TO THE NEXT LEVEL WITH ARCINOVA FAST FORWARD TO MARKET WITH ARCINOVA - - PowerPoint PPT Presentation

TAKE PHARMACEUTICAL DEVELOPMENT

TO THE NEXT LEVEL WITH ARCINOVA

FAST FORWARD TO MARKET WITH ARCINOVA

Discovery Preclinical Clinical Market Integrated scale-up & manufacturing

• Shorten your time to clinic

− Integrated project teams on site reduces ‘hand-over’ time − Pragmatic application of cutting edge technologies to reduce development time − Partnership with global discovery service provider addresses scale-up challenges up-front − Partnership with global CRO ensures seamless hand over into the clinic

• Reduce your risk of failure

− Drug substance, analytical and drug product development needs are taken into account at all stages

Trusted discovery partners Trusted clinical partners

LOCATION

One Single Facility Site Area:~12.8ha Building Footprint ~10,000 m2 (2/3 laboratory space)

MODERN, WELL-EQUIPPED SITE WITH A RICH HISTORY…

• Over 200 customers worldwide
• > 80 US/Canada
• > 80 Europe
• 18 in Japan
• Biotechs, speciality pharma, large pharma
• Over 180 staff

WHAT MAKES US DIFFERENT?

WHAT MAKES US DIFFERENT?

• Big company track record/compliance

− 38 years successful delivery of projects − Continuity… as Arcinova supported 10 INDs and 20 IMPDs since 2016 − Exemplary quality/compliance record…

• Speed, agility and flexibility of a small company

− Competitive lead times − Full range of contract structures (fee for service, FTE, multi-FTE, etc.) − Facility, setup and culture to deliver highly bespoke/custom projects

• Fully integrated provider all under 1 roof…

MHRA average IMP GMP Feb 2017 API GMP June 2019 Critical 0.5 Major 8 Other 12 5 3

INTEGRATEDDRUG DEVELOPMENTALL UNDER ONE ROOF

ARCINOVA

• Dedicated project leaders for every project
• Transparency and regular client communication
• Strong project measurement and continuous improvement culture

PROJECT LEADERSHIP

Dr Ellie Row, Head of Client Services

Integrated suite of services under 1 roof, unified project culture

ARCINOVA

• Grammes to multi kilos
• GMP/non-GMP
• Candidate to phase 2 and beyond (low volume)

DRUG SUBSTANCE

LEADERSHIP

Dr Paul Quigley >30 years scale-up experience

TRACK RECORD

• >30 projects since 2018
• >50 clients
• Often complex chemistries (>10 steps)

CAPABILITIES

• 11 PR&D, 4 manufacturing chemists
• 3 x 5L streams
• 2 x 20L streams
• 2 x 100L streams (online end 2020)
• Flow chemistry

− Flowsyn − Salamander

• High temperature

− 200°C flow, 300°C trickle bed

• High pressure (200Bar flow, 100 tb)
• Filter drying 500g to 15Kg

DRUG SUBSTANCE – Why Arcinova?

Reduce your costs

• Typical 50% reduction in manufacturing cost from initial to

phase I ready process

Shorten your time to clinic

• Pragmatic deployment of technology, engagement with

analytical and formulation development on-site can save months of development time

DRUG SUBSTANCE CASE STUDY

Integrated Project for US Biotech Client

• Requires a complex

synthesis

• Drug product

isolated as an amorphous solid

• Poor solubility
• No saltform

available

• Develop a route(s)

towards an analogue in 15 weeks

• Improve scalability
• Improve solubility
• Perform a salt

screenprotocol

• A shorter synthesis

was developed

• Solubility of the final

drug form was markedly improved

• Six salt forms tested
• The new analogue

showed similar activity towards the biological target Challenge: Rapid development of a scalable route towards an analogue of a new drug substance, with definition of an

• ptimal salt form for formulation

Customer: US Biotech client developing combined Small Molecule / Biologic immunotherapy treatments Outcome: ARCINOVA developed two process route options to the drug substance and selected one on the basis of scalability and process economy. The API free base was generated and a rapid salt screening protocol

