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May 1, 2010 (Vol. 30, No. 9)

Leveling Downstream Process Bottlenecks

Alternatives to Traditional Unit Operations Are Now Available to Alleviate Very Real Logjams

  • Perfect Model

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    Aspentech provides services to facilitate debottlenecking of downsteam processing through efficient scheduling of shared resources.

    One general debottlenecking approach is based on process modeling, a specialty of Philip Lyman, Ph.D., director of process simulation at CRB Consulting Engineers. Clients usually have a bottleneck in mind before they turn to CRB.

    “They want to make sure that the bottleneck is at the desired location, and that every other operation they don’t want to be the bottleneck has plenty of capacity.” Modeling helps to locate the bottleneck, eliminate it, and identify the next bottleneck. The process continues, iteratively and incrementally, to debottleneck the entire facility. Lessons learned during this exercise are applied to the process moving forward.

    Almost anything can become a bottleneck, for example, a recipe constrained into existing equipment not designed or specified for it may cause overutilization in one or more areas. Another is in support equipment like buffer prep or hold, clean-in-place skids, or shared utilities. One self-imposed bottleneck, scheduling of work shifts, may be overcome by extending work hours to 12 or 24 per day from eight, or to weekends.

    “Many different components have to come together, in the end, to generate your desired throughput. Equipment cleaning and turnaround of equipment, utilities for the main process and support equipment, and overarching everything is people or labor. It’s quite difficult to identify a bottleneck after a cursory view of the process. You have to get into it and study it.”

    CRB uses several tools for downstream debottlenecking, including Super Pro Designer and Schedule Pro from Intelligen, and discrete event simulation packages like FlexSim (FlexSim Software). All of these software packages are popular outside of pharmaceutical and bioprocessing. “And sometimes, just a simple Excel spreadsheet model will give us the answers we need,” says Dr. Lyman. “It depends on the problem we’re solving.”

    Jamie Hintlian, vp of pharmaceuticals at Aspentech, makes the case for applying more sophisticated software-based tools for scheduling and managing the thousands of combinations of time, materials, and processes arising during biopharmaceutical production.

    “Producers of small molecule drugs have never had to deal with the complexity in scheduling and planning that biomanufacturers do.” Process industries dealing with only a handful of resources to juggle can often handle scheduling by hand, or with a spreadsheet, and arrive at some ideal combination of operations. “But if you are dealing with hundreds of resources, no single person can oversee them all.”

    One Aspentech client, a contract manufacturer, had to deal with more than 3,000 “activities” for one process. When complexity reaches this level, particularly in a regulated environment, it may be inappropriate to employ home-brewed solutions, Hintlian cautions. “This is where systems help, and if you have the right system you can squeeze not just a few percentages more out of your operations, but dozens of additional capacities that you could never uncover by virtue of their sheer numbers.”

  • In-Line Buffer Dilution

    Upstream-downstream capacity mismatches, a major source of downstream bottlenecks, arise because downstream operations cannot match upstream’s volumetric productivity. Downstream capacity can be increased by adding equipment, but each new column takes up space. Since buffer concentrations differ from step to step, added operations often require dedicated buffer prep and/or storage tanks.

    In-line buffer dilution—the mixing of buffers “on the fly” from concentrates—significantly reduces buffer storage and prep, reserving precious floor space for ramping up capacity. Benefits of in-line dilution include maximizing existing tankage while minimizing cleaning and associated validation of larger tanks.

    Asahi Kasei Bioprocess (AKB) has introduced an in-line dilution technique, IBD™, that reportedly offers several advantages to conventional in-line dilution, among them more accurate dilution and fewer out-of-spec buffers.

    AKB uses in-line, temperature-controlled conductivity and pH measurements, rather than more conventional volumetric or flow-based methods, to determine buffer concentrations. The company claims pH control of 0.1 units.

    “Since we control dilution based on critical process parameters rather than through mass or volume estimates, the accuracy and precision of the dilute buffer output are uncoupled from the accuracy and precision of the formulated concentrate buffers,” says Kimo Sanderson, vp at Asahi Kasei. In-line measurements are critical components of both quality by design and process analytical technology.

    Standard IBD systems turn over 1,200 L/hr of buffer; custom-built units can process from 60 to 6,000 L/hr.


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