This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes staffing (personnel), chemistry, reaction platforms, postreaction processing, analytical, regulatory, and factors that influence the adoption of continuous manufacturing. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufacturing executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chemistry, while postprocessing and analytical remain in the very early stages of development and implementation.
The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches to a key 1H-4-substituted imidazole intermediate ( 5). In a first generation approach, rapid optimization and scale-up of a challenging cyclization reaction was demonstrated in a PFR under GMP conditions to afford 29 kg of protected product 2. This material was further processed in batch equipment to deliver di-HCl salt 4. This first generation approach highlights the rapid development of chemistry in research-scale PFRs and speed to material delivery through linear scale up to a pilot-scale PFR under GMP conditions. In a second generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for rapid and data-rich reaction optimization of both a key cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1 kg demonstration runs in a 0.22 L PFR for both continuous steps and shows the potential of commercialization from a lab hood footprint (1−2 MT/year).
A batch process was developed to produce 1-(azidomethyl)-3,5-bis-(trifluoromethyl)benzene, 1, in 94% yield by an efficient nucleophilic substitution reaction between 3,5-bis-(trifluoromethyl)benzyl chloride, 4, and sodium azide. Hydrazoic acid (HN3), a toxic volatile compound with explosive properties, can be formed in the reactor headspace during conventional batch processing that requires significant engineering controls. In order to improve the overall safety profile, the process to produce azide 1 was optimized for operation in a microcapillary tube reactor. In addition, azide 1 was prepared in a simple biphasic solvent system using phase-transfer catalysis which results in an overall low e-factor. The product was purified via wiped film evaporation (WFE) technology.
Development of a
small volume continuous process that used a combination
of batch and flow unit operations to manufacture the small molecule
oncolytic candidate merestinib is described. Continuous processing
was enabled following the identification and development of suitable
chemical transformations and unit operations. Aspects of the nascent
process control strategy were evaluated in the context of a 20 kg
laboratory demonstration campaign, executed in walk-in fume hoods
at a throughput of 5–10 kg of active pharmaceutical ingredient
per day. The process comprised an automated Suzuki–Miyaura
cross-coupling reaction, a nitro-group hydrogenolysis, a continuous
amide bond formation, and a continuous deprotection. Three of the
four steps were purified using mixed-suspension, mixed-product removal
crystallizations. Process analytical technology enabled real-time
or nearly real-time process diagnostics. Findings from the demonstration
campaign informed a second process development cycle as well as decision
making for what steps to implement using continuous processing in
a proximate manufacturing campaign, which will be described in part
2 of this series.
A flow Barbier process
was developed to produce a key intermediate
in the edivoxetine·HCl registered sequence. The control strategy
was developed based on a critical understanding of integrated parameters
and design space requirements for a continuous stirred tank reactor
(CSTR) process. In this flow Barbier process, the Grignard reagent
formation and reaction occurs in a single CSTR, with quenching of
the resulting tetrahedral intermediate in a second CSTR. Real time
Process Analytical Technology (PAT) monitoring was used to assist
process development and understanding. The postquench liquid–liquid
separation was continuous, and the quenched intermediate flowed directly
into a neutralization CSTR to minimize the epimerization potential
of the quenched intermediate. The optimized process was run for 80
consecutive hours in 2 L CSTRs where magnesium was recharged every
4 h for the first half of the continuous campaign and every 8 h for
the second half with no quantifiable differences in performance. The
Barbier process delivered in situ >99% ee which
is
sufficient for telescoping into the next step. The process development
is intended to support a Quality by Design (Qbd) regulatory submission.
Efficient continuous
Grignard and lithiation processes were developed
to produce one of the key regulatory starting materials for the production
of edivoxetine hydrochoride. For the Grignard process, organometallic
reagent formation, Bouveault formylation, reduction, and workup steps
were run in continuous stirred tank reactors (CSTRs). The lithiation
utilized a hybrid approach where plug flow reactors (PFRs) were used
for the metal halogen exchange and Bouveault formylation steps, while
the reduction and workup steps were performed in CSTRs. Relative to
traditional batch processing, both approaches offer significant advantages.
Both processes were high-yielding and produced the product in high
purity. The two main processes were directly compared from a number
of perspectives including reagent and operational safety, fouling
potential, process footprint, need for manual operation, and product
yield and purity.
The large-scale manufacture of complex
synthetic peptides is challenging
due to many factors such as manufacturing risk (including failed product
specifications) as well as processes that are often low in both yield
and overall purity. To overcome these liabilities, a hybrid solid-phase
peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach
was developed for the synthesis of tirzepatide. Continuous manufacturing
and real-time analytical monitoring ensured the production of high-quality
material, while nanofiltration provided intermediate purification
without difficult precipitations. Implementation of the strategy worked
very well, resulting in a robust process with high yields and purity.
Technology transfer
of a small volume continuous (SVC) process
and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib
are described. A hybrid batch-SVC campaign was completed at a contract
manufacturing organization under cGMP. The decision process by which
unit operations were selected for implementation in flow for the cGMP
campaign is discussed. The hybrid process comprised a Suzuki–Miyaura
cross-coupling reaction, a nitro-group hydrogenolysis, a continuous
amide bond formation, and a continuous deprotection. A continuous
crystallization using two mixed suspension, mixed product removal
(MSMPR) crystallizers and a filtration with in situ dissolution were employed for purification between the two SVC steps.
Impurity levels were monitored using both online process analytical
technology (PAT) and offline measurements. The continuous processing
steps operated uninterrupted for 18 days to yield the drug substance
in solution at a throughput of 12.5 kg/day. Crystallization in batch
mode afforded 183 kg of the drug substance in specification. Success
of the campaign was attributed to robustness of the control strategy
and to the multiyear partnership in continuous manufacturing between
the development organization and the contract manufacturer. Key learnings
are offered from the perspectives of both the development organization
and the contract manufacturer.
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