicology Chronic toxicology Cyto- and genotoxicity Immunotoxicity Carcinogenicity Reproductive toxicology Genomics In vitro toxicology Tissue Cross Reactivity ADME and Pharmacokinetics Lead optimization Wound Healing

Species Rat Mouse (including

genetically modified mice for carcinogenicity and immunological investigations) Rabbit Guinea Pig Hamster Dog Minipig Domestic pig Non-human primate

(Cynomolgus and Rhesus NHP)

Routes of administration Oral Inhalation (including

intratracheal and intranasal) Intravenous Continuous intravenous infusion Subcutaneous Dermal Intradermal Intramuscular Intraperitoneal Intravaginal and Intraurethral Intrarectal Intravesicular Ocular (including subretinal

and intravitreal) Intrathecal Intraarticular

General Toxicology (Acute to Chronic)With over 40 years of experience, the toxicity testing capabilities of CiToxLAB comprise a vast array of designs, ranging from acute single dose studies to carcinogenicity studies, including specialty dose routes such as inhalation and infusion. All studies are fully GLP compliant in accordance with current guidelines or custom-designed for particular needs.

CiToxLAB’s four facilities are located in France, North America, Denmark and Hungary. We offer close to 60, 000 m2 of vivarium and supporting laboratories for the conduct of general and specific toxicology studies on: pharmaceuticals, biotechnology products and medical devices. Our clients include an impressive list of major pharmaceutical and biotech companies.

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Study types Acute toxicology Short-term immunotoxicity Subchronic Chronic Skin sensitization and

photoirritation Repeat dose Carcinogenicity

StaffOver 800 staff, including: Project managers Study directors Immunologists Veterinary surgeons Pathologists Toxicologists Animal technicians Analytical and bioanalytical

experts Regulatory specialists

Infrastructure Housing capacity for 27 000

rodents

Species Rat Mouse (including genetically

modified mice) Guinea pig Hamster

Routes of administration Oral gavage Dietary Intravenous Inhalation (including intranasal,

nose-only exposure system) Continuous intravenous infusion Subcutaneous Dermal Intradermal Intramuscular Intraperitoneal Ocular (including subretinal

and intravitreal) Endoscope-assisted

administration

Rodent ToxicologyRodents are the species of choice for the safety testing of chemicals, foods and many pharmaceuticals. All four CiToxLAB facilities offer a wide variety of rodent protocols, from single dose to carcinogenicity studies. CiToxLAB works with all major suppliers to obtain a range of conventional and genetically modified strains. Our study directors and pathologists have extensive experience in the interpretation of in vivo and post-life data from rats, mice and other rodent species.

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Study types Acute toxicology Short-term immunotoxicity Subchronic Chronic Safety pharmacology Pharmacokinetics

and Toxicokinetics Efficacy



Infrastructure Over 130 rooms designed for

dog housing Housing capacity for 1 600+

dogs

Specialties Permanent dog colonies

for telemetry and pharmacokinetics Model development services Intraperitoneal Intravaginal and intraurethral Intrarectal Intravesicular Ocular (including subretinal

and intravitreal) Intrathecal Intraarticular

Dog ToxicologyThe dog is the most common non-rodent species used for the safety testing of medicinal products and chemicals. Such studies are routinely performed at all four CiToxLAB facilities. The animals are housed and handled in accordance with the latest international regulations, and animals are socialized whenever possible. Dogs are available from a variety of approved suppliers.

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Study types Acute toxicology Short-term immunotoxicity Subchronic Chronic Safety pharmacology Pharmacokinetics

& Toxicokinetics Efficacy



Infrastructure Over 100 rooms designed for

non-human primate housing Housing capacity for 1 800

non-human primates Multiple state-of-the-art surgical

suites

Strains Cynomolgus (Mauritius, China,

Vietnam, Philippines) Rhesus (China)

Routes of administration Oral (gavage, capsules, pills) Intravenous (bolus or

continuous infusion ; also available with vascular access port “ cath-in-cath ”) Subcutaneous Dermal Intradermal Intramuscular Intraperitoneal Intranasal Intravaginal and intraurethral Intrarectal Ocular (including subretinal

and intravitreal) Endoscope-assisted

administration (e.g. directly into the duodenum)

Non-human primate ToxicologyNon-human primate (NHP) studies are required for the safety testing of medicinal agents (including biotechnology products) that cannot be evaluated in other non-rodent species due to species-specific differences in pharmacology or metabolism. The CiToxLAB facilities in France and North America offer studies in Cynomolgus and Rhesus NHP. Only purpose-bred NHP are used, and these are obtained from approved breeders in four different countries. The on-site pathologists are familiar with the spontaneous lesions that can occur in the animals from each source. An extensive panel of biomarkers has been validated for use in toxicology studies.

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Study types Acute toxicology Subchronic Chronic Reproductive and embryofetal Local tolerance Implantation

Infrastructure 33 rooms designed for

minipig housing Housing capacity for 800+

minipigs

Routes of administration Oral

- Gavage - Capsule - Dietary admixture Intravenous

- Bolus - Continuous infusion Intraocular Subcutaneous Intramuscular All other standard routes

Specialty studies Dermal and wound healing The skin structure and the

physiology of the epidermis in the minipig resembles that of humans more closely than in any other species. Sparse hair covering makes the minipig very suitable for dermal administration of test articles.

Juvenile Juvenile studies are required

for pediatric indications by Regulatory Authorities. The FDA now offers patent extensions for products for which the indications are expanded to include children.

Continuous infusion and intravenous

Minipigs are very amenable to intravenous procedures, both short- and long-term. We perform both continuous infusion and vascular access port studies in minipigs.

Safety pharmacology studies Implanted telemetry for

cardiovascular monitoring (DSI system)

Jacketed External Telemetry (JET) for monitoring cardiovascular and respiratory functions (Ponemah, DSI systems)

Functional Observational Battery (FOB)

Minipig ToxicologyThe minipig is a good laboratory animal model for many aspects of human physiology and metabolism. For this reason, it is becoming increasingly popular as an alternative to the dog or non-human primate for non-rodent safety testing. The CiToxLAB facility in Denmark has routinely performed studies in minipigs since they pioneered the use of this species in the 1980s. Minipig studies are also available at our CiToxLAB France, North America and Hungary facilities.

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Our services

Study Types

REACHMechanistic Toxicology

Routes of Administration and Know-How

Bioanalysis and Pharmacokinetics

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Efficacy ModelsCiToxLAB offers a wide range of efficacy models in support of drug discovery. Development of new models is undertaken by a team of experts, including veterinary surgeons, immunologists, physiologists, pharmacologists, toxicologists and animal health technologists. Proof-of-principle and screening studies are individually designed and conducted according to strict norms of quality, while providing the flexibility required according to the stage of development.

CiToxLAB has access to a large network of industry-recognized experts to enhance the range of efficacy models that we offer by providing expertise in dermatology, electrocardiology, radio-oncology, ophthalmology, pharmacophysiology and many other fields of preclinical research.

Imaging technologies are a cornerstone of our efficacy models, with ultrasonography, CT-scan, magnetic resonance imaging, fluoroscopy and digital radiography ; all available for the optimal assessment of scientific endpoints.

