Mechanistic Modeling the ultimate QbD tool for process - PowerPoint PPT Presentation

Mechanistic Modeling the ultimate QbD tool for process understanding Marcus Degerman, Lars Sejergaard, Ernst Broberg Hansen, Ann-Merete Ludvig, Else Bang Riis, Janus Krarup, Arne Staby WCBP 2011

Modeling in Process I ndustry Cracker plant in Stenungsund Feedstock • Naphtha Products • Ethane • Ethylene • Propane • Propylene • Butane • Every 4 hours the process is re-optimized. • Training room

Definition of Quality by Design “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.” - Q8, Pharmaceutical Development, ICH

W hat is a m odel? from http: / / www.merriam-webster.com/ • one who is employed to display clothes or other merchandise • a description or analogy used to help visualize something that cannot be directly observed Basic principles Assum ptions & Data • a system of postulates, data, and inferences presented as a theories mathematical description of an entity or state of affairs; also: a computer simulation based on such a system

”I've always seen modeling as a stepping stone.” - Tyra Banks

Basic QbD elem ents Process Risk assessm ent understanding CQAs Models CPPs DoE One-parameter evaluation Design space Parameter ranges Control space PAT etc… Release testing

Case study - Size Exclusion Chrom atography 1.4 1.2 • HMW P 1 • dim er UV absorption 0.8 • m onom er • total UV 0.6 • Pooling 0.4 0.2 0 0 0.2 0.4 0.6 0.8 1 Volume (CV)

Risk Assessm ent • CQAs • Potency 1.4 • Pool concentration 1.2 • Impurities • Dimers 1 UV absorption • HMWP 0.8 • CPPs • Flow rate 0.6 • Column length 0.4 • Feed volume 0.2 • Feed concentration* • Peak collection 0 0 0.2 0.4 0.6 0.8 1 Volume (CV) * CQA for previous step

Chrom atography m odel 1. Basic principles/ theories • Convection and dispersion in the packed column • Mass transfer into the particles • Diffusion within the pores • (Adsorption/ desorption kinetics) • Hypothesis • (Steric Mass Action) • Function 2. Assumptions • Interaction effects • Homogeneous column • Lumped mass transfer kinetics • Aggregates • dimer • octamer • No aggregate formation during processing 3. Data • Varying flow rate • Test of hypothesis • Varying column length • Calibration • Varying load volume

Mechanistic m odel Packed Colum n: ∂ ⎛ ⎞ ∂ ∂ ∂ ⎛ ⎞ 2 c ( ) c 1 ⎜ ⎟ ε ⋅ + ⋅ − ε ⋅ ε ⋅ + − ⋅ = ⎜ ⎟ 1 p 1 c k 1 c 0 ⎜ ⎟ ∂ ∂ ∂ ∂ 1 d 1 P 1 ⎝ ⎠ 2 ⎝ ⎠ t t x Pe x Pore diffusion: ∂ ( ) c = − p 1 st c c ∂ p 1 1 1 t

Calibration experim ents Experiment 2 Experiment 1 2 3 1.5 2 OD OD 1 1 0.5 0 0 • Experim ent 0 0.5 1 0 0.5 1 CV CV • Sim ulation Experiment 3 Experiment 4 2.5 3 2 1.5 2 OD OD 1 1 0.5 0 0 0 0.5 1 0 0.5 1 CV CV

Design of Sim ulations • Column length: 2 levels • Flow rate: 2 levels • Pooling front: 3 levels • Pooling trailing edge: 3 levels • Feed concentration: 6 levels • Level of dimers and aggregates set at highest level in feed. 216 ”experiments”

Sensitivity analysis 1 Yield 0.8 0.6 0.04 Aggregates 0.02 0 0.04 Dim er 0.02 0 1 Pool 0.5 conc. 0 0 1 2 20 30 40 0 2 4 0 0.2 0.4 0 0.2 0.4 Flow Feed Pool Pool Length rate conc. front T.E.

5 4 Fe e d conce ntr a tion ( g/ L) 3 Pool concentration 2 1 0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Pool concentration ( g/ L)

5 4 Fe e d conce ntr a tion ( g/ L) 3 2 1 0 100% 95% 90% 85% 80% 75% 70% 65% 60% 55% 50% Yield Yield

5 Feed concentration 4 Fe e d conce ntr a tion ( g/ L) 3 2 Pooling front 1 Aggregates 0 6.0% 5.0% 4.0% 3.0% 2.0% 1.0% 0.0% HMWP ( total)

Lab verification experim ents • “W orst case” conditions • All experim ents at low colum n length and high flow rate # Effect Feed Feed concentration volume 1 Low pool concentration 0.5 5% Low yield 2 High aggregate level 0.75 9% 3,6,7 Set point 1.5 5% 4 High concentration ~3 2% 5 High load ~3 3%

Process is robust w ith regard to concentration Pool concentration ( g/ L) 1.00 0.90 0.80 Experim ental 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 0.00 0.20 0.40 0.60 0.80 1.00 Sim ulation Feed concentration 0.5g/ L gives a worst case pool concentration of 0.35g/ L.

Process is robust w ith regard to HMW P dim er + HMW P • Process is robust 4.0% • Feed concentration of 3.5% 0.75 g/ L confirmed as 3.0% Experim ental worst case regarding HMWP. 2.5% • Error at low HMWP due to 2.0% 1.5% • analysis error 1.0% • dimer, octamer 0.5% 0.0% 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 % % % % % % % % % Sim ulation

Docum entation Risk assessm ent Model report • CPPs • Theory • Assumptions • Data (Calibration) Process verification study protocol • Full factorial study by simulation • Model reduced experimental design Process verification report • Verification of process • Verification of model • Parameter ranges • CPP/ KP/ non-CPP

W hat do w e m odel? • Chromatography • Ion exchange • Size exclusion • Hydrophobic interaction • Reversed-phase • Reactions • Acylation • PEGylation • Activation • We just started with • Freeze-drying • Freezing-thawing

Mechanistic m odels are versatile tools • Knowledge space • Model space • Design space • Control space 1 . Process understanding 2 . Model-based developm ent 3 . Process control 4 . Process support / Trouble shooting

Mechanistic m odeling is sound science • Process understanding anchored in theories/ first principles • supported by the scientific community • Interaction effects built into the models

Mechanistic Modeling the ultimate QbD tool for process understanding Marcus Degerman, Lars Sejergaard, Ernst Broberg Hansen, Ann-Merete Ludvig, Else Bang Riis, Janus Krarup, Arne Staby WCBP 2011