Peptide Manufacturing Scale-up Considerations · SPPS • On resin, as protected peptide • 1 kg...
Transcript of Peptide Manufacturing Scale-up Considerations · SPPS • On resin, as protected peptide • 1 kg...
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www.cordenpharma.com
Experts taking care.
Peptide Manufacturing Scale-up Considerations
Robert Topping PhDDistinguished Scientist
CordenPharma Colorado
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Peptide Manufacturing Scale-up Considerations
Agenda
•What is Large Scale?•Opportunities and Issues• Impacts of Large Scale
• SPPS• Purification• Isolation
•Addressing Scale-up Factors•Safety, Health & Environmental
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What is Large Scale Manufacturing of Peptide API? SPPS
• On resin, as protected peptide• 1 kg to 500 kg per batch
Solution Phase (Hybrid)• Fragment condensations in solution• Side chain elaboration in solution• Oxidative folding• 10-500 kg per batch
Purification (RP, SEC, Concentration, IEX)• Contained peptide per injection• 0.2 kg to 2.5 kg
Isolation (Precipitation, Lyophilization, Spray drying)• Net peptide mass• 1 kg to 40 kg per batch
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Opportunities of Large Scale
Commercial Forecasts Dependent on Indication / Therapeutic Dose / size of patient population Does large scale make sense over larger number of small batches?
• Too few batches?
Fewer batches Less analytical burden
Economic savings Labor hours per kg decreases Bulk materials costs lowered at scale
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Issues to Address / Manage at Large Scale Equipment capital, maintenance, utilities costs
Variability from clinical / tox / pivotal batches (smaller scale) Quality differences – impurity profiles, physical characteristics Parameter differences – causes new issues not seen at small scale
Batch genealogy / campaigning Raw materials
Sufficient number of quality vendors at scale? Consistency, variability between vendors Changes in quality as a vendor scales up Storage needs
Waste management Minimize, recycle or repurpose
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Issues to Address / Manage at Large Scale (continued)
Risks Safety
• Large volume solvent handling• Large volume waste management• Large mass of coupling reagents
Quality• Different impurity profile• Multiple vendors = variable RM quality
Economic• More eggs in one basket • What lot size can vendors supply?
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Equipment – Cost, Footprint & Utilities
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Impacts of Large Scale Operationally, What Changes from Small Scale to Large Scale?
Time Cycle time per kg decreases Overall cycle time increases Stability in-process
Mixing rates Less efficient mixing
Heat transfer rates Exothermic quenches
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SPPS Issues at Large Scale – Mixing
Initial Lack of batch reaction homogeneity Mixing isn’t initiated until resin can be mobilized by solution
Variability / localized stoichiometry control Fmoc removal – dibenzofulvene end-capping Base-catalyzed impurities during Fmoc removal Cleavage from CTC resin under acidic SPPS (HOBt/DIC)
Efficiency of SPPS washes
Physical / Mechanical integrity of resin
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Purification Issues at Large Scale
Equipment size at high pressure
Can large scale column / resin serve dual purposes Purification / Concentration / Ion exchange Advantages and disadvantages
Cost of RP resin Lifetime of RP resin
• Physical / Mechanical integrity Cleaning of RP resin Repacking requirements Compliance issues
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Purification Issues at Large Scale – Physical Changes Aggregation / Precipitation are dependent on:
Structure / sequence Concentration Solvent / water content Temperature pH Salt concentration / identity Agitation Time Equipment MOC
Parameters need to be understood and controlled Causes column plugging, loss of column performance, loss of yield
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Purification Issues at Large Scale – Chemical Changes Isomerization / Multimer formation
Dependent on:• Structure / sequence• Concentration• Solvent / water content• Temperature• pH• Salt concentration• Time
Quality of solvents (reactive impurities) Impacts quality, changing separation challenges,
lowered yield
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Isolation - Lyophilization
Expensive equipment at scale Multiple static trays
Homogeneity Limited to volatile buffer salts Capacity and throughput equipment limitations Management of organic solvents from purification Residual solvents Manual discharge operations Low bulk density at large scale becomes a packaging issue
Handling difficulty due to static Excellent dissolution properties
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Isolation - Precipitation
High capacity, scaleable Mixing and heat transfer issues
Equipment requirements Precipitation vessel Feed vessel Filter (ANFD) and receiver
Homogeneity addressed Batch-wise precipitation Drying in ANFD (mixing)
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Isolation - Precipitation (continued) Purge of non-volatile buffer salts
Wall cake Yield loss Homogeneity issue
Residual solvents
Higher bulk density Better handling properties
Dissolution issues
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Addressing Scale-up Factors
Scale-down demonstrations of large-scale operations• Feed rates / times• Stir times• DOE – make sure large scale equipment can execute parameter range
Stability – chemical and physical• Characterize factors impacting stability• Demonstrate times for stability-sensitive operations• Evaluate MOCs• Can peptide aggregation in solution be prevented or reversed?• What is the purge capability of new impurities?
