PHARMACEUTICAL SERVICES

Laboratory & Assurance Solutions PHARMACEUTICAL SERVICES

Total Quality Assurance for Pharmaceutical Development and Manufacturing

Across your product lifecycle, our expertise brings you the insight you need to accelerate pharmaceutical, biopharmaceutical or medical device product development. Our assurance solutions allow you to identify and mitigate risks associated with products, processes, operational and quality management systems, assets and supply chains. Our specialists bring many years of experience across a variety of product areas including: • Innovative and Generic Pharmaceuticals • Orally Inhaled and Nasal Drug Products • Peptides, Proteins • Nutritional Products, Dietary • Biosimilars Supplements • Monoclonal Antibodies • Consumer Healthcare and Cosmetics • Antibody-drug Conjugates • Medical Devices • Oligonucleotide Therapeutics • Veterinary Medicines • Vaccines • Over-the-Counter (OTC) Drugs

2 Achieving Total Quality You can rely on our global network of experts, Assurance laboratories and specialists to deliver support We have delivered flexible including analysis, bioanalysis, formulation Our scientists, regulatory experts and auditors development, biologics characterization, contract services to the work with you at every stage of development specialist inhalation development expertise, global pharmaceutical and manufacturing, providing responsive, regulatory consultancy, risk assessment, quality compliant solutions. auditing and industry for over 25 years At Intertek, our wealth of experience and solutions. depth of industry knowledge enables our clients to navigate the challenges of new product development, scale up, manufacturing and market release whilst minimising risks and meeting regulatory criteria accurately. We respond precisely to your needs with solutions that go beyond just “testing” to help you achieve total quality assurance.

Laboratory Services Assurance Solutions

EARLY STAGE LATE STAGE POST MARKET PRECLINICAL CLINICAL CLINICAL POST APPROVAL SURVEILLANCE & DEVELOPMENT DEVELOPMENT PRODUCTION LABORATORY SERVICES GLP and GCP Bioanalytical Services & Biomarkers GMP and CMC Laboratory Services Pharmaceutical Analysis, Stability and Formulation Development Extractables/Leachables Packaging Support Process Development Analytical Support ASSURANCE SOLUTIONS Toxicology and Impurity Risk Assessment Consulting Product Development Strategies Regulatory Affairs CMC Support & Guidance Toxicology Consultancy

Supplier GXP Auditing Solutions, Inspections and Gap Analysis Global Supply Chain Management Solutions & Supply Chain Surveillance Process Quality , Risk Analysis and Process Improvement Environmental Mapping, Inspection and Calibration Process, Facility or Equipment Qualification Sustainability and Asset Integrity Management

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Bioanalytical Services

With over 20 years of experience conducting regulatory bioanalysis studies, we deliver FDA/EMA compliant bioanalytical solutions that optimise value for your development programs

Bioanalysis plays a critical role in the Unique bioanalytical expertise assessment of drug safety and efficacy Our teams are adept in method development, and we understand that each project will method validation and transfer of efficient We apply our bioanalytical present its own unique challenges. Applying and accurate methods which are optimized our 20 years of experience in conducting for your compound. Projects are assigned expertise and industry regulatory bioanalytical studies, our teams to and managed by experienced Principal insight to design strategic work closely with you to ensure that the Investigators with support from teams of best possible solutions are delivered. Project Managers, Project Coordinators, Senior and efficient bioanalytical To help you to make informed decisions Scientists and Chemists. We provide: faster, our Good Laboratory Practice • Bioanalysis for Large and Small Molecules programs (GLP) and Good Clinical Practice (GCP) • Immunogenicity & Neutralizing Antibody compliant laboratories provide clinical Assays kit preparation, sample handling and • Antibody Drug Conjugate (ADC) LC-MS management capabilities, fully integrated and Immunochemistry Services with automated data capture and reporting systems using the latest bioanalytical • Long History of Bioanalytical Support for platforms. Biosimilar Drug Development Our bioanalytical experts have developed • Post Marketing Antidrug Antibody (ADA) methods for thousands of different assays compounds, providing phase-appropriate, • Demonstrated Expertise in Ocular Tissue small molecule and large molecule • Clinical Kit Preparation, Sample Handling & bioanalytical support, high-throughput Management sample bioanalysis, pharmacokinetic, toxicokinetic and pharmacodynamic support, immunogenicity and biomarker assays.