• undertaken. A solubility study was undertaken which showed optimal solubilisation at a set pH. The client was

delighted and has filed provisional IP. The drug substance analogue shows superior solubility to the prime API. The case study demonstrates the power of the integrated drug substance / drug product development capacity at Arcinova. Client’s current Drug Substance ARCINOVA Objectives Project Conclusions

ARCINOVA

• Preclinical to post marketing testing
• Microbiology
• Stability testing

ANALYTICAL SCIENCES

LEADERSHIP

David Wilson >30 years in analytical sciences

TRACK RECORD

• >300 projects
• >100 clients

CAPABILITIES

• 19 analysts
• Chromatography

− Potency, impurities/degradation products − Enantiomers, residual solvents − Quantification of GTI’s − Cleaning verification methodology

• Range of detection types

− UV, DAD, N2 Emission, Radiochemical, MS, ICP-MS, Conductivity, Fluorescence, CAD − HPLC/UPLC, Intrinsic/conventional dissolution − Infrared/UV spectroscopy, high resolution mass spectrometry − Karl Fischer water content, water activity − Walk-in ICH compliant stability chambers − Photostability testing − 14C and high potency handling capabilities

ANALYTICAL SCIENCES – Why Arcinova?

Your challenging problems solved

• Track record of resolving non-routine characteristics

associated with drug substances and excipients

Shorten your time to clinic

• Engagement with on-site DS and DP teams can save months
• f development time

ANALYTICAL SCIENCES CASE STUDY

Chromatographic Development and the Application of a Diverse Service Range

Challenge: Development of a modern, single, chromatographic procedure for a marketed tablet product that would allow the resolution and quantification of four active species and each of their associated impurities / degradation products. Customer: Multinational Consumer Goods Company Outcome: A single LC gradient procedure capable of resolving the multiple species involved, was successfully developed and validated. Application of the methodology revealed a previously unknown impurity in the product batches provided. In order to help the client reach an informed conclusion regarding this situation, a diverse range of in-house services were engaged.

Client able to Make Informed Decisions New Impurity Found

ARCINOVA

• Preclinical and clinical formulation
• Salt selection
• Polymorph studies
• Physical characterisation and excipient selection

FORMULATION DEVELOPMENT

LEADERSHIP

Professor Stephen Byard >35 years in pharmaceutical and sciences Secretary of the RSC NMR Group

TRACK RECORD

• >100 projects
• >60 clients

CAPABILITIES

• 12 FD scientists
• 500 MHz solid-state and solution-state NMR
• High-resolution mass spectrometry
• ICPMS
• X-ray diffraction, Thermal analysis
• Laser diffraction, Particle size
• Nitrogen/krypton sorption surface area

dynamic vapour sorption

• Attenuated total reflectance and diffuse

reflectance infrared spectroscopy

• Semi-automated crystallisation

FORMULATION DEVELOPMENT – Why Arcinova?

Your challenging problems solved

• Proven ability to resolve previously intractable

formulation challenges

Shorten your time to clinic

• Engagement with DS team ensures early attack on potential

formulation issues

FORMULATION DEVELOPMENT CASE STUDY

Drug Substance Salt Selection

Challenge: To manufacture drug substance and screen a selection of corresponding pharmaceutically acceptable salt

• forms. From the resulting salt forms, choose a candidate which exhibits optimal characteristics for

formulation and bioavailability. Customer: US Biopharmaceutical. Outcome: API was manufactured at ARCINOVA, and a series of salts subsequently produced. Each salt form was assessed with respect to salt formation, solubility, hygroscopicity, crystallinity, polymorph tendency, chemical stability and particle size/morphology. An optimal salt form was identified and manufactured at ARCINOVA.