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Safety, Health & Environmental
Toxicity assessment of reagents Genotox risk assessment
Safety aspects of coupling reagents Operational risk assessment “Thermal Stability Assessment of Peptide Coupling Reagents
Commonly Used in Pharmaceutical Manufacturing”• Org.Proc. Res. Dev. 2018, 22, 1262
Environmental regulations of solvent usage NMP
Solvent recovery & waste management “Sustainability Challenges in Peptide Synthesis and Purification:
From R&D to Production”• J. Org. Chem. 2019, 84(8), 4615.
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CordenPharma Overview
Full-Service CDMO Organized under 5 Technology Platforms
€ 311 Million Total Sales (2018)
9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Labs)
1,570 Employees
Your Full-Service CDMO Partner
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CordenPharma Brussels
CordenPharma Peptide Facility Overview
Peptides (LPPS+SPPS) Spray drying expertise Dinucleotides Leader in Solution-Phase Peptide
Synthesis & Prod.
Small to Mid scale SPPS
Pharmaceutical Commercial & Clinical API Supplies
Worldwide Compliance standards Development by QbD
CordenPharma Colorado
(HAPI) Peptides SafeBridge Cat. 4 Certification Largest Peptide Production &
Purification capacity worldwide Proprietary Precipitation
Isolation Technologies Pharmaceutical Commercial &
Clinical API supplies Worldwide Compliance
standards Development by QbD
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Integrated Resource for the Development & Manufacture of Advanced Intermediates and APIs for Global Pharmaceutical and Biotechnology Industries
Development & Manufacture of Complex Synthetic Peptides & Conjugates
Development & Manufacturing of Highly Potent, Cytotoxic & Non-Cytotoxic APIs
Excellent Track Record in Development from Early Stage to Launch
SafeBridge® IV Certified
Location: Boulder, Colorado USA Acquisition: September 2011 Employees: 205
Core Competencies• Leader in Development &
Manufacture of Synthetic Peptides• Process Analytical Technology &
Track Record in Regulatory Filing• Development & Scale-up of Highly
Potent & Oncology APIs
CordenPharma Colorado
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www.cordenpharma.com
Experts taking care.
Robert Topping, Ph.D.Distinguished ScientistCordenPharma [email protected]: +1 303-938-6474
Inquirieswww.cordenpharma.com/contact-us/
THANK YOU!
mailto:[email protected]
Peptide Manufacturing Scale-up ConsiderationsPeptide Manufacturing Scale-up ConsiderationsWhat is Large Scale Manufacturing of Peptide API?Opportunities of Large ScaleIssues to Address / Manage at Large ScaleIssues to Address / Manage at Large Scale (continued)Equipment – Cost, Footprint & UtilitiesImpacts of Large Scale �Operationally, What Changes from Small Scale to Large Scale?SPPS Issues at Large Scale – MixingPurification Issues at Large ScalePurification Issues at Large Scale – Physical ChangesPurification Issues at Large Scale – Chemical ChangesIsolation - LyophilizationIsolation - PrecipitationIsolation - Precipitation (continued)Addressing Scale-up FactorsSafety, Health & EnvironmentalCordenPharma OverviewCordenPharma Peptide Facility OverviewCordenPharma ColoradoSlide Number 21