Our centres of excellence Our Centre of Excellence in San Diego, CA, USA, spans 46,000 square feet of laboratories, offices and sample storage. Our 30,000 square foot European laboratory is located in Manchester, UK, and together our facilities are positioned to expedite delivery of fast and cost-effective bioanalysis results for global clients.

Diverse bioanalytical technologies Our innovative use of technologies means that, no matter how complex your samples, we can accommodate the chemistry or biology of your analytes as well as any matrix interferences. Technologes include immunochemistry, Electrochemiluminescence, GC-MS, LC-MS/MS, qPCR, Nuclear Magnetic Resonance Spectroscopy (NMR), Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) and Surface Plasmon Resonance (SPR).

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Large molecule bioanalysis Small molecule LC-MS services CASE STUDY We have extensive experience in the With over 20 years of experience of development, validation, and sample analysis development and validation of quantitative Novel Approaches for An Enzyme of quantitative and qualitative GLP and non- LC-MS/MS methods for novel drugs and Activity Assay regulatory immunoassays in support of clinical metabolites, our scientists deliver robust A client desired an activity assay for a and preclinical studies for therapeutic drugs, and reproducible bioanalysis solutions that PEGylated enzyme for which a commercial synthetic peptides, humanized monoclonal apply validated methods in a high-throughput colorimetric assay was available. The antibodies, chimerics, conjugated drugs, environment to accelerate development colorimetric assay did not meet the growth factors, hormones and cytokines. times for proprietary and generic drugs across performance criteria for regulated work. An many types of biological matrices. We apply immunoassay was then developed but was • Quantitative Ligand Binding Assay regulatory guidelines to a diverse array of subject to significant matrix effects. Capabilities platform technologies including ICP, NMR and • Quantitative ELISAs for Proprietary Our Solution GC. Compounds Development of a replacement assay was • Method Development & Validation complicated by endogenous substrate and • Immunogenicity Studies - High Throughput GLP & GCP Sample enzymatic product.To overcome this, the • Neutralization Cell-based Assay Analysis specificity of LC-MS/MS was employed and Development, Validation and Sample an activity assay developed using a stable Analysis - Pre-clinical & Clinical Bioanalysis labeled substrate which produced a labeled • Radioimmunoassays (RIA), Enzymatic - Bioequivalence & Bioavailability Studies product, which could be differentiated from Assays • Non-GLP Rapid Discovery-Phase the endogenous analyte. • Fluorometric Assays, Luminescence Bioanalysis Benefit Delivered to our Client Assays - In Vitro Screening Bioanalysis A enzymatic activity LC-MS/MS assay was • Biotinylations & Ruthenium Labeling - Tissue Bioanalysis developed and successfully validated to regulatory standards. The method was used • Mode of Action Studies - Early Pharmacokinetic (PK) Studies in multiple pharmacokinetic studies and • Bioanalytical LC-MS/MS for Biologics - Lead Optimization Studies enabled the client to move forward with • Affinity Interactions by SPR • Bioanalysis in Ocular Tissues and Fluids their drug development program. • NMR approaches for PEGylated • Clinical Kit Preparation, Sample Handling & Biomolecules Management • NMR Approaches for PEGylated APIs Biomarker assays • Bioanalysis for trace metals using We deliver discovery and clinical biomarker ICP-MS solutions to support your precision medicine • GC-MS approaches for volatiles strategy enabling you to better predict • Oligonucleotide LC-MS immunochemistry the long-term safety and efficacy of your and immunogenicity. products. Our dedicated biomarker team has expertise in the qualification and validation of biomarkers using ELISA, and ECL platforms (including multiplexing, prototypes and custom multiplexing and Luminex) in multiple matrices and anticoagulants.

