Contract Research Services

HarlanLaboratories

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Table of Contents

Overview | 2

General Services

General Toxicology | 3

Reproductive Toxicology in Rats and Rabbits | 3

Pathology and Histopathology | 4

Genotoxicity and Cell Biology | 4

Metabolism | 5-6

Environmental Sciences | 7

Regulatory Affairs | 7

Pharmaceutical Services

Special Services for Pharmaceuticals | 8–9

Medical Device Services

Special Services for Medical Devices | 10

Chemical Services

Special Services for Chemicals | 11

Agrochemicals and Biocides

Special Services for Agrochemicals and Biocides | 12

Alternative Methods

Special Services in Alternative Methods | 13–14

Screening Assays | 15

Global Availability and Support | 16–17

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Harlan Laboratories Contract Research Services

is a leading provider of essential, non-clinical

contract research and services to the chemical,

pharmaceutical, biotech, medical device and

agrochemical industries. Our focus is providing

the services you need to optimize the discovery

and safety of new medicines and chemicals.

Our CRS division has nearly 1,300 employees

in 7 countries, but we act locally, understanding

the value of close relationships and collaboration

with our clients.

As important as good customer service and

relationships are, it’s really all about scientific

excellence. Today, research is outsourced

more than ever, and researchers need to have

confidence in their supplier partners. Stability,

reliability, consistency, and quality are all

essential. That’s what Harlan Laboratories offers

with our passion for science and decades of

proven expertise, both in research models and

services and in contract research services.

Our Expertise throughout our European facilities offers a full range of non-clinical services to the Pharmaceutical, Chemical and Agrochemical industries:

• Toxicology and Pathology• Genotoxicology and Cytotoxicity testing• Analytical Chemistry• Physico-chemical Analysis• Bionanalytics, including Pharmaco/Toxicokinetic

evaluation• Protein Analytics• Immunology• Animal Metabolism• Pharmacodynamic models• Screening in early product development• Predictive and Mechanistic Toxicology• Pharmaceutical Quality Control• Ecotoxicology• Environmental Fate• Plant Metabolism• Regulatory Affairs and Consulting• Program Management• Contract Archiving• Quality Assurance

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General ToxicologyHarlan Laboratories performs a full range of toxicology studies to support the pharmaceutical, chemical,

and agrochemical industries. These studies are performed to fulfil global regulatory guidelines and in

accordance with good laboratory practice regulations. We offer:

• Single dose and repeat dose studies through to 2 year carcinogenicity studies in rodents and chronic studies in non-rodents

• Rodents, rabbits, dogs, minipigs and primates

• Transgenic mice including transgenic carcinogenicity studies

• Routes of administration include oral (manual or semi-automated gavage, capsule and feeding), dermal, intraperitoneal, intravenous (bolus and short infusion manually and by continuous infusion in catheterized rats and dogs), intramuscular, subcutaneous, intratrachaeal, intranasal and inhalation

• Neurotoxicity

• In Vivo Micro-CT evaluation especially for bones

Reproductive Toxicology in Rats and RabbitsOur experienced toxicologists, fetal pathologist and technical staff have extensive expertise and offer a

complete range of developmental and reproductive toxicology studies, including:

• Fertility

• Embryo-fetal development

• Pre and postnatal development

• Maternal Function

• Routes of administration include oral, dermal, intraperitoneal, intravenous (bolus and infusion), intramuscular, subcutaneous and infusion, intrachaeal and inhalation.

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Pathology and HistopathologyThe Pathology department is highly experienced in the performance of all general study types including

cancer studies and neurotoxicity, medical devices and exotic animals. It’s our goal to always finish your

studies on time and to your complete satisfaction.