Optical Microscopy Salt formA Solid-state NMR 20 mW Dynamic VapourSorption Scanning ElectronMicroscopy Differential ScanningCalorimetry Salt formB

ARCINOVA

• Preclinical to phase 2, oral & IV
• Cytotoxics & radiolabelled compounds
• Nanocrystals

DRUG PRODUCT MANUFACTURE

LEADERSHIP

Dr Simon Fuller >35 years pharmaceutical manufacturing experience

TRACK RECORD

• >60 projects
• >30 clients

CAPABILITIES

• 6 DP manufacturing scientists
• Oral
• Capsules, powder in a vial, dry blends

10,000 per batch

• Molded chewable tablets

1,000 per batch

• Solutions/emulsions/suspensions

20L/per batch

• IV – suitable to support human AME and

phase I studies

• Quantos, Xcelodose, 3P R1000
• Esco homogeniser
• Emulsiflex and milling technologies

DRUG PRODUCT MANUFACTURE – Why Arcinova?

Reduce your costs

• Scalable capacity, ensuring flexible service delivery across

phase 1 and phase 2 clinical trials

Shorten your time to clinic

• Proven track record for accelerated product

manufacture and clinical delivery

• Fully integrated packaging, labelling and distribution

DRUG PRODUCT MANUFACTURE (INTEGRATED) CASE STUDY

API Manufacture, Formulation Development, Capsule Product Manufacture

Challenge: The client required accelerated First in Human and Phase II trials for an oral dosage form. Clinical studies to be completed in Europe. Required a fully integrated package, to include API manufacture, Formulation Development, GMP Clinical Manufacture, IMP Packaging, Labelling & Assembly, Distribution to clinical sites and CMC dossier compilation. Customer: Small biotech (Europe). Outcome: Completed API manufacture, associated method development and validation, API stability studies and formulation

• development. Drug product Stability Studies completed, GMP Clinical manufacture of API in a capsule, QC testing,

QA release, IMP packaging, labelling and assembly, QP certification and distribution to the clinical site. CMC dossier submission completed. Phase I and Phase II studies completed, and molecule successfully sold to alarge pharmaceutical company with continued support from Arcinova.

ARCINOVA

• 14C preclinical and clinical studies
• Environmental impact studies
• Stable isotope (e.g. 2H, 13C, 15N, 18O) labelled compounds

for mass spectroscopy standards

ISOTOPE LABELLING

LEADERSHIP

Dr Alan McNeil >20 years radiosynthesis experience

TRACK RECORD

• >30 years successful delivery on-site
• 200 project completed
• >100 clients

CAPABILITIES

• 10 IL chemists
• Stainless steel and glass manifolds
• 5 x Agilent 1200 HPLCs with radio flow

detectors

• 1 x Scintillation analyser
• 4 x Preparative GILSON HPLC units
• Electronic autoradiography system
• Bruker MicroTOF LCMS
• Agilent GCMS

ISOTOPE LABELLING – Why Arcinova?

Shorten your time to clinic

• Non-GMP for ADME/QWBA typically 3 months

delivery from PO

• GMP for hAME studies typically 10 months from PO
• Placing both preclinical and clinical studies with us avoids

reworks (use late stage intermediates as start points)

Trust us to deliver OTIF

• 98% delivery rate as Arcinova (1 very challenging project

where scope was changed – still a repeat customer)

ISOTOPE LABELLING CASE STUDY

Radiosynthesis via Chemically Unstable Intermediate

Challenge: Process chemistry route to API required hydrogenation, then salt formation. The hydrogenation product was chemically unstable until the salt was formed. On a large scale, this was adequately controlled. In radiochemical trials, the larger dilution and higher catalyst loading required for the very small-scale synthesis led to increased degradation of the unstable intermediate and unacceptable yield. Customer: US Biopharmaceutical Company Outcome: A flow hydrogenation reactor was used; as the chemically unstable product was formed it was fed directly into the salt formation vessel. This greatly reduced degradation. Successful [14C]synthesis was carried out to support both non-clinical and clinical trials. Precursor (stable) Hydrogenation Salt formation Intermediate (unstable) Time of manipulation minimised by using flow reactor Salt (stable)

ARCINOVA

• Preclinical, clinical and post-launch services
• Analysis of biological samples (plasma, excreta, tissues)
• Develop, validate and apply MS-based assays (LC-MS, GC-MS, ICP-MS)
• Impurity and metabolite structural identification