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GMP and CMC Laboratory Services

Through specialist laboratory services for complex products, we help you to accelerate your development process and support your post-marketing requirements

Chemistry, manufacturing and controls Stability studies raw material characterisation and sourcing, (CMC) development strategies and Good With a network of ICH stability storage formulation development, scale up, pilot Manufacturing Practice (GMP) laboratory facilities in the UK, USA and Australia, we batch manufacturing and testing, cleaning services play a key role in reaching your next offer an extensive capacity and a range of development and validation, GMP batch milestone. We provide regulatory-driven, conditions including climatic walk-in chambers manufacturing and GMP release testing with phase-appropriate, CMC laboratory and GMP and cabinets as well as freezer storage. QP release, we offer a one source solution for analytical services that can help you to Our stability teams provide professionally supplies for use in Phase I and II clinical trials. identify sources of risk early in development managed cGMP stability programs for even and provide sufficient information to help you the most complex of dosage forms including Extractables and leachables studies meet the stringent regulatory requirements orally inhaled and nasal drug products Extractables and leachables studies are of registration and production. (OINDP), biopharmaceuticals, medical devices conducted in accordance with regional or vaccines. guidance, GMP PQRI recommendations, Integrated formulation & analytical and United States Pharmacopeia (USP) development Elemental impurity analysis and risk requirements. Our experience in method Our formulation development scientists assessment development for controlled extractables are experienced across a range of dosage Our elemental impurities experts can help you studies, coupled with our vast knowledge of forms including orally inhaled and nasal to develop a compliance strategy to achieve leachable compounds, means that we can drug products (OINDP), oral, solid, liquid and successful implementation of guidance such anticipate and identify potential sources of transdermal or topical. Strategic integration as ICH Q3D / USP General Chapter <232>, risk. We support a wide range of closure or of formulation development with analytics ‘Elemental Impurities – Limits’. Our teams delivery systems such as pre-filled syringes, ensures a detailed understanding of the design tailored analytical programs involving parenteral products, OINDP and bioprocessing pharmaceutical materials, their compatibility, both screening studies and toxicological equipment. We conduct glass delamination physical properties and stability. risk assessment of the data if required. and extractables studies for glass packaging. Additionally, we can develop and validate Scientific support is available at every stage methods tailored to your specific products. of the testing program, including toxicological risk assessment of identified extractables / leachables. Clinical trial supplies manufacturing services Our clinical trial supplies manufacturing services are delivered from our state-of- the-art GMP compliant facility supporting investigational medicinal product (IMP) or investigational new drugs for clinical trials around the world. Integrated with

Service Overview • Preformulation and Physical Characterisation • GMP Pharmaceutical Analysis • GMP Quality Control Testing • Method Development & Validation • Reference Standard Certification • Biopharmaceutical CMC Solutions • Impurities and Particulates Analysis • GMP Stability Studies • Clinical Trial Supplies Manufacturing • GMP Batch Release Testing Services • Extractables / leachables • Regulatory Affairs • Glass Delamination Studies • GMP Auditing and Supply Chain Assurance • Elemental Impurities • GMP Training Sessions and eLearning • Formulation Development For Staff

6 INTERTEK PHARMACEUTICAL SERVICES Inhalation and Nasal Product Development

Our inhaled and nasal product development team focus on the critical parameters that can affect Our unique project the efficacy of drug delivery to the intended target across all respiratory product classes management approach including dry powder inhalers (DPIs), pressurised enables you to interact metered dose inhalers (pMDIs), nebulisers and nasal sprays (solution, suspension or dry directly with our scientists powders), as well as a range of novel respiratory at every stage of the delivery systems. We have been working in the inhaled and nasal process. fields for over 25 years and have the necessary experience to support the entire product development process, delivering formulation development / optimisation, product performance testing, stability / CMC support and clinical manufacturing services that are designed to provide the right information at the right time.

