Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice

Nasr, Moheb; Krumme, Markus; Matsuda, Yoshihiro; Trout, Bernhardt L.; Badman, Clive; Mascia, Salvatore; Cooney, Charles L.; Jensen, Keith D.; Florence, Alastair J.; Johnston, Craig; Konstantinov, Konstantin; Lee, Sau L.

doi:10.1016/j.xphs.2017.06.015

Cited by 103 publications

(68 citation statements)

References 9 publications

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“…For the continuous variables such as the manufacturing rate, the PDF f 1 (x) was defined as shown in Eq. (7).…”

Section: Mcsmentioning

confidence: 99%

“…The potential benefits of continuous manufacturing are ease of scale-up, flexibility in demand change, and the capability of reducing the number of operators [5]. Ongoing discussions on the regulatory aspects such as control strategy [6,7] are consolidating the way to implement this new technology, which promises to make some of the units or even the entire process continuous [8]. However, the progress in continuous manufacturing requires coping with the increased complexity in the process design.…”

Section: Introductionmentioning

confidence: 99%

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Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing

et al. 2020

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This paper presents a new method for process synthesis and economic assessment for solid drug product manufacturing, considering continuous manufacturing as a prominent process alternative. Of the three phases of drug development, phase II was targeted where the dosage form, formulation, and processing technology are determined. For a comprehensive alternative generation, a superstructure was developed that covered 9452 options for the unit level, which was combined with two options on the formulation strategy. The generated alternative was assessed by a net present value calculation model, which was adapted for dynamic cash flow consideration in the drug lifecycle. The model can incorporate uncertainty in the drug development and manufacturing in the result, and can perform global sensitivity analysis by Monte Carlo simulation. The method was demonstrated in a case study where two different scenarios regarding the price of the active pharmaceutical ingredient and the demand for the product were assumed. The results showed that when the demand and price are both low, the labor-related costs are dominant, and in the opposite case, the material-related costs become relevant. We also introduce the prototype version of the software "SoliDecision," by which the presented method was implemented for industrial application.

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“…For the continuous variables such as the manufacturing rate, the PDF f 1 (x) was defined as shown in Eq. (7).…”

Section: Mcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The regulatory agencies strongly support continuous manufacturing, provided the manufactures develop a well understood robust process that can meet the product quality attributes under controlled manufacturing steps (Nasr et al, 2017). However, the lack of experience in getting regulatory approval for continuous bioprocessing creates an uncertainty in the industry (Stock et al, 2014).…”

Section: Process Characterizationmentioning

confidence: 99%

Progression of continuous downstream processing of monoclonal antibodies: Current trends and challenges

Somasundaram

Pleitt

Shave

et al. 2018

Biotech & Bioengineering

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Rapid advances in intensifying upstream processes for biologics production have left downstream processing as a bottleneck in the manufacturing scheme. Biomanufacturers are pursuing continuous downstream process development to increase efficiency and flexibility, reduce footprint and cost of goods, and improve product consistency and quality. Even after successful laboratory trials, the implementation of a continuous process at manufacturing scale is not easy to achieve. This paper reviews specific challenges in converting each downstream unit operation to a continuous mode. Key elements of developing practical strategies for overcoming these challenges are detailed. These include equipment valve complexity, favorable column aspect ratio, protein-A resin selection, quantitative assessment of chromatogram peak size and shape, holistic process characterization approach, and a customized process economic evaluation. Overall, this study provides a comprehensive review of current trends and the path forward for implementing continuous downstream processing at the manufacturing scale.

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“…After the first International Symposium on Continuous Manufacturing of Pharmaceuticals (ISCMP) [42], the researches and results related to this topic have become more and more popular, and the first FDA Pharmaceutics 2019, 11, 654 5 of 23 approved drug product (Orkambi TM ) demonstrated the success of the new trend. The renovation of regulatory aspects became timely, which was one of the main topics on the second ISCMP in 2016 [43]. The white paper of the conference follows the previously accepted FDA and International Conference on Harmonization (ICH) guidelines [44][45][46][47] and on that basis, process monitoring and control have been emphasized peculiarly on the conference [43].…”

Section: The Current State Of Continuous Productionmentioning

confidence: 99%

Continuous Formulation Approaches of Amorphous Solid Dispersions: Significance of Powder Flow Properties and Feeding Performance

et al. 2019

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Preparation and formulation of amorphous solid dispersions (ASDs) are becoming more and more popular in the pharmaceutical field because the dissolution of poorly water-soluble drugs can be effectively improved this way, which can lead to increased bioavailability in many cases. During downstream processing of ASDs, technologists need to keep in mind both traditional challenges and the newest trends. In the last decade, the pharmaceutical industry began to display considerable interest in continuous processing, which can be explained with their potential advantages such as smaller footprint, easier scale-up, and more consistent product, better quality and quality assurance. Continuous downstream processing of drug-loaded ASDs opens new ways for automatic operation. Therefore, the formulation of poorly water-soluble drugs may be more effective and safe. However, developments can be challenging due to the poor flowability and feeding properties of ASDs. Consequently, this review pays special attention to these characteristics since the feeding of the components greatly influences the content uniformity in the final dosage form. The main purpose of this paper is to summarize the most important steps of the possible ASD-based continuous downstream processes in order to give a clear overview of current course lines and future perspectives.

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Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving From Theory to Practice

Cited by 103 publications

References 9 publications

Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing

Superstructure-based process synthesis and economic assessment under uncertainty for solid drug product manufacturing

Progression of continuous downstream processing of monoclonal antibodies: Current trends and challenges

Continuous Formulation Approaches of Amorphous Solid Dispersions: Significance of Powder Flow Properties and Feeding Performance

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