BIOANALYTICAL SERVICES

LEADERSHIP

Stuart McDougall >25 years bioanalysis experience Team Leader for the Global Bioanalytical Consortium (GBC) Member of the Europeam Bioanalytical Forum (EBF)

TRACK RECORD

• > 470 projects completed
• > 80 clients

CAPABILITIES

• 37 bioanalysts (to 43 in 2020)
• 7 UPLC-MS/MS, 2 GC-MS/MS, 4 ICP-MS, LC-ICP-

MS/MS, 2 High Resolution LC-MS

• (Thermo Oribtrap and Sciex 6600 TOF)
• Automated extraction systems, including

Thermo Versette MSIA and Thermo Kingfisher IA

• Fully integrated electronic architecture, including

Thermo Watson LIMS, Thermo Integration Manager, Waters Nugenesis SDMS and LabNotes ELN

• Specialists in elemental analysis
• Specialists in insulin bioanalysis

BIOANALYTICAL SERVICES – Why Arcinova?

Trust us to deliver

• 2% batch failure rate vs industry standard 5%

You can start your project rapidly

• Managed growth, responsive approach means lead times are

typically 6 weeks against an industry standard of ~12 weeks

BIOANALYSIS CASE STUDY

Analysis of Insulin Analogues

Challenge: A client has developed new product to fulfil an unmet patient need. Pivotal clinical studies require highly sensitive, precise measurement of multiple insulin analogues from a small volume of plasma. Our existing methodologies have enabled successful proof of concept and non-regulated PK studies to be completed, but did not meet the precision necessary for regulatory acceptance. Customer: European Biotech Company. Outcome: Following a demonstration in the autumn, a new mass spectrometer was purchased, installed and verified for insulins analysis within four months, in time to meet the client’s timeline for a key clinical trial. Analysis for the trial commenced in the spring, and the system is now analysing samples around the clock.

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 Instrument Response Nominal Conc. 1 2 3 4 5 6 7 8 9 10 11 12 13 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 Instrument Response Nominal Conc.

Old system 2 points excluded r2 = 0.98 New system: 0 points excluded r2 = 0.99

min 2.00 4.00 6.00 % 100 7.160e+003 Glargine 3.80 517.28 5.17e2 4.71 4.98

ARCINOVA

• Preparation of CMC documents for regulatory dossiers

REGULATORY & CONSULTANCY

LEADERSHIP

Sheila Lawson >25 years CMC experience

TRACK RECORD

• >30 projects successfully completed

CAPABILITIES

• IMPDs, INDs or their equivalent, including those

for radiolabelled materials

• Provision of a in-silico molecule assessments

against a range of endpoints

• DEREK, Lead scope, Multicase
• Review of technical CMC documents either

authored in house or as a service

Arcinova – Your Trusted Partner

• >> Fast forward to market with a seamless transition from discovery to the clinic
• Fully integrated provider all under 1 roof
• + Big company experience >> small company responsiveness
• Dedicated project management, passion for performance and improvement

Current client satisfaction score across all projects

88%

CSO, Wilson Therapeutics AB, commented:

“We have worked extensively with the Arcinova team over the last years on bioanalytical applications in support of our global clinical studies as well as basic research. For anyone in need of state-of-the-art bioanalytical solutions delivered by a competent, diligent, and dedicated team, Arcinova is an option to consider. And they’re fun to work with too”

CUSTOMER FEEDBACK

“In my opinion, this group is doing an amazing job!!! They have been great about covering requests, they process requests quickly, and the data/reports appear to be of high quality!!”

