30 SpectrOSCapy 23(9} September 2008 www.spectroscopyonline.

com

The Use of Process Analytical

Technology in Biofuels
Production
Biofuels such as biodiesel and bioethanol are now the main alternatives to fossil fuels in
one of the most pollutant human activities: transportation. Presently, feedstocks for bio-
fuels production are all of natural origin, are subject to uncontrolled seasonal variations,
and for economic reasons, pricing and availability of these feedstocks follows the
dynamics of the grain commodity markets. Here we report on the use of process analyti-
cal technology (PAT) in the above context. We show that PAT is capable of mapping raw
materials, fingerprinting process trajectories, and calibrating for the most important
quality specifications, both for individual chemical and physical attributes or for com-
bined quality attributes, thus leading to more consistent and economically viable
processes.

Jos C. Menezes, Pedro Felizardo, and M. Joana Neiva-Correia

P rocess analytical technology (PAT) (1) is a landmark
in the acceptance of process systems engineering tools
in modern biopharmaceutical and pharmaceutical
manufacturing. It is often said that PAT has already matured
in many other processing areas and that it is up to industries
like pharma to adopt those best-established practices. In
actuality, this is not completely true. Many chemical
processes use on-line monitoring for control purposes, but
the in-process control specifications (IPC) measured are
typically univariate and limited in information content
about the product and process {for example, temperature or
single compositions). By contrast, the aim of PAT is to use
high-level quality specifications typically obtained by multi-
parametric in-situ, on-line techniques such as process spec-
troscopies (for example, manipulating a process based upon
the entire sample matrix spectra and not a single compound
signal).
Furthermore, any PAT strategy developed for a dynamic
process whose trajectory strongly depends upon the starting
conditions (for example, complex and natural raw materials.
as in biofliel production) must take into account information
from previous processing stages if a precise endpoint is to be
achieved consistently after processing.
One possible and obvious general strategy to develop PAT
applications should therefore involve monitoring intensifica-
tion (that is, multiple quality specifications measured simul-
taneously and morefrequentlyin all relevant processing steps);
tools to pull together the information of several processing
batches (building a design space); and systems engineering
tools to analyze several runs of the entire process (thus de-
scribing the interactions between process components). We
have developed and applied such a strategy successfully in the
biomanufacturing of small and large molecules for some years
already (2,3) and have tested its general value in other processes
also involving natural and complex starting materials (crude
oil refining, biodiesel production, beer brewing, and so forth)
(4-7).
Biofuels are produced in a sequence of large batch opera-
tions involving multiple phases, a biochemical reaction, and
several separation-purification steps. The final product must
 www.spectroscopyonline.com
comply with multiple quality specifica-
tions despite the variabity in the raw
materials and the complexity in the unit
operations used in their processing.
Overall, biofuels production is amenable
to PAT implementation in the same
manner as a pharmaceutical process
given the correlation between stages and
the carryover of fingerprints or even
more so if one examines process eco-
