Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing

CH09CH12_Burcham ARI 13 May 2018 8:21
Annual Review of Chemical and Biomolecular

Engineering
Continuous Manufacturing
in Pharmaceutical Process
Development and
Annu. Rev. Chem. Biomol. Eng. 2018.9:253-281. Downloaded from www.annualreviews.org
Access provided by University of Newcastle upon Tyne on 06/12/18. For personal use only.
Manufacturing
Christopher L. Burcham,1 Alastair J. Florence,2
and Martin D. Johnson1
1
Small Molecule Design and Development, Eli Lilly and Company, Lilly Research Laboratory,
Indianapolis, Indiana 48525, USA; email: cburcham@lilly.com, johnson_martin_d@lilly.com
2
EPSRC Future CMAC Hub, Strathclyde Institute of Pharmacy and Biomedical Sciences,
University of Strathclyde, Glasgow, G11XQ United Kingdom;
email: alastair.florence@strath.ac.uk
Annu. Rev. Chem. Biomol. Eng. 2018. 9:253–81 Keywords

The Annual Review of Chemical and Biomolecular continuous manufacture, pharmaceuticals, drug substance, drug product
Engineering is online at chembioeng.annualreviews.org
https://doi.org/10.1146/annurev-chembioeng- Abstract
060817-084355
The pharmaceutical industry has found new applications for the use of con-
Copyright c 2018 by Annual Reviews. tinuous processing for the manufacture of new therapies currently in de-
All rights reserved
velopment. The transformation has been encouraged by regulatory bodies
as well as driven by cost reduction, decreased development cycles, access
to new chemistries not practical in batch, improved safety, flexible manu-
facturing platforms, and improved product quality assurance. The transfor-
mation from batch to continuous manufacturing processing is the focus of
this review. The review is limited to small, chemically synthesized organic
molecules and encompasses the manufacture of both active pharmaceutical
ingredients (APIs) and the subsequent drug product. Continuous drug prod-
uct is currently used in approved processes. A few examples of production of
APIs under current good manufacturing practice conditions using continu-
ous processing steps have been published in the past five years, but they are
lagging behind continuous drug product with respect to regulatory filings.
253
INTRODUCTION
The pharmaceutical industry has undergone an enormous degree of transformation in the past
decade, brought on by several disparate factors and ever-increasing challenges. One of these trans-
formations is the use of continuous processing for the manufacture of new therapies currently in
development. Continuous manufacturing is not new to the pharmaceutical sector; however, the
manner in which it is being applied is quite different from how it has been used in the past. Pre-
vious use of continuous processing was driven largely by high-volume products, similar to the
motivating factor for use of continuous processes in the commodity chemicals sector. Although
high volume might still be a driver toward continuous manufacturing, it is no longer the only
factor. Other drivers for the transformation from batch to continuous include reducing develop-
ment costs for new medicines (1–3) and increasing flexibility to produce smaller annual volumes
of targeted therapies for smaller patient populations (4). Regulatory agencies are also pushing
for the modernization of pharmaceutical manufacturing (5, 6) and use of continuous manufactur-
ing to transform the pharmaceutical industry (7). Certainly, encouragement from the regulatory
agencies has facilitated the transformation from batch processing to continuous manufacturing in
the pharmaceutical sector. Other factors responsible for the shift include increased worker health
and safety (8, 9), decreased environmental impact (10), decreased cycle time (11, 12), improved
product quality (13–15), and decreased cost of manufacture (16–18). The benefits of continuous
processing for drug substances are not the same as those realized for drug products.
It is difficult to identify one event or even a sequence of events that have catalyzed the con-
version from batch to continuous processing in the pharmaceutical industry. Regardless of the
catalyst, the change has occurred: Lilly (19, 20), Pharmatech, Vertex (15), Pfizer (21), Novartis
(22), Johnson & Johnson (23, 24), Amgen (25), and GSK (26) have all made significant investments
in continuous processing. The increased interest over the past decade in the continuous manu-
facture of pharmaceuticals has spawned a large body of academic research in the area, as well as
topic-specific conferences (27). One such conference held in 2014 resulted in a large volume of po-
sition papers (28–36), the body of which provides an in-depth industrial and academic perspective
on opportunities and challenges in the area, including highlighting the importance of sharing case
studies. Several industry–academia consortia have also formed. Examples of these consortia in-
clude the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS,
United States) (http://erc-assoc.org/content/erc-structured-organic-particulate-systems),
the Synthesis and Solid State Pharmaceutical Centre (SSPC, Ireland) (http://www.sspc.ie/),
the Continuous Manufacturing and Advanced Crystallization Hub (CMAC, UK) (https://www.
cmac.ac.uk/), the Research Center for Pharmaceutical Engineering (RCPE, Austria) (http://
www.rcpe.at/en/about-us/), the Enabling Technology Consortium (members from the United
States, European Union, and Asia) (37), and many others. The theme of each of these centers is
the modernization of pharmaceutical manufacturing, with a common focus on continuous man-
ufacture.
The manufacturing transformation from batch processing to continuous processing is the
focus of this review. The review is limited to small, chemically synthesized organic molecules and
encompasses the manufacture of both active pharmaceutical ingredients (APIs) and the subsequent
drug product. Medicines are delivered to a patient in many forms, e.g., sterile injections, oral
dosage forms (both solid and liquid), transdermal patches or creams, inhalers, ophthalmic drops,
and implants. This review concentrates on solid oral dosage forms, with some reference to sterile
injectable products, as solid oral dosages make up the majority of the market (by volume) for
innovative medicines. Continuous manufacturing by its nature implies an integrated system of
unit operations, with constant flow (steady or periodic) and use of model-based control. Although
a few of the case studies presented in this review have some focus on the elements of systems
254 Burcham · Florence · Johnson

integration and control, there are multiple recent reviews (33) and case studies (38, 39) on systems
integration and process control in the literature. The review that follows begins with examples
of continuous manufacturing specific to drug substance and then enabling technologies for drug
substance continuous processes. Next, examples highlighting continuous manufacturing of drug
product are presented, followed by examples of enabling technologies for drug product continuous
manufacture. The review concludes with comparisons of the two areas as well as comments on
the potential for further integration.
CONTINUOUS MANUFACTURING APPLIED TO DRUG SUBSTANCE

Continuous flow chemistry has been demonstrated in the production of gram to metric ton quanti-
ties of pharmaceutical APIs in many academic and industrial labs and manufacturing plants. Recent
reviews of flow chemistry (40, 41) provide many excellent examples. Continuous crystallization
is often used in conjunction with flow chemistry; two recent review articles provide a current
synopsis of the field (42, 43). The examples of application of flow chemistry that follow have
been selected to illustrate the benefits of continuous processing when applied to pharmaceutical
intermediates and final drug substance.
Drivers for Implementation to Drug Substance Manufacture

In the case of production of drug substances, many of the motivators for a continuous versus a batch
process are the same as for the commodity chemical sector, but without the added criterion that the
product is of high volume. The pharmaceutical industry has historically been a promoter of green
process chemistry. Lessening of the environmental impact of a process through the reduction
of waste; increased yields; energy conservation; and the minimized usage of environmentally
hazardous solvents, replacing them with safer alternatives (44), are all benefits of continuous
processing (10). Other advantages for the use of continuous versus batch processing include (4)
1. Increased safety by minimizing reaction volumes and maximizing heat-transfer rates for
reactions with hazardous reagents, potential for thermal runaway, or large exotherms.
2. Higher pressure capabilities for reactions with hazardous and reactive gases, such as hydro-
gen, carbon monoxide, carbon dioxide, syn-gas (mixture of CO and H2 ), and ammonia, and
for superheated reactions.
3. A wider temperature operating window, for example, −80◦ C to 300◦ C with continuous
reactors versus −20◦ C to 120◦ C for standard batch reactors.
4. Improved product quality assurance due to steady state operation, feedback control, and
real-time product quality information by online process analytical technologies (PAT).
5. Yield and selectivity with opportunity for improved quality control for fast reactions in series
with unstable intermediates.
6. All-at-once addition, coaddition, fast heat-up, and/or fast cool-down, which can increase
yield and decrease impurities for some reactions.
7. Cost benefits in terms of reduced development costs, lower equipment costs due to smaller
equipment sizes and smaller recurring costs once implemented.
8. Use of disposable or dedicated equipment to reduce the risk of cross-contamination, e.g.,
for cytotoxic API production in inexpensive, dedicated, or disposable equipment sets.
9. Shorter, more agile supply chains (45–47). Pharmaceutical production often requires ship-
ping of API to a different site for final drug product formulation. This can lead to longer
cycle times from the production of API to final drug product availability, making it difficult
to respond to short-term changes in demand (36).
www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 255

H2
HO OH HO O
Ethanol, water
Figure 1
Partial hydrogenation of a biphenol performed in a packed bed reactor (49).
Process Chemistry at the Research Scale

Plug flow reactors (PFRs) and packed bed reactors (PBRs), ubiquitous in the chemical process in-
dustry, are equally as versatile for the synthesis of pharmaceuticals at both research and production
scales. At research scale, solids formation in a PFR or PBR can present challenges due to the small
scale of the equipment. As a consequence, only homogeneous conditions are typically used in the
PFRs. The literature is rich with examples of application of PFRs or PBRs; the examples that
follow are highlighted as they illustrate applications to pharmaceutically relevant reaction types.
There are many challenges associated with PBRs due to the nonsteady-state operation and
complex mixing dynamics. However, they do provide utilization of a solid catalyst in a continuous
process. An example of the use of a PBR at research scale is that for the research-scale production
of (R)- and (S)-rolipram (48). Multiple continuous reactions were conducted over a series of packed
catalyst beds with telescoped consecutive reactions without the isolation of intermediates. Chirality
was installed on the advanced intermediates by using fixed chiral heterogeneous catalysts. A new
polysilane-supported palladium/carbon catalyst was developed to enable a nitro group reduction
in a continuous hydrogenation reactor. These APIs were produced only at gram scale under
non-GMP conditions. The sequential pack bed PFRs used in many flow efforts at research scale
are difficult to scale up to manufacturing because of heat and mass transfer challenges, packing
consistency, and consistency of catalyst performance. In contrast to homogeneous catalysis, there
are little or no published cGMP production examples using them.
Ley and coworkers (49) demonstrated the use of a PFR in an integrated continuous and batch
process to make research-scale quantities of an antimalarial drug candidate. A continuous selective
partial hydrogenation of a biphenol (see Figure 1) was done in a packed catalyst bed reactor.
Continuous acetylation of a phenol group was accomplished in a simple 10-mL fluoropolymer
(perfluoroalkoxy alkane, PFA) coil (PFR) at room temperature, combining a phenol and acetic
anhydride with 5 mol % dimethylaminopyridine (DMAP) and 4.5 equivalents of triethylamine
in a simple tee mixer. A continuous Griesbaum oxidation reaction accomplished co-ozonolysis
with an oxime and a ketone. One of the advantages of the flow chemistry–enabled route is that it
avoided the use of a genotoxic 4-(2-chloroethyl)morpholine.
Researchers at Cambridge, in conjunction with Pfizer, describe the integration of three contin-
uous chemistry steps and three continuous workup steps for the synthesis of 2-aminoadamantane-
2-carboxylic acid in a research laboratory (50). The goal was an intelligent self-controlling platform
for a system of reactions and separations with process control and sufficient autonomy to reduce
the number of required operators. A three-layered approach was applied to the process control,
which consisted of the chemistry, in-line separations, and information layers. The flow train had a
Grignard reaction, aqueous quench, adsorption on a charcoal bed, liquid–liquid phase separation
with computer-controlled interface height, solvent exchange distillation, Ritter reaction, a high-
pressure cyclization reaction, ozonolysis, and hydrolysis (Figure 2). Surge vessels between steps
were used to keep them decoupled, allowing one part of the flow train to be stopped temporarily
for troubleshooting without the need to shut down the adjacent continuous steps. Only 0.005 mol
of product was made in a 150-min telescoped continuous process, but this was an important proof
of concept. The main benefit of continuous over batch was to prevent the accumulation or
isolation of an explosive intermediate, highlighting the increase in production safety for a
high-energy material.
O3, acetone, water O O