CUSTOMER FEEDBACK

Customer Project Manager commented:

Customer Project Manager commented:

“Thanks for all your work in getting the IMPDs finalized! This is indeed a major milestone that is being reached today. Many thanks to all of you for an extraordinary contribution”

CUSTOMER FEEDBACK

Customer Project Manager commented:

“Overall I was very satisfied by the service

• ffered

and communications throughout the project. I would have no concerns about recommending to use again for other projects”

CUSTOMER FEEDBACK

“Very pleased with the delivery of this project… ensured that we were kept up to date during the process and the material was delivered within the timescale”

Customer Project Manager commented:

CUSTOMER FEEDBACK

ARCINOVA

ADDITIONAL CASE STUDIES

DRUG PRODUCT CASE STUDY

Accelerated Manufacturing Programme at ARCINOVA

Challenge: A strategy of rapid clinical progression – dose determination to manufacture and to patient administration within 4 days, necessitating a timeline of dose determination to shipping of product to the remote clinical site within 48 hours - repeated for escalating clinical dose levels. Customer: Japanese Big-Pharma Corporation. Outcome: Standard manufacturing procedures replaced with project specific procedures, managed through change control, enabling timelines for dose determination/manufacturing order approval to shipment to the clinic to be reduced from 2-3 weeks to 48 hours.

DRUG SUBSTANCE CASE STUDY

Thermal Rearrangement – A Continuous Approach

Challenge: Thermal rearrangement of 7.5 kg of an API intermediate – A technically challenging and labour intensive process in batch with a typical yield of 50% and a poor impurity profile. Reaction conditions: Diphenyl ether, 180°C, 2 hours (followed by acid-base extraction and solvent switch into dichloromethane then ethanol). Customer: US Biotech. Outcome: The process was run continuously using a coil reactor and superheated ethanol as solvent. The yield and purity of the product were increased. The overall throughput was improved due to a shortened residence time and the number of human manipulations was reduced. As a result the implementation of flow led to significant time and cost savings. Batch Flow Yield of Stage 3 50% 99% Purity of Stage 3 85% 97% Equipment Time

• 71% in Flow

Chemist Time

• 92% in Flow

Raw Material Costs

• 63% in Flow

Batch vs. FlowComparison In terms of space time yield (): Flow (= 670 g L-1 h-1) is 10 times more efficient than batch (= 64 g L-1 h-1). In terms of throughput: A 60 mL continuous coil reactor (producing 42 g h-1) is 3.5 times more productive than a 20 L batch vessel (producing 12 g h-1) once all handling manipulations are taken into account. 160°C Pump

250 psi

Pressure Regulator Starting Material Rearrangement Product 20 min

ANALYTICAL SCIENCES CASE STUDY

Analytical and Microbiological Support to Clinical Research Unit

Challenge: Development and validation of analytical and microbiological methods for Intravenous (IV) products manufactured extemporaneously (EP) at Clinical Research Unit. Testing of isotopically labelled (14C, 13C, 15N) or unlabelled clinical EP products pre and post dosing to allow administration to patients within 24 to 48 hours. Customer: UK Clinical Research Unit (CRU), serving both small scale independent biotechs and large scale pharma. Outcome: Bioburden, Sterility, Bacterial Endotoxins, Assay/Impurities and Radiochemical Purity methods developed and validated against approved protocols prior to use in CRU Manufacturing Process Validation (Process Simulation Testing, Component Compatibility and Stability Studies) and testing of final Investigational Medicinal Products.

Component compatibility and stability testing of approved formulation Method Validation

• Assay
• Impurities
• Radiochemicalpurity

Other tests…

• Radioactive

Concentration

• Sub-visible

Particulates

• Osmolality

Support for Process Simulation Tests(PSTs)

• Incubation
• Inspection
• Fertility check

ARCINOVA Analytical Chemistry ARCINOVA Microbiology

Drug substance method development and validation

• Microbial

enumeration

• BET

Drug productmethod development and validation

• In-process bioburden
• Sterility
• Bacterial Endotoxin

Test (BET)

ISOTOPE LABELLING CASE STUDY

Stable Isotope Labelling

Challenge: MPK and Bioanalysis need to quantify parent and metabolite drug concentrations in biological samples from non-clinical and clinical trials. Customer: Multiple, biotechnology and large-pharma. Outcome: In most cases, a Stable Isotope Labelled (SIL) standard optimises analysis, resulting in a more robust high throughput assay. The SIL has the same chromatographic retention time, extraction properties and stability as the analyte. SIL use is recommended by the European Medicines Agency (EMA) and the FDA. Design Considerations: Sufficient labels to ensure no

• verlap between the natural

abundance if m/z ion of the analyte and the labelled standard. Labelling in a non-labile position

Unlabelled drug Labelled drug

Design Considerations:

• Direct deuterium exchange on the final product

– Provides a cluster of masses – Not applicable to all compounds.