Available efficacy models

Rodents Sepsis Skin burn Hypoxemic (in mice) Vascular permeability (in mice) Tumor

Non-human primates Anemia Bone marrow flow cytometry analysis Telemetry and cytokine profiling

Dogs Anesthetized hypoxemic Cardiac pacing Atrial effective refractory period

Rabbits Arterial restenosis Heptanol induced corneal ulcer Hemostasis

Multi-Species Dialysis in pigs and dogs Endoscopy (gastroscopy,

duodenoscopy and colonoscopy) in dogs, minipigs, pigs and non-human primates Endotoxemic shock with core body

temperature measurements using telemetry & cytokine profiling Gastric emptying time in dogs,

non-human primates and rats Glomerular filtration rate using

CT-Scan in dogs and pigs Intravesical (urinary bladder)

in rats, dogs, minipigs and non-human primates Wound healing in mice, rats, rabbits,

pigs and minipigs Whole body irradiation in dogs,

non-human primates and rats Biomedical devices

Infrastructure Multiple surgical suites Separate areas for pre- and

post-operative care

Equipment X-ray Fluoroscopy Ultrasound Micro-isolator caging Laminar hoods Microsurgery DEXA

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Genetic ToxicologyCiToxLAB group provides over 25 years of experience and expertise in the performance of standard genotoxicity studies in our modern facility, along with testing of pharmaceuticals, biopharmaceuticals, cosmetics, industrial chemicals, agrochemicals, feed and food additives, as well as other types of test item including medical devices. We can make the appropriate recommendations on how to proceed on a case-by-case basis and how to test even the most unusual products.

Our tests comply with the latest versions of the guidelines issued by the ICH and OECD and are performed in accordance with the current OECD Good Laboratory Practice regulations to ensure their acceptability to regulatory authorities worldwide.

Study types

GLP Genotoxicity: Bacterial reverse mutation test

(the Ames test) - OECD 471 Mammalian chromosome aberration

(cytogenetic) in vitro test using cultured human lymphocytes OECD 473 Mammalian cell gene mutation in vitro

test using mouse lymphoma L5178Y tk +/- cells - OECD 476 Mammalian erythrocyte micronucleus

in vivo test in mice and rats - OECD 474

Screening Genotoxicity:We offer screening versions of the genotoxicity tests, which are useful during the early development of new products. These can be designed to meet the specific requirements of each Sponsor. Mini-Ames BlueScreen™ Mini-micronucleus

In vitro ToxicologyOur tests comply with latest versions of the guidelines issued by the ICH and OECD and are performed in accordance with the current OECD Good Laboratory Practice regulations to ensure their acceptability to regulatory authorities worldwide.

Study types Cytotoxicity - Acute toxicology - Mechanistic toxicology (e.g.

oxidative stress)

Skin or eye irritation and corrosion - BCOP - 3D models

Skin sensitization - Peptide reactivity - MUSST assay

Phototoxicity - 3T3NRU - 3D skin models

Cutaneous penetration - Automized process using dynamic

Frantz cells

Immunotoxicology - ADCC - Chemotaxis - Lymphocyte proliferation - NK assay

ReportingAll in vitro toxicology reports are optimized to be available within 2 weeks after the end of the experimental phases.

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Safety Pharmacology CiToxLAB is an industry leader in GLP-compliant safety pharmacology, offering fully-validated test systems to support international regulatory requirements (e.g. ICH S7A & ICH S7B). A large, dedicated team of experienced veterinary scientists and surgeons is involved in all aspects of validation and study conduct and is supported by a network of recognized experts in cardiovascular, respiratory and central nervous system physiology and pharmacology. CiToxLAB offers a variety of large and small animal models, using state-of-the-art technologies, to complete the safety pharmacology core battery of studies. Supplementary or follow-up studies are offered using tailored solutions for comprehensive pharmacodynamic investigations.

Our colonies of pre-instrumented telemetered dogs, minipigs and non-human primates allow us to provide optimal timelines using well-established conscious animal models. Validated computerized ECG analysis combined with expert review by board certified veterinary cardiologists ensure that electrocardiographic and hemodynamic data are thoroughly and expertly evaluated. Our team benefits from over twenty-five years of experience using various models for in-depth cardiovascular investigations.

In-house data, obtained with various positive control drugs, is also available to better assess pharmacodynamic responsiveness, sensitivity and reproducibility of the cardiovascular, respiratory and neurological safety pharmacology models.

Safety pharmacology core battery Cardiovascular system in conscious

dogs, NHP and minipigs Respiratory system in conscious

rats (head-out or whole body plethysmography), dogs, NHP and minipigs Central nervous system (Modified Irwin

Screen or Functional Observational Battery (FOB) in rats, mice, dogs and NHP)

Safety pharmacology endpoints integrated in toxicology studies Extensive expertise with

biotechnology-derived drug candidates and cancer drugs

Jacketed External Telemetry (JET):

- Respiratory system in conscious rats (head-out or whole body plethysmography), dogs, NHP and minipigs

- FOB in rodents, dogs, NHP and minipigs

Early safety pharmacology hERG Anesthetized guinea pig or rabbit:

ECG, ABP, LVP and QA

Follow-up studies Fully instrumented cardiovascular

models in anesthetized dogs, non-human primates and minipigs Pulmonary arterial pressure in dogs

and non-human primates Complete respiratory mechanics in

anesthetized dogs and non-human primates Blood gases and blood pH in all

species Electroencephalography (EEG) by

telemetry in dogs and non-human primates Electroretinography (ERG) in rabbits,

dogs and non-human primates

Supplemental safety pharmacology studies Gastrointestinal safety pharmacology

in rats, dogs and non-human primates Renal function models in rats, dogs

and non-human primates

Equipment and infrastructure Data Science International telemetry

system (Ponemah) EMKA Technologies & Notocord Industry’s largest telemetry system Hans Rudolph & Scireq respiratory

system Dedicated rooms for safety

pharmacology Multiple surgical suites Imaging (X-ray and fluoroscopy)

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Available species Rat Mouse Rabbit Minipig Dog Non-human primate

All species can be dosed from 4 to 7 days of age by the oral or subcutaneous routes. In rats, the intravenous route is feasible from about 10 days of age.

Available techniques in rodents Behavioral tests: 3-T, Morris and

Cincinnati mazes Immune assessments:

lymphocyte subsets, cytokine determinations, functional tests Detailed histopathology of CNS

and immune system Bone densitometry (in vivo)

CiToxLAB Scantox (Denmark) is the global leader in juvenile minipig studies

Available techniques Implanted vascular access ports for

intravenous administration from 7 days of age Ophthalmoscopy from 3-4 weeks old ECG from 7 days old Clinical pathology from 7 days old Twice-daily toxicokinetic sampling

from 7 days old and 5 times-daily from 21 days of age Tests for learning and memory are

being developedPlease enquire for details.

Juvenile ToxicologyA Pediatric Investigation Plan (PIP) is now an essential component of marketing authorization applications for all new drugs in Europe and North America, whether or not the medicine is intended for use in children. Where drugs are intended to be administered to children, the PIP should include appropriate studies in animals at a stage of development that is relevant to the human population who will be exposed.

CiToxLAB has extensive experience of conducting juvenile toxicity studies in accordance with the requirements of the FDA and EMA.

