www.cordenpharma.com

Experts taking care.

Peptide Manufacturing Scale-up Considerations

Robert Topping PhDDistinguished Scientist

CordenPharma Colorado

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

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

2

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

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

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?

Equipment – Cost, Footprint & Utilities

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

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

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

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

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

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

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)

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

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?

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.

16

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

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

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

www.cordenpharma.com

Experts taking care.

Robert Topping, Ph.D.Distinguished ScientistCordenPharma Coloradorobert.topping@cordenpharma.comT: +1 303-938-6474

Inquirieswww.cordenpharma.com/contact-us/

THANK YOU!

mailto:robert.topping@cordenpharma.com

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