nomics and its associated logistics. In
fact, a recent study by the U.S. Depart-
ment of Agriculture (8) has shown that
storage tanks make up for one third of
new biodiesei facility construction costs.
So streamlining raw material acceptance
and final product release (shipping out)
would mean that storage capacity and
its associated costs couid be cut down
from about a month to a few days. Also,
the final product cost structure shows
that there is a strong case in favor of
using PAT throughout raw materials
qualification, production process mon-
itoring and supervision, and end-prod-
uct multiparametric release (Figure 1).
The logistics associated with the produc-
tion of large quantities of a commodity-
type product by batch operations, with
strict quality specifications, increases the
need to reduce end-product variability
as well to use fast multiparametric qual-
ity control to achieve safe and fast release
and reduce inventory. Once an overall
quantitative description of a process is
in place, a PAT strategy for closed loop
control and overall process management
can be devised based upon the elements
in Figure 2, applied on a plantwide per-
spective.
Process Monitoring
Large volumes of highly informative
data are of course much easier to ob-
tain with on-line multiparametric tech-
niques (for example, in-situ spec-
troscopy) than with fast at-!ine
monoparametric techniques. Multi-
parametric techniques, which more
than monitoring a limited number of
parameters are able to take a whole
sample's matrix fingerprint, have the
potential to capture the combined ef-
fects of important chemical and phys-
ical attributes of a sample. One such
technique is near-infrared spectroscopy
(NiR), which isa widely known method
September 2008 23(9) SpectfOUopy 31
HjO (mg/kg) MeOH (mg/R^) C18:3 (%)
<500 <2000 < 12
How PAT can be important:
Investment costs (storage) and profit margins
Raw material Raw material Product
Vegetable oils Biofuel
Vegetable oils
Algae oils Algae oils
Waste frying oils Waste frying oils
Animal fats Animal fats
Sugar feedstock Sugar feedstock
Figure 1: Biofuels production from a systems engineering PAT perspective with a focus on quality
assurance (QA) and quality control (QC) for improved economics
for its capacity for accurate process
monitoring of complex matrices (9).
NIR is a highly versatile technique with
a well-established process monitoring
track record in several processing in-
dustries. Provided that a person profi-
cient in chemometrics is involved, who
also knows about the process (that is,
its dynamics and main influencing fac-
tors and sources of variability), robust
Figure 2: PAT constitutive blocks within a risk-
and accurate calibrations can he estab-
based/iean-manufacturing context
lished that will be valid across different
process scales or simar-in-nature pro-
cessing steps (3-7,10) (Table I). The Process Supervision
road less traveled in this area though is Process supervislt)n takes into consid-
the use of NIR as a process fingerprint- eration several types of variables at once
ing technique, taking advantage of its (that is, it is multivariate) as opposed to
intrinsic ability to capture a sample's monitoring. Process supervision is not
chemical and physical information, thus only monitoring in perspective (the in-
avoiding the need for calibration devel- coming monitored data point for a vari-
opment and making the most of the able is plotted and compared with that
availability of on-line in-situ measure- variable's history along the batch); it is
ments for batch supervision (Figure 3). a high-level way of comparing the run-
31 Spectroseopy 23(9) September 200a www.spectroscopyonline.com