• Deuterium exchange on an intermediate, that is then

converted to final product – Allows exchange on a chemically simpler molecule, with less chance of degradation

• Synthesis from a labelled precursor

– Provides single isotopomer rather than a cluster – Can use 13C and 15N as well as deuterium, which may be advantageous

ISOTOPE LABELLING CASE STUDY

API Development for a US Biotech Client

Challenge: Rapid development of a scalable route towards an analogue of a new drug substance, with definition of an

• ptimal salt form for formulation.

Customer: US Biotech client developing combined Small Molecule / Biologic immunotherapy treatments. Outcome: ARCINOVA developed two process route options and selected one on the basis of scalability and process

• economy. The API free base was generated and a rapid salt screening protocol undertaken. A solubility study was

undertaken which showed optimal solubilisation at a set pH. The client was delighted and has filed provisional IP. The drug substance analogue shows superior solubility to the prime API.

• Requires a complex

synthesis

• Drug product

isolated as an amorphous solid

• Poor solubility
• No saltform

available Clients Current DrugSubstance ARCINOVA Objectives

• Develop a route(s)

towards an analogue in 15 weeks

• Improve scalability
• Improve solubility
• Perform a salt

screenprotocol

• A shorter synthesis

was developed

• Solubility of the final

drug form was markedly improved

• Six salt forms tested
• The new analogue

showed similar activity towards the biological target Project Conclusions

DRUG PRODUCT CASE STUDY

Intravenous Formulation Phase 1 Study Challenge

Challenge: API exhibited multiple physical forms and solvates, and was chemically unstable. Two intravenous formulations (bolus and maintenance dose) were required, with the maintenance dose to be administered over a 3-day period (3 litres in total) for phase I studies. Aqueous solutions exhibited inherent physical instability. Customer: Small biotech, USA based. Outcome: Extensive physical characterisation of the drug substance was completed. Long term stability studies were initiated in ICH conditions. IV formulations were successfully that were chemically and physically stable for > 3- days and that could be administered in a Phase I study. Analytical methodologies were validated to support product stability. Manufacturing process for sterile extemporaneous manufacture transferred to clinic. Worked with Arcinova Dossier team for IND submission. Microbiology methods developed and transferred. Long-term API stability studies completed, and excellent stability profile. Client successfully completed Phase I trials and has entered Phase II.

Client has:

• Successfully

completed Phase ITrials

• Hasentered

Phase II

API Studies Ongoing Excellent Stability Profile

Completed full physical characterisation/

• ptimisation
• f the drug substance

DevelopedIV formulations that were chemically/ physically stable Developed& validated product methods Worked with clinic to transferprocess for sterile extemporaneous manufacturer Microbiology methods developedand transferred

BIOANALYSIS CASE STUDY

Biochemical Assay Optimisation, Validation & Application

Challenge: Build and validate an assay to measure non-haem iron in tissues thereby supporting one of the pivotal objectives for a regulatory non-clinical safety study. Customer: UK Specialty-Pharma Company. Outcome: A GLP-compliant assay for quantification of non-haem iron in liver, kidney and spleen was validated. Analysis of non-clinical samples was achieved. Results supported continued development of the molecule in question.

• Procedures for tissue extraction of non-haem iron were optimised and partnered with a colorimetric assay.
• Following validation, the assay was used to support a non-clinical study: non-haem iron was detected in all tissues and

exhibited a dose-response.

• The data supported the aims of the study and proved the utility of a non-haem iron assay in a GLP setting.

2 4 6 8

spleen kidney cortex liver

Non-haem iron (nmol/well)

Non-haem iron in tissue

neat 1 in 2 1 in 3 2 4 6 8 10

Low QC Mid QC High QC

Non-haem iron (nmol)

Non-haem iron inter-assay precision and accuracy