DART: Developmental And Reproductive ToxicologyAn integrated evaluation of potential risks to reproduction and development is an essential component of marketing authorization applications for all new drugs. CiToxLAB offers this expertise.

With over 40 years of experience and expertise, CiToxLAB can perform a full range of reproductive and developmental toxicity studies in accordance with current international guidelines (ICH, OECD, US EPA, etc) for pharmaceutical, biopharmaceutical, veterinary, chemical, agrochemical, food and consumer products.

CiToxLAB has comprehensive historical control databases (rat and rabbit fetuses as well as fetal abnormalities in minipigs). This extensive experience allows our staff to conduct standard studies as well as highly specific custom projects.

Study types• Fertility and early embryonic

development to implantation (ICH S5, segment I)

Effects on embryo-fetal development (ICH S5, segment II) Effects on pre- and post-natal

development, including maternal function (ICH segment III) Multigeneration (OECD) Extended one-generation Sexually mature non-rodents with

male or female reproductive function parameters (treatment at a specific time of the cycle possible) Uterotropic assays (juvenile or

castrated) Hershberger assays (juvenile or

castrated)

Species Rodent (rat and mouse) and

non-rodent (rabbit) species required by international guidelines. Historical data for different strains Minipig Non-human primate

(Macaca fascicularis): available 2012 (ICH S5, segment II)

Routes of administration Oral: gavage, dietary admixture,

drinking water Intravenous: bolus, slow injection,

continuous infusion, cycles (vascular access port) Other parental routes: subcutaneous,

intradermal, intramuscular, intraperitoneal Dermal Other routes: please consult

Specialty servicesWe offer a range of possible options that can be included in routine studies or in tailored studies, in order to meet specific needs. Neurobehavioral testing - FOB - Learning and memory: our state-

of-the-art facilities and equipment include multiple T mazes: 3T or 9T (Cincinnati water maze) and Morris water maze (circular pool of water, no T)

Sperm analysis (rodent and non-rodent) including motility, morphology and concentration

Histopathology - Male reproductive organs including

testicular staging - Female reproductive organs

including estrous cycle staging

Toxicokinetics, pharmacokinetics: parental blood samples, fetal tissues, fetal blood, amniotic fluid, milk Evaluation of visceral/soft tissues:

fresh visceral dissection or fixed tissues (examination of rat, rabbit and minipig fetal head) Evaluation of effects on the skeleton:

single or double staining, X-ray, DXA, pQCT, microCT, clinical chemistry, histomorphometry Genomics: a large variety of tissues

can be collected and analyzed (PCR, Affymetrix micro-chips)

Support services Dedicated customized unit for the

preparation of dosage forms Analytical chemistry for formulation

analysis (results obtained prior to administration) Statistical analysis

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CarcinogenicityFor products where prolonged or lifetime exposure may occur in humans, it is always necessary to consider performing carcinogenicity studies. CiToxLAB has performed more than 100 carcinogenicity studies. The traditional study designs involve exposure of rodents to the test item for up to two years, with an extensive pathological examination at the end of the study to detect any tumours that may be present in the tissues of the animals. CiToxLAB has more than a dozen board certified pathologists.

DisciplineCiToxLAB routinely performs these studies using all of the standard guidelines, including those of the EU (CPMP), ICH, FDA, EPA, JMHW, JMAFF and OECD. The basic design of the study is similar for all of these guidelines, although for agrochemicals and industrial chemicals it is possible to combine one of the carcinogenicity studies with the long-term chronic toxicity study.

SpeciesThe choice of animal strain and diet is very important. CiToxLAB routinely uses: Wistar Han rats CD-1 mice Sprague-Dawley rats

Specialty servicesIn ICH guideline S1B, the possibility of using alternative models for carcinogenicity testing is described. An extensive evaluation of these models was performed under the auspices of the International Life Sciences Institute (ILSI) of the Health and Environmental Sciences Institute (HESI), Washington DC. The use of some of the models is becoming more common, particularly for submissions to the US FDA.

CiToxLAB has been very active in the evaluation of these models as part of the ILSI program.

CiToxLAB can offer the following models: p53+/- mouse model Tg-rasH2 mouse model

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Biocompatibility of medical devicesCiToxLAB offers extensive services in medical device testing, principally safety/compatibility testing according to ISO 10993 including custom-designed testing programs for each device we are asked to assess. With over 20 years of experience in designing packages, our experts take into consideration the various guidelines, the nature and construction of the device, its use, and its mode and duration of patient contact.

Study typesCiToxLAB can perform all standard biocompatibility tests. In addition, customized tests can be designed and validated, as necessary.

Cytotoxicity test (in vitro) Sensitization test - Local lymph node assay - Guinea pig maximization test

(GPMT)

Irritation - Single or cumulative exposure

in accordance with the intended clinical use

- Intracutaneous reactivity - Topical (skin, buccal cavity, vagina,

urethra, rectum)

Test for systemic toxicity (acute or repeated exposure) Genotoxicity - Ames test (OECD 471) - Gene mutation test (OECD 476)

Implantation test - Muscular or subcutaneous

implantation in rabbits Hemolysis and coagulation tests Carcinogenicity and reproductive

toxicity tests

Species Rabbit Guinea pig Mouse Rat Minipig Hamster

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HistopathologyCiToxLAB histology laboratories can offer all routine procedures, along with special techniques such as immunohistochemical and fluorescence staining on paraffin, frozen or plastic blocks.

State-of-the-art equipment including GLP-validated software (Provantis, Pathdata, Bone, Cell D) are dedicated to histology operations.

Our team of certified and experienced veterinarians, pathologists and technical staff has a wealth of expertise in evaluating the safety of pharmaceutical, veterinary pharmaceutical, biotechnological, medical device, chemical, agrochemical, food and consumer products, in rodents and non-rodents.

Proficient routine expertise

Necropsy: Skilled prosectors Whole and upper body perfusion

in rodent and non-rodent species Special collection procedures for

immunohistochemistry, genomics, neurotoxicology and electron microscopy Quick and careful tissue collection for

RNA or DNA extraction Bone collection for histomorphometry Online data acquisition (organ weights

and gross observations)

Histology: Highly experienced staff Organ trimming according to RITA-like

instructions for rodent species Organ trimming according to RITA-like

instructions for non-rodent species Consistent presentation of tissues on

slides Paraffin, frozen and methacrylate

embedding Standardized and special staining

procedures Paraffin, plastic and cryosectioning Immunohistochemical and

fluorescence staining of paraffin embedded or frozen tissues

Pathology: Experienced board certified

veterinary pathologists (ACVP and ECVP) Evaluation of a wide range of studies

in rodents and non-rodents, from acute to chronic oral administration, injection/infusion, dermal, inhalation, irradiation and local (incl. wound healing) toxicity, developmental and reproductive, intravesical and carcinogenicity studies Glossary defined according to the

international recommendations for terminology Historical control data from rodents

and non-rodents for use with toxicology and carcinogenicity studies Routine internal peer review Immunotoxicology Testicular and ovarian staging Histomorphometry to quantify tissue

changes Online data acquisition Digital imaging, high resolution

photographs, telepathology Board certified pathologists may read

or review your slides at your facility

Histopathology (CNTD)

Specific expertise

Tissue Cross Reactivity:CiToxLAB offers high quality in vitro Tissue Cross Reactivity (TCR) for the immunohistochemistry screening of therapeutic antibodies.