Soybean oil
Palm oil
Co za c

Iodine index

-0.10 -0.05 0.00 0.05 0.10

Scores on PC 1 (70.0%)
Figure J: Fourier transform-NlR fingerprinting of different raw materials, showing intra-origin variation associated with different feedstocks
processing, enables adulteration detection or better raw material selection (for example, for increased iodine index). (ABB MB-160 with a SOLVAS
transflectance probe).

oversight of specific industries. It seems,

liowever, that the pharmaceutical indus-
0,10
Vegetable try is misguided by imposing constraints
? In-process oil in the operating space (space spanned
samples
by operating and manipulated variables)
(M \ as opposed to achieving the highest per-
' ^ \ ^
't 0.00 * formance possible in the control space

t
res or

(imposing constraints around the de-

S-o,os
1/1
n 1 rt
-U,1(J^
-0,10
Figure 4: Process spectroscopy-based monitoring and supervision of reaction completion, (ABB
MB-160 with a SOLVAS transflectance probe).
ning batch against previous batches (for
example, mapping the running batch
trajectory over the nominal batch tra-
jectory). While taking a batch perspec-
tive by analyzing several historical
batches in a consolidated manner, PAT
as a process supervision tool has signif-
icant potential in process analysis and
understanding. If in addition to histor-
ical batches with built-in nominal vari-
ability (acceptable variability) non-nom-
inal batches are available (that is, out of
specification, abnormal, or designed
,1
-0,05 0,00 0,05 0.10
Scores on PC 1(92.0%)
well established in the chemical process-
batches), a broader operating region can
be explored. In this case, a very reliable
picture can be drawn of the process by
establishing the interrelation among
very diverse process and product vari-
ables, highlighting different phenom-
ena and process kinetics (process
phases). Essential concepts in the PAT
context are those of quality by process
design, and design, operating, and con-
trol spaces (1,11). The application of
such concepts offers different opportu-
nities depending upon the regulatory
sired multivariate target made by mul-
tiple quality specifications). The biofuel
industry, on the contrary, has not yet re-
alized the enormous potential in lean-
ing its manufacturing operations toward
PAT and the correct control paradigm
ing industries for at least 20 years: that
operating variables are to be manipu-
lated based upon monitoring the mul-
tivariate quality specifications control
space ( 1 ! ). We have demonstrated at in-
dustrial-pilot conditions the capabili-
ties of in-process NIR for both process
monitoring and supervision (10) and in
similar to real conditions in large
enough design spaces (4-7). Figure 4
shows that from start to end, the trans-
esterification step can be monitored by
in-situ on-line NIR.
 www.spectroscopyonline.com
PAT: A Systems Perspective
As an overall picture emerges of the en-
tire multistage process, based upon a
more accurate picture of its constitutive
unit operations, integration of this dis-
tributed knowledge into a plant- or
process-wide perspective is of signifi-
cant value in the PAT context. In fact,
this can enable the anticipation and
.solving of problems that might have a
negative impact downstream (for exam-
ple, accepting or rejecting a certain raw-
material lot or simply deciding on a
blend of different lots) (3). Finally, the
use of PAT is not limited to existing
processes and products but is especially
attractive in the scale-up and research
and deveiopment of new processes and
products. PAT is especially effective in
scale-up. Because PAT involves consid-
eration of all monitored variables and
not only an empirical selection of some
of those variables, and since in-process
monitoring techniques are normally
multiparametric (for example, NIR
spectra of a whole sample), they will be
more suited to capturing scale effects
present in the sample's matrix that show
up clearly in a consolidated multivari-
ate analysis of quality and operating
variables. This, in turn, will help the
skillful engineer or scientist to pinpoint
and solve scale-up problems, resulting
in much faster and safer process devel-
opment efforts.
Conclusion
The potential of PAT in manufacturing
areas other than the pharmaceutical in-
dustry is far from properly exploited,
mainly due to the insufficient use of in-
trinsically multiparametric monitoring
tools (i.e., NIR), the disregarding or in-
effective use of available process infor-
mation (data on historical batches or on
raw-material lots), and the lack of a
process- or plant-wide perspective for
the proposed PAT strategy. Figure 5
points Out possible answers to Figure 1,
thus summarizing what can be achieved
with PAT in biofuei production.
Acknowledgments
PF thanks The Portuguese National Sci-
ence Foundation (FCT) for his Ph.D.
grant (SFRH/BDE/15566/2005). We
thank three of the major biodiesel sup-
September 2008 23(9) Spectrostopy 13
PAT-based biofuel production
Assessing raw-materials variability
-Complex raw-materials (RM): fast qualification schemes (QC)
-Opportunity for RMs supervisory systems (QA)
-Formulating mixed lots of RMs for targetd specifications
Handling RM variability during processing
-Monitoring quality attributed in-process at-line or on-line
-Process supervision (for example, multivariate trajectories)
-Controlling critical to quality parameters
End-product quality control
-Biofuels multiparametric QC (for example, conformity index)
-Blending operations for targeted specifications
Figure 5: The opportunities for PAT thinking in biofuel production.
pliers in Portugal. Iberol SA and Space using multivariate near infrared spec-
SA for supplying industrial samples of troscopy models (submitted for publi-
biodiesel and raw-materials oils; Bioveg- cation in J. NIR Spec. 2008).
etal SA for allowing us to test in their (7) P. Baptista, P Felizardo, J.C. Menezes,
industrial pilot-plant some of our pro- and MJ. Neiva-Correia, Multivariate
posed concepts. We dedicate this paper near infrared spectroscopy models for
to our past and present M.Sc. and Ph.D. predicting the iodine value, CFPP, kine-
students whose names appear in our ref- matic viscosity at 40 "C and density at
erences. 15 "C of biodiesel, Talanta (2008) (in
press, doi: 10.1016/j.talanta.
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