Biochemical Engineering Journal 133 (2018) 219–239

Contents lists available at ScienceDirect

Biochemical Engineering Journal

journal homepage: www.elsevier.com/locate/bej

Review

Challenges and opportunities in lactic acid bioprocess design—From

economic to production aspects
Regiane Alves de Oliveira a,∗ , Andrea Komesu b , Carlos Eduardo Vaz Rossell c ,
Rubens Maciel Filho a
a
Laboratory of Optimization, Design and Advanced Process Control, School of Chemical Engineering, University of Campinas—Unicamp, 500 Albert Einstein
Av, Campinas, 13083-852, Brazil
b
Department of Marine Sciences, Federal University of São Paulo—UNIFESP, 144 Carvalho de Mendonça St, Santos, 11070-100, Brazil
c
Interdisciplinary Center of Energy Planning (NIPE), University of Campinas - Unicamp, 330 Cora Coralina St, Campinas, 13083-896, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Lactic acid is an already consolidated bioproduct in the world market. It has many applications, such as:
Received 9 August 2017 the production of biodegradable polymers, substitution of plastics from oil, and new uses in medicine.
Received in revised form 28 February 2018 Besides this, new applications are being discovered every year, especially in chemical industries as a
Accepted 3 March 2018
building-block molecule. The lactic acid market is in constant growth and the fact that the final products
Available online 7 March 2018
are able to comply with environmental laws as green, renewable and biodegradable products contributes
to the tendency of continuous growth in the next few years. With all of this in mind, this paper will explore
Keywords:
the main aspects of the sector, as well as market tendencies, production chain, and innovation.
Lactic acid
Applications © 2018 Elsevier B.V. All rights reserved.
Global market
Feedstock
Lactic acid bacteria
Downstream

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
2. New lactic acid applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
3. Global market and techno-economic aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.1. Corbion–Purac (Netherlands) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.2. Galactic (Belgium) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
3.3. NatureWorks LLC – Cargill (USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
3.4. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
4. Lactic acid biorefineries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
5. Life-cycle assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
6. Fermentation feedstock for lactic acid production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
6.1. Starchy materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.2. Lignocellulosic biomass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.3. Microalgae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.4. Food waste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.5. Glycerol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.6. Feedstocks concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
7. Lactic acid bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
7.1. Nutritional requirements for lactic acid bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

∗ Corresponding author. Tel.: +55 19983490710.

E-mail address: raoliveira@feq.unicamp.br (R. Alves de Oliveira).

https://doi.org/10.1016/j.bej.2018.03.003
1369-703X/© 2018 Elsevier B.V. All rights reserved.
220 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239

7.2. Choosing micro-organisms – desirable characteristics of Lactobacillus sp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

7.3. Metabolic pathways for lactic acid production by Lactobacillus sp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
7.4. Main metabolic characteristics of Lactobacillus sp. under stress conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
7.5. Genetically engineering lactic acid bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
8. Lactic acid separation and purification – downstream processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
WEB references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

