Published on March 6, 2014
Drug Actives from Bench to Market Nitto Avecia: Cincinnati Site Overview ©Nitto Denko Avecia Inc. All Rights Reserved
Cincinnati Site History 1993: Production site in Cincinnati built by Marion Merrell Dow for the manufacture of clinical candidates 1995 – 2013: Ownership changes of Cincinnati facility January 2013 1995 Hoechst acquires Site from Dow to form Hoechst Marion Roussel 1999 Hoechst Marion Roussel And Rhone Poulence Rorer Form Aventis 2001 Girindus acquires Site Solvay Organics acquired 76% of Girindus in August 2005 Girindus oligo and small molecule CMO assets purchased from Solvay by Nitto Avecia in January 2013: Creates one service provider from two complementary and respected firms Oligo, small molecule, and radiolabeling services, with two manufacturing sites and expanded support services ©Nitto Denko Avecia Inc. All Rights Reserved
Nitto Avecia Acquired by Nitto Denko in 2011, and formally becoming Nitto Denko Avecia Inc. in 2012, Avecia continues to provide exceptional services and expertise across a broad range of oligonucleotide APIs. Avecia supplements Nitto Denko‟s existing health care businesses, which include Transdermal drug delivery systems Medical tapes Other nucleic acid based technologies, including solid supports for oligonucleotide synthesis. ©Nitto Denko Avecia Inc. All Rights Reserved
Development and cGMP Production Center ©Nitto Denko Avecia Inc. All Rights Reserved
Project Management Ensures the right resources are in place at the right time for project success All project managers have laboratory experience and are trained in cGMP requirements Provides a team organizational structure that incorporates our customer into the team Delivers timely and accurate communications, including weekly updates Thorough planning of tasks Formal kickoff package to ensure clear communication of project goals to all team members Manufacturing Team Members Include Production, QA, QC, & R&D Personnel as Required ©Nitto Denko Avecia Inc. All Rights Reserved
FDA Inspected Quality Systems Nitto Avecia has maintained an excellent audit history with the US FDA and also undergoes ~20 client audits annually FDA Inspection Type Date Result Biennial cGMP inspection (unannounced inspection) February 2007 No 483 or objectionable findings Biennial cGMP inspection (unannounced inspection) August 2010 No 483 or objectionable findings Pre-Approval Inspection January 2011 Approved Biennial cGMP inspection (unannounced inspection) February 2012 No 483 or objectionable findings ©Nitto Denko Avecia Inc. All Rights Reserved
Small Molecule Development cGMP Manufacturer of Small Molecule APIs ©Nitto Denko Avecia Inc. All Rights Reserved
Business Focus Production of Small Molecule API & Intermediates Process development and scale-up Production of drug actives and intermediates under cGMP conditions Capable of commercial production Custom radiochemistry services Full regulatory and analytical support ©Nitto Denko Avecia Inc. All Rights Reserved
Small Molecule API: Process Typical Project for Phase 1 4 tasks plus associated secondary goals (characterization, reference standard, etc.) Task 1 – Screening, process development and optimization work – decision on viability of the proposed process for scale-up Task 2 – Analytical method development and phase appropriate method qualification / validation Task 3 - non-cGMP demonstration batch of 100s of grams to multi kg quantities used for tox studies, formulation work and/or reference standard Task 4 - cGMP production ©Nitto Denko Avecia Inc. All Rights Reserved
Small Molecule Capabilities 5 modern organic synthesis labs for R&D and early chemical development work 5 cGMP kilogram-scale labs cGMP Pilot Plant – up to 200 L reactors High pressure hydrogenation – up to 150 bar Licensed radiochemistry facility ©Nitto Denko Avecia Inc. All Rights Reserved
