Process Modeling and Control Challenges in the Pharmaceutical Industry
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1 Process Modeling and Control Challenges in the Pharmaceutical Industry Phil Dell rco Team Leader, Process Safety and Design, GSK Pharmaceuticals
2 utline Introduction: What do pharma engineers do? Current Practice: what do we do for modeling and control now? Reaction engineering Crystallization Drying Better Practice: What are we working towards? Some examples Needs infrastructure technical
3 Realities of Pharmaceutical Processes: igh Attrition, Few Campaigns Number of Compounds Early Toxicology, Phase I (30-50 candidates) Phase III/NDA (1-3 candidates) Numerous early stage candidates which will not survive from Phase I to Phase II/III Early objectives (first plant, large scale lab campaigns) enable chemistry not much eng input ver 80% of batches in our pilot plants are one-off Perhaps only 5-6 total campaigns prior to filing Late stage objectives (Phase II supply and beyond) develop detailed models determine critical parameters understand equipment limitations
4 Introduction: Pharmaceutical Research and Development We are a batch process industry essentially no continuous processes why? Many products don t make it to market Batch reactors offer flexibility over continuous reactors in that they are adaptable for many products and unit operations Volumes continuously change through the lifetime of a product. Again, batch reactors are adaptable GMP We are an industry dominated by chemists many plant campaigns are one-off; little engineering needed sometimes difficult to get sufficient eng. Input to projects
5 Chemistry Dominated Industry Ratio of Chemical Engineers to Chemists Across Industry FTE ratio Chemical Engineers to Chemists* : :10 1:12 GSK (total) GSK (w/o plant) Merck Merck AG Pharmacia Novartis Eli Lilly Astra Zeneca BMS DuPont Merck Aventis Schering Plough Abbott In general, chemists dictate the way processes are conceived and executed. Engineering input is often secondary
6 Technology Transfer Process Engineering - Input Level to Projects P.A.T. Process design optimisation - eat/mass transfer -crystallization/ particle eng. -Separations - Environmental, etc.. Time Process Control Design Unit operation optimisation Final process Plant Configuration (5th make) Rte optimisation Plant Configuration (4th make) Rte development Plant Configuration (3rd make) Process flow optimisation New route Plant Configuration (2nd make) Rte selection support Plant Configuration (1st make) Route Design Chemistry ptimisation Robustness Studies Synthetic Chemistry Activity Chemical Engineering Activity
7 Key Unit perations- Synthetic Chemicals Extractions: In general, every process stage has an average of greater than 1 extraction. Distillations (Batch): on average, 1 distillation per stage Reactions: A given chemical stage has 1-4 chemical transformations Crystallizations: Critical for defining physical properties of final drug product Filtration: Both final product and intermediates Drying: Every final product is dried. Probably most empirical field. Environmental: solvent recovery, biotreatment, incineration Chromatography: infrequent currently, but becoming more common
8 Key Unit perations: Biopharmaceuticals Fermentations- most critical step. Determines complexity of separations chain and product yield Ultrafiltration- removes cellular material from fermentation broth Exclusion chromatography- purification by size separation Ion chromatography- purification by ionic charge Dialysis- buffer exchanges
9 Manufacturing Limitations to Complex Control Strategies We are in general Low Tech with respect to Reaction Engineering Many of our vessels in pilot plant and manufacturing are jack of all trades, but master of none nearly 70% of existing GSK vessel capacity is glass lined, radial impeller (e.g., retreat curve, crow s foot, cryobat) little flexibility for difficult mixing problems Roughly 50% of our manufacturing capacity relies on crude control banded control using following options: steam, hot water, cold water, fridge, jacket hold, jacket drain We have little in the way of sophisticated process analytics which might provide opportunity for better control.
10 Current Practice: Reaction Engineering Collect kinetic data, often semiquantitative Estimate parameters, or determine boundary conditions Determine crude optimum either graphically, through DE Program DCS Sequence to obtain crude optimum Do to large number of early phase compounds, expedient but not perfect methods required (80% engineering) We often use sub-optimal data (IR traces, reaction calorimetry, PLC PAR s) and model in these domains While parameter estimation is often numerically performed (not always!), optimization tends to be crude Tools: MatLab, iq, DynoChem
11 Crude Modeling: Using ReactIR data to improve a reaction Rate constant k 1 (formation of methylthiol product and rate constant of impurity formation k 2 : k 1 / k 2 75 Improve ratio of rate constants by changing reaction temperature. Conc. (mol/l) Reactant, pred Product, pred Imp, pred Reactant, act Product, act For 100% conversion of starting thiol: eq MeI 94.4% Product 5.6% Impurity More MeI only increases di- Methyl impurity % Time (s) K, MeI Ar S Ar SMe + KI + 2 2
12 Desired Practice: Reaction Engineering Collect kinetic data, quantitative Estimate statistically significant parameters, or determine boundary conditions Use parameters to define an optimal operating policy Improve optimization based on further experimentation Program DCS Sequence to obtain optimum Would like to improve level and quality of modeling Will never be perfect due to time constraints, but better optima, better extrapolation possible Broaden use of optimization tools?