+
N O then MnO2 N O HN OH
O
Figure 2
Continuous ozonolysis performed in a plug flow reactor (50).
O O O
+ Ph3P Dimethylformamide
Aryl Aryl
Figure 3
Continuous Wittig reaction of an aldehyde (51).
Continuous processing has been demonstrated to offer an increased yield compared to batch
microwave reactions. Nabumetone is used to treat pain, inflammation, and other symptoms of
osteoarthritis and rheumatoid arthritis. Multiple strategies were used to produce this API and
related compounds at research scale (51). A Wittig reaction (Figure 3) at 210◦ C was performed
continuously using a Uniqsis FlowSyn reactor system subject to a 10-min residence time in a 10-
mL stainless steel tube. This is above the thermal decomposition temperature of the solvent and
therefore may not be recommended in flow or batch, but it would be a higher risk in batch because
of lower heat transfer area per unit volume and the larger reactor size. A continuous aldol reaction
at 70◦ C was done in the FlowSyn reactor 10-mL stainless steel reaction coil with 7.5-min residence
time. These reactions were followed by selective hydrogenation to the desired 4-aryl-2-butanones.
Rolipram, pregabalin, phenibut, baclofen, and gabapentin were synthesized in the lab at re-
search scale using an interchangeable chemical assembly system (52). Five individual continuous
reaction modules were linked together in different arrangements to enable the production of a va-
riety of APIs, avoiding purification of intermediates. β-Amino acids, γ-amino acids, and γ-lactams
were three different classes of molecules that were produced using the interchangeable continuous
modules (Figure 4). Each module was constructed from small-scale pumps, feed solution bottles,
mixing tees and micromixers, PFRs with back pressure regulators, an H-cube reactor, and liquid–
liquid separators. These modules were developed for oxidation, olefination, Michael addition,
hydrogenation, and saponification reactions. Safety hazards of nitromethane are reduced when
running the Michael addition continuous versus batch because of the smaller reactor volume, but
the hazards of handling nitromethane are still high. It is unlikely that a nitromethane reaction
would be run in a pharmaceutical manufacturing facility because of its potential to detonate if
heated or shocked, but if it ever were used it would be a flow-enabled route. It may be possible
to generate explosive chemicals like nitroalkanes and immediately consume them in small flow
reactors in series, so that the amount present at any time is small and the explosive chemical is not
handled or accumulated.
Table 1 provides a summary of other applications of PFRs and PBRs in the synthesis of APIs and
intermediates as demonstrated at research scale. While the PBR and photochemistry examples in
O2N
O O
Nitromethane
O O
Figure 4
Michael addition of nitromethane to unsaturated esters to yield nitro esters (52).

Table 1 Examples of packed bed reactors (PBRs) and plug flow reactors (PFRs) used at research scale for the synthesis of
pharmaceutical compounds or intermediates
Compound Reactor, size, and type Challenges Advantages
Imatinib mesylate (53, 54) Vapourtec R2+, 2–10-mL Poor solubility of nitro- and No manual handling of
PFR, multiple PBRs guanidine-substituted intermediates
intermediates
Efavirenz (55) 2-mL PBR Copper-catalyzed formation of Multiple reactions in one
an aryl isocyanate operation
1-mL and 5-mL PFRs in series nBuLi lithiation and coupling Multiple reactions in one
operation
(E/Z)-tamoxifen (56) Vapourtec flow platforms, with Heat and mass transfer Pure (E/Z)-tamoxifen with an
PFA precooling loops and challenges for fast (E/Z)-ratio of 25:75
small PFA coiled tube reactors organometallic reactions with

n-butyllithium,
phenylmagnesium bromide,
and DIBAL-H
Triaminophloroglucinol Fixed PtO2 catalyst PBR Exothermic continuous Avoided isolation of an
(57) ammonium nitrate/sulfuric explosive intermediate
acid nitration
Cookson’s dione, a bridged Quartz reactor, positioned Absorption of UV in batch Better transparency for UV
pyrrolidine, and a around a 5-kW Hg lamp UV reactor light than the typical FEP
hydroxyl lactam (58) light source (fluorinated ethylene
propylene) tubing
Artemisinin (59) FEP photoreactor with a Absorption of UV in batch Photochemistry for
medium-pressure Hg lamp reactor singlet-oxygen generation
PTFE Fully continuous synthesis Integrated process
(polytetrafluoroethylene)
26-mL PFR
the table present attractive opportunities, these have significant challenges for scale-up to cGMP
manufacturing, such as heat and mass transfer and inconsistent activity over time. Continuous
processing for the production of imatinib (53, 54) provided an advantage by eliminating the
manual handling of intermediates. A key transformation of the synthesis of efavirenz (55) used
flow chemistry in a PBR to telescope in that same step with a cyclization reaction to install a
carbamate core and a series of PFRs to synthesize a trifluoromethyl ketone. The production of
(E/Z)-tamoxifen (56) demonstrated that flow chemistry is effective for organometallic reactions,
and for telescoping of the anionic reaction products. Handling of explosive intermediates was
avoided using flow for the production of triaminophloroglucinol (57).
Photochemical reactions have also been demonstrated in flow and shown to be beneficial to
batch processes as scale is increased. In one example, kilogram-per-day quantities of advanced
pharmaceutical intermediates were produced by a continuous photochemical reaction (58). In an-
other example, dihydroartemisinic acid was converted to artemisinin in continuous flow without
isolation or purification of intermediates (59). Small-diameter tubing was coiled around the light
source, allowing all of the solution to have high light exposure. Dichloromethane, an undesirable
solvent for toxicity reasons, was used as the nonflammable solvent as oxygen gas was fed to the
continuous reactor. The laboratory continuous reactor system was capable of 200 g of artemisinin
per day. The residence time in the photoreactor was approximately 2 min. Hock cleavage, oxida-
tion, and condensations were conducted in a PFR with a residence time of approximately 2.5 min.

For both of these examples, the photoreactions were not scalable in batch due to the short distance
light passes through the solution before it is absorbed. However, scalability of these reactions in
flow still presents many engineering challenges with penetration distances, heat generation and
removal, and material of construction.
The examples provided in this section demonstrate the advantages of continuous processing for
the production of pharmaceuticals and pharmaceutical intermediates. However, these were only
demonstrated at research scale (1 g/day to 1 kg/day production rates); therefore, the examples
do not represent scale-up challenges, for example, heat and mass transfer. Using PFRs and PBRs
typically requires homogeneous solutions at all scales, since clogging and fouling can be more
problematic at research scale because of the small diameters. However, this limitation is eclipsed
by the many safety and quality benefits the technology provides.
Continuous Drug Substance Processes in Current Good Manufacturing

Practices Production
Continuous processing has been used in the manufacturing of small-molecule drug substance to
achieve benefits of higher yield, safety, quality, new chemistries not feasible in batch equipment,
reduced production costs, smaller reactor volumes, reduced cross-contamination potential, quality
assurance of online high-performance liquid chromatography (HPLC), yield and purity advan-
tages of multi-stage countercurrent separations, elimination of isolations, extreme temperatures,
and high-pressure hydrogenations. Examples of each of these benefits are given in the following
paragraphs for processes operated under cGMP conditions.
A significant milestone in the adoption of a new technology for the manufacture of a pharma-
ceutical product is the use of the technology in a cGMP process. In the past decade, perhaps the
first large investment in this utilization of continuous processing in synthesis of drug substances
was the commitment to the technology made by Novartis.
In 2007, Novartis began investing heavily in the design and development of continuous process
and equipment, both internally and externally (60). Since then, they have created a multipurpose
continuous pilot and production plant, capable of cGMP manufacturing up to 15 tons per year
of API. Their drivers for implementing continuous manufacturing were yield, safety, quality, and
new chemistries not feasible in batch equipment. Novartis currently estimates that half of the re-
actions in their portfolio are feasible for continuous manufacturing, of which approximately 10%
show benefits compared with batch; however, this excludes processes with solids, until technolo-
gies are created for solids in flow. They also avoid or minimize the number of crystallization steps
in continuous manufacturing by telescoping synthetic steps. They achieved continuous manufac-
turing of an API with continuous countercurrent extraction and recycle of one of the reagents,
which reduced production costs and led to the investment in the new continuous manufacturing
plant. Novartis has used continuous reactors and separation steps in series for a metalation reac-
tion, electrophilic addition and oxidation, which improved the yield by 50% compared with batch.
They converted a reaction of an arylmagnesiate and a lactam to continuous to reduce by-products
and replaced two 10,000-L batch reactors with a 16-L PFR.
Continuous processing has also demonstrated benefits when used for the manufacture of
oncolytic drugs or for other scenarios in which cross-contamination is a serious risk. Oncolytic1
drugs and highly potent compounds require increased containment control to ensure the health
and safety of the workers manufacturing the product. Many engineering controls (e.g., isolators)
1
Oncolytic compounds are designed to destroy cells, typically cancerous cells; however, they can be nonspecific, causing death
to healthy cells as well.

Carbonate
Toluene Water
Reagent 1 Reagent
Reagent 2
RI HPLC
Solvent exchange HPLC
distillation
τ=2h Static
Counterflow Oven Coiled
heat exchanger Surge mixer
coiled SS PFA
reactor tank reactor
20 bar 3 mixer-settler τ=4h 80°C
130°C τ=2h τ=3h
τ = 1.2 h
Methanol, MTBE, formic acid

Methanol
RI HPLC
To next step
Coiled
MSMPR 1 MSMPR 2 Stirred tank PFA
20°C 20°C 0°C reactor
τ=1h τ=1h Dual filter τ=1h 25°C
and dissolve-off τ=4h
τ=1h
Figure 5
Continuous flow scheme for the production of prexasertib monolactate monohydrate (61). Abbreviations: HPLC, high-performance
liquid chromatography; MSMPR, mixed suspension, mixed product removal; MTBE, methyl tert-butylether; PFA, perfluoroalkoxy
alkane; RI, refractive index; SS, stainless steel.
are available to afford worker safety while handling these classes of compounds. The best method
of prevention is to avoid handling the material completely or, if that is not possible, to minimize
handling to decrease the opportunity for worker exposure. An example of this was the manufacture
of a pharmaceutical intermediate under cGMP for prexasertib monolactate monohydrate, an on-
colytic and highly potent API. The intermediate was manufactured in a Lilly manufacturing plant
to produce 24 kg of API (61) at 3 kg/day throughput. The API has a relatively low projected annual
material demand because of its high potency. The continuous process train consisted of eight unit
operations in series (Figure 5), spanning four synthetic route steps (Figure 6). The continuous
processing train was run in three separate sections due to an inadequate number of fume hoods.
The final crystallization, filtration, and drying were conducted in batch. Online high-performance
liquid chromatography (HPLC) was used at the outlet of each continuous reactor to quantify
reaction conversion and concentrations of key impurities. Online refractive index was used after
two of the continuous reactors to monitor changes in product concentration and characterize
residence time distributions (RTDs). The first continuous reaction in series, a reaction with
hydrazine to form a pyrazole, had significant safety advantages compared with the batch because
it used less excess hydrazine overall and orders of magnitude less hydrazine was present in the
1.4 L PFR. Continuous crystallization and semi-continuous filtration and dissolution eliminated
manual handling of the toxic intermediate. Removal of formic acid by solvent exchange distillation
also eliminated an isolation step. The three–coiled tube reactors made from PFA or stainless
steel were inexpensive to create, allowing for disposal and therefore avoiding the possibility of
cross-contamination with other APIs. The successful proof of concept prompted the decision

OMe O O
O O O O Br NHBoc
MeO NMe2 4 NMe2
NMe2 K2CO3, DMF NH2OH*HCl
O
OH OH
77% yield
2 3 5 NHBoc
2 steps
Step 2
NH2
O O Step 1 N CN
O O N NaOH
CN O
EtOH NH2NH2, AcOH N
MeOH/THF, 130 °C N Cl
85% yield O H 9
O 2 steps 91–98% yield O N-ethylmorpholine
6 NHBoc DMSO, 85 °C
NHBoc 7 NHBoc
8
N Step 3 N N
HN CN Step 4
HN CN HN CN
N O N Lactic acid O N
O
N Formic acid N distillation N
N 25°C N THF/water N
H H H
O 88% yield O 78–86% yield O H2O
2 steps
NHBoc NH2 NH3X
10
Solution in formic acid 12: X = L-lactate
11: X = Mesylate
MeSO3H, EtOAc
Figure 6
Synthetic route for the continuous production of prexasertib monolactate monohydrate (61).
for Lilly to invest in a small-volume continuous manufacturing plant in Ireland that has 11 fume
hoods, so that this entire continuous process and others like it can run simultaneously (47).
The facility is designed for 10 kg per day of final isolated API produced by three- to four-step
synthetic routes all running simultaneously. The facility is not designed to make drug product.
Drug product manufacturing facilities in different locations are established for continuous drug
product. Linking them end-to-end at one facility would have serious practical issues today and is
not necessary to realize some of the benefits of continuous manufacturing.
Additional examples of cGMP production of APIs or pharmaceutical intermediates are listed in
Table 2. In the first example, a high-pressure thermal tube reactor was used for a thermal cycliza-
tion for cGMP production of an advanced intermediate (62). In the second example, a thermal
deprotection reaction was run in a Hastelloy R
coiled tube reactor because of the high temperature
and pressure requirements (63). The throughput in the continuous reactor was 36 kg/day. In the
third example of cGMP production, a reductive amination was conducted in a pipes-in-series bub-
ble flow reactor at a rate of 100 kg/day (64). The reaction was performed with dissolved catalyst, at
20◦ C and 50 bar of hydrogen pressure with a 12-h mean residence time. Reagent gas and reagent
solutions flowed co-currently through the reactor in the upward direction through large-diameter
pipes and down through small-diameter tubing. The pipes were connected in series rather than in
parallel to increase the gas/liquid mass transfer rates throughout and to decrease the overall axial
dispersion number.
The examples provided in this section demonstrate that the advantages of continuous process-
ing demonstrated at research scale are transferable to the operations under cGMP conditions.