Small Molecule – cGMP Pilot Plant Reactors - 80°C to +150°C and 0.03 to 10 bar 1 x 200 L Glass Lined Reactor 2 x 120 L Glass Lined Reactors 2 x 120 L Hastelloy Reactors 2 x 80 L Glass Lined Reactors 1 x 40 L Hastelloy Reactor 1 x 50 L Chemglass Reactor with Julabo heater/chiller Solids Handling Nutsche Filters and Centrifuges HEPA Filtered Drying and Packaging Areas Prep Medium-Pressure Chromatography Wiped-Film Distillation Capability ©Nitto Denko Avecia Inc. All Rights Reserved
Small Molecule – Purification Capabilities Flash columns for Scale-up 5 cm ID x 80 cm glass column (#50 & 75/50 fittings) 20 cm ID x 80 cm glass column (#50 & 75/50 fittings) 20 cm ID x 100 cm glass columns (#50 & # 50 fittings) Teledyne Isco Companion XL Medium pressure columns for up to 1.5 kg Hypersep HPLC 11 cm ID jacketed column with bed heights to 35 cm 20 cm ID jacketed column with bed heights to 35 cm ©Nitto Denko Avecia Inc. All Rights Reserved
Summary FEATURES BENEFITS Tightly knit team of chemists with many years of experience in manufacturing, process development and scale up Smoother transition from small to large scale and an optimized process for manufacturing We understand the importance of customer‟s timelines and budget Track record of delivering projects on time and within budget Understanding that our success hinges on quality, communication and service Greatest value for the price, we will be in regular contact to keep you informed about your project, and we will put forth the utmost effort in delivering on our promises ©Nitto Denko Avecia Inc. All Rights Reserved
Unique Offering: Radiolabeling ©Nitto Denko Avecia Inc. All Rights Reserved
Radiochemistry Custom radiolabeling with carbon-14 and tritium Re-purification of radiolabeled APIs cGMP radiosyntheses Blending of radiolabeled API for clinical studies Radiolabeling of oligonucleotides Carbon-14 and tritium labeling of the bases Tritium exchange Purification by prep HPLC if required Release of labeled compounds by UV HPLC, radio HPLC, radio TLC, 1H NMR, chiral HPLC Stable labeling of APIs ©Nitto Denko Avecia Inc. All Rights Reserved
Radiochemistry Experienced cGMP radiochemistry Licensed to handle 14C, 3H, 32P, 35S, and 125I radioisotopes Radiochemistry area includes 4 hot labs and 2 cold labs Radio-detection is conducted in the common area by: TLC HPLC Scintillation Counting ©Nitto Denko Avecia Inc. All Rights Reserved
Oligo Radiolabeling Services Custom Radiolabeling with Carbon-14 or Tritium Carbon-14 and Tritium Labeling of the Bases or Linkers Tritium Exchange Purification by prep HPLC if required Release of labeled compounds by: UV HPLC, Radio HPLC, Radio TLC, 1H NMR, Chiral HPLC cGMP Radiosynthesis available Stable labeling of APIs Other Services Blending of Radiolabeled API for Clinical Studies Repurification of Radiolabeled APIs ©Nitto Denko Avecia Inc. All Rights Reserved
SUMMARY FEATURES BENEFITS Experienced radiochemists with decades of experience in radiosynthesis Track record of delivering on time within budget We have extensive experience in radiosynthesis including novel 14C labeled precursors Our experience allows us to develop improved labeling strategies for our clients to insure greater project success Environmental stewardship is taken seriously; we will not engage in questionable practices or source radioisotopes from disreputable sources Your program, company and environment will be protected ©Nitto Denko Avecia Inc. All Rights Reserved
Oligonucleotide Services ©Nitto Denko Avecia Inc. All Rights Reserved
Oligos from R&D to Commercial Production Process Development and Scale Up Process Validation Radiolabeling of Oligonucleotides Conjugation of Oligonucleotides to small molecules, lipids, etc. Collaboration with specialized companies for small non-cGMP scales CMC Documentation ©Nitto Denko Avecia Inc. All Rights Reserved
Oligos from R&D to Commercial Production Segregated cGMP manufacturing areas for small and large scale production AKTA 100, OP 400, and TechniKrom Synthesizers to accommodate cGMP projects from small to large scale. Lab- and Industrial-scale purification systems Classified clean rooms for downstream processing ©Nitto Denko Avecia Inc. All Rights Reserved