13 Reaction Engineering: Biopharmaceuticals Biopharmaceutical fermentations tend to be very complex systems, with many potentially important parameters shear dissolved gas levels (C 2, 2 ) p fermentation by-products Many side reactions possible for proteins: similar reactive sites (e.g., a monoclonal antibody may have multiple histidine groups) Downstream purification operations are extensive: perhaps unit operations to get fermentation product into a formulated product Single batches typically run for ~ 15 days. End value of batch can be 1 million US for 1000 L fermentor
14 Biopharmaceutical Modeling Problem: Deamidation of a Protein Neat Protein/Buffer d[ mab] = N cell * Viability * k0 2k1 *[ mab] dt d[ deamida] = 2k1[ mab] k2[ deamida] dt d[ deamidb] = k2[ deamida] dt Protein/Buffer w/cells Many unknowns in model: how do various parameters affect cell growth rate constant (different for almost any two experiments) ow would optimum harvest time vary across natural variability of k o
15 Need for new process analytical technologies: mechanistic inferences, potentially kinetic information to drive model development. Example: electrospray mass spectrometry, real-time data
16 Typical Setup for Reaction Monitoring by ES/MS PUMP #2 PUMP #3 100:1 Flow Splitter PUMP #1 PLC VIALS PUMP #4 Temperature Controller Mass Spectrometer
17 Proposed Reaction Mechanism Using bserved Intermediate Reaction Mechanism proposed to be that proposed by Knoevenagel, rather than that proposed by ann and Lapworth [A] C R [P] m/z 86 N [A - ] [P + ] [B] C R N + R' [BP+] m/z R' N [A - ] C R R R - N -C 2 R' N R R' N + C R - 2 [N] m/z 419 [M] [L] m/z 320 [A - ]
18 Current Practice: Crystallization Data Collection: solubility, MSZW, kinetic time scales, crude particle size measurements Preliminary Crsytallization Design Robustness studies around mixing, seeding, addition rates, etc. Final Crystallization Design Models: typically simple Semi-quantitatively driven analytical issues: what is particle size? Data collection techniques: probably underdeveloped relative to other fields
19 Solubility Measurement: Example of basic collected data using IR methods. Automated, rapid, accurate, and routine. Solute Conc. (g/g solvent) Solute Concentration, Toluene Solute Conc., 1:1 EtAc/Cyclohexane Solute Conc., n-butanol Temperature Temperature (C) Time (min) System calibrated in 0.5 days for 4 solvents; PLS fit to calibration standards. ~ 6 g material required, ~ 4 g recovered. In ~24 hours, solubility mapped out in 4 solvents.
20 Kinetic Information: Qualitative Desupersaturation Monitoring For a typical crystallization design, crystallization monitoring occurs after measuring solubility, MSZW Time scales for crystal growth under different seeding, cooling conditions are inferred from turbidity, Lasentec, and IR signals From this basis, boundary conditions are determined Qualitative Design Lasentec Counts (1-500 microns) Lasentec Counts Turbidity utput Temp (C) Turbidity utput/temp (C) Time (seconds)
21 Desired Practice: Crystallization Data Collection: solubility, MSZW, kinetic data, better particle size, desupersaturation measurements Preliminary Crsytallization Design Additional kinetic data, paremeter estimation Validate model, improve parameter estimation Use models for senstivity analysis on systems Implementation of control on plant (as opposed to DCS sequence) is possible due to high value of product Perform robustness experiments based on sensitivity Need for improved analytical methods for data collection While we may never be able to model accurately in the domain of FDA accepted particle size methods, we can use models to indicate sensitivity of process to changes. This would improve robustness of process. Due to high value of product at this stage, active control strategies on plant would attract investment Some good academic activity in this area (Rawlings, Braatz)
22 Drying: The forgotten field x Drying influences product sizes perhaps more strongly than crystallization unit operations, yet there is very little research in drying modeling ow do we explain/correlate particle breakage in filter dryers (f(mechanical properties, geometry)) ow do we explain agglomeration phenomena? slurry ex reactor 0.13 m^2 filter dryer, non-sonicated Tumble Dryer, non-sonicated after drying after screening x slurry ex reactor 0.03 m^2 filter dryer, non-sonicated 0.13 m^2 filter dryer, non-sonicated Tumble Dryer, non-sonicated after drying after screening
23 Industry Needs: Infrastructure More hiring of graduates from control and modeling programs ChE hires tend to be from crystallization, chemistry oriented programs---> tend to have weaker math/modeling skills Integration of best practice optimization algorithms, approaches into commercial software (e.g. MatLab) Training and implementation sessions from modeling and control community
24 Industry Needs: Technical (1) Integration of detailed mixing effects into modeling Consideration of pharma used process analytical tools (Raman, IR, Lasentec?, NIR) in development of control schemes: how would we take complex data, reduce it quickly, and allow its feedback? Some academic effort into modeling drying processes Close work with PAT community to improve model development and control strategies for crystallization and reaction engineering New PAT s to enable better models: electrospray MS? Ultrasound? Etc...
25 Industry Needs: Technical (2) Additional resource into crystallization modeling and control Detailed consideration of biopharmaceutical reaction engineering: how to best model cellular systems
26 Summary As an industry, we are in general not state of the art in modeling and control Pharma is chemistry rather than engineering driven Significant scale-up constraints due to plant configurations Significant infrastructure and technical needs that can be addressed by modeling and control community Advancement in modeling is relatively straightforward; advancement in control is longer term
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