Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing

Engisch, William E.; Muzzio, Fernando J.

doi:10.1007/s12247-015-9238-1

Cited by 145 publications

(75 citation statements)

References 31 publications

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“…However, high antigen content and efficiency of plant material processing are not the only necessary conditions required to produce potential oral medicines. It should be equally important to ensure a stable antigen expression and/or uniformised and repeatable production of initial material to be processed as it is for pharmaceuticals from herbal and medicinal plants (Parveen et al 2015; Engisch and Muzzio 2016). …”

Section: Introductionmentioning

confidence: 99%

Micropropagation of transgenic lettuce containing HBsAg as a method of mass-scale production of standardised plant material for biofarming purposes

et al. 2016

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Key message Micropropagation protocol of transgenic lettuce bearing S-, M- and L-HBsAg was developed for increased production of uniformised material for oral vaccine preparation. AbstractEffective manufacturing of plant-based biopharmaceuticals, including oral vaccines, depends on sufficient content of a protein of interest in the initial material and its efficient conversion into an administrable formulation. However, stable production of plants with a uniformised antigen content is equally important for reproducible processing. This can be provided by micropropagation techniques. Here, we present a protocol for micropropagation of transgenic lettuce lines bearing HBV surface antigens: S-, M- and L-HBsAg. These were multiplied through axillary buds to avoid the risk of somaclonal variation. Micropropagation effectiveness reached 3.5–5.7 per passage, which implies potential production of up to 6600 plant clones within a maximum 5 months. Multiplication and rooting rates were statistically homogenous for most transgenic and control plants. For most lines, more than 90 % of clones obtained via in vitro micropropagation had HBsAg content as high as reference plants directly developed from seeds. Clones were also several times more uniform in HBsAg expression. Variation coefficients of HBsAg content did not exceed 10 % for approximately 40–85 % of clones, or reached a maximum 20 % for 90 % of all clones. Tissue culture did not affect total and leaf biomass yields. Seed production for clones was decreased insignificantly and did not impact progeny condition. Micropropagation facilitates a substantial increase in the production of lettuce plants with high and considerably equalised HBsAg contents. This, together with the previously reported optimisation of plant tissue processing and its long-term stability, constitutes a successive step in manufacturing of a standardised anti-HBV oral vaccine of reliable efficacy.

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Section: Introductionmentioning

confidence: 99%

Micropropagation of transgenic lettuce containing HBsAg as a method of mass-scale production of standardised plant material for biofarming purposes

et al. 2016

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“…While RTD has been traditionally used for liquid or gas based chemical reactors, application of RTDs has been expanded to solid systems in the polymer and catalyst industries . Engisch et al studied the traceability of a continuous direct compaction system. They obtained the RTD and the cumulative distribution function F ( t ) of the direct compaction process from tracer experiments.…”

Section: Introductionmentioning

confidence: 99%

Continuous fluidized bed drying: Residence time distribution characterization and effluent moisture content prediction

et al. 2020

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The mixing and drying behavior in a continuous fluidized bed dryer were investigated experimentally by characterizing the residence time distribution (RTD) and incorporating a micromixing model together with the drying kinetics obtained from batch drying. The RTD of the dryer was modeled using a tank‐in‐series model. It was found that a high initial material loading and a low material flow rate resulted in a reduced peak height and broaded peak width of the RTD curve. To predict the continuous dryer effluent moisture content, we combined: (a) the drying kinetics as determined in a batch fluidized bed dryer, (b) the RTD model, and (c) micromixing models—segregation and maximum mixedness models. It was found that the segregation model overpredicted the effluent moisture content by up to 5% for the cases we have studied while the maximum mixedness model gave a good prediction of the effluent moisture content.

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“…In fact, changes in material throughput related to market demand can also be seen as a disturbance which needs to be compensated for to assure product quality. [8][9][10][11] The next step is to use the acquired knowledge and monitoring tools to control the continuous feeding of the raw materials. Therefore, the concept of continuous pharmaceutical manufacturing does still not completely align with the design, analysis, and controlframework proposed in the FDA's PAT guidance.…”

Section: Introductionmentioning

confidence: 99%

Liquid‐to‐solid ratio control as an advanced process control solution for continuous twin‐screw wet granulation

et al. 2018

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Assuring compliance of intermediate and final quality attributes in a continuous pharmaceutical manufacturing campaign is of utmost importance. Application of corrective actions might be required in real‐time. This work exemplifies the steps needed to identify a linear pulse transfer function for the dynamic behavior of the granule liquid‐to‐solid ratio (%w/w) at the end of the granulation unit of a commercial ConsiGmaTM‐25 production line. Near‐infrared spectroscopy was used to monitor the granule composition in‐line. The outcome for both the tracking and regulator problem using either conventional or model predictive control was implemented and evaluated. Dynamic setpoints were correctly followed and an RMSE of 0.25%w/w with respect to the setpoint was obtained when inducing artificial disturbances. Important practical challenges were also tackled. Examples are fouling, computational limitations, and the limited flexibility of the automation software. Applying the proposed advanced process control solution offers an answer to upstream material flow rate deviations. © 2018 American Institute of Chemical Engineers AIChE J, 64: 2500–2514, 2018

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Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing

Cited by 145 publications

References 31 publications

Micropropagation of transgenic lettuce containing HBsAg as a method of mass-scale production of standardised plant material for biofarming purposes

Micropropagation of transgenic lettuce containing HBsAg as a method of mass-scale production of standardised plant material for biofarming purposes

Continuous fluidized bed drying: Residence time distribution characterization and effluent moisture content prediction

Liquid‐to‐solid ratio control as an advanced process control solution for continuous twin‐screw wet granulation

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