Oligonucleotide Manufacturing Portfolio DNA, Phosphodiesters and Phosphorothioates Aptamers with various backbones RNA, Phosphodiesters and Phosphorothioates Oligonucleotide PEGylation 2„- modified RNA DNA/RNA with modified backbones Duplex RNA Radiolabeling (35S, Gapmers (XXX-DNA-XXX) Peptide Conjugates 14C, 3H) Chimeras (DNA/RNA/LNA/2‟ mod RNA) ©Nitto Denko Avecia Inc. All Rights Reserved
Manufacturing Train 1: Smaller Scales Suitable for producing cGMP lots up to ~50 g AKTA 100 Oligo-DNA/RNA Synthesizer 0.1 – 8 mmol = 300 mg to 30 g per synthesis batch ©Nitto Denko Avecia Inc. All Rights Reserved
Manufacturing Train 1: Smaller Scales AKTA Purifier (max. flow rate 100 mL/min) Desalting FMI Metering Pump (1.2 L/min max flow) Total Membrane Area 0.1 – 0.4 m2 ©Nitto Denko Avecia Inc. All Rights Reserved
VirTis Genesis 35 XL Freeze Dryer Space for 6 Lyoguard Freeze-Drying Trays of up to 1.8 L each Gore membrane allows for water or solvent removal without chance of spills or product contamination from freeze drier Full range of vacuum, temperature control, barometric endpoint and moisture analysis Shelf pull-down to -40°C in 30 minutes or less, with efficient, utility saving compressors ©Nitto Denko Avecia Inc. All Rights Reserved
Manufacturing Train 2: Mid Scale Suitable for producting cGMP lots up to ~1 kg OligoPilot 400TM DNA/RNA Synthesizer 6 – 60 mmol = 20g to 250g per synthesis batch Multiple synthesis batches can be combined to increase overall batch size Purification Systems BioProcess (max. flow rate 2 L/min) (low pressure chromatography) HiperSep Skid (max. flow rate 1 L/min) (high pressure chromatography) Freeze Drier (12 LyoguardsTM up to 1.8 each) ©Nitto Denko Avecia Inc. All Rights Reserved
OligoPilot 400 DNA/RNA Synthesizer ©Nitto Denko Avecia Inc. All Rights Reserved
BioProcess Low Pressure System ©Nitto Denko Avecia Inc. All Rights Reserved
Manufacturing Train 3 - Large Scale Suitable for producing multi-kg cGMP lots TechniKrom DNA/RNA Oligo-Synthesizer 10-120 mmol = 30g to 400g per synthesis TechniKrom HPLC Skid 3L/min max flow at 1000 psi Dedicated Desalting System 30/L min max retentate flow Total membrane area 0.5 - 4.0m2 Freeze Drier (2 x 15 LyoguardsTM up to 1.8L each) ©Nitto Denko Avecia Inc. All Rights Reserved
TechniKrom DNA/RNA Synthesizer ©Nitto Denko Avecia Inc. All Rights Reserved
Purification TechniKrom HPLC Skid with 20 and 30 cm Varian Columns ©Nitto Denko Avecia Inc. All Rights Reserved
Summary FEATURES BENEFITS Experience in development of robust, reproducible processes High quality product from preclinical through commercial production Extensive experience in a wide range of oligonucleotide chemistry We can quickly solve difficult chemistry issues History of successful FDA inspection Easier route for manufacture and commercialization Experience in analytical method development and validation for oligonucleotides State of the art methods applied to manufacture ©Nitto Denko Avecia Inc. All Rights Reserved
Summary FEATURES BENEFITS Extensive experience in CMC preparation and filing Expert resource for easier filing process Active participation in “CMC Working Group” for Oligonucleotides and Tides Advisory Board Access and involvement to latest opinions and FDA thinking on guidance and specific requirements for oligonucleotides Licenses to key manufacturing technology No IP barriers to commercialization Dedicated project management You receive accurate and timely communication about your project. Nitto Denko support for the business Sustainable business and access to capital if needed for expansion ©Nitto Denko Avecia Inc. All Rights Reserved
Process Development & Validation Capabilities ©Nitto Denko Avecia Inc. All Rights Reserved