Inhalation and nasal product development / testing services Alongside typical drug product specification testing such as identification, assay, degradation products, moisture and pH, our OINDP services include drug delivery characterisation, Expertise: aerodynamic particle / droplet size distribution, • Method Development / Validation CASE STUDY spray pattern/plume geometry, physical • Bioequivalence Studies characterisation for particle size, droplet size and • Comparator Studies Supporting our client’s novel device powder rheology. With extensive experience in development method development and validation, we also • Device / Excipient Compatibility Studies An innovative developer of inhalation perform GMP compliant clinical batch and finished • Quality by Design (QbD) Studies medicines wanted to ensure that its new product release testing, EU Import Testing and • ICH and Accelerated Stability Studies inhaler design was suitable for registration offer flexible resources for raw materials quality • Formulation Development control testing. Our Solution • Clinical Trials Materials Manufacturing Intertek characterised the parameters To address the control of leachables from that define performance and function device components, we apply our unrivalled • Product Characterisation Studies (e.g. (critical quality attributes). The effects knowledge of polymer materials and patient in-use / misuse, spacer and of long term storage (stability study) and expertise within extractables / leachables cleaning studies, etc.) simulated patient use / mis-use were studies to drug / packaging interaction areas. • Device Verification Testing studied. • Foreign Particulates Analysis and Benefit Delivered to our Client Formulation development Identification Our experts confirmed that the device Intertek’s integrated formulation and displayed consistent performance across analytical teams carry out early stage pre- The development of inhaled biologics 60 days in use and the medicine was formulation support, solubility screening, brings together two of our core strengths; stable for three years under recommended drug-excipient compatibility, stability testing formulation development for inhalation storage guidelines. We were able to and device selection support to aid clients verify that the design was suitable for technologies and biological product working to develop more efficient devices and our clients to proceed with their market characterisation, in particular, applying formulations with both small molecule and release, which was successful. methodologies to assess potential biologic drug substances. degradation routes.

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Biopharmaceutical Services

In an era where financial prudence is a necessity, getting your analytical or bioanalytical strategy right the first time is more important than ever

Tailored analytical packages Ensuring a safe and efficacious Protein therapeutics can present significant product Ensuring the purity, analytical challenges. Our characterisation Our GLP bioanalysis capabilities include packages are tailored to your biomolecule and developing and validating assays for identity, safety and quality reflect the requirements of ICH Guidelines pharmacokinetic (PK), toxicokinetic (TK), of your biopharmaceutical to meet the analytical challenges of a ‘well immunogenicity and biomarker studies characterized’ or ‘specified’ biological product. to evaluate efficacy and safety from product is critical to Programs encompass many different early discovery through to late stage analytical techniques and provide information clinical studies. Core services include success ranging from evaluation of physicochemical immunochemistry and LC-MS/MS technology properties and structural features including to provide sensitive and versatile support primary, secondary and higher order structure for customers’ development programs in full Our thought-leaders have over 25 years of and assessment of post-translational regulatory compliance (FDA, EMA and OECD experience in biopharmaceutical development modifications. Programs also include GLP regulatory standards). We also offer support across a wide range of product types. determination of biological potency and industry-unique instrumentation to support We provide regulatory-led, phase-appropriate, assessment of purity / impurity profiles. complex products, for example; quantitative tailored analytical program design and GLP NMR which is an ideal tool for bioanalysis of or GMP compliant laboratory services which PEGylated biomolecules. help you to navigate the challenges of Biopharmaceutical development development, regulatory submission, and support manufacturing. • GLP Clinical & Preclinical Bioanalysis (PK, With broad capabilities in India, Europe ADA, Nab) (UK, France, Switzerland) and the USA, our • Immunogenicity Studies experts provide strong scientific and technical • Analytical Programme Design leadership coupled with project management • Structural Characterisation (ICH Q6B) CASE STUDY and regulatory support to drive your development and manufacturing programs • Physicochemical Properties (ICH Q6B) Antibody Drug Conjugate (ADC) forward. • Biophysical Characterisation Characterisation • Comparability Studies A client developed an ADC drug product with an innovative linker technology. They • Biosimilar Programmes Analytical programme design across a wished to understand the structure of range of product types • Process Residuals Determination the drug-linked species and the effect of • Recombinant Proteins & Glycoproteins • Product Related Impurities Determination conjugation on biological activity. • Bispecifics • Purity and Impurity Assessment Our Solution • Monoclonal Antibodies • GMP Potency / Cell Based Assays We performed characterisation studies to evaluate the antibody structure, drug load • Antibody-Drug Conjugates • Method Development & Validation distribution, individual drug load variants • Peptides • Extractables / Leachables and the drug-to-antibody ratio (DAR). An • Biosimilars & Biobetters • GMP Quality Control Testing assessment of the impact of conjugation • Growth Factors • GMP Batch & Final Product Release chemistry on the biological function • PEGylated Proteins Testing included binding and effector function studies. • Interferons • ICH Stability Studies • Interleukins • Forced Degradation Studies Benefit Delivered to our Client Our experts delivered the insight the client • Oligonucleotide Therapeutics • Drug Delivery / OINDP Expertise required to understand the drug load • Vaccines, Viral Vectors, VLPs distribution, the impact of conjugation and confirmed other structural parameters, allowing the client to progress towards their next milestone.