Table 2 Examples of continuous processes in the synthesis of pharmaceutical compounds or intermediates under current
good manufacturing practice conditions
Compound Reactor, size, and type Challenge Advantage
29 kg of an advanced 7.1-L, high-pressure, Batch scale-up due to the Scaled up with unchanged yield
intermediate (62) high-temperature PFR impurity formation during the and selectivity because of the
slow heat-up consistently fast heat-up time at
all scales
150 kg of API (63) 12-L reactor inside a steam High temperature and pressure Small reactor size did not have a
shell at 150◦ C, 250 psig, and requirements batch reactor capable of this
100-min mean residence time pressure and temperature, fast
heat-up and cooldown
2,000 kg of 360-L vertical pipes-in-series Capital investment for a Capital investment about 10×
intermediate (64) bubble flow reactor high-pressure batch autoclave lower flow versus batch
Abbreviations: API, active pharmaceutical ingredient; PFR, plug flow reactor.
The examples span production rates from 3 kg/d to 100 kg/d with application for fully integrated
multi-step processes, or single step reactions between batch processes.
Emerging Technologies for Drug Substance Manufacture

One benefit of continuous manufacturing is the ability to intensify a process. This is especially
true for production of APIs and pharmaceutical intermediates. Although not common, the use
of two technologies, membrane separations and intermittent flow reactors, is emerging, both of
which provide further process intensification and process miniaturization. Mobile on-demand
continuous plants perhaps are the amalgam of all of these technologies, offering the promise of
multi-step chemical processing in the space of a refrigerator, allowing for production of materials
in remote locations.
Membrane separations. Membrane separations offer an alternative to the use of crystallizations

or distillations to remove unwanted compounds from a process stream. These compounds might
be impurities or by-products from a chemical reaction. They might also be the replacement of one
process solvent for another to enable a subsequent step in the chemical process. One implementa-
tion of membrane separations is illustrated in a continuous alcohol oxidation. The oxidation was
performed with hydrogen peroxide, a cost-effective and green alternative to the typical heavy met-
als or organic stoichiometric oxidants (65). Hydrogen peroxide oxidation is generally too much
of a safety risk in batch, but it was enabled safely by continuous reaction in a laboratory in a
Corning advanced flow reactor. The biphasic liquid–liquid reaction used a phase transfer catalyst,
tributylammonium hydrogen sulfate, and a zinc-substituted polyoxotungstate catalyst. The phase
transfer catalyst was mostly removed in a continuous three-stage countercurrent extraction train
using membrane separators.
Asymmetric hydrogenation of ketones is an important transformation in pharmaceutical syn-
thesis for installing chiral centers in advanced intermediates. However, the homogeneous catalysts
and ligands are expensive, and removal of the heavy metals from the product is required to achieve
stringent low concentrations in the final product. Use of a membrane to filter out, recycle, and
reuse the catalyst–ligand complex has the potential to reduce the required loadings by more than an
order of magnitude, and it separates the metals from the product immediately after the reaction is

complete. A Noyori asymmetric hydrogenation catalyst, ruthenium diphosphine/diamine, used in

hydrogenation of α-tetralone, was separated from the reaction product by continuous nanofiltra-
tion and recycled (66). The 50-mL research-scale test system used organic solvent nanofiltration,
which is also called solvent-resistant nanofiltration, which can be used with nonpolar, polar protic,
and polar aprotic solvents. The substrate-to-catalyst ratio was approximately 250 in the reactor, but
the overall effective substrate-to-catalyst ratio was approximately 5,000 because the catalyst was
continuously recycled back to the reactor in a 24-h experiment. Some ruthenium was not recycled,
such that product had a ruthenium concentration of approximately 200 ppb, and the enantiomeric
selectivity gradually declined from 96% to 93%, but this proof-of-concept system with continuous
solvent-resistant nanofiltration has potential to improve asymmetric hydrogenation processes.
The liquid-phase homogeneous catalytic N-oxidation of alkylpyridines using hydrogen per-
oxide as the oxidant has several significant hazards in batch reactors. This type of reaction has
potential for thermal runaway because the heat release can trigger product decomposition, and
decomposition of hydrogen peroxide in stoichiometric excess can result in flammability issues with
alkylpyridines. A tube-in-tube continuous membrane reactor was designed to overcome the safety
hazard. The concept is to dose hydrogen peroxide in a controlled fashion to the alkylpyridine by
the trans-membrane pressure difference across the inner porous ceramic tube (67). The idea is
that two immiscible liquid phases could be separated by the ceramic membrane, and the positive
pressure would result in the transport of the oxidizing agent from the peroxide to the pyridine
side. Porous ceramic membranes with aluminum, silicon, and titanium oxides have been used for
catalyzed reactions in other industries, but this would be an application unique to pharmaceuticals.
Advances in more chemical-resistant membranes should increase the utilization of membranes
for continuous processes. Likewise, more selective membranes will also drive utilization of this
technology, perhaps eliminating distillations and all but the final crystallization in future contin-
uous processes.
Intermittent flow stirred tank reactors. Intermittent flow is a practical alternative to continu-
ous stirred tank reactors (CSTRs) or PFRs for heterogeneous reactions with slow, positive order
reaction kinetics. If the reaction is a homogeneous liquid, or liquid and gas, then continuous PFRs
are usually the best choice to achieve full conversion of reagents in the minimum reaction time.
However, PFRs may become blocked for reactions in which solids form. It may also be difficult
to keep solids and liquids sufficiently mixed throughout the length of a PFR if the required re-
action time is long. CSTRs are able to handle the heterogeneous mixtures, but they suffer from
lower conversion of reagents for the same reactor mean residence time compared with PFRs if
the reaction rate is positive order (68). An effective solution to this problem is an intermittent
flow stirred tank reactor. The reactor fills, holds processing material for a specific amount of time
to complete the reaction following batch kinetics, and then either partly or completely empties.
The fully automated cycle repeats continually. Intermittent flow stirred tank reactors (IFSTRs)
have many of the same characteristics as truly continuous reactors. The reactor stays at a con-
stant temperature at all times; material flows in and out, providing for a large number of volume
turnovers per day; and the reactor is much smaller than a batch reactor. The reason the inter-
mittent flow reactor is smaller than batch is due to the relatively high number of turnovers. If
the reaction time is 30 min, then the intermittent flow reactor is approximately 100 times smaller
in reactor volume compared with batch, assuming a 48-h start-to-start cycle time for batch cam-
paigning. Processed materials are heated or cooled continuously on the way into the reactor
through heat exchangers and then cooled or heated continuously through heat exchangers on the
way out the reactor. Therefore, heat-up and cooldown are fast compared with traditional batch
reactions.

Table 3 Examples using intermittent flow stirred tank reactors (IFSTRs)

Tsukanov et al.
White et al. (69) (16) Kopach et al. (9) Cole et al. (70) Cole et al. (8)
Application Thermal Enantioselective Cryogenic Li, Nitro group Suzuki coupling
cyclization Aza-Henry coupling, quench reduction
Advantages of IFSTR Solids Solids Solids Safety with hydrogen Mixing sensitive
precipitation, precipitation, precipitation due to reactor size; liquid-liquid
extreme safety with nitro powdered catalyst reaction;
temperature and alkanes due to particles too small kinetics too slow
pressure reactor size for packed bed PFR for PFR with
static mixing
Time per reactor 8 40 5 17 23
turnover (min)
Recycle Yes: starting Yes: starting No No No
material material and
catalyst
Sequestered catalyst No No No Yes: 30–50 turnovers No
Temperature (◦ C) 265 −20 −78 60 60
Heat/cool time to 3 0 2.5 4 2.5
reaction temperature
(min)
Pressure (psig) 610 0 0 60 0
Reactor volume (mL) 25 250 250 1,000 250
Demonstrated number 700 16 - 107 109
of turnovers
Intermediate produced 300 25 - 1,900 1,000
(g)
Abbreviation: PFR, plug flow reactor.
Five examples of intermittent flow stirred tank reactors are summarized in Table 3. The table
explains the reason for this reactor choice; the productivity in terms of volume turnovers, time, and
amount of material produced; reaction conditions; and whether recycle or catalyst sequestering
was used.
Mobile on-demand continuous plants. The concept of mobile on-demand continuous plants
is to offer the ability to miniaturize API production to produce oral or topical liquid doses of
medicines from a continuous process. The Defense Advanced Research Project Agency (DARPA)
supported a reconfigurable, refrigerator-sized, continuous manufacturing platform in which APIs
could be made with end-to-end synthesis. Examples of drugs produced are diphenhydramine hy-
drochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride (71). PFA tube flow
reactors, back pressure regulators, membrane liquid–liquid separation units, buffer tanks, precip-
itation tanks, filters, semi-batch crystallizers, and formulation vessels all fit inside the portable
unit. The process was interrogated in a real-time process by inline Fourier-transform infrared
spectroscopy. Synthesis of fluoxetine required the most complex arrangement of continuous unit
operations: 4 reactors, 4 separators, and 11 pumps. The final drug product was not a typical
solid dosage but instead a concentrated aqueous or alcohol-based formulation with a short shelf
life.

Another DARPA-supported project using a similar mobile on-demand continuous plant pro-
duced ibuprofen at a rate of 8 g/h (72). Total mean residence time for the reactions and separations
in series was 3 min. The process included a solvent-free Friedel–Crafts acylation, an oxidation
using iodine monochloride, hydrolysis, continuous work-up, and one in-line liquid–liquid separa-
tion. One molar HCl was used for quenching the Friedel–Crafts acylation, and the resulting two
liquid phases were separated with a membrane, such that the solvent-free product was in one flow
stream and the by-products were in an aqueous waste stream. The exothermic quench and the
potential for HCl vapors were handled safely by use of continuous processing.
Opportunities. Significant advances in the development of continuous manufacturing platforms

for the production of drug substances have occurred. However, many unmet technology needs
still exist. Robust solutions are needed for handling slurries in flow to eliminate the potential for
line blockage or sedimentation. The accurate charging of solids into continuous reactors does not
exist at a scale of 10 kg/day or smaller. Charging solids is made more difficult in the case of reaction
systems, as the solids must be charged continuously, often into a hot solvent solution. Continuous
filtration and cake washing and drying, particularly at the scale of 10 kg/day or smaller, is equally
limited, with few commercial off-the-shelf systems available. End users, technology companies,
and academia must work together to accelerate innovation in the development of new, reliable
technical solutions (35).
CONTINUOUS MANUFACTURING APPLIED TO DRUG PRODUCT
Batch Processing
The manufacture of solid oral dosage forms begins by blending drug substance with solid excipients
and finishes with compressing the blend into a tablet or filling the blend into a capsule (73, 74).
Excipients are selected to provide the appropriate mechanical properties necessary to ensure that
a tablet can be formed under compression but also readily disintegrate when exposed to water in
an immediate-release product. Excipients may be used to slow disintegration or dissolution in a
modified-release product. Additional excipients may be used to increase the wettability of the drug
substance, to ensure uniform dispersion of the drug substance in water after table disintegration,
to increase the solubility of the drug substance, or to prevent spoilage or degradation. Regardless
of the role of the excipient, uniform blending of the excipient and drug substance is required to
ensure accurate and uniform dosing of a drug in the final dosage form administered to the patient.
Variants of typical batch drug product manufacturing processes are illustrated in Figure 7,
with the simplest being a direct compression process. In this case, a blend of an excipient and drug
substance is formed in a large batch blender and is then passed to a tablet press. Blend uniformity
can be increased through granulation of the powder blend immediately after blending to avoid
segregation. Granulation can also improve powder handling and powder flow, mitigating the effect
of low bulk densities or anisotropic crystal morphologies of the pure API. Wet granulation is a
mature process that has been widely used to form granules prior to final dosage-form formation
via tableting. In this case a binder, such as polyvinylpyrrolidone or hydroxypropyl methylcellulose
(HPMC), is dissolved in a binding fluid (often water) that is sprayed over a powder bed that is mixed
under high-shear conditions (high-shear wet granulation) such that the powder bed is uniformly
wet with the binder solution. The binder solution creates liquid bridges between the particles
within the blend to form wet granules. The wet granules then are dried, often in a fluidized bed
dryer, resulting in heterogeneous particles. The size of the granules might be milled to provide
a uniform granule size. Historically, a high-shear wet granulation process is a batch process,