Validation Stages Pre-Stage 1 Validation – Targeted Optimization Investigate/increase robustness Improve efficiency Mixture of single variable and multivariate (DOE) studies Stage 1 Validation – Process Definition Risk Analysis, typically Failure Mode Effects and Criticality Analysis Design Space or Proven Acceptable Range Studies using custom DOE on a qualified Small Scale Manufacturing Model Identify Critical Process Parameters Support validations – analytical methods, cleaning, filter, shipping Stage 2 Validation – Process Performance Qualification 3 Validation Batches May run support validations in parallel ©Nitto Denko Avecia Inc. All Rights Reserved
Stage 1: Process Definition Failure Mode Effect and Criticality Analysis (FMECA) Identifies Potential Critical Process Parameters Repeated Over the Course of Development UNIT OP or PROCESS STEP Synthesis SUBUNIT OP POTENTIAL FAILURE MODE API CQAs AFFECTED POTENTIAL EFFECT(S) OF FAILURE Presence of N-1 Purity, impurities due to Batch failure, Coupling impurities or incorrect activatorlow yield yield to-amidite ratio POTENTIAL SEV CAUSE(S) OF OCC FAILURE 4 Equipment failure 1 CURRENT PROCESS CONTROLS Automated synthesis method, qualified system DET 4 KNOWL RPN EDGE 2 16 COMMENTS Delivered volumes have not been off target for any process. If a volume was delivered incorrectly, it would not be detected until synthesis was complete. CHANGE CONTROL SINCE REC’D ACTIONS STRATEGY PIVOTAL Yes Optimization and PAR study will be run on this parameter. Automated synthesis method, qualified system Table also includes: Item Numbers Responsible Person Completion Date ©Nitto Denko Avecia Inc. All Rights Reserved
Risk Table Risk Level Description Rating High A risk level so high that remediation action is required RPN > 20 Medium A moderate level of risk that may require remediation action; to be decided by team 9 > RPN < 20 Low A risk level low enough that no remediation action is required RPN < 9 Selection of parameters for inclusion in Characterization Studies Assess the level of impact of each potential CPP on the critical quality attributes determined by a specific process step Provides a rational and defensible approach for decision to include or exclude parameters associated with medium risk failure modes ©Nitto Denko Avecia Inc. All Rights Reserved
Document Tree ©Nitto Denko Avecia Inc. All Rights Reserved
Stage 3: Lifecycle Qualification Trending via statistical analysis Process parameters In-process testing results Additional testing (characterization) results (for a while) Release testing results Cleaning Facility and equipment performance Continuation of routine activities Preventative maintenance Calibration Periodic re-qualification of process, equipment, and facility ©Nitto Denko Avecia Inc. All Rights Reserved
Benefits to Sponsor Companies We have worked at both ends of the QbD spectrum Experience and comfort with minimalistic and full-on QbD Able to blend both approaches to achieve customer‟s desired outcome Customer is not tied to a single “Validation Approach” and resulting package We will provide you with a Validation Package that meets YOUR needs by employing the appropriate strategy. ©Nitto Denko Avecia Inc. All Rights Reserved
Quality Assurance and Quality Control Capabilities ©Nitto Denko Avecia Inc. All Rights Reserved
Quality System Overview Quality Unit Responsibilities SOPs Certificate of Analysis Release of raw materials Certificate of cGMP Compliance Batch Records Stability protocol Deviation Investigations Audits IQ/OQ Complaints Cleaning Verification GMP Training Finished product release Change Control ©Nitto Denko Avecia Inc. All Rights Reserved
Selected Analytical Test Capabilities UPLC and HPLC by UV-, RI-, Fluorescence and ELSDDetection LC/MS Endotoxins / Bioburden Heavy Metals Melt Temperature ©Nitto Denko Avecia Inc. All Rights Reserved
Selected Analytical Test Capabilities Multinuclear NMR Residual Solvents Sodium Water Content by Karl Fischer Capillary Gel Electrophoresis Additional testing is offered upon special request ©Nitto Denko Avecia Inc. All Rights Reserved
Experience and Reliability from the First Gram www.avecia.com ©Nitto Denko Avecia Inc. All Rights Reserved
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