1. Introduction ogy, chemistry, genomics and molecular biology to work together,

in order to reach a sustainable and economically viable production
The lactic acid molecule contains a chiral carbon and may be chain of lactic acid for supplying the market.
found in two different isomeric forms: L and D. The proportion of
each isomer confers different physical properties to the final prod- 2. New lactic acid applications
uct. It makes enantiomeric purity a crucial factor for lactic acid
industrial production, as in the manufacture of biodegradable plas- Lactic acid has a wide range of industrial applications as shown
tics and polymers as poly(lactic acid) (PLA). The D-lactic acid isomer in Fig. 1. It is a high value-added product that has been gain-
in high doses is considered harmful to humans and can cause aci- ing market share with each year [17–19]. Recently, it has been
dosis or de-calcification [1,2]. Therefore, the L-lactic acid isomer is highlighted in the environmental, ecological, and medical areas,
preferred by the pharmaceutical and food industries [3]. This fact especially as a building-block molecule. In addition, it has been used
corresponded to a higher demand for the product at the beginning for a long time in the food industry. When lactic acid is produced
of the 2000s [4]. Demand continues to increase due to many medical by homo-fermentation, it is possible to achieve high selectivity and
applications that make use of PLA [5]. conversion with no CO2 delivery.
It is well known that chemical production leads to racemic mix- In the food industry, lactic acid is well known because it can be
tures of DL-lactic acid [4,6–8]. This fact makes it impossible to used in various forms as an additive. It may also result from the
control the chemical and physical properties of the final product. It presence of a contaminant micro-organism in some types of food.
is also unsuitable for use in the food, pharmaceutical, and medical It is used mainly in the isomeric form L, since this is the only form
industries. that the human body is adapted to assimilate [11,13]. It is employed
Some industries require a high enantiomeric purity of lactic acid as an additive, acidulant, flavouring and emulsifier, apart from also
for specific applications. This fact also contributes to lactic acid inhibiting sporulation of bacteria in processed foods [3,20–22].
production via fermentation being more attractive instead of chem- For the pharmaceutical industry, lactic acid is used in the pro-
ical production. This is especially relevant when lactic is used as a duction of cosmetics, formulating ointments, anti-acne solutions,
monomer for polymers applied in the medical, pharmaceutical and humectants, and controlled-release drugs [1,3,20,21,23]. In this
food industries.
Lactic acid production via fermentation has several advantages
when compared to chemical syntheses, such as: low-cost sub-
strates, relatively lower temperatures, lower energy consumption,
better environmental concerns, high purity [9–11] plus ease of cre-
ating products with tailor-made characteristics.
Industrially, about 90% of all lactic acid produced worldwide is
derived from bacterial fermentation [12–15]. The most widely used
method of lactic acid production is batch fermentation. The yield
of lactic acid in this case is 90–95% w/w, according to the initial
sugar content used [5]. During lactic acid fermentation, the main
parameters to be considered are: pH, temperature, initial substrate
concentration, and nitrogen concentration. These variables directly
affect the rate and therefore the performance of the fermentation
[4,16].
The lactic acid industry has many challenges to be overcome
in the following years. In regards to the fermentation process, the
biggest challenges are: the price of the substrates, food compe-
tition, strains, inhibition due to substrate or product, and waste
generation. In addition, the process of separation and purification
is crucial for this development, since many applications require a
product with high purity, such as the medical and pharmaceuti-
cal areas. Along with these challenges come environmental issues,
with increasingly severe legislation regarding the use of solvents
and waste generation, seeking a sustainable production chain.
This paper intends to discuss the current state of lactic acid pro-
duction and the importance of the connection between distinct
areas in the development of a productive chain of lactic acid. It
shows the importance of connecting the areas of engineering, biol-
Fig. 1. Lactic acid industrial applications.
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
case, the L-lactic acid isomer is also the most used because of its
compatibility with the human body.
In the chemical industry, lactic acid has gained ground every
year. Its versatility of applications has created a positive outlook
for investments, enabling the emergence of new products based on
the molecule (Fig. 1). It has a wide range of applications, such as the
production of organic solvents [3,20] and building-block molecules
[24]. Furthermore, motivated by environmental concerns at the end
of the 90s, lactic acid has emerged as a potential chemical com-
pound for the production of renewable and biodegradable plastics
from sugar fermentation [1,3,25–27]. The highlight of renewable
and biodegradable plastics from lactic acid has existed since the
early 2000s in the production of poly(lactic acid) (PLA) [28] for
production of food packaging and many plastic utensils, which
replaced products made from raw petroleum [1,29]. The monomer
for the production of PLA provides a wide versatility of use and
favourable characteristics, such as: biodegradability, biocompati-
bility, elasticity, and also a well-controlled release profile of drugs
[23,30]. PLA is considered one of the most promising biodegrad-
able plastics [28], mainly due to its high chemical resistance, which
is advantageous for the manufacture of fibre and film, while its
heat resistance is favourable for the production of many uten-
sils, such as cups and trays [31,32]. However, its use in industry
when produced via the biochemical pathway is still restricted
due to the high cost of lactic acid production when compared
with petrochemical compounds [33]. These expenses are always
associated with production steps such as fermentation and down-
stream.
Another promising field of application for lactic acid at the
moment is the medical area, with use in tissue regeneration,
surgical sutures, fracture fixation, implants and ligaments, car-
tilage repair, meniscus, bone replacement, and oral surgeries.
These uses are already approved by the American Food and Drug
Administration (FDA) [23,34,35]. PLA can be also used in the
form of screws, pins, clamps, and boards. The main advantages
of PLA prostheses and implants are their high strength, lack of
rejection, and the ability of being completely reabsorbed by the
body. It makes surgeries to remove patients’ implants unneces-
sary [36], which reduces expenses with medical procedures and
facilitates patient recovery. For these applications, the fermen-
tation route is very suitable. In this case, products with specific
characteristics are required, and it depends on the lactic acid iso-
mer used. PLA and its copolymers have been in clinical use for
many years, and have been proven to be biocompatible and safe
[23].
In summary, lactic acid has applications in the following sectors:
personal and home care, biodegradable plastics, as a building-
block for poly(lactic acid) (PLA), as a biodegradable polymer,
food and beverage (fermentation agent, food preservative and
de-contaminant, nutrition fortifier, acidulant, flavour enhancer,
acidic nature of selected food-grade organic acids), pharmaceuti-
cals, mosquito repellent, many industrial applications, and animal
health. The newest achievements are related to applications
of heteropolysaccharides (HePS), immune-stimulant, antioxidant,
cryoprotectant, pre-biotic activity, and viscosifier (http://markets.
businessinsider.com).
Key companies are constantly introducing new uses and prod-
ucts in the market as “Graphene-enhanced PLA Filaments for 3D
Printing; PLA Formulation for 3D Printing Filament Providing High
Impact Strength and Heat Resistance; PLA Resin from Second Gen-
eration Feedstocks; a Unique, High-Quality grade L-Lactic Acid”.
Also, NatureWorks claims to be developing a commercial scale
methane to lactic acid conversion (http://markets.businessinsider.
com).
221
3. Global market and techno-economic aspects
Lactic acid is commonly sold as an 88% solution [37]. The
price varies with the application (e.g., food, pharmaceuticals, and
PLA) and a range of $1.30–$2.30/kg was reported in 2011, nowa-
days reaching around $3.0–$4.0/kg (https://www.pharmacompass.
com). In general, the price of lactic acid will follow the