• Necropsy of all general animal species routinely used in regulatory toxicology

• Routine tissue trimming, embedding, cutting and staining including Special stains

• Special techniques

- Cryomicrotome

- Plastic embedding and ultrathin sections

- Diamond saw and grinding

• Automated immunostaining

• In situ hybridization

• Fish and snail pathology

• Microscopy

- Stereomicroscopy

- Fluorescence

- Image analysis

Genotoxicity and Cell BiologyOur study directors are recognized experts in the fields of

cell biology, genetic toxicology and biocompatibility. They

are members of both national and international scientific

working groups and are actively engaged in research projects

sponsored by the national and EU authorities. As such, our

clients benefit from advice based on the latest scientific

and regulatory thinking. Their expertise in the areas of

immunology, molecular biology and in vitro metabolism is

also available to our clients. Our services include:

• Ames, HPRT, mouse lymphoma test

• Chromosome Abberation test in vitro and in vivo, both bone marrow and mouse spermatogonia

• Photomutagenicity

• Micronucleus test in vitro and in vivo

• UDS assay in vitro and in vivo

• COMET assay in vitro and in vivo

• DNA binding/adducts

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MetabolismHarlan Laboratories supports our clients with ADME studies and programs in all phases of the discovery

and development pipeline. These include Lead Optimization programs by in vitro and in vivo PK screening

as well as PK or toxicokinetic profiling, mass balance and distribution studies for development projects.

Metabolite profiling and identification provides a rationale for the selection of animal species in

toxicology studies. Harlan also provides solutions for occupational and consumer studies of chemicals,

agrochemical products and veterinary pharmaceuticals.

• 14C, 3H and 125I radiolabelled materials

• All relevant species

• All routes of administration

• CYP interaction, inhibition, induction

• Metabolic stability with liver S9 preparation

• Phase II reactions such as conjugation

• Protein binding

• Dermal penetration

• HPLC, GC, CE, TLC

• LC-MS/MS and GC-MS

• QWBA

• Real time QPCR

• ICP-MS

AnalyticsandBioanalytics

The analytical departments of Harlan Laboratories feature state of the art instrumentation and

methodology. Techniques routinely available for new chemical entities include HPLC, HPLC-MS/MS,

High-Resolution-MS, GC, GC-MS, GPC, UV/Vis, FTIR, AAS, NMR. For biologicals ELISA, RIA,

electrophoresis, capillary electrophoresis, real-time QPCR and in vivo bioassays are routinely available.

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Analyticaldataandresultswillbeprovidedtosupporttoxicologicalandecotoxicologicalstudiessuchas:

• Development of analytical methods and method validation

• Analysis of dose preparations for toxicity studies

• Bioanalysis in plasma, urine and tissues

• Biochemical analysis of biologics

• In vivo bioassays

Inaddition,wehaveextensiveexperienceandexpertiseinthetestingofphysico-chemicalpropertiesfor

agrochemicalandchemicalnotificationsandcanofferthecompletepackageofphysico-chemicaltestsrequired

forREACH.Servicesinclude:

• Physico-chemical properties

• Hazardous properties

• Pharmacopoeial and other physicochemical testing

• Quality control of drugs and API under GMP

• Establishment of specification for API drug development

• Stability testing (according to ICH guideline)

• Product characterization

• Identification and characterization of active ingredients and formulations

• Testing of containers and packaging materials

• Certification of reference material

• Polymer Analysis

• Migration studies and modeling

• Extraction studies

• Identification of unknown contaminants, metabolites and degradation products

• Workplace exposure monitoring

• Residue analysis

• 5-batch analysis

• Storage stability to EU/OPPTS US EPA guidelines

• Client-defined, custom-designed analytical studies

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Environmental SciencesHarlan Laboratories offers extensive expertise in the conduct of aquatic and terrestrial ecotoxicological

studies on industrial chemicals, agrochemicals, biocides, and more recently on veterinary medicines

and pharmaceutical products. The studies are performed according to the international test guidelines

of OECD, EU, EPA/OPPTS, ISO and JMAFF. For a refined risk assessment, higher-tier studies under more

realistic environmental conditions are available, such as studies in water sediment systems in laboratories

or outdoor mesocosm pond studies. Our ecotoxicity team has extensive expertise in the evaluation of

difficult substances with challenging physio-chemical properties (e.g. low water solubility, instability,

volatility, strong adsorption or colouration). The ecotoxicology team is supported by the modern

analytical laboratories of Harlan Laboratories which offer analytical techniques suitable for use in all

biophysical matrices encountered in ecotoxicological studies. Services include:

