Continuous Manufacturing- Part 2
ABSTRACT: This article, which is Part 2 of the series on continuous manufacturing focuses on the uptake of continuous manufacturing by the pharmaceutical industry for both API and drug products, scaleup to pilot scale and successes in commercialization. Adoption of continuous manufacturing by CRO’s/CDMO’s is also reviewed. Challenges associated with continuous manufacturing are outlined.
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Industrial Adoption of Continuous Pharmaceutical Manufacturing
Continuous manufacturing has been common in certain sectors like the oil and gas for a long time. However pharmaceutical industry has been slow to catch onto this concept and has adapted it only since about 2005 and has produced success, albeit limitedly, at commercial scale in the past decade.
API manufacturing processes typically have more steps and therefore is more complex when compared to solid dosage manufacturing. But with continuous anufacturing’s production efficiencies, interest in and adoption of continuous API manufacturing should increase once approvals comes through.
At a pilot plant level, the first continuous manufacturing plant was demonstrated in 2013 by Mascia et al. when Ali-ski-ren hemi-fuma-rate was synthesized, purified, crystallized, and subsequently formulated into the desired DP while mitigating solids handling issues and removing the need for intermediate solvent swaps between unit operations1. In 2016, Adamo et al. also demonstrated a compact, end-to-end production of multiple DPs with different APIs 2. In 2016, Monbaliu et al. developed an automated system for the end-to-end CPM of lidocaine hydrochloride 3. In 2019, Cole et al. described the end-to-end CPM of merestinib (a new biliary tract cancer drug) from synthesis to crystallization 4, 5 The above-mentioned demonstrations were implemented on pilot or production plant level. In 2017, Eli Lilly’s continuous API GMP facility could produce 3 kilograms a day of prexasertib monolactate monohydrate, a chemotherapy candidate for clinical trials.6 The process links each stage in the process to quality-control systems, combining synthesis with purification and crystallization. It also enables chemistries that would be impossible or too dangerous using traditional methods.
The implementation of continuous manufacturing at production level has begun to appear more prevalently in recent years for plant subsystem and plantwide designs.7-9 Vertex committed to continuous Or-ka-m-bi (containing lumacaftor and iva-caf-tor for cystic fibrosis treatment) tableting.10In 2016, Janssen received FDA approval for the continuous tablet production for Pre-zi-s-ta, whose API, da-ru-na-vir, is used as part of HIV/AIDS combinative treatments.
US-FDA has publicly backed continuous manufacturing, and this has also reflected in the product approvals for the US market in Table 1. have been approved by the US-FDA and have been launched in the US market.
GSK began continuous production of amoxicillin at a fully continuous plant in Singapore 12 and also began a continuous line for daprodustat (an anemia medication). 13-14GSK believes that anywhere between one-third and one-half of their drug portfolio could be transitioned to continuous manufacturing.15 In addition to building the Singapore plant for GSK, Zeton, a global equipment and process tec...
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