Innovations in Pharmaceutical Manufacturing on the Horizon Technical Challenges, Regulatory Issues, and Recommendations (2021) / Chapter Skim
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2 Innovations in Manufacturing Drug Substances
2 Innovations in Manufacturing Drug Substances
Pages 12-22
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From page 12... ...
In this chapter, the committee Replacement of Traditional Process explores innovations for manufacturing bulk, purified Technologies with Atypical Alternatives APIs. Specifically, the committee discusses innovations in unit operations, process intensification, and process The physicochemical or biophysical properties of stream compositions that are associated with the upstream new APIs and changes in the composition of process and downstream processing of APIs.
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From page 13... ...
technologies, completely new types of unit operations that exploit physical phenomena that have not previ New Formats and Operating Strategies ously been harnessed in traditional manufacturing pro for Existing Process Technologies cesses are emerging. In the synthesis of small-molecule drugs, new types of reactors that enable photochemical New formats and operating strategies are being cre- and electrochemical reactions are being developed (Tom ated for existing unit operations to increase efficiency and 2020)
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From page 14... ...
has classified process; for example, a novel, high-throughput capture process intensification according to how it is achieved -- step during purification might have lower selectivity than by manipulating the supporting infrastructure of an existtypical capture operations and transfer a greater share of ing process without changing unit operations or operatthe purification burden to later polishing steps. Third, the ing parameters, by changing operating parameters within robustness of new unit operations to accommodate varia- existing unit operations, by changing raw-material use in tions in feed stream flows while maintaining consistent existing unit operations, or by substantially changing prooutput stream characteristics and to provide long-term cess flow with disruptive technologies (BPOG 2017b)
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From page 15... ...
Similarly, for small-molecule APIs, precedence is in setting a facility or process footprint. Intensified cell- provided by continuous drug-product processing, which culture operations place increased demands on media- has extended traditional continuous unit operations, such solution preparation in that fed-batch bioreactor media as tableting and capsule-filling steps, to end-to-end drugneeds to scale with cell-number density, and a perfusion product formulation and filling processes (Burcham et al.
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From page 16... ...
For example, it is used in perfusion cell-culture be more complex than the process control implemented systems with cell recirculation, batch ultrafiltration and for less intensive operations and processes. The integrated diafiltration operations based on retentate recirculation, operation might also be more reliant on specialized raw and mixed-suspension–mixed-product removal crystal- materials, media, or consumables than the separate unit lization with mother-liquor recirculation.
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From page 17... ...
reveal cell-stress levels during high-concentration cell culture and lead to culture media and feeding enhance PROCESS INNOVATIONS THAT CREATE ments that result in improved product quality by narrow NEW STREAM COMPOSITIONS ing the distribution of product variants formed. Further improvements in production of biologics New stream compositions arise from upstream op- are likely to come from alternative hosts, including new erations that incorporate innovations in synthetic chem- mammalian cell lines (for example, human cell lines)
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From page 18... ...
. That apcell-culture and harvest steps have not been eliminated proach would necessitate an array of process innovations, from the process; rather, they have been placed ahead including the introduction of a novel host-cell line that of the product biosynthesis step to supply and refresh, can carry out the incorporation during protein synthesis, as needed, the active biosynthetic reagents, which have the use of an unnatural amino acid in the culture media, finite half-lives.
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From page 19... ...
and expression systems will likely require customized "Co-processed" small-molecule APIs in which downstream processing steps to ensure efficient removal a nonactive excipient, additive, or carrier component is of any system-specific contaminants. As discussed above, added during the production of a drug substance -- typi- a variety of process innovations will likely be required for cally in particle formation, crystallization, or drying op- producing novel modalities, such as antibody–drug conjuerations -- can offer the possibility of improved stability gates, and the stability of the new conjugate will also have of a desired solid state or tailored API physical properties implications for formulation operations and for process (Schenck et al.
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From page 20... ...
, other relevant Manufacturing USA institutes stability date be set at the point of manufacture of the co- (including America Makes, the Smart Manufacturing processed API rather than when the co-processed API is Institute, and the Rapid Advancement in Process Intenconverted to a drug product. The effect of that difference sification Deployment Institute)
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From page 21... ...
R Brady, continuous viral inactivation.
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From page 22... ...
2020. Innovations in Development of Synthetic Small Molecule Drug Substance.
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