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Regulatory Analytical Packages (ICH Q6B)

Structural Characterisation

Amino Acid Sequencing/ Sequencing studies and peptide mapping using a broad range of enzymatic or chemical digestion followed by Mass Spectrometry Peptide Mapping: (LC-MS/MS or MALDI-TOF MS).

Amino acid composition: Pharmacopeia methods.

Terminal amino acid sequence: Confirmation of N- and C-terminal sequences and evaluation of modifications and / or heterogeneity.

Assessment of the degree and positions of both expected and mis-matched disulphide bridges by extended LC-MS/MS study and Disulphide bridge mapping: colorimetric test for free sulfhydryl groups. Glycosylation studies typically including levels of monosaccharides and sialic acid, N/O linked glycan profiling (NPLC, HILIC, IEX or Carbohydrate structure: CE-LIF), enzymatic digest and MALDI –TOF or LC-MS/MS. Physico-chemical Properties

Molecular weight of intact proteins by MALDI-MS, ESI-MS and LC-MS supported by orthogonal techniques such as MALLS, Molecular weight: and SDS-PAGE.

Isoform pattern: Isoform and impurity studies using PAGE, SDS-PAGE, IEF, CE, HPLC.

Extinction coefficient: Determination and Validated Extinction Coefficient studies.

LC patterns: For ID, homogeneity, purity – HPLC, UPLC, SEC, RP HPLC, IEX, AEX.

Spectroscopic patterns: CD, FTIR, 1D & 2D NMR, Fluorescence, UV-Visible.

Electrophoretic patterns: CE(CZE), cIEF, CGE, cSDS, SDS and NATIVE PAGE, Western Blot.

Concentration: Lowry , BCA, Total AA, Total Nitrogen, Bradford.

Aggregation studies: SEC (MALLS), DLS, Western Blot, CE, Gel Electrophoresis, SEM/TEM.

Process Impurities: Residual host cell DNA by qPCR, Residuals (such as antibiotics, antifoaming agents).

Potency Assays

To support characterisation, stability, comparability testing and product release, for example, Complement-dependent cytotoxicity Cell-based Assays: (CDC), Antibody–dependent cell cytotoxicity (ADCC) and Neutralisation and Proliferation Assays.

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Scientific and Regulatory Services

We deliver innovative and effective solutions that address complex product development, toxicological, and safety issues to our clients worldwide.