• Acute and chronic Daphnia toxicity

• Algal growth test

• Acute and chronic toxicity in fish

• Fish early-life-stage tests

• Fish bioaccumulation

• Earthworm toxicity

• Activated sludge respiration inhibition

• Ready and inherent biodegradation

• Hydrolysis tests

• Adsorption/desorption screening and full studies

• Soil sediment simulation tests

• Effects on soil microorganisms

• Effect on non-target arthropods including honeybees

• Soil litterbag studies

• Short term plant toxicity

• Field Trials and plant metabolism

• Environmental fate and modeling

• Avian studies

• Mesocosm studies

Regulatory AffairsOur regulatory affairs managers and risk assessment experts provide seamless development and

execution of regulatory strategies. We maintain close contact with major authorities and thus remain on

top of the latest developments in regulatory requirements. Our vast experience and in-depth knowledge

ensures that your projects are managed by true experts who enable you to bring your product to market

in a rapid and cost-effective manner.

Further details on our regulatory affairs services are presented in the industry specific special services sections.

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Special Services for PharmaceuticalsThe first administration of a new investigational medicinal product in human beings is a very important

step in the development of a new drug. The transition from non-clinical to early clinical development

marks a milestone in the destiny of the compound.

Based on our extensive and globally recognized expertise, the multidisciplinary team of specialists

in Harlan Laboratories provides a truly integrated service for new chemical entities, biologicals and

phytopharmaceuticals from strategic development planning, through project performance, up to dossier

preparation for clinical trial authorization or product registration.

Pharmacokinetics(PK)andBioanalytics

The early screening of several lead substances to select candidates for a pre-clinical test program is one of the most critical points in the drug development. Harlan Laboratories has established a range of rapid and cost effective of techniques to make drug discovery more successful.

• Single and multiple administration via oral, dermal, intraperitoneal, intravenous (bolus and infusion), intramuscular, subcutaneous and infusion, intrachaeal, intranasal and inhalation.

• Rodent, Rabbit, Dog, Minipig and Primate

• Automated blood sampling

• Bioanalytics including LC-MS/MS, High-Resolution-MS, GC-MS, RIA, Elisa, CE and RT-PCR

• Bioanalytics and toxicokinetics (TK) in toxicity studies

• PK evaluation using WinNonLin or PK Solutions

• Pharmacodynamic and efficacy models for central and peripheral nervous system, cardiovascular and respiratory system, gastrointestinal and renal system and specialized efficacy studies

SafetyPharmacology

Safety pharmacology studies contribute to the risk assessment of NCEs in pharmaceutical development by identifying undesirable pharmacodynamic properties before the first administration to man (Phase I). These studies can also be used to evaluate adverse effects observed in toxicology or early clinical trials and to investigate the mechanism(s) underlying them. Safety pharmacology studies should be performed in accordance with the ICH S7A and S7B guidelines and to GLP. Harlan Laboratories has over 14 years of experience in performing safety pharmacology studies in compliance with GLP and our services include:

• Central Nervous System

- Modified Irwin Screen

- Functional Observation Battery

• Cardiovascular system

- Telemetered animals

- Anaesthetized animals

- In vitro HERG-1 assay

- Guinea Pig papillary muscle

• Wide range of disease models

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Specialdevelopmentprograms

Our experienced program managers offer specialized, tailor made programs of toxicological studies fulfilling all requirements which are necessary for taking a new active pharmaceutical ingredient first time in man. These “Fast-into-man” study packages benefit from comprehensive program management in very close cooperation with the client and provide a time- and cost-effective way to initiate clinical phase I studies.

