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Pilot-scale process development and scale up for antifungal production

机译：中试工艺开发和扩大抗真菌生产规模

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摘要

A pilot-scale fermentation was developed for an antifungal compound produced by a filamentous fungus. Replacement of galactose with lactose (20-fold cost savings) and a threefold phosphate reduction (15 to 5 g/L) improved productivity 2.5-fold. Addition of supplements-glycine, cobalt chloride, and trace elements-resulted in a further twofold productivity increase, greater process robustness, and less foaming which reduced antifoam addition tenfold (30 to <3 mL/L). Mid-cycle lactose limitations were addressed by raising initial lactose levels (40 to 120 g/L) resulting in another twofold productivity increase. Overall, peak titers increased tenfold from 45 ± 9 to 448 ± 39 mg/L, and productivities improved from 3 to 25 mg/L day. Despite its high productivity, process scale up was challenged by high broth viscosity (5,000-6,000 cP at 16.8 s~(-1)). Gassed power requirements at the 600 L scale (4.7 kW/1,000 L) exceeded available power at the 15,000 L scale (3.0 kW/1,000 L), and broth transfer to the downstream isolation facility was hindered. Mid-cycle broth dilution with up to five 10 vol% additions of 12 wt% lactose solution or whole medium-reduced viscosity three- to fivefold (1,000-1,500 cP at 16.8 s~(-1), gassed power within scale-up limits (2.5 kW/1,000 L), and peak titer by up to 45%. The process was scaled up to the 15,000 L working volume based on constant aeration rate (vvm) and peak impeller tip speed, raising superficialrnvelocities at similar shear. This strategy maximized mass transfer rates at target gassed power per unit volume levels, and along with controlled broth viscosity, precluded multiple dilution additions. A final titer of 333 mg/L with one dilution addition was achieved, somewhat lower than expected, likely owing to inhibition from some unmeasured volatile compound (not believed to be carbon dioxide) during an extended period of high back-pressure in the early production phase.
机译：针对丝状真菌产生的抗真菌化合物，进行了中试规模的发酵。用乳糖代替半乳糖（节省20倍的成本）和减少三倍的磷酸盐（15至5 g / L）可将生产率提高2.5倍。添加补充剂-甘氨酸，氯化钴和微量元素可进一步提高生产率两倍，提高工艺稳定性，减少起泡，从而将消泡剂的添加量减少十倍（30至<3 mL / L）。通过提高初始乳糖水平（40至120 g / L）解决了周期中乳糖的局限性，从而使生产率进一步提高了两倍。总体而言，峰值滴定度从45±9增加到448±39 mg / L，增加了十倍，生产率从3到25 mg / L天提高了。尽管其生产率高，但工艺规模仍受到高肉汤粘度（在16.8 s〜（-1）时为5,000-6,000 cP）的挑战。 600 L规模（4.7 kW / 1,000 L）的瓦斯功率要求超过了15,000 L规模（3.0 kW / 1,000 L）的可用功率，并且阻碍了肉汤向下游隔离设施的转移。循环发酵液稀释，最多添加5种10 vol％的12 wt％乳糖溶液或整个中等粘度降低的粘度三到五倍（在16.8 s〜（-1）时为1,000-1,500 cP，充气功率在放大范围内） （2.5 kW / 1,000 L），最高滴定度可达45％，基于恒定的曝气速率（vvm）和叶轮叶尖最高速度，该工艺可扩展至15,000 L的工作体积，从而在类似剪切力下提高了表面速度。在单位体积目标气化功率下获得最大的传质速率，并控制肉汤粘度，因此无需添加多种稀释液，最终稀释效价为333 mg / L，且添加一种稀释液，略低于预期，可能是由于在生产初期的一段长时间的高背压下，一些不可测量的挥发性化合物（不被认为是二氧化碳）。

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  • 来源
    《Bioprocess and Biosystems Engineering》 |2009年第4期|443-458|共16页
  • 作者

    Beth Junker; Andre Walker; Michelle Hesse; Michael Lester; Diane Vesey; Jens Christensen; Bruce Burgess; Neal Connors;

  • 作者单位

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

    Fermentation Development and Operations, Merck Research Laboratories, Rahway, NJ, USA;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    fungal; pilot plant; scale-up; antifungal; secondary metabolite;

    机译：真菌试验工厂;放大;抗真菌药次生代谢物;

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