Toxicology consulting Scope of services • Toxicology Consulting Intertek provides expert toxicology consulting • Product Development Strategies • Non-clinical Study Design services to pharmaceutical, biotechnology, • Product Classification in Various Markets • Scientific Program Management and medical device companies. Intertek’s • Regulatory Affairs Consulting Board-certified experts and their teams offer • Data and Report Review and clients years of scientific research and hands- • INDs, CTAs, IDE, IMPD, BLA, NDAs, NDSs, Interpretation on industry experience. MAAs, 510(k)s, PMAs, Briefing Documents, • Expert Reports and Literature Reviews Investigator’s Brochures, Annual Reports, • GLP Monitoring (Facility and In-Life ) Integrated Summaries Our team includes Eurotox and Board- • Risk Analysis and Safety Assessments • Device Establishment Registration certified toxicologists and RAC-certified (Impurities, Extractables & Leachables, regulatory affairs specialists who possess • Post-Marketing Activities (e.g. Label Excipients) broad experience in product development, Review) • Medical and Scientific Writing data review, and toxicology issue resolution. • Regulatory Strategies and Guidance • Assistance with Due Diligence • Management of Interactions and Regulatory support Negotiations with Regulatory Agencies Intertek regulatory professionals possess • Chemistry, Manufacturing and Controls extensive knowledge of the applicable (CMC)Regulatory Support and Guidance legislations and regulations which govern pharmaceutical and medical products (and other regulated or notifiable materials) in North America, Europe, and many other jurisdictions around the world. We continually survey regulatory policies and practices to provide clients with timely information that reflects developments and changes. Our understanding of the intricacies and processes of regulatory agencies is unsurpassed. The combination helps our clients to develop cost effective and successful regulatory strategies which are ‘right the first time’.

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Scientific and Regulatory Services Supply Chain Assurance Solutions

Delivering supply chain assurance, which allows you to power ahead safely and with total confidence

SUPPORTING COMPLEX SUPPLY OPTIMISING PRODUCTIVITY CHAINS Helping you to drive Processes, facilities and equipment improvement, manage risk Supplier audit and assessment With an expert team of engineers and and optimize productivity Through cost-effective GMP shared supplier inspectors we provide calibration, inspection, audit and inspection services, we help you and qualification for facilities, processes and to ensure that all regulatory requirements your equipment. Through comprehensive (FDA, MHRA) are met. Our online platforms risk analysis and planning we help you to In today’s global marketplace, pharmaceutical offer supplier assessment that drives implement process improvement. supply chains can be complex, involving improvement and informed decision-making. Gmp training sessions and e-learning a multitude of suppliers, facilities and production processes. Global supply chain compliance for staff platforms Your primary business focus will be on Training from our GMP experts or cost- leveraging competitive advantage through We supply Global Supply Chain Compliance effective eLearning modules, drive a robust, efficient, sustainable pharmaceutical Platforms which reduce demands on staff positive impact on your compliance and supply chains and manufacturing. that time through effective scheduling, tracking, manufacturing goals. demonstrates excellence in quality and automated reporting, data mining and Occupational hygiene analytics. compliance. Our supply chain solutions help Occupational hygiene inspection sampling you to ensure supply chain quality, and Sustainability assurance for the and testing for a safe and healthy working security whilst assessing and mitigating risks supply chain environment. to achieve total product quality assurance. Our sustainability assurance experts help We can help you to optimise productivity and Asset integrity management (AIM) you meet global green regulatory goals and drive improvements to achieve manufacturing Our specialist AIM programs incorporate achieve green supply chain management. that demonstrates excellence in efficiency, design, maintenance, inspection, process quality and compliance. Pharmaceutical supply chain safety, mechanical integrity, corrosion, surveillance for counterfeit or metallurgy, operations and process support falsified medicines and risk analysis to help protect integrity of Tailored pharmaceutical supply chain infrastructure and equipment. Through our AIM surveillance programs built upon our many expertise - coupled with our corrosion testingw years of experience in anti-counterfeit - we can help extend production asset lifetimes investigation from World Health Organisation and reduce downtime. (WHO) prequalified and GMP laboratories. Production contamination resolution Helping to avoid costly long-term plant shut- down or delayed release of materials, our specialists examine products, plant processes and your supply chain to identify and resolve contamination. Environmental mapping, inspection and certification Our inspections team conduct facilities and equipment calibration, as well as validation, ongoing monitoring and mapping for facilities and cleanrooms, helping to optimise operations.

11 Americas Europe Asia / Australasia

USA +1 800 967 5352 UK +44 161 721 5247 India +91 9819117214 Canada +1 905 542 2900 +44 1763 261648 +91 7045312819 Switzerland +41 61 686 4800 China +86 21 6073 7735 France +33 2 32 09 36 36 Australia +61 3 9316 4600 [email protected] [email protected] [email protected] intertek.com/pharmaceutical