RegulatoryAffairs

Our regulatory affairs managers and risk assessment experts work together to provide seamless development and execution of regulatory strategies. We stay in close contact with major authorities and thus remain on top of the latest developments in regulatory requirements

• Advice on regulatory requirements and testing strategies

• Negotiation with authorities

• Preparation of registration dossiers

• Compilation of dossiers including CTD

• Follow up on submissions

• Dealing with deficiency lists and variations

• Preparation of drug master files

• Applications for certificates of suitability

• Expert opinions, reviews

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Special Services for Medical DevicesHarlan Laboratories knows the special regulations for the assessment of efficacy and safety for medical

devises. Our deep expertise can assist with the regulatory requirements, testing and reporting required

for approval.

OurServicesinclude:

• In vitro assessment of cytotoxicity and genotoxicity

• In vitro and in vivo assessment of efficacy / feasibility of intended application

• In vivo safety assessment according to standard guideline procedures

ToxicologicalprofilingofmaterialsforMedicalDevices

Material characterization by biological and toxicological evaluation with acute, subacute, subchronic and chronic toxicological studies.

BiocompatibilitytestingofMedicalDevicesaccordingtoISO10993

• Strategic planning of study program

• Genotoxicity, carcinogenicity, reproductive toxicity

• Hemocompatiblity, static and dynamic systems

• Cytotoxicity

• Implantation, e.g. vascular stents

• Vascular grafts, bioresorbable polymers, histopathology

• Osseous implantation (rabbit and sheep) with CT-/MRI-monitoring

• Intracranial implantation

• Determination of ethylene oxide sterilization residuals

• Determination of material degradation, irritation and sensitization

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Special Services for ChemicalsREACH offers the opportunity to reduce costs, perform the appropriate testing according to regulations,

and provides guidance on producing quality Technical Dossiers and Chemical Safety Reports. Harlan

Laboratories has vast experience in the worldwide regulatory process for substances and our experts

assess data requirements, ensure that the correct tests are performed, and achieve acceptance in the

regulatory community. Services include:

• Strategic planning of test programs and registration strategies

• Project Management and study monitoring of test programs in toxicology, analytics and ecotoxicology

• Data analysis and interpretation

• Data compensation appraisals

• Liaison with regulatory authorities and scientific bodies

• Expert reports

• Risk assessments

• Product safety evaluations

• Dossier compilation and submission

• Literature searches/inventory checks

• Product defense

• Regulatory compliance check and certification

• Task force and consortia management

REACHServices

• Client representation and consortia management

• SIEF negotiations

• Portfolio examination

• Development of intelligent testing strategies

• Preparation of Technical dossiers and chemical safety assessments

• Seminars and training

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Special Services for Agrochemicals and BiocidesOur vast experience and in-depth knowledge ensures that your projects are managed by experts who

help bring your product to market quickly and cost-effectively. Services include:

Testprograms

• Strategic planning of intelligent test programs

• Project Management and study monitoring of test programs

• Data analysis and interpretation

• Design and protocol development of higher-tier studies

• Residue studies

DevelopmentandRegistration

• Regulatory compliance review

• Dossier preparation (OECD/BPD) and submission

• Electronic submissions (CADDY, IUCLID, R4BP)

RegulatorySupport

• Data compensation appraisals

• Liaison with regulatory authorities and scientific bodies

• Expert reports

• Literature searches/inventory checks

• Risk assessment across all scientific disciplines

• Regulatory strategies

• Liaison with regulatory agencies

• Product defense

• Product safety evaluations

• Issue management

Partnership

• Task force management and technical advice, client representation

• Management of global registrations

• Management of development programs

• Global logistics

• Seminars and training

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Special Services in Alternative MethodsHarlan is committed to the principle of the 3R´s of Replacement, Reduction and Refinement and few

companies can match our range of services and depth of experience in non-animal alternative methods.

Harlan is pro-active in the development and use of in vitro and ex vivo methods. We partner with

researchers and clients in pre-validation and formal validation studies to achieve your testing needs.