Standard preliminary and definitive protocols, GLP or non-GLP, performed according to FDA recommendations State-of-the-art equipment: Ventana

Discovery XT® and DAKO® autostainer Link 48 to maximize repeatability Full range of frozen normal human

tissues available from multiple donors with patient history Full range of frozen normal animal

tissues available from several species including Cynomolgus, Rhesus, dog, rat, mouse, rabbit, or minipig Frozen pathological tissues available

as positive controls High resolution photographs to

illustrate the representative staining in your GLP audited report Semi-quantitative evaluation by a

board certified veterinary pathologist Internal peer review

Tissue collection for RNA or DNA extraction:CiToxLAB provides a complete set of services in molecular pathology and genomics (transcriptomics).

Specifically trained team in order to: - Collect the tissues in a very short

time to avoid RNA degradation - Precise trimming procedures

to avoid contamination with adjacent tissues

Extensive list of tissues in rodent and non-rodent species CiToxLAB offers molecular pathology

services with real-time PCR (rt-PCR) and quantitative PCR (Q-PCR)

Bone and joint research:CiToxLAB provides a complete set of services (in vivo and ex vivo) for the evaluation of the effects of products on the skeleton (pharmacological and toxicological effects).

Bone densitometry: standard radiology, DXA, pQCT, micro-CT Plastic embedding State-of-the-art histomorphometry

with validated software for measurement of static and dynamic parameters Complete set of blood and urine bone

markers in rodent and non-rodent species

Image analysis: Histomorphometry is performed using

validated computerized image analysis software to efficiently quantify the user-defined changes for a wide range of parameters Trained technical staff under the

supervision of pathologists GLP or non GLP projects Multiple digital image workstations Comprehensive reports with statistical

analysis if required

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Immunology ServicesSeveral facilities in the CiToxLAB group offer immunology services and provide industry-leading expertise in the conduct of GLP-compliant immunotoxicology evaluations. Our experts are abreast of the evolving regulatory requirements and are able to offer guidance in study and program design.

Assessment of autoimmunity Assays for anti-dsDNA and

anti-nuclear antibodies Markers of TH2 activation in rodents

prone to developing autoimmune reactions Screening for other auto-antibodies in

nonclinical toxicology studies

Adverse immunostimulationOur experts can advise on how to proceed in this rapidly evolving area of concern Panels of cytokines Inflammation biomarkers (CRP,

fibrinogen, etc.)

Species commonly usedNon-human primate, dog, rat, mouse and minipig.

Study types Extended histopathological

examination of lymphoid tissues and organs T-dependent antibody responses

(KLH) Immunophenotyping for quantitation

of lymphocyte lineages or biomarker expression Cell mediated immunity (NK and CTL

Cytotoxicity) Immunohistochemical staining for cell

lineage and apoptosis markers in fixed tissues

Pseudoallergic reactions Direct histamine release Complement activation

Contact hypersensitivity LLNA Magnusson-Kligman and Buehler Photo-LLNA

CiToxLAB offers the full range of immunology-based support services necessary for the development of biotechnology-derived therapeutics, along with the experience and expertise necessary to conduct any required immunotoxicology studies.Whether developing a protein, nucleic acid or cell-based therapeutic, our staff can provide full support, from toxicology species justification, through assay development, to final report submission.

Support services Immunogenicity analysis,

including development of antidrug antibody and neutralizing antibody assays Bioanalytical immunoassays for

toxicokinetic and pharmacodynamic studies Tissue cross reactivity studies on a

full panel of frozen human and animal tissues in support of monoclonal antibodies and other ligand binding therapeutics Drug activity assays in support of

toxicology species justification Quantitative gene expression for

biomarker analysis Biodistribution and genomic

integration analysis of nucleic acid therapeutics Biodistribution and drug activity

assays for enzyme products Biodistribution of cell-based

therapeutics with PCR, immunohistochemistry and flow cytometry.

Infrastructure BSL2 capable Modern laboratories in Europe and

North America Dedicated, separate rooms for: - Tissue culture - Molecular biology - General immuno-assays

www.citoxlab.com

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Dermal StudiesWith more than 25 years of experience in the use of minipigs, supported by scientific staff with many years of experience in the pharmaceutical industry, and specialized in dermal products, CiToxLAB is your ideal partner for the development of drugs intended for dermal use.

From 2003 to 2011, CiToxLAB performed approximately 300 minipig studies, including 50 by the dermal route. We have also performed 15 dermal studies in rats.

We offer wound healing studies to investigate the efficacy and safety of dermal drugs, and during the last 6 years we have performed approximately 35 wound healing studies in minipigs.

In addition to the following studies, CiToxLAB offers a full first-in-man support service, plus a full range of studies to support Phase II and III clinical trials.

Species Minipig Rabbit Rat Mouse Guinea pig

Study types (specific to dermal application) Toxicology – acute to chronic Local tolerance Sensitization

(local lymph node assay and guinea pig maximization) Phototoxicity Pharmacokinetic (transdermal

absorption and bioavailability) Safety pharmacology Efficacy (including tensile strength

measurements)

Product types Gels Creams Ointments Patches Transdermal devices

Study typesNose-only and oronasal Single dose Subchronic Chronic

Aerosol generations of Liquids Powders Gases

Species Rodent Dog Non-human primate

Experience and staff CiToxLAB has over 25 years of

experience with various animal species given single or repeated nose-only and oronasal exposure to liquids or powders. The inhalation teams at CiToxLAB are

also supported by our experienced board certified pathologists and analytical and bioanalytical teams, who work closely with the inhalation experts.

Current infrastructureStudies are performed in purpose-built laboratories with back-up systems (pumps, ventilation, generators, etc.). The facilities are also equipped as follows:

Seven rodent suites (nose-only) Each containing 5 or 6 exposure units

(accommodates sham control, vehicle control and 4 test item dose levels) Each unit can accommodate up to 80 rodents Each unit physically and spatially

separated (walk-in ventilated hoods)

Five large animal suites (oronasal) Each containing up to 4 exposure units Each unit can accommodate up to 8 animals Physical and spatial separation of

control group exposure units to prevent cross-contamination Exposure masks available for various

species (e.g. dog)

Technology and equipment

Rodent exposureNose-only exposure using a directed flow (flow-past) system that minimizes test item requirements: Prevents re-breathing Restraint designed to minimize

thermal stress Maintains homogeneous breathable

atmosphere at all levels of the inhalation tower Each exposure unit can accommodate

up to 80 animals

Large animal exposureOronasal exposure using a directed flow (flow-past) system that minimizes test item requirements: Prevents re-breathing Each exposure unit can accommodate

up to 8 animals and can be used with various species

In addition, the system can accommodate various generating equipment depending on test item (e.g. clinical nebulizers and dust generators)

Supporting services Analytical and bioanalytical (HPLC and

LC-MS/MS) Pathology Immunology Toxicokinetics Efficacy animal models (COPD,

asthma, nicotine)

Inhalation Toxicology ServicesCiToxLAB group offers studies by inhalation in Canada and Hungary. These studies may be performed in rodents, dogs and non-human primates.

www.citoxlab.com

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Continuous Intravenous InfusionCiToxLAB offers acute to chronic continuous intravenous infusion in all major laboratory species. Our staff includes industry-recognized experts with wide experience in the design, conduct and interpretation of continuous intravenous infusion studies.

This extensive experience of the intravenous infusion of biotechnology-derived and other pharmaceutical products, allows us to provide our clients with guidance on optimal vehicles, formulation conditions, pH and osmolality ranges, and maximum and minimum recommended infusion rates and volumes, as well as providing input on drug compatibility, background pathology and other issues unique to the intravenous infusion delivery route.

Species Minipig Rabbit Rat Mouse Guinea pig

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Surgical CapabilitiesCiToxLAB’s large dedicated team of experienced veterinary surgeons, combined with our custom built and fully equipped surgical suites, allows us to offer routine and customized surgical models, including orthopedic and soft-tissue procedures. Aseptic technique and attention to pre-and post-operative care are essential, and are accomplished using specifically equipped and designated procedure rooms, with a large and qualified staff of animal health technicians. In-house imaging technologies allow us to fine-tune surgical procedures and to conduct non-invasive follow-ups.

Through close collaboration with our clients and our extensive network of recognized experts in a variety of disciplines, CiToxLAB has earned a reputation of being an innovator in the development of specialized models and procedures and for its ability to apply these models to GLP studies.

Available surgical models

Rabbit Arterial restenosis Hemostasis Heptanol induced corneal ulcer

Rat Bile duct catheter Continuous lymph collection Kidney transplantation Internal carotid catheterization

(rodent model for cerebrovascular administration)

Non-human primate Cerebrospinal fluid collection EEG monitoring using telemetry Continuous intracerebral

(parenchyma) infusion Kidney transplantation

Dog Femoral trochleoplasty and other

orthopedic models Administration under intervention

radiography (cerebral artery infusion, prostatic artery, etc.)

Non-invasive cerebrospinal fluid sampling catheter Intraarticular injection and synovial

fluid collection Kidney transplantation Vascular access port (VAP) Subcutaneous and intramuscular

implantations

Multi-species Left ventricular pressure and

pulmonary arterial pressure Dialysis models in pigs and dogs Disease models (cardiac hypertrophy,

cardiac insufficiency, myocardial infarction & diabetes) Duodenal catheters in dogs, non-

human primates and rats Continuous lymph collection in dogs,

minipigs and rats Femoral and jugular vein catheters

in dogs, non-human primates, pigs, minipigs and rats Ileal catheters in dogs, non-human

primates and rats Intraarticular injection and synovial

fluid collection in dogs, non-human primates, minipigs, pigs and rats Intrathecal catheters in dogs and

non-human primates

Jejunal catheters in dogs, non-human primates and rats Portal vein catheters in dogs,

non-human primates and rats Surgical (incisional and excisional)

wound healing models in mice, rats, rabbits, pigs and minipigs Telemetry in dogs, minipigs,

non-human primates, rats and mice Vascular access port (VAP) in rats,

dogs, non-human primates and minipigs Subcutaneous and intramuscular

implantations in rats, rabbits and minipigs

Infrastructure Multiple surgical suites (HEPA-filtered) Separate areas for pre- and

post-operative care

Equipment X-ray Fluoroscopy Ultrasound Micro-isolator caging Laminar hoods Multiple microsurgery stations

SpeciesRat, dog, non-human primate, rabbit and minipig

Telemetry StudiesAs part of its safety pharmacology services, CiToxLAB offers the industry’s largest capacity for telemetry studies, thus making us an industry leader in the conduct of conscious cardiovascular safety pharmacology studies. In addition to implanted telemetry, our team offers a large range of non-invasive telemetry models using DSI jacketed external telemetry. Our telemetry studies are conducted using rigorously validated test systems, and are designed to support international regulatory requirements (e.g. ICH S7A & ICH S7B). A large, dedicated team of experienced veterinary scientists and surgeons is involved in all aspects of validation and study conduct and is supported by recognized experts in electrocardiography.

Our colonies of pre-instrumented telemetered beagle dogs, Cynomolgus NHP and Göttingen minipigs allow us to provide optimal timelines, using well-established conscious animal models. Validated computerized ECG analysis combined with expert review by board certified veterinary cardiologists ensure that electrocardiographic and hemodynamic data are thoroughly and expertly evaluated.

Our team also offers a wide range of continuous video-EEG models for seizure liability, sleep scoring, spectral analysis and other CNS evaluations. World-renowned consultant neurologists specializing in seizure assessment, movement disorders and sleep studies provide thorough data interpretation using state-of-the-art analysis tools.

Our telemetry studies often incorporate additional assessments, including respiratory function, thus maximizing the data available from a single study.

Species Rat Dog Non-human primate Minipig Guinea pig Permanent dog, non-human primate

and minipig implanted telemetry colonies

Equipment and infrastructure: Several Data Science International

telemetry systems Industry’s largest telemetry capacity Modern surgical facilities and

recording environment for telemetry, equipped with continuous video monitoring Hans Rudolph & Scireq respiratory

system Dedicated animal rooms for safety

pharmacology Multiple surgical suites Imaging (X-ray and fluoroscopy)

Telemetry capacity More than 120 animals concurrently Continuous high resolution EEG-video

in 12 animals simultaneously

Quantitative parameters Arterial blood pressure (systolic,

diastolic, mean) Left ventricular pressure ECG intervals Activity Core body temperature Pleural pressure Biopotentials (ECG, EEG, EMG)

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BioanalysisCiToxLAB offers GLP-compliant bioanalytical services for nonclinical studies performed in-house and for studies conducted in a Sponsor’s facility. Analysis of plasma/serum or other biological matrices is performed to determine the concentration of the test substance for pharmacokinetic/toxicokinetic analysis. CiToxLAB performs method development of new compounds or method transfer of existing methods. In each case, the method is fully validated according to GLP principles.

EquipmentMultiple systems at each facility include: HPLC systems with a variety of

detection methods GC systems with a variety of detection

methods LC-MS LC-MS/MS LC-ICP/MS UV spectrophotometer

Activities Method development Method transfer Method validation Sample analysis to support

pharmacokinetic/toxicokinetic studies and inhalation toxicology studies Dried blood spot sample analysis

Support services Several highly experienced senior

bioanalytical chemists are available to provide sponsors experienced staff with scientific and regulatory guidance Chemists are supported by

well-trained analysts with experience in bioanalytical method development/ method validation/sample analysis using LC-MS/MS or other technologies

AnalysisCiToxLAB offers GLP-compliant analytical chemistry support for all types of nonclinical study performed in-house or at the client’s facility. Analysis of test formulations is performed to confirm the concentration, homogeneity and stability. We can perform method development of new compounds or method transfer of existing methods. In each case, the analytical method is fully validated according to GLP principles.

EquipmentMultiple HPLC systems at each facility

Activities Method development Method transfer Method validation Sample analysis to support toxicology

studies: - Solutions - Suspensions - Dietary admixtures - Atmosphere (inhalation studies)

Support services Several highly experienced senior

analytical chemists are available to provide sponsors experienced staff with scientific and regulatory guidance Chemists are supported by well-

trained analysts with experience in analytical method development/ method validation/ sample analysis using HPLC or other technologies

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Pharmacokinetic/Toxicokinetic Studies/ADMECiToxLAB offers 32, 000m2 of vivarium and supporting laboratories for the conduct of GLP-compliant pharmacokinetic and toxicokinetic studies on pharmaceuticals and biotechnology-derived products.

Studies are conducted in all rodent and non-rodent species, including non-human primates and minipigs, to determine the time course of a drug candidate and its major metabolites after drug administration. These studies are supported by CiToxLAB’s bioanalytical and immunology services which provide LC-MS/MS, GC-MS/MS, HPLC and immuno-assay (e.g. ELISA) analyses in biological matrices.

Non-compartmental modelling is conducted using fully GLP validated WinNonLin software. In addition, to routine blood collection (e.g. sublingual, retro-orbital sinus or tail vein in rats), our technicians use a specialised jugular sampling technique to collect serial blood samples from individual rats without the need for anesthesia or cannulation. Intrajugular catheters, which do not require surgery, are routinely used in minipigs.

Study durations Single dose Repeated dose

Species Rodent Dog Non-human primate Rabbit Mini and micropig Poultry Marmoset

Routes of administration Oral (gavage, capsules, pills) Intravenous (bolus) Intravenous infusion (intermittent,

cyclic and continuous) Subcutaneous Dermal Inhalation Intradermal Intramuscular Intraperitoneal Intrathecal Intranasal Intravaginal/intraurethral Intrarectal Intravesicular Intravitreal Intratracheal instillation Ocular Endoscope-assisted administration

(e.g. directly into the duodenum) Intraportal Intraarticular

Bioanalytical support 7 LC-MS/MS GLP-validated analytical software GC-MS LC-ICP/MS ELISA Dedicated scientists

Specialties Radiolabelled studies Permanent dog, non-human primate

and minipig PK colonies Custom-designed PK studies using

surgical and non-surgical techniques (in vivo drug-drug interaction, Pgp interaction, brain penetration, CSF collection, enterohepatic recirculation, etc.) In vitro plasma/blood partitioning,

plasma protein binding In vitro cutaneous penetration

Drug MetabolismCiToxLAB offers GLP-compliant preclinical studies, designed to investigate absorption, distribution, metabolism, and excretion (ADME), to support drug discovery, safety evaluation and clinical development programs.

Equipment Metabolism cages for mice, rats, dogs,

non-human primates, minipigs CO2 rodent cages (Metabolica) Fully validated ß-counters : (Beckman

LS600YA and Perkin Elmer Tri-Carb 2910TR) Sample Oxidizer (307 Perkin Elmer) HPLC/UV/on-line radioactivity

(LB507A Radioactivity monitor)

Services Mass balance/excretion studies

including CO2 collection and bile excretion Analysis of all matrices (blood/serum/

plasma, urine, feces, milk, saliva, tears, bile and tissues)

Isotopes used: 14C, 3H Establishing mass balance and

excretion routes of an administered radioactive drug candidate is important in order to determine compound distribution and assist the interpretation of toxicology findings. An understanding of excretion routes in animals provides guidance in the evaluation of patients with compromised physiological functions (e.g hepatic and renal impairment).

Tissue distribution studies (QTD) Knowing the time course of a drug

candidate’s tissue distribution after administration may help to understand the mechanism and course of action, and this helps explain any observed toxicity. These studies provide an estimate of human exposure to radioactivity (dosimetry) in human radiolabelled mass balance/ excretion studies.

QTD studies can be combined with mass balance studies, plasma/blood pharmacokinetics in a single protocol to save time and money.

FacilitiesDedicated laboratory with controlled access and multiple formulation rooms to prevent cross-contamination.

Species Rodent Dog Non-human primate Minipig Rabbit Poultry

Specialties• Mass balance studies in rodents,

minipigs, dogs and non-human primates

• Specialized techniques in PK/mass balance sampling for rodents and non-rodents

• Fully validated instrumentation to comply with regulatory agencies

Support services Bioanalytical Chemistry Pharmacokinetic modelling

(WinNonLin)

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Services REACH Data Gap Analysis CLP classification QSAR, SAR, literature search, data

waivers Robust Summaries Advice, guidance and full regulatory

support for dossier preparation and submission Data submission in ECHA format

(IUCLID 5) Full support for the whole registration

process Project management Representation - Third Party and Only

Representative Physical chemistry Genetic toxicology Analytical services Acute and chronic mammalian

toxicology by the oral, dermal or inhalation routes Reproductive toxicology, including

multigeneration rodent (one, two or extended generation studies) and avian reproduction Ecotoxicology (aquatic, terrestrial,

avian) Soil studies Bioaccumulation and other long-term

environmental studies

Registration of all existing chemicals manufactured, imported, transported, used as intermediates or placed on the market in Europe should be completed by the appropriate REACH deadlines. All new chemicals are subject to the same regulations. Similar regulations exist in a number of other world regions, CiToxLAB can provide consultancy on national requirements. Since May 2009, the Hungarian facility has had a partnering agreement with CS Regulatory Ltd, an ISO 9001:2008 accredited organization with 40+ years experience of regulatory submissions, providing our clients in the chemical industry with a complete service offering full regulatory assistance and safety evaluations.

Services include REACH Specialist: advice, compliance

and consultancy packages for chemicals

Worldwide registration of chemicals

Production of chemical safety documents

- Material Safety Data Sheets (CLP/Ext-SDS / GHS formats)

- Chemical Safety Reports - Hazard Assessments

CLP Regulation - Correct classification of mixtures - “Late” CLP notification to the

inventory - Preparation of Material Safety Data

Sheets

Experience Our facility in Hungary has extensive experience in REACH projects with a wide range of chemicals, including metals and other inorganic chemistry, as well as a wide range of physical forms of organic chemicals and mixtures. The facility is able to deal with difficult substances where special procedures are required to allow testing to be performed across the full range of study types from aquatic toxicology to long-term inhalation toxicology.

Tests required REACH testing schedules are dependent on the number of tonnes produced per year, but involve a wide range of tests from simple physico-chemical studies to long-term mammalian toxicology tests. The time required to complete such testing programs is as follows:>1 tonne/annum substances ~ 3 months

>10 tonnes/annum substances ~ 6 months

>100 tonnes/annum substances ~ 10 months

>1000 tonnes/annum substances ~ 3 years

REACH timelines1 June 2013 Deadline for registration of phase-in substances > 100 tonnes/annum1 June 2018 Deadline for registration of phase-in substances > 1 tonne/annum

REACH & CLP ServicesCiToxLAB has close to 30 years of experience in working with the chemical industry and offers all the studies that are required under REACH (Registration, Evaluation and Authorization of Chemical Substances). All of our studies are performed according to GLP regulations and follow standard OECD guidelines.

Environmental ScienceCiToxLAB has more than 15 years of experience in supporting the studies for environmental assessment required for EMA registration, agrochemical registration and industrial chemical notification.

This service is located at our site in Hungary, with a research focus on environmental quality with regard to safety of the natural environment. The fully GLP-compliant purpose-built facility and state-of-the-art instrumentation provide an efficient and reliable service to their global client base.

Services Aquatic ecotoxicology Terrestrial ecotoxicology Bacterial toxicity and biodegradation Environmental fate

Aquatic ecotoxicologyStudies conducted within CiToxLAB Hungary include, but are not limited to: Acute and prolonged toxicity to fish Acute toxicity and reproduction tests

in daphnia magna Algal growth inhibition test Lemna toxicity test

Our ecotoxicology team has extensive experience and expertise in the testing of difficult substances with challenging physico-chemical properties (e.g. low water solubility, instability or coloration).The fish toxicity studies are performed routinely in rainbow trout, carp and zebra fish.Our analytical laboratory offers analytical techniques suitable for use with all matrices used in aquatic ecotoxicology studies.

Terrestrial ecotoxicologyWe offer a variety of terrestrial ecotoxicology studies, with significant experience in a range of species: Acute oral and contact toxicity to

honey bees Laboratory and extended laboratory

toxicity studies with non-target arthropods (NTA) Acute and extended toxicity

(reproduction) to earthworms Acute and reproductive toxicity to

springtails (Collembola) Avian acute studies, dietary studies

and reproduction studiesOur ecotoxicology team has vast experience in performing avian studies with different test species.

Bacterial toxicity, biodegradation testing and environmental fate The following types of studies are conducted under this category: Activated sludge respiration inhibition

test Bacterial toxicity (Pseudomonas

putida) Ready biodegradability Adsorption/desorption Hydrolysis studies

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Physical ChemistryCiToxLAB Hungary offers close to 30 years experience in the physical chemistry area, along with a full range of studies necessary to support global product registration.

CiToxLAB offers a comprehensive product characterization service to the agrochemical and chemical industries.

CiToxLAB Hungary offers fast and flexible start times in order to support your global registration activities. Our dedicated analytical team can provide:

Typical study types Physical state pH Melting point/boiling point Relative density Vapour pressure Water solubility Hydrolysis Soil adsorption/desorption Surface tension Dissociation constant Viscosity Partition cœfficient Flammability Auto-ignition temperature Oxidizing properties

Additionally, CiToxLAB offers a comprehensive range of CIPAC methods supporting high temperature, low temperature and long-term regulatory storage stability/shelf life studies for agrochemical, biocide, veterinary and pharmaceutical global testing requirements.

The guidelines supported include: EU directive 91/414 annex II,

and 1107/2009 (active ingredient) EU directive 91/414 annex III,

and 1107/2009 (formulations) OECD guidelines 101 – 123 inclusive EU CLP and REACH guidelines

Structure-Activity Relationship (SAR) AnalysisWith over 20 years of experience and expertise, CiToxLAB can provide a full SAR analysis and expert reporting. CiToxLAB has extensive background knowledge and experience in the requirements for the regulatory authorities as well as in screening and predictive toxicology.

The system used is a computer package which predicts the toxicity of molecular structures based on a defined set of rules. These rules are specified and regularly updated through collaboration with experts in the majority of large pharmaceutical companies, and regulatory authorities, such as the US-FDA. A Cooperative Research and Development Agreement (CRADA) exists between the software supplier and the ICSAS (Informatics and Computational Safety Analysis Staff) group at the US Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) and the CFSAN (Center for Food Safety and Applied Nutritian) group. The results are quickly obtained from the chemical structure, with no need to use chemicals or animals. SAR provides an estimate of toxicity, which can be used in regulatory submissions, to select candidate and identify possible toxic impurities.

Key functions Identification of the genotoxic or

neurotoxic potential of chemical structures It predicts whether a chemical has

mutagenic or carcinogenic properties It predicts whether a chemical will be a

skin sensitizer It is a high throughput screen for

genotoxicity/mutagenicity It highlights a wide range of potential

toxicological hazards, from irritancy to hepatotoxicity The SAR system is used in conjunction

with literature and available data to compile expert reports

ServicesExpert reports on the genotoxic potential of pharmaceutical impurities (FDA and EMA submissions)Expert reports on the genotoxic or neurotoxic potential of metabolites (EU agrochemical submissions) Screening candidate molecules to

identify those least likely to cause toxicity Evaluating leading candidate

molecules, to help prioritize safety tests (“Cross The Biggest Hurdles First”, or “Fail Early–Fail Cheap”) Determination of what organizations

like the FDA or EPA may identify when you submit Helping to anticipate questions from

regulatory agencies

Evaluating the risks from intermediates and impurities, thus often avoiding the need for synthesis and toxicology testing of minor components of technical products Identifying the potential risks of

intermediates for the different synthetic routes, as part of the decision process for route selection Troubleshooting - to aid in the

identification of the root causes of mutagenic or sensitization issues in batches of final products SAR will play a major role in the

REACH process, in the triage of molecules for priority testing, and as a screen to avoid direct testing

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Lead Optimization: LeadScreen™CiToxLAB France offers services to clients in the pharmaceutical industry to optimize the selection of lead candidates for drug development with our LeadScreen™ package of tests. Key services have been optimized for the non-regulatory environment to offer quality data in a timely manner.

LeadScreen™ services cover the areas of genotoxicity, safety pharmacology, pharmacokinetics and multi-endpoint in vivo toxicology. Key decisions can be made faster, saving time and money in the development of drugs. Choosing the right lead candidate can take as little as 14 days.

Study types

LeadScreen Tox Core Study - In life data - Clinical pathology - Histopathology

In vivo genetic toxicology

Genomics - Toxicogenomics - CYP induction - DrugMatrix™

Toxicokinetics

Biomarkers - Wide range including troponine

and kindey injury biomarkers

LeadScreen Genotox MiniAmes Micronucleus in vitro BlueScreen HC™

LeadScreen Pharmacokinetics - In vivo half-life - In vivo bioavailability

devTOX™ & cardioTOX™ Stemina hES lines

LeadScreen Safety In vivo QT prolongation Other CV parameters

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Key areas of expertise Customized toxicogenomics study

design (relevant species selection, choice of appropriate time-points and dose-levels, sequenced organ sampling at necropsy) Large panel of DNA/RNA/µRNA

extraction procedures to ensure top level quality DNA/RNA/µRNA from more than 50 tissues, fluids, cells and swabs from rodents and non-human primates Monitoring/detection of DNA and RNA

sequences using real-time quantitative PCR (Applied Biosystems 7900 HT Fast) GLP-compliant gene therapy products

biodistribution regulatory studies Whole transcriptome profiling (RNA

and µRNA ) on Affymetrix Genechip® arrays (whole genome and Gene ST arrays, µRNA arrays) Clinical genotyping with Affymetrix

Human SNP 6.0 arrays Complete data analysis (from

preprocessing up to pathway analysis)

Study types

LeadScreen™ study packageCiToxLAB France proposes the following simple toxicogenomics study design for the investigation of toxic mechanisms and toxicity prediction, using a dose/time combination that produces maximum impact on gene expression. This design may be customized to your specific objective. 1 control and 2 test item-treated

groups (up to maximum tolerated dose) with 3 animals per group

27 chips (3 tissues: e.g. kidney, liver, heart; 3 groups; 3 animals per group) Complete Sponsor-customized data

analysis (from preprocessing up to pathway analysis and prediction scoring with DrugMatrix) Reporting in 10 days with raw data

transferred onto a secured FTP server

Gene expression analysisCiToxLAB France offers gene expression analysis services based on either Affymetrix chips or real time PCR. Array based studies include :

µRNA 2.0, Human Genome U133 Plus 2.0; Mouse Genome 430 2.0; Rat Genome 230 2.0; Canine Genome 2.0; Porcine and Bovine genome; Human Gene ST 1.0; Rat Gene 1.0 ST and Mouse Gene 1.0 ST Clinical genotyping (SNP clusters and

copy number analysis) with Genome Wide Human SNP 6.0 arrays Real Time qPCR with Applied

Biosystems 7900 HT Fast technology and Taqman® chemistry, Taqman® Low-Density Array (TLDA) formats available (from 12 to 380 simultaneous gene detections with simplicate to quadruplicate) Absolute quantitative simplex/

multiplex PCR and RT-PCR, including validation of qPCR or RT-qPCR assays (specificity, reproducibility, stability, range linearity, detection limit, inhibition monitoring) Quantification of any transcripts

with a known sequence (up to 380 transcripts on one card)

Biodistribution of gene therapy products Regulatory biodistribution studies are a pivotal requirement during the preclinical safety evaluation of gene therapy vectors (viral DNA or RNA, plasmid, antisense). They provide essential safety data on the persistence of DNA or RNA in the organs and its dissemination throughout tissues and fluids. CiToxLAB France provides a complete biodistribution study solution which includes: In vivo phase under BSL1/BSL2

conditions Enhanced necropsy procedures

in order to avoid organ-to-organ contaminations RNA and DNA extraction from tissues,

fluids and swabs (separate treated and control group extraction rooms) Absolute quantitative simplex/

multiplex PCR and RT-PCR including validation of qPCR or RT-qPCR assays (specificity, reproducibility, stability, range linearity, detection limit, inhibition monitoring, extraction yields and limits) All the study phases are GLP-compliant

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MetabolomicsCiToxLAB, working in collaboration with Stemina Biomarker Discovery, offers a broad suite of metabolomic services focused on identifying metabolites and biomarkers of many biological processes. By focusing on the small molecules, either secreted or consumed by cells, the metabolomics platform is capable of identifying metabolite patterns associated with toxicity, cellular responses to drugs or chemicals, or biomarkers associated with disease.

Our team has experience in working with a spectrum of clients that include pharmaceutical, chemical, agricultural, and cosmetics companies. In addition to the identification of biomarkers, Stemina’s proprietary metabolomics database maps significantly changed small molecules to the molecular pathways in which they reside. The workflow begins with biological sample acquisition, sample preparation and evaluation by high performance liquid chromatography coupled to high resolution mass spectrometry, followed by univariate and multivariate bioinformatic analysis, data mining, evaluation, and interpretation.

Technologies employed Cell culture, including stem cells,

primary cells, and differentiated cells such as neural and cardiomyocytes. Chromatography methods include

HILIC Hydrophilic Interaction Chromatography, C18 Reverse Phase Chromatography, and other selected methods. LC/MS utilizing the latest in high

resolution instrumentation including TOF and QTOFs incorporating both positive and negative electro-spray ionization methods. Bioinformatic platform uses LC/MS

feature identification, alignment, and standardization protocols followed. by both uni- and multi-variant model development and validation. Biomarker confirmation by

MS/MS fragmentation and comparison to reference standards. Metabolites identified are confirmed and evaluated in relation to biological pathways. Often, multiple metabolite perturbations are observed in a single pathway.

Experience counts We routinely analyze materials and supernatant from cell culture, human tissue and body fluids, and plant samples.

Our team has extensive experience in metabolomic analysis with a specialization in the use of human derived stem cells for performing many of these tests. We routinely conduct studies in embryonic stem (hES) cells, induced pluripotent stem (iPS) cells, as well as a variety of cell types based on selective differentiation into cells such as cardiomyocytes.

Stemina was founded in 2006 and has its state-of-the-art facilities in the United States. Stemina has partnered with CiToxLAB to provide its metabolomic and cell based assays in Europe.

Routine Service Offerings DevTOX-hES : Evaluation of test

compounds for the potential to cause developmental toxicity in human systems. In addition to a prediction of the toxicity of the compound, Stemina’s devTOX assay provides information on the metabolic pathways which are disrupted by the test compound.

DevTOX-iPS : Similar to the DevTOX-hES above, but utilizing induced pluripotent stem (iPS) cells. This test is often attractive to those organizations which prefer to avoid using embryonic-derived cells. CardioTOX : iPS derived cardiomyocytes

are used to evaluate the potential of compounds to induce cardiotoxicity.

www.stemina.com

Global expertise, Local response

Toxicology servicesGeneral toxicology:

- Rodents - Non-rodents: dogs, NHPs and minipigs

InfusionInhalationDermalOcularImmunotoxicologyReproductive toxicology including minipigs and NHPsCarcinogenicity studies also in rasH2 and p53+/- miceGenetic toxicology: ICH compliant packageIn vitro toxicology : BCOP, MUSST, DPRA, Photo 3T3, Episkin™Agrochemical / Chemical / REACHQSAR Physical chemistryEcotoxicology: wide range of test species

Safety pharmacologyCV telemetry / ECG / BPJacketed External Telemetry (JET) / ECG / BPRespiratory / plethysmography / JET telemetryCNS / EEGEarly safety pharmacology

DMPK and biomarkersRadiolabelled DMPK: in all speciesBioanalysis LC-MS/MS, GC-MS/MS, LC-ICP/MS, ELISA, RIAToxicogenomics, miRNA: Affymetrix™ / Accredited service providerImmunology: 10-color flow cytometer, Luminex, Mesoscale

Specialized expertisesJuvenile studies including minipigsFertility studies in rodents and NHPsRadiation safety and efficacy studiesTissue Cross Reactivity: human and animal tissue banksGene therapy vector biodistribution via qPCRES cell testing: devTOX™ and cardioTOX™ (with Stemina) Lead optimization and predictive toxicology services: Leadscreen™

CiToxLAB Group companies

CiToxLAB FrancePhone +33 (0)2 32 29 26 26 Email [email protected]

B.P. 563, 27005 Evreux cedex - France

CiToxLAB North AmericaPhone +1 888 353 2240Email [email protected]

445, Armand-Frappier Blvd,Laval, Quebec H7V 4B3 - Canada

CiToxLAB HungaryPhone +36 88 545-300Email [email protected]

Veszprém, Szabadságpuszta, 8200 - Hungary

CiToxLAB ScantoxPhone +45 56 86 15 00Email [email protected]

Hestehavevej 36A, EjbyDK-4623 Lille Skensved - Denmark

atlanbioPhone +33 (0)2 51 10 01 00Email [email protected] www.atlanbio.com

1 Rue Graham Bell - Z.I de Brais B.P 40309, 44605 Saint Nazaire Cedex - France

Also represented by

Media Services Ltd JapanPhone +81 3 3666 9915Email [email protected]

Fuji 16 Bldg 7F1-11-2 Nihonbashi Kayabacho, Chuo-ku,Tokyo 103-0025 - Japan

Croen Research Inc.Phone +82 31 888 9390Email [email protected]

Advanced Institutes of Convergence Technology - B-6th Fl., 864-1, lui-dong, Yeongtong-gu, Suwon-si - Gyeonggi-do, 443-270, Korea

Partner company

SteminaPhone +1 608 204 0104E-mail [email protected] www.stemina.com

504 South Rosa Road, Suite 150Madison, Wisconsin 53719

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www.citoxlab.com

Discover our citoxlab nonclinical services

Technology

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