a
Tablet press
Blender
b
Tablet press
Blender High-shear Blender

wet granulation Fluid bed
dryer
c
Tablet press
Blender Roller compaction Milling

Blender
Figure 7
Batch drug product manufacturing: (a) direct compression, (b) wet granulation, and (c) roller compaction. Arrows represent batch
transfers between unit operations.
followed by fluidized bed drying often also run as a batch process. Alternatively, wet granulation
can be performed in a fluidized bed granulator. The powder blend is fluidized as binder solution is
atomized to wet the powder. Fluidized bed granulation offers the advantage that both granulation
and drying occur within the same piece of equipment.
More recently, dry granulation processes have become common, providing equivalent
densification of material, improvement in powder flow, and avoidance of segregation as offered
by wet granulation, but without the need to dry the granule after addition of the binder solution.
Roller compaction is a continuous dry granulation process; a powder blend is fed via an auger to a
pair of counter-rotating disks or rollers. The powder is compressed between the rollers, forming
a solid ribbon that is subsequently milled, typically through a conical mill or a hammer mill, into
smaller granules.
Additional excipients may then be blended with the granules before the blend is formed into
the final dosage form. Vervaet & Remon (75) provide additional examples of various wet and dry
granulation technologies.
The final powder blend (granules, powder, or a mixture) is ultimately formed under compres-
sion in a tablet press into a tablet. In the case of a capsule, the blend is filled into a capsule with
minimal or no compression using a capsule filling machine. Both the capsule filling machine and
the tablet press operate continuously at very high speeds, producing up to 106 tablets (76) and
4 × 105 capsules per hour (77). Often a coating is applied to the tablets after compression in an-
other batch operation. Both tableting and encapsulation are inherently continuous operations, and
the tableting operation has historically been bracketed with batch operations: powder blending in
large batch blenders and coating in large batch coating systems.
Drivers for Implementation to Drug Product Manufacture

The downside of batch drug product processing is the fixed batch size of the operation, providing
very little flexibility in scale-up of the process without introduction of a larger batch blender. The

larger blender requires additional process validation and regulatory approval, as well as larger-scale
facilities. Scale-up to larger blenders may require more than 10 times the API quantity as the prior
scale. High-shear wet granulation and tablet coating are also scale dependent and would have the
same hurdles to overcome with an increase in scale. Use of continuous manufacturing for drug
products results in increased batch size flexibility, as the lot size can be established by a run time
and not by the volume of a batch blender or tablet coater size. This is attractive for low production
volumes and allows production to easily respond to changes in demand, for example, where new
indications are added. In addition to flexibility, continuous manufacture of drug product also
allows for a reduction in process steps, process intensification, increased productivity, higher level
of in-specification product, and reduced development time (31). Many of these benefits result in
cost savings (78).
Continuous Powder Blending

Fully continuous processes for the production of solid oral dosage forms require continuous blend-
ing of drug substance with excipients. However, continuous blending of powders is more complex
than it is for liquids, as it requires precise feed-rate control of dry materials. Tubular blenders are
most often used for powder blending. Both radial and axial blending must be active as the powder
traverses the length of the blender to ensure powder uniformity and avoid segregation or ag-
glomeration of components (31). Continuous blender performance is highly dependent upon the
capability of the feed system to minimize variability and ensure consistent and accurate dosing of
components into the blending process (79). Short-lived, small variations in feed composition can be
filtered by the blending process; however, approaches for dynamic control of feed rate are desirable
to manage fluctuations in powder flow through the feed mechanism. For example, loss-in-weight
feeders composed of a refill hopper, a feed hopper, weight sensors, and a feed screw can continu-
ously measure the weight of material being fed and vary the feed rate via the screw speed (Figure 8).
Wet Granulation
Wet granulation is widely used in the manufacture of dosage forms to improve the flow properties,
homogeneity, and compressibility of powder blends prior to tableting. Granulation involves bind-
ing primary powder particles together using a liquid binder to make larger agglomerates or granules
with improved properties and the required composition (80). The binder typically includes water
or a volatile solvent and polymer. A review comparing high-shear batch and continuous twin screw
wet granulation processes highlights that continuous operation requires reduced liquid addition
(81). The addition of liquid binder provides a reliable means of inter-particle bridge formation;
however, this may not be suited to all active ingredients. Theophylline, for example, has been
API Excipient 1 Excipient 2 Excipient 3 Excipient 4 IR
Tablet press
Blender
Figure 8
Direct compression continuous manufacturing train. Abbreviations: API, active pharmaceutical ingredient;
IR, infrared spectrometer.

shown by Raman and near-infrared (NIR) spectroscopy to undergo an undesirable transforma-

tion to theophylline monohydrate during wet granulation using aqueous binding solution (82).
Drying subsequently removes residual moisture from the granulated wet mass to achieve a dry
granule mass that can subsequently be screened to provide a more uniform size distribution for
input to tableting.
Recognizing the advantages offered by wet granulation combined with those of continuous
manufacture, Roche, the University of Basel, and Glatt Ltd. developed a quasi-continuous moist
agglomeration process (83, 84). The equipment consists of multiple agglomeration units (high-
shear wet granulator and sequential fluid bed dryers), all of the same size and easily numbered out
when product demands require high production, removing the concern of scale-up. Continuous
granulation can also be carried out using continuous spray or fluid bed agglomeration (85, 86) and
extrusion technologies (75).
Twin screw granulation in particular has gained prominence in recent years and has been re-
viewed extensively (87). This has been assisted in part by the availability of commercial continuous
platforms. For example, the ConsiGma-25TM continuous system integrates high-shear wet gran-
ulation in a twin screw granulation module with semi-continuous drying in a segmented dryer
and continuous tableting. This direct coupling of continuous unit operations in a single platform
allows for efficient approaches to process optimization at scale. The influence of process vari-
ables (throughput, screw speeds, screw configurations, temperature, and binder addition mode)
on granule and tablet attributes can be investigated in single experimental runs. By adjusting the
number of kneading elements, barrel temperature, and binder addition method during granulation
of theophylline for 125-mg tablets, the granule and tablet quality were optimized to achieve the
required compression and release performance (88). However, scale-up of continuous twin screw
granulation processes cannot be achieved by a linear increase in material throughput across dif-
ferent platforms (89). One practical approach to this exploits a quasi-continuous platform capable
of producing small- and large-scale batches from the same equipment (83). This has been shown
to deliver flexible supply coupled with a 200% increase in output from a 30-L semi-continuous
granulation process compared with a 900-L classical batch platform (84).
Considerable efforts have been invested in understanding the underlying mechanisms involved
in granulation processes to enable rational process design by exploiting regime maps (90–92)
and population balance models (93–95). Similarly, the importance of instrument configuration
and associated process variables has been studied extensively (88, 96). The effect of raw material
variability on the ability to process and on the quality attributes of granules and final dosage form
needs to be understood to achieve a robust process (81, 97).
A variety of PATs have been investigated for application in continuous granulation processes,
including spectroscopic (NIR, Raman) and optical methods to monitor and enable feedback control
of blend uniformity and particle size, respectively (98). Significantly, continuous granulation is
now also being exploited in commercial supply. OrkambiTM is an oral solid dosage form product
produced by Vertex for the treatment of cystic fibrosis. The product is a fixed-dose combination
tablet containing two actives, lumacaftor (200 mg) and ivacaftor (125 mg), and was approved by
the Food and Drug Administration (FDA) in 2015 (99, 100). The approved process combines
loss-in-weight powder feeding, twin screw wet granulation, fluid bed drying and milling, blending
and compression, and film coating unit operations. An important business driver for the adoption
of continuous manufacture for this new product, in addition to achieving consistent, high-quality
product, was the ability to finalize the formulation and process at commercial scale and avoid
costly scale-up (101). The process can also be operated on a flexible basis to meet market needs.
In-process controls were implemented at different stages of the process chain using gravimetry at
pre- and post-granulation blending stages, temperature measurements for drying, laser diffraction

for granule sizing, NIR spectroscopy for moisture content during drying and for potency at final
blend and in milled granules, and Raman spectroscopy for drug substance form and film coat
thickness. Tablet weight, hardness, and thickness data were also collected. These rich in-process
data enabled the development of a real-time release testing dissolution model, enhancing the
assurance of product quality through more comprehensive analysis than end product testing allows
and removing the need to wait for offline laboratory-based testing.
Dry Granulation
Continuous dry granulation processes are of moderate complexity, between wet granulation and
direct compression. Dry granulation is a convenient approach to increase particle size and/or bulk
density in powder blends, easing powder handling and final transformation into tablets or capsules
without the need to add additional liquid to the blend. This method therefore requires fewer
process stages than wet granulation without liquid addition and drying. It is therefore well-suited
to drug substances that are sensitive to moisture or thermal decomposition. Drug substances and
excipients are blended in the required proportions before being compressed between two counter-
rotating rollers into compacted ribbons, which are then milled into granules. These can then be
blended with final excipients, such as a lubricant, before being compacted into tablets. A range
of equipment (e.g., roller geometry and shape; gravity or screw feed), process (e.g., feed speed,
roller speed, compaction pressure), and formulation (e.g., binders or lubricants) parameters can
impact the product quality, and several equipment designs are available (102). The gaps between
rollers, roller speed, and compression force can all typically be varied, with the applied force
being a key process parameter. Consistent compaction of the powder bed is important to achieve
consistent granule attributes. Different equipment designs are available to maintain powder bed
feed composition and dimensions entering the rollers to deliver consistent ribbon density and
tensile strength. These in turn impact granule properties and performance in tableting and final
product quality. Real-time control of ribbon density using PATs has been investigated using NIR
coupled with a PCA model to identify qualitative changes in ribbon density as a result of changes
in operational parameters (103). Terahertz pulse imaging has also been shown to have utility in
identifying differences in density across the width of the ribbon, which can lead to variability in
granule attributes (104).
In the absence of a binder liquid, the material properties of the dry powder blend are of critical
importance, dictating the response to the compaction force and granulation performance. Solid
binders must undergo plastic deformation and be able to bind particles in the formulation blend
through inter-particle surface interactions. These include synthetic polymers, such as copovidone
and crospovidone, or naturally derived polymers, such as microcrystalline cellulose and HPMC.
In test formulations comprising 10% w/w of different binders under identical conditions, the
effect of different binders was observed on granule flow, tensile strength, and tablet capping (105).
Specific structure-performance relationships for binders remain poorly defined, and the particle
size of excipient components, polymorphic form, and specific surface area have all been shown
to be critical material properties that can impact granule size and tablet hardness for a placebo
formulation (106).
Direct Compression
In the simplest incarnation of a continuous drug product process, a uniform powder blend would
pass directly to a tablet press or feed into a capsule filling machine. Blend uniformity is critical
for such an operation because powders of different sizes or densities can segregate; however, this

can be monitored through the use of online sensors and PATs capable of real-time analysis of the
powder composition (107–113).
Roth et al. (114) provide a case study for a continuous direct compression process for a low-
dose tablet, evaluating the impact of content uniformity of the product as a function of the powder
blending dynamics. The study demonstrated that target potency for the low-dose tablet achieved
a relative standard deviation of less than 3.5% across a broad range of processing conditions.
Recently, researchers at AstraZeneca provided a case study for continuous direct compression
for an extended-release product (115). Extended-release products use a polymeric matrix designed
to retard the dissolution of the product through the properties of the polymer as well as the
distribution of the drug within the powder blend. Product formed with the HPMC-based excipient
used in the study has historically been formed using a wet granulation process. Conversion to
direct compression in batch is hindered as the excipient and resultant blend are typically very poor
flowing. To enable the continuous direct compression process, larger HPMC particles were used,
but this required a long processing time until steady state operation was achieved. However, the
study also demonstrated that similar performance could be achieved with smaller–particle size
HPMC, provided a high mixing speed was used.
PrezistaR
, a treatment for HIV produced by Janssen, was the first approval (April 2016) by the
FDA for a change in production method from an existing batch process to a continuous process.
The process uses an integrated series of unit operations in a single line comprising weighing,
milling, blending, continuous direct compression, and coating. The API, darunavir, and excipients
are fed using loss-in-weight feeders to a continuous blender, which transfers the blended powder
into a tablet press, where powder is compressed and uncoated tablets are transferred into a pan
coater for the final coating stage. NIR was used to monitor powder blend and to assay tablets, with
mass flow rates, screw speed, level, air flow, temperature, and humidity monitored across other
stages as part of the control strategy. Benefits of the transformation from batch to continuous have
included building proprietary knowledge and developing improved product understanding and,
through achieving reduced cost of goods, improved yields and supply chain flexibility (116).
Emerging Technologies for Drug Product Manufacture

Three emerging technologies are highlighted that provide further process intensification for the
continuous manufacture of drug products. These techniques include co-spray drying, hot melt
extrusion, and printing technologies. The first two of these also provide an advantage of improving
bioavailability of poorly soluble drug substances, whereas printing technologies offer an alternative
to compression to manufacture oral dosage forms.
Co-spray drying. Co-spray drying offers an alternative to traditional granulation techniques.

Gonnissen et al. (117–120) have developed a coprocessing operation to develop a compressible
powder, avoiding the need for granulation. The process involves formation of an aqueous sus-
pension of the drug substance and excipients and spray drying of the suspension to provide a
compressible granule without the need for powder blending. This approach also offers the advan-
tage of combining particle formation and isolation into a single stage.
Hot melt extrusion. Increasingly, new drug substances are highly lipophilic and show very
poor aqueous solubility in their crystalline form, limiting dissolution rate and oral bioavailability.
The potential to exploit the enhanced solubility benefits, accessible via the amorphous state,
has led to increased interest in amorphous pharmaceuticals (121). This creates stability issues
with the risk of phase separation or recrystallization; formulation using polymers can be used

to stabilize the amorphous form against recrystallization, as well as to aid wetting and inhibit
recrystallization in the gastrointestinal fluid. Hot melt extrusion (HME) is a convenient means
to co-process insoluble drug substance with polymers and other excipients, such as plasticizers.
Extrusion processes involve coaddition of drugs and excipients at the required composition, which
are carried in conveying elements while being heated to liquefy the polymer and dissolve the drug
and any other components. Mixing is achieved in kneading elements before the homogeneous melt
is extruded through a die that controls the size and shape of the extruded strand. The extruder
can be configured with multiple mixing and conveying zones, variable temperature regions, and
different die diameters, giving considerable flexibility. The strand is cooled to solidify before
being pelletized into granules, which can be compressed into tablets or filled into capsules. Stable
glassy solutions produced from HME have been shown to yield good tableting properties under
compression. Conveying and mixing are affected by single or, more commonly, two rotating
screws held in a temperature-controlled block. HME therefore lends itself to compounds that are
thermostable up to the melting point of the carrier polymer.
NIR, mid-IR, Raman, UV/Vis, terahertz, and ultrasonic methods have all been demonstrated
for in-line and online process analytics for detecting crystallinity in HME processes (122, 123).
IR has been used to identify stabilizing intermolecular interactions between celoxib and several
polymers and to confirm the formation of an amorphous solid dispersion (124). Multivariate data
analysis of the responses from multiple polymer-drug extruded formulations shows that where
amorphous solutions are formed, the resulting tablet tensile strength is improved compared with
tablets prepared from physical mixtures of the components. This was attributed to reduced particle
sizes in the tablet die resulting from fragmentation of the glass.
Amorphous polymer dispersions remain complex systems, and there are now several products
on the market. Further work is required to optimize the formulation design of amorphous solid
dispersions and their processing to address the challenges of low-solubility medicines. Alterna-
tive post-processing of extrudate, such as calendering, injection molding, die-face palletization,
and fused deposition 3D printing, affords alternative means to prepare intermediate particles of
controlled composition for facile processing through to final dosage-form production.
Printing technology. Liquid dispensing technologies (LDT) have been developed to manufac-
ture tablets. They were developed by GSK (125, 126) to produce low-dose tablets comprising
high-potency APIs while removing the need for high containment. LDT involves dispensing mi-
croliter droplets of a liquid formulation containing the highly potent API onto a concave inert
tablet core. The droplet is then dried to leave a solid residue of drug on the surface of the tablet,
which can then be coated. Real-time droplet volume measurement by imaging ensures accurate
liquid dosing onto the tablet, and post drying online NIR imaging ensures the location and form
of API, providing dose verification on each tablet and enabling real-time release. Operating con-
tinuously, the commercial integrated LDT platform can produce 2 × 106 tablets per day. The
technology has been implemented by GSK at pilot and commercial scale and offers several ad-
vantages, including scale-independent process performance and simplification of formulation, by
minimizing the risk of API-excipient incompatibilities. Dissolution performance is also indepen-
dent of the carrier tablet formulation.
Another emerging technology with promise for application in continuous manufacturing is re-
ferred to as particle replication in non-wetting templates (127). This uses highly non-wetting
perfluoropolyether-based elastomer molds that allow the recovery of uniform, reproducible
nanoparticles or microparticles while avoiding issues associated with traditional imprint lithog-
raphy. Molecules can be incorporated in the pre-polymer mix to achieve the required loading in
particles whose size and morphology are controlled by the mold. This approach shows promise for

delivery of a range of therapeutic agents where nanoparticles or monodisperse particles with pre-
cisely controlled shape and attributes are required, for example, for inhalation, and has been
demonstrated for 2-μm cubic doxorubicin microparticles (128) and 200-nm cylindrical nanopar-
ticles for controlled release of silyl-ether prodrugs of camptothecin, dasatinib, and gemcitabine
(129). This approach for unimodal particle size and precise control over morphology and shape
can be implemented continuously through roll-to-roll methods and is being developed toward
commercial applications (http://www.liquidia.com).
INTEGRATION OF DRUG SUBSTANCE AND DRUG

PRODUCT MANUFACTURING
Although there has not been any GMP demonstration of the integration of a continuous drug
substance process with a continuous drug product process, collaborators in MIT and Novartis
have demonstrated end-to-end continuous production with drug substance and drug product
for aliskiren hemifumarate tablets. The formulated tablets were produced by an end-to-end fully
continuous process from API starting materials to final drug product in laboratory enclosures (130).
A 45 g/h API was produced and formulated in the plant with a footprint of only approximately 18
square meters. This was the first example of end-to-end continuous production with drug substance
and drug product combined. Advanced intermediates were continuously fed into the plant, in which
two synthetic steps were conducted, including the purifications. The final API in finished tablets
flowed out the other end of the plant. The demonstration campaign was done under non-cGMP
conditions. One of the main advantages of end-to-end continuous processing is the opportunity
for on-demand production. Batch manufacturing, with steps run individually, material testing
and release protocols, and transport of materials between facilities, often in different countries,
can take up to 12 months from the first synthetic step to market release of the finished tablet.
In stark contrast, the mean residence time from API starting materials to formulated tablets
was approximately 2 days in the fully continuous process. The 14 continuous unit operations in
series included reaction, phase separation, crystallization, filtration/wash, extrusion, and molding.
Continuous processing enabled the first reaction in the sequence to run solvent free because of
the temperature and pressure capabilities of the PFR and in-line separation. One of the main
advantages of integrating the drug substance and drug product continuous processes was that
the glidant was introduced in the upstream unit operations. The first excipient, SiO2 , was added
before drying the crystals in the final isolation. This was an advantage because the final crystals were
needle-shaped with poor flowability. By metering the SiO2 into the process prior to drying, the
accuracy of mass metering into the tablet formation was improved. This exemplifies a potentially
significant opportunity afforded by integrated continuous processes not only to remove nonvalue
adding steps but to enable alternative approaches to manage and control the manufacturability of
materials through the introduction of functional excipients at different stages than is the norm in
traditional batch manufacturing.
COMPARISON OF DRUG SUBSTANCE TO DRUG PRODUCT

CONTINUOUS PROCESSING
A one-size-fits-all control strategy does not hold across the manufacture of both drug substance
and drug product. An approach best suited for one end would limit the other and not be ap-
propriate. Continuous drug product mean residence time is on the order of minutes, whereas
continuous drug substance residence time might be on the order of days, with continuous crys-
tallization often being the slowest stage. A large spike in the drug substance process may result

Ethyl
acetate Water Antisolvent
Wash
IR
Eight parallel
130°C Pump 1 Backpressure membrane
melting tank regulator separators
Mixer
Filter
Oven MSMPR 1 MSMPR 2
coiled SS 5°C 5°C
reactor τ=4h τ=4h
Pump 2 High pressure
130°C τ=4h
melting tank Oven
NaOH Fumaric acid Silicon dioxide
pH
14 microfiltration
membranes
Mixer
Decanter Filter
Stirred
Coiled
τ=2h Sieve columns MSMPR 3 MSMPR 4 Stirred tank Rotary
PFA reactor dryer
tank τ = 15 h 10°C –10°C
τ=2h Low pressure τ=4h τ=4h
Figure 9
Continuous flow scheme for the production of aliskiren (130). Abbreviations: IR, infrared; MSMPR, mixed suspension, mixed product
removal; PFA, perfluoroalkane; SS, stainless steel.
in an inconsequential perturbation well within acceptance limits in the product due to the large
RTD in the overall system. However, a similar spike in the drug product process might readily
impact a unit dosage form due to the short residence time in the system and the small discrete
product that is formed. Because of this, the required frequency of analytical measurements is much
different for drug substance versus drug product. The end-to-end continuous process for aliskiren
had a total mean residence time of 47 h (130). This process consisted of two continuous reactors,
five separators, four crystallization vessels, two filters, and two dilution vessels (Figure 9). The
continuous process that was run in three separate segments in cGMP manufacturing at Lilly had
a mean residence time of 24 h, but this did not count the time in surge between steps (Figure 5).
The continuous unit operations included three reactors, countercurrent extraction, two solvent ex-
change distillations, two crystallization vessels, one filtration, one quench, and two CSTR quench
vessels (61). When this process runs with all segments linked, assuming the surge between steps
is reduced to approximately 8 h each, the total mean residence time will be approximately 40 h.
This process does not include continuous crystallization, filtration, and drying. If these are in-
corporated in the future, the total residence time will be approximately 2 days for the continuous
process.
Continuous drug product processes benefit from automated diversion based on PAT-derived
signals or on process parameters. If a process parameter is out of range for a short time period, or if
a validated PAT measurement shows a problem, then the process keeps running but the product is
diverted during that time period. Continuous drug substance processes, however, can be designed
for ease of stopping and restarting. Therefore, automated stopping may be used more often than
automated diverting. If a process parameter is out of range, the automation can stop the process
for troubleshooting of the problematic unit before it is out of range long enough to cause any

quality issues. Then, the process can be restarted without the need to divert any material. The
main difference is that drug substance continuous processes are often easy to pause and restart
compared with drug product processes. The control strategy for each process must be based on
understanding the relevant process dynamics and their impact on critical quality attributes.
Surge vessels are used in continuous drug substance manufacturing processes for several rea-
sons. Surge vessels may be used for decoupling the unit operations; simplifying operational lo-
gistics, startup and shutdown transitions, and automation and control; allowing brief stoppages
of individual unit operations for troubleshooting or scheduled cleanouts of crystallizers or slurry
reactors; providing distinct points where the quality of the material can be assessed and forward
processed or diverted; and dampening out process disturbances. The surge vessels increase overall
RTD of drug substance continuous processes. Hoppers feeding a blend to a tablet press might be
the only surge vessel in a continuous drug product process (Figure 8). This enables use of off-line
analytics for approval to forward process in drug substance by sampling from the surge vessels.
In contrast, off-line analytics is typically not frequent enough for drug product processes. A wide
variety of PATs have been developed and demonstrated for monitoring and control of continuous
processes, enabling strategies to provide quality assurance of all material throughout the process
and ultimately real-time release testing to become more widely implemented in pharmaceutical
manufacturing.
Lot genealogy is an important consideration and is a change from what has been done for batch
processing. Lot genealogy for a batch process consists of understanding what was charged into the
process and verifying that all of the components were uniformly well mixed in the final product.
For continuous processing, feed streams are periodically recharged, perhaps sourcing materials
from different lots. Understanding the movement of these components through the process train
is important to establish lot genealogy and is afforded only through intimate process knowledge
and use of process flowsheet modeling (131). This combined with the decision of how to identify
a batch of material (either by processing time or by volume of material produced) allows for
establishment of deviation boundaries in the process, which are important should material quality
be brought into question.
SUMMARY
Decreased time to market, research and development expenditure, environmental impact, and
cost, as well as increased product quality and encouragement from regulatory bodies, have all con-
tributed to a paradigm shift in the manufacturing processes used to make tomorrow’s medicines.
Development and manufacturing organizations across the innovative pharmaceutical sector have
embraced continuous manufacturing platforms, breaking from a long tradition of batch manufac-
turing. A recent article in The Wall Street Journal (132) declared, “For decades, drug makers have
used cutting-edge science to discover medicines but have manufactured them using techniques
dating to the days of the steam engine.” Although the shift may not be quite that dramatic, it is very
impactful. Further advances and utilization are expected to occur. The new chemistries enabled
by continuous reactions have resulted in many academic research papers in the past decade. Most
of these focus on the reaction steps. Continuous reactors include plug flow tubes, microreactors,
photoreactors, packed catalyst beds, and continuous and intermittent flow stirred tanks. They
also include several continuous separations unit operations, such as countercurrent extraction,
membrane separation, packed bed adsorption, solvent exchange distillation, crystallization, filtra-
tion, and drying. Continuous drug product processes include powder blending, wet granulation,
dry granulation, direct compression, fluidized bed, spray drying, and HME. Opportunities exist
for the integration of drug substance and drug product processes, as the MIT Novartis project

demonstrated. Opportunities also exist for integration of continuous tablet coating and continu-
ous packaging into pharmaceutical manufacture. For commercially marketed medicines, contin-
uous drug product processes are more commonplace than continuous drug substance processes,
partly due to the increased complexity of the drug substance fully continuous equipment trains.
Compared with drug product processes, continuous drug substance processes have two to three
orders of magnitude longer overall mean residence times, a larger number and diversity of unit
operations, less frequent analytical measurements, and greater use of surge.
The recent use of continuous manufacturing in the pharmaceutical sector offers multiple oppor-
tunities for the chemical engineering profession. Although many challenges have been overcome,
as demonstrated by the examples provided, others remain. Further process intensification and
equipment downsizing, especially for particulate processes, for both drug substance manufactur-
ing (filtration, isolation, and drying) and drug product (blending, compaction, and compression)
provide many areas for chemical engineers to make further advances to the field. Numerical mod-
eling is needed for understanding and predicting the complex chemical transformations, impurity
formation, impurity removal, overall process residence time distributions, deviation boundaries,
and lot genealogy. Real-time release testing and advanced process control algorithms, both sta-
tistical process control and model predictive process control, are other areas in which chemical
engineers can continue to transform the industry.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
The authors would like to thank Drs. Jean Tom, James Wesley, and Scott May for their thoughtful
and insightful reviews of multiple drafts of this manuscript.
LITERATURE CITED
1. DiMasi JA, Grabowski HG, Hansen RW. 2016. Innovation in the pharmaceutical industry: new estimates
of R&D costs. J. Health Econ. 47:20–33
2. Price WN II. 2014. Making do in making drugs: innovation policy and pharmaceutical manufacturing.
Boston Coll. Law Rev. 55:491
3. Munos B. 2009. Lessons from 60 years of pharmaceutical innovation. Nat. Rev. Drug Discov. 8:959–68
4. Collins PC. 2017. Development and implementation of continuous manufacturing processes for API. Presented
at 3rd FDA/PQRI Conf. Adv. Prod. Qual., Rockville, MD
5. Food Drug Adm. 2004. PAT—a framework for innovative pharmaceutical development, manufacturing, and
quality assurance. Guid. Ind., Food Drug Adm., Silver Spring, MD. https://www.fda.gov/downloads/
drugs/guidances/ucm070305.pdf
6. Food Drug Adm. 2004. Pharmaceutical cGMPs for the 21st Century—A Risk-Based Approach. Silver Spring,
MD: Food Drug Adm.
7. Lee SL, O’Connor TF, Yang X, Cruz CN, Chatterjee S, et al. 2015. Modernizing pharmaceutical
manufacturing: from batch to continuous production. J. Pharm. Innov. 10:191–99
8. Cole KP, Campbell BM, Forst MB, McClary Groh J, Hess M, et al. 2016. An automated intermittent
flow approach to continuous Suzuki coupling. Org. Process Res. Dev. 20:820–30
9. Kopach ME, Cole KP, Pollock PM, Johnson MD, Braden TM, et al. 2016. Flow Grignard and lithiation:
screening tools and development of continuous processes for a benzyl alcohol starting material. Org.
Process Res. Dev. 20:1581–92

10. Poechlauer P, Colberg J, Fisher E, Jansen M, Johnson MD, et al. 2013. Pharmaceutical roundtable study
demonstrates the value of continuous manufacturing in the design of greener processes. Org. Process Res.
Dev. 17:1472–78
11. Nasr MM, Krumme M, Matsuda Y, Trout BL, Badman C, et al. 2017. Regulatory perspectives on con-
tinuous pharmaceutical manufacturing: moving from theory to practice: September 26–27, 2016, Inter-
national Symposium on the Continuous Manufacturing of Pharmaceuticals. J. Pharm. Sci. 106:3199–206
12. Almaya A, De Belder L, Meyer R, Nagapudi K, Lin HH, et al. 2017. Control strategies for drug product
continuous direct compression—state of control, product collection strategies, and startup/shutdown
operations for the production of clinical trial materials and commercial products. J. Pharm. Sci. 106:930–
43
13. Aksu B, De Beer T, Folestad S, Ketolainen J, Linden H, et al. 2012. Strategic funding priorities in the
pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).
Eur. J. Pharm. Sci. 47:402–5
14. Rantanen J, Khinast J. 2015. The future of pharmaceutical manufacturing sciences. J. Pharm. Sci.
104:3612–38
15. Fisher AC, Lee SL, Harris DP, Buhse L, Kozlowski S, et al. 2016. Advancing pharmaceutical quality:
an overview of science and research in the U.S. FDA’s Office of Pharmaceutical Quality. Int. J. Pharm.
515:390–402
16. Tsukanov SV, Johnson MD, May SA, Rosemeyer M, Watkins MA, et al. 2016. Development of an
intermittent-flow enantioselective Aza-Henry reaction using an arylnitromethane and homogeneous
Brønsted acid-base catalyst with recycle. Org. Process Res. Dev. 20:215–26
17. Li J, Trout BL, Myerson AS. 2016. Multistage continuous mixed-suspension, mixed-product removal
(MSMPR) crystallization with solids recycle. Org. Process Res. Dev. 20:510–16
18. Seifert T, Sievers S, Bramsiepe C, Schembecker G. 2012. Small scale, modular and continuous: a new
approach in plant design. Chem. Eng. Process. Process Intensif. 52:140–50
19. The Irish Times. 2016. Eli Lilly to invest €35m in Kinsale plant. The Irish Times, April 5. https://www.
irishtimes.com/business/health-pharma/eli-lilly-to-invest-35m-in-kinsale-plant-1.2598781
20. ISPE. 2017. 2017 ISPE Facility of the Year award winners announced. ISPE Newsletter, Feb. 6.
https://www.ispe.org/news/2017-facility-year-category-winners
21. Congdon K. 2015. Inside Pfizer’s modular manufacturing PODs. Pharmaceutical Online. https://www.
pharmaceuticalonline.com/doc/inside-pfizer-s-modular-manufacturing-pods-0001
22. Garguilo L. 2017. Novartis and the arrival of the continuous manufacturing facility. Outsourced Pharma,
Feb. 8. https://www.outsourcedpharma.com/doc/novartis-and-the-arrival-of-the-continuous-
manufacturing-facility-0001
23. Stanton D. 2016. J&J success will spur pharma’s shift to continuous manufacturing, Rutgers. in-
PharmaTechnologist.com, April 20. http://www.in-pharmatechnologist.com/Processing/J-J-success-
will-spur-shift-to-continuous-manufacturing-Rutgers
24. MacDonald G. 2016. Janssen working on other continuous processes post US FDA OK for Prezista.
in-PharmaTechnologist.com, April 12. http://www.in-pharmatechnologist.com/Processing/Janssen-
working-on-other-continuous-processes-post-US-FDA-OK-for-Prezista
25. Palmer E. 2015. Vertex, J&J, GSK, Novartis all working on continuous manufacturing facili-
ties. FiercePharma, Feb. 9. http://www.fiercepharma.com/supply-chain/vertex-j-j-gsk-novartis-all-
working-on-continuous-manufacturing-facilities
26. Taylor P. 2015. GSK and Pfizer team up on continuous manufacturing project. in-
PharmaTechnologist.com, Nov. 3. http://www.in-pharmatechnologist.com/Processing/GSK-and-
Pfizer-team-up-on-continuous-manufacturing-project
27. Plutschack MB, Pieber B, Gilmore K, Seeberger PH. 2017. The hitchhiker’s guide to flow chemistry.
Chem. Rev. 117:11796–893
28. Allison G, Cain YT, Cooney C, Garcia T, Bizjak TG, et al. 2015. Regulatory and quality considerations
for continuous manufacturing. May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci.
104:803–12
29. Badman C, Trout BL. 2015. Achieving continuous manufacturing. May 20–21, 2014 Continuous Man-
ufacturing Symposium. J. Pharm. Sci. 104:779–80

30. Baxendale IR, Braatz RD, Hodnett BK, Jensen KF, Johnson MD, et al. 2015. Achieving continuous
manufacturing: technologies and approaches for synthesis, workup, and isolation of drug substance.
May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm. Sci. 104:781–91
31. Byrn S, Futran M, Thomas H, Jayjock E, Maron N, et al. 2015. Achieving continuous manufacturing for
final dosage formation: challenges and how to meet them. May 20–21, 2014 Continuous Manufacturing
Symposium. J. Pharm. Sci. 104:792–802
32. Konstantinov KB, Cooney CL. 2015. White paper on continuous bioprocessing. May 20–21, 2014
Continuous Manufacturing Symposium. J. Pharm. Sci. 104:813–20
33. Myerson AS, Krumme M, Nasr M, Thomas H, Braatz RD. 2015. Control systems engineering in
continuous pharmaceutical manufacturing. May 20–21, 2014 Continuous Manufacturing Symposium.
J. Pharm. Sci. 104:832–39
34. Nepveux K, Sherlock J-P, Futran M, Thien M, Krumme M. 2015. How development and manufac-
turing will need to be structured—heads of development/manufacturing. May 20–21, 2014 Continuous
Manufacturing Symposium. J. Pharm. Sci. 104:850–64

35. Page T, Dubina H, Fillipi G, Guidat R, Patnaik S, et al. 2015. Equipment and analytical companies
meeting continuous challenges. May 20–21, 2014 Continuous Manufacturing Symposium. J. Pharm.
Sci. 104:821–31
36. Srai JS, Badman C, Krumme M, Futran M, Johnston C. 2015. Future supply chains enabled by continuous
processing—opportunities and challenges. May 20–21, 2014 Continuous Manufacturing Symposium.
J. Pharm. Sci. 104:840–49
37. Welch C, Faul MM, Tummala S, Papageorgiou CD, Hicks F, et al. 2017. The Enabling Technologies
Consortium (ETC): fostering precompetitive collaborations on new enabling technologies for pharma-
ceutical research and development. Org. Process Res. Dev. 21(3):414–19
38. Lakerveld R, Benyahia B, Braatz RD, Barton PI. 2013. Model-based design of a plant-wide control
strategy for a continuous pharmaceutical plant. AIChE J. 59:3671–85
39. Lakerveld R, Benyahia B, Heider PL, Zhang H, Wolfe A, et al. 2015. The application of an automated
control strategy for an integrated continuous pharmaceutical pilot plant. Org. Process Res. Dev. 19:1088–
100
40. Jensen KF. 2017. Flow chemistry—microreaction technology comes of age. AIChE J. 63:858–69
41. Gutmann B, Cantillo D, Kappe CO. 2015. Continuous-flow technology—a tool for the safe manufac-
turing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 54:6688–728
42. Wang T, Lu H, Wang J, Xiao Y, Zhou Y, et al. 2017. Recent progress of continuous crystallization.
J. Ind. Eng. Chem. 54:14–29
43. Zhang D, Xu S, Du S, Wang J, Gong J. 2017. Progress of pharmaceutical continuous crystallization.
Engineering 3:354–64
44. Jacoby R, Pernenkil L, Harutunian S, Heim M, Sabad A, Deloitte. 2015. Advanced Biopharmaceutical
Manufacturing: An Evolution Underway. New York: Deloitte. https://www2.deloitte.com/content/
dam/Deloitte/us/Documents/life-sciences-health-care/us-lshc-advanced-biopharmaceutical-
manufacturing-white-paper-051515.pdf
45. O’Brien M. 2016. Powders to tablets in minutes: implementation of a portable, continuous, miniature, and
modular (PCMM) factory in a warehouse. Presented at FDA-AIChE Workshop Adopt. Contin. Manuf.,
Bethesda, MD
46. Madurawe R. 2016. Continuous manufacturing: achieving the vision of modernizing pharmaceutical manufac-
turing. Presented at FDA-AIChE Workshop Adopt. Contin. Manuf., Bethesda, MD
47. McManus E. 2016. Design and implementation of a small footprint continuous API facility for portfolio com-
mercialization. Presented at FDA-AIChE Workshop Adopt. Contin. Manuf., Bethesda, MD
48. Tsubogo T, Oyamada H, Kobayashi S. 2015. Multistep continuous-flow synthesis of (R)- and (S)-
rolipram using heterogeneous catalysts. Nature 520:329–32
49. Lau SH, Galvan A, Merchant RR, Battilocchio C, Souto JA, et al. 2015. Machines versus malaria: a
flow-based preparation of the drug candidate OZ439. Org. Lett. 17:3218–21
50. Ingham RJ, Battilocchio C, Fitzpatrick DE, Sliwinski E, Hawkins JM, Ley SV. 2015. A systems approach
towards an intelligent and self-controlling platform for integrated continuous reaction sequences. Angew.
Chem. Int. Ed. 54:144–48

51. Viviano M, Glasnov TN, Reichart B, Tekautz G, Kappe CO. 2011. A scalable two-step continuous flow
synthesis of nabumetone and related 4-aryl-2-butanones. Org. Process Res. Dev. 15:858–70
52. Ghislieri D, Gilmore K, Seeberger PH. 2015. Chemical assembly systems: layered control for divergent,
continuous, multistep syntheses of active pharmaceutical ingredients. Angew. Chem. Int. Ed. 54:678–82
53. Hopkin MD, Baxendale IR, Ley SV. 2010. A flow-based synthesis of imatinib: the API of Gleevec. Chem.
Commun. 46:2450–52
54. Hopkin MD, Baxendale IR, Ley SV. 2013. An expeditious synthesis of imatinib and analogues utilising
flow chemistry methods. Org. Biomol. Chem. 11:1822–39
55. Correia CA, Gilmore K, McQuade DT, Seeberger PH. 2015. A concise flow synthesis of efavirenz.
Angew. Chem. Int. Ed. 54:4945–48
56. Murray PRD, Browne DL, Pastre JC, Butters C, Guthrie D, Ley SV. 2013. Continuous flow-processing
of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow syn-
thesis of (E/Z)-tamoxifen. Org. Process Res. Dev. 17:1192–208
57. Cantillo D, Damm M, Dallinger D, Bauser M, Berger M, Kappe CO. 2014. Sequential nitration/
hydrogenation protocol for the synthesis of triaminophloroglucinol: safe generation and use of an ex-
plosive intermediate under continuous-flow conditions. Org. Process Res. Dev. 18:1360–66
58. Elliott LD, Berry M, Harji B, Klauber D, Leonard J, Booker-Milburn KI. 2016. A small-footprint,
high-capacity flow reactor for UV photochemical synthesis on the kilogram scale. Org. Process Res. Dev.
20:1806–11
59. Levesque F, Seeberger PH. 2012. Continuous-flow synthesis of the anti-malaria drug artemisinin. Angew.
Chem. Int. Ed. 51:1706–9
60. Bodmann K, Marti R. 2015. 12. Freiburger Symposium 2015: smart solutions in the chemical process
& product development—case studies from the chemical industry. Chimia 69:698–707
61. Cole KP, Groh JM, Johnson MD, Burcham CL, Campbell BM, et al. 2017. Kilogram-scale prexasertib
monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science 356:1144–50
62. May SA, Johnson MD, Braden TM, Calvin JR, Haeberle BD, et al. 2012. Rapid development and scale-
up of a 1H-4-substituted imidazole intermediate enabled by chemistry in continuous plug flow reactors.
Org. Process Res. Dev. 16:982–1002
63. Frederick MO, Calvin JR, Cope RF, LeTourneau ME, Lorenz KT, et al. 2015. Development of an
NH4 Cl-catalyzed ethoxy ethyl deprotection in flow for the synthesis of merestinib. Org. Process Res. Dev.
19:1411–17
64. May SA, Johnson MD, Buser JY, Campbell AN, Frank SA, et al. 2016. Development and manufacturing
GMP scale-up of a continuous Ir-catalyzed homogeneous reductive amination reaction. Org. Process Res.
Dev. 20:1870–98
65. Peer M, Weeranoppanant N, Adamo A, Zhang Y, Jensen KF. 2016. Biphasic catalytic hydrogen peroxide
oxidation of alcohols in flow: scale-up and extraction. Org. Process Res. Dev. 20:1677–85
66. O’Neal EJ, Lee CH, Brathwaite J, Jensen KF. 2015. Continuous nanofiltration and recycle of an asym-
metric ketone hydrogenation catalyst. ACS Catal. 5:2615–22
67. Cui X, Mannan MS, Wilhite BA. 2017. Segregated-feed membrane reactor design for alkylpyridine
N-oxidation: implications for process safety and intensification. Ind. Eng. Chem. Res. 56:3822–32
68. Levenspiel O. 1998. Chemical Reaction Engineering. Hoboken, NJ: Wiley. 3rd ed.
69. White TD, Alt CA, Cole KP, Groh JM, Johnson MD, Miller RD. 2014. How to convert a walk-in hood
into a manufacturing facility: demonstration of a continuous, high-temperature cyclization to process
solids in flow. Org. Process Res. Dev. 18:1482–91
70. Cole KP, Johnson MD, Laurila ME, Stout JR. 2017. An automated repeating batch with catalyst recycle
approach to nitro group hydrogenolysis. React. Chem. Eng. 2:288–94
71. Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, et al. 2016. On-demand continuous-flow
production of pharmaceuticals in a compact, reconfigurable system. Science 352:61–67
72. Snead DR, Jamison TF. 2015. A three-minute synthesis and purification of ibuprofen: pushing the limits
of continuous-flow processing. Angew. Chem. Int. Ed. 54:983–87
73. Lieberman HA. 1990. Pharmaceutical Dosage Forms: Tablets, Vol. 2: Second Edition, Revised and Expanded.
Abingdon, UK: Taylor & Francis

74. Lachman L, Lieberman HA, Kang JL. 1976. The Theory and Practice of Industrial Pharmacy. Philadelphia:
Lea & Febiger. 2nd ed.
75. Vervaet C, Remon JP. 2005. Continuous granulation in the pharmaceutical industry. Chem. Eng. Sci.
60:3949–57
76. Am. Pharm. Rev. 2017. Pharmaceutical Tablet Press Machine/Rotary Tablet Press. Fishers, IN: Am. Pharm.
Rev. http://www.americanpharmaceuticalreview.com/25310-Pharmaceutical-Manufacturing/
25344-Pharmaceutical-Tablet-Press-Machine-Rotary-Tablet-Press/
77. Manufacturing Chemist Pharma. 2017. FEC40 Capsule Filling Machine can produce up to 400,000 cap-
sules/hour. Manufacturing Chemist Pharma, Jan. 30. https://www.manufacturingchemist.com/news/
article_page/FEC40_Capsule_Filling_Machine_can_produce_up_to_400000_capsuleshour/
125304
78. Schaber SD, Gerogiorgis DI, Ramachandran R, Evans JMB, Barton PI, Trout BL. 2011. Economic
analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Ind. Eng. Chem.
Res. 50:10083–92
79. Pernenkil L, Cooney CL. 2006. A review on the continuous blending of powders. Chem. Eng. Sci.
61:720–42
80. Suresh P, Sreedhar I, Vaidhiswaran R, Venugopal A. 2017. A comprehensive review on process and
engineering aspects of pharmaceutical wet granulation. Chem. Eng. J. 328:785–815
81. Beer P, Wilson D, Huang Z, De Matas M. 2014. Transfer from high-shear batch to continuous twin
screw wet granulation: a case study in understanding the relationship between process parameters and
product quality attributes. J. Pharm. Sci. 103:3075–82
82. Jorgensen A, Rantanen J, Karjalainen M, Khriachtchev L, Rasanen E, Yliruusi J. 2002. Hydrate formation
during wet granulation studied by spectroscopic methods and multivariate analysis. Pharm. Res. 19:1285–
91
83. Leuenberger H. 2001. New trends in the production of pharmaceutical granules: batch versus continuous
processing. Eur. J. Pharm. Biopharm. 52:289–96
84. Werani J, Gruenberg M, Ober C, Leuenberger H. 2004. Semicontinuous granulation—the process of
choice for the production of pharmaceutical granules? Powder Technol. 140:163–68
85. Loh ZH, Er DZ, Chan LW, Liew CV, Heng PW. 2011. Spray granulation for drug formulation. Expert
Opin. Drug Deliv. 8:1645–61
86. Glatt Technol. Innovative Technologies for Granules and Pellets. Moscow: Glatt Technol. https://www.
glatt.com/fileadmin/user_upload/content/pdf_downloads/AB_innovative_technologies_en_
111017.pdf
87. Seem TC, Rowson NA, Ingram A, Huang Z, Yu S, et al. 2015. Twin screw granulation—a literature
review. Powder Technol. 276:89–102
88. Vercruysse J, Córdoba Dı́az D, Peeters E, Fonteyne M, Delaet U, et al. 2012. Continuous twin screw
granulation: influence of process variables on granule and tablet quality. Eur. J. Pharm. Biopharm. 82:205–
11
89. Djuric D, Kleinebudde P. 2010. Continuous granulation with a twin-screw extruder: impact of material
throughput. Pharm. Dev. Technol. 15:518–25
90. Kumar A, Dhondt J, Vercruysse J, De Leersnyder F, Vanhoorne V, et al. 2016. Development of a process
map: a step towards a regime map for steady-state high shear wet twin screw granulation. Powder Technol.
300:73–82
91. Hapgood KP, Litster JD, Smith R. 2003. Nucleation regime map for liquid bound granules. AIChE J.
49:350–61
92. Iveson SM, Litster JD. 1998. Growth regime map for liquid-bound granules. AIChE J. 44:1510–18
93. Barrasso D, Walia S, Ramachandran R. 2013. Multi-component population balance modeling of contin-
uous granulation processes: a parametric study and comparison with experimental trends. Powder Technol.
241:85–97
94. Iveson SM. 2002. Limitations of one-dimensional population balance models of wet granulation pro-
cesses. Powder Technol. 124:219–29

95. Chaturbedi A, Bandi CK, Reddy D, Pandey P, Narang A, et al. 2017. Compartment based population
balance model development of a high shear wet granulation process via dry and wet binder addition.
Chem. Eng. Res. Des. 123:187–200
96. Vercruysse J, Burggraeve A, Fonteyne M, Cappuyns P, Delaet U, et al. 2015. Impact of screw config-
uration on the particle size distribution of granules produced by twin screw granulation. Int. J. Pharm.
479:171–80
97. Fonteyne M, Wickstrom H, Peeters E, Vercruysse J, Ehlers H, et al. 2014. Influence of raw material
properties upon critical quality attributes of continuously produced granules and tablets. Eur. J. Pharm.
Biopharm. 87:252–63
98. Fonteyne M, Vercruysse J, Dı́az DC, Gildemyn D, Vervaet C, et al. 2013. Real-time assessment of
critical quality attributes of a continuous granulation process. Pharm. Dev. Technol. 18:85–97
99. Food Drug Adm. 2015. FDA approves new treatment for cystic fibrosis. News Release, July 2
100. Yu L. 2016. Continuous manufacturing has a strong impact on drug quality. FDA Voice, April
12. https://blogs.fda.gov/fdavoice/index.php/2016/04/continuous-manufacturing-has-a-strong-
impact-on-drug-quality/
101. Swinney KA. 2016. Drug product continuous manufacturing: from business case to commercial manufacturing.
Presented at 2nd Int. Symp. Contin. Manuf. Pharm. Implement. Technol. Regul., Cambridge, MA
102. Kleinebudde P. 2004. Roll compaction/dry granulation: pharmaceutical applications. Eur. J. Pharm.
Biopharm. 58:317–26
103. Acevedo D, Muliadi A, Giridhar A, Litster JD, Romanach RJ. 2012. Evaluation of three approaches
for real-time monitoring of roller compaction with near-infrared spectroscopy. AAPS PharmSciTech
13:1005–12
104. Zhang J, Pei C, Schiano S, Heaps D, Wu CY. 2016. The application of terahertz pulsed imaging in
characterising density distribution of roll-compacted ribbons. Eur. J. Pharm. Biopharm. 106:20–25
105. Mangal H, Kirsolak M, Kleinebudde P. 2016. Roll compaction/dry granulation: suitability of different
binders. Int. J. Pharm. 503:213–19
106. Kushner J IV, Langdon BA, Hiller JI, Carlson GT. 2011. Examining the impact of excipient material
property variation on drug product quality attributes: a quality-by-design study for a roller compacted,
immediate release tablet. J. Pharm. Sci. 100:2222–39
107. Shi Z, McGhehey KC, Leavesley IM, Manley LF. 2016. On-line monitoring of blend uniformity in
continuous drug product manufacturing process—the impact of powder flow rate and the choice of
spectrometer: dispersive vs. FT. J. Pharm. Biomed. Anal. 118:259–66
108. Laske S, Paudel A, Scheibelhofer O. 2017. A review of PAT strategies in secondary solid oral dosage
manufacturing of small molecules. J. Pharm. Sci. 106:667–712
109. Hertrampf A, Müller H, Menezes JC, Herdling T. 2015. A PAT-based qualification of pharmaceutical
excipients produced by batch or continuous processing. J. Pharm. Biomed. Anal. 114:208–15
110. Vanarase AU, Järvinen M, Paaso J, Muzzio FJ. 2013. Development of a methodology to estimate error
in the on-line measurements of blend uniformity in a continuous powder mixing process. Powder Technol.
241:263–71
111. Osorio JG, Stuessy G, Kemeny GJ, Muzzio FJ. 2014. Characterization of pharmaceutical powder blends
using in situ near-infrared chemical imaging. Chem. Eng. Sci. 108:244–57
112. Mateo-Ortiz D, Colon Y, Romañach RJ, Méndez R. 2014. Analysis of powder phenomena inside a Fette
3090 feed frame using in-line NIR spectroscopy. J. Pharm. Biomed. Anal. 100:40–49
113. Gladd T. 2016. Merck’s path to continuous manufacturing for solid oral dose products: What stands
in the way? Life Science Leader, Dec. 8. https://www.lifescienceleader.com/doc/merck-s-path-to-
continuous-manufacturing-for-solid-oral-dose-products-what-stands-in-the-way-0001
114. Roth WJ, Almaya A, Kramer TT, Hofer JD. 2017. A demonstration of mixing robustness in a direct
compression continuous manufacturing process. J. Pharm. Sci. 106:1339–46
115. Lakio S, Tajarobi P, Wikström H, Fransson M, Arnehed J, et al. 2016. Achieving a robust drug release
from extended release tablets using an integrated continuous mixing and direct compression line. Int.
J. Pharm. 511:659–68

116. Belder LD. 2016. Business Case Drivers and Deployment Strategies in the Current Landscape for Continuous
Drug Product Manufacturing. Presented at 2nd Int. Symp. Contin. Manuf. Pharm. Implement. Technol.
Regul., Cambridge, MA
117. Gonnissen Y, Gonçalves SI, De Geest BG, Remon JP, Vervaet C. 2008. Process design applied
to optimise a directly compressible powder produced via a continuous manufacturing process. Eur.
J. Pharm. Biopharm. 68:760–70
118. Gonnissen Y, Gonçalves SI, Remon JP, Vervaet C. 2008. Mixture design applied to optimize a directly
compressible powder produced via cospray drying. Drug Dev. Ind. Pharm. 34:248–57
119. Gonnissen Y, Remon JP, Vervaet C. 2007. Development of directly compressible powders via co-spray
drying. Eur. J. Pharm. Biopharm. 67:220–26
120. Gonnissen Y, Remon JP, Vervaet C. 2008. Effect of maltodextrin and superdisintegrant in directly
compressible powder mixtures prepared via co-spray drying. Eur. J. Pharm. Biopharm. 68:277–82
121. Hancock BC, Zografi G. 1997. Characteristics and significance of the amorphous state in pharmaceutical
systems. J. Pharm. Sci. 86:1–12

122. Hitzer P, Bauerle T, Drieschner T, Ostertag E, Paulsen K, et al. 2017. Process analytical techniques for
hot-melt extrusion and their application to amorphous solid dispersions. Anal. Bioanal. Chem. 409:4321–
33
123. Treffer D, Wahl P, Markl D, Koscher G, Roblegg E, Khinast JG. 2013. Hot melt extrusion as a con-
tinuous pharmaceutical manufacturing process. In Melt Extrusion: Materials, Technology and Drug Product
Design, ed. MA Repka, N Langley, J DiNunzio, pp. 363–96. New York: Springer
124. Grymonpre W, Verstraete G, Van Bockstal PJ, Van Renterghem J, Rombouts P, et al. 2017. In-line
monitoring of compaction properties on a rotary tablet press during tablet manufacturing of hot-melt
extruded amorphous solid dispersions. Int. J. Pharm. 517:348–58
125. Clarke A, Doughty D, Khinast J, Rantanen J. 2017. Development of liquid dispensing technology
for the manufacture of low dose drug products. In Continuous Manufacturing of Pharmaceuticals, ed. P
Kleinebudde, J Khinast, J Rantanen, pp. 551–75. Hoboken, NJ: John Wiley & Sons
126. Clarke A, Phillips D. Liquid Dispensing Technology (LDT). Brentford, UK: GSK. https://www.gsk.
com/media/2758/liquid-dispensing-technology-leaflet.pdf
127. Euliss LE, DuPont JA, Gratton S, DeSimone J. 2006. Imparting size, shape, and composition control of
materials for nanomedicine. Chem. Soc. Rev. 35:1095–104
128. Petros RA, Ropp PA, DeSimone JM. 2008. Reductively labile PRINT particles for the delivery of
doxorubicin to HeLa cells. J. Am. Chem. Soc. 130:5008–9
129. Parrott MC, Finniss M, Luft JC, Pandya A, Gullapalli A, et al. 2012. Incorporation and controlled release
of silyl ether prodrugs from PRINT nanoparticles. J. Am. Chem. Soc. 134:7978–82
130. Mascia S, Heider PL, Zhang H, Lakerveld R, Benyahia B, et al. 2013. End-to-end continuous manufac-
turing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. Angew. Chem.
Int. Ed. 52:12359–63
131. O’Connor T. 2016. How process models can facilitate quality risk management for emerging technologies.
Presented at FDA-AIChE Workshop Adopt. Cont. Manuf., Bethesda, MD
132. Rockoff JD. 2015. Drug making breaks away from its old ways: “Continuous-manufacturing” process
can improve quality control, speed output. Wall Street Journal, Feb. 8

CH09_FrontMatter ARI 18 May 2018 8:34
Annual Review of
Chemical and
Biomolecular
Engineering
Volume 9, 2018
Contents
Autobiography of Ronald W. Rousseau

Ronald W. Rousseau p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Single- to Few-Layered, Graphene-Based Separation Membranes
Fanglei Zhou, Mahdi Fathizadeh, and Miao Yu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p17
From Multiscale to Mesoscience: Addressing Mesoscales in Mesoregimes
of Different Levels
Jinghai Li and Wenlai Huang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p41
Toward Constitutive Models for Momentum, Species, and Energy
Transport in Gas–Particle Flows
Sankaran Sundaresan, Ali Ozel, and Jari Kolehmainen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p61
Stable Radical Materials for Energy Applications
Daniel A. Wilcox, Varad Agarkar, Sanjoy Mukherjee, and Bryan W. Boudouris p p p p p p p p83
Biodegradable Polymeric Nanoparticles for Therapeutic
Cancer Treatments
Johan Karlsson, Hannah J. Vaughan, and Jordan J. Green p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Critical Comparison of Structured Contactors for Adsorption-Based
Gas Separations
Stephen J.A. DeWitt, Anshuman Sinha, Jayashree Kalyanaraman,
Fengyi Zhang, Matthew J. Realff, and Ryan P. Lively p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 129
The Energy Future
John Newman, Christopher A. Bonino, and James A. Trainham p p p p p p p p p p p p p p p p p p p p p p p p 153
Confined Flow: Consequences and Implications for Bacteria and Biofilms
Jacinta C. Conrad and Ryan Poling-Skutvik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175
Molecular Modelling for Reactor Design
Frerich J. Keil p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 201
Biomolecular Ultrasound and Sonogenetics
David Maresca, Anupama Lakshmanan, Mohamad Abedi,
Avinoam Bar-Zion, Arash Farhadi, George J. Lu, Jerzy O. Szablowski,
Di Wu, Sangjin Yoo, and Mikhail G. Shapiro p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 229
vi
CH09_FrontMatter ARI 18 May 2018 8:34
Continuous Manufacturing in Pharmaceutical Process Development

and Manufacturing
Christopher L. Burcham, Alastair J. Florence, and Martin D. Johnson p p p p p p p p p p p p p p p p p 253
Crystal Engineering for Catalysis
Jeffrey D. Rimer, Aseem Chawla, and Thuy T. Le p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 283
Engineered Ribosomes for Basic Science and Synthetic Biology
Anne E. d’Aquino, Do Soon Kim, and Michael C. Jewett p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 311
Shale Gas Implications for C2 -C3 Olefin Production:
Incumbent and Future Technology
Eric E. Stangland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 341
Nanoscale Optical Microscopy and Spectroscopy Using

Near-Field Probes
Richard J. Hermann and Michael J. Gordon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 365
Advances in Multicompartment Mesoporous Silica Micro/Nanoparticles
for Theranostic Applications
Jian Liu, Tingting Liu, Jian Pan, Shaomin Liu, and G.Q. (Max) Lu p p p p p p p p p p p p p p p p p p 389
Microkinetic Analysis and Scaling Relations for Catalyst Design
Ali Hussain Motagamwala, Madelyn R. Ball, and James A. Dumesic p p p p p p p p p p p p p p p p p p p 413
Indexes
Cumulative Index of Contributing Authors, Volumes 5–9 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451

Cumulative Index of Article Titles, Volumes 5–9 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 454
Errata
An online log of corrections to Annual Review of Chemical and Biomolecular Engineering

articles may be found at http://www.annualreviews.org/errata/chembioeng
Contents vii

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Continuous Manufacturing in Pharmaceutical Process Development and Manufacturing

Uploaded by

Copyright:

Available Formats

CH09CH12_Burcham ARI 13 May 2018 8:21

Annual Review of Chemical and Biomolecular

Annu. Rev. Chem. Biomol. Eng. 2018. 9:253–81 Keywords

254 Burcham · Florence · Johnson

CONTINUOUS MANUFACTURING APPLIED TO DRUG SUBSTANCE

Drivers for Implementation to Drug Substance Manufacture

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 255

Process Chemistry at the Research Scale

O3, acetone, water O O

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 257

small PFA coiled tube reactors organometallic reactions with

258 Burcham · Florence · Johnson

Continuous Drug Substance Processes in Current Good Manufacturing

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 259

Methanol, MTBE, formic acid

260 Burcham · Florence · Johnson

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 261

Abbreviations: API, active pharmaceutical ingredient; PFR, plug flow reactor.

Emerging Technologies for Drug Substance Manufacture

Membrane separations. Membrane separations offer an alternative to the use of crystallizations

262 Burcham · Florence · Johnson

complete. A Noyori asymmetric hydrogenation catalyst, ruthenium diphosphine/diamine, used in

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 263

Table 3 Examples using intermittent flow stirred tank reactors (IFSTRs)

Abbreviation: PFR, plug flow reactor.

264 Burcham · Florence · Johnson

Opportunities. Significant advances in the development of continuous manufacturing platforms

CONTINUOUS MANUFACTURING APPLIED TO DRUG PRODUCT

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 265

Blender High-shear Blender

Blender Roller compaction Milling

Drivers for Implementation to Drug Product Manufacture

266 Burcham · Florence · Johnson

Continuous Powder Blending

API Excipient 1 Excipient 2 Excipient 3 Excipient 4 IR

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 267

shown by Raman and near-infrared (NIR) spectroscopy to undergo an undesirable transforma-

268 Burcham · Florence · Johnson

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 269

Emerging Technologies for Drug Product Manufacture

Co-spray drying. Co-spray drying offers an alternative to traditional granulation techniques.

270 Burcham · Florence · Johnson

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 271

INTEGRATION OF DRUG SUBSTANCE AND DRUG

COMPARISON OF DRUG SUBSTANCE TO DRUG PRODUCT

272 Burcham · Florence · Johnson

NaOH Fumaric acid Silicon dioxide

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 273

274 Burcham · Florence · Johnson

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 275

276 Burcham · Florence · Johnson

Manufacturing Symposium. J. Pharm. Sci. 104:850–64

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 277

278 Burcham · Florence · Johnson

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 279

280 Burcham · Florence · Johnson

systems. J. Pharm. Sci. 86:1–12

www.annualreviews.org • Continuous Manufacturing in Pharmaceuticals 281

Autobiography of Ronald W. Rousseau

Continuous Manufacturing in Pharmaceutical Process Development

Nanoscale Optical Microscopy and Spectroscopy Using

Cumulative Index of Contributing Authors, Volumes 5–9 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451

An online log of corrections to Annual Review of Chemical and Biomolecular Engineering