Immunology

• Lymphocyte blastogenesis

• Analysis of natural killer cell activity

• Analysis of macrophage function

ReproductiveToxicology

• Embryonic mouse stem cell test

Toxicity

• Assessment of starting dose for acute systemic toxicity using neutral red uptake

• Target organ toxicity with primary cells and cell lines from various organs

• Balb/3T3 neutral red uptake for phototoxicity evaluation

EyeIrritancy

• Bovine corneal opacity and permeability test (BCOP)

• Hens egg chorionallantoic membrane test (HET-CAM)

• Reconstructed human corneal epithelial models (e.g. EpiOcular)

• Rabbit and chicken enucleated eye tests (REET and CEET)

SkinCorrosivity

• Reconstructed human skin equivalents for assessment of skin corrosivity (OECD 431)

• Transcutaneous electrical resistance assay (TER; OECD 430)

• Corrositex membrane barrier test (OECD 435)

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SkinIrritancy

• Reconstructed human skin equivalents for assessment of skin irritancy (EU B 46)

BarrierSystems

• Dermal Penetration using flow-through diffusion cells and human and pig isolated skin systems

• Intestinal uptake using CaC0-2 absorption models

• Blood brain barrier systems using pig brain microvascular endothelial cells

Invitrometabolism

• Interspecies comparative metabolism

• Selective human cytochrome P450 metabolism

• Human cytochrome P450 inhibition

• MDR (P-glycoprotein) interaction assays

Carcinogenicity

• Cell transformation assays for detecting initiators and promotors: Balb/c3T3 assay and Syrian hamster embryo (SHE) cell assaySelective

InsilicoSafetyModelling

• Structure activity relationship by computerized models (TOPKAT and DERE)

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Screening AssaysHarlan Laboratories knows assay development, early screening and drug development. Compounds at

early research stages are screened to gain data on safety and efficacy. Tests include in vitro screening of

adsorption, distribution, metabolism, excretion, and toxicity and genotoxicity.

• Comet assay

• DNA binding/adducts

• Screening Ames, micronucleus, mouse lymphoma and Comet assays

Cell-basedassays

• Phototoxicity

• Cytotoxicity

• Cell line characterization

• Cell transformation assay (SHE, Balb/c 3T3)

Biochemicalanalysis

• Virus safety

• Prion Safety

Otherendpoints

• PK screen with automated blood sampling

• QT prolongation (HERG)/other ion channels

• Oxidative stress

• Endocrine toxicology

• Enzymology

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Global availability and support

At Harlan Laboratories, we have a passion for science and for developing solutions to help you achieve

your goals. With contract research services, research models, and laboratory animal diets, we can support

your global research needs.

ContractResearchServices

Our locations in 7 countries across Europe and Asia can assist with non clinical research needs for the pharmaceutical, biotech, medical device, chemical, and agrochemical industries.

ResearchModelsandServices

Harlan Laboratories is committed to the welfare and quality of our animal models. Our veterinary, scientific and quality staffs are committed to ensuring our company mission –helping you do research better. Our global line of research models includes mice, rats, rabbits, dogs and primates.

Teklad®GlobalDiets

Harlan Laboratories’ Teklad Diets have grown to be an industry leader by concentrating on reducing research variables through quality and consistency. Our nutritionists provide support and technical advice to help with your diet selection. Our diets are available world-wide.

Harlan, Harlan Laboratories, the Harlan logo and Teklad Global Diets are trademarks of Harlan Laboratories, Inc.

© 2010 Harlan Laboratories, Inc.

Find out more

We’reHarlanLaboratories.

Andwe’reheretohelpyou

doresearchbetter.

Contact your sales representativeor visit us on the Web at www.harlan.com

Corporate Headquarters

HarlanLaboratories,Inc.

8520 Allison Pointe Blvd., Suite 400

Indianapolis, IN 46250

800 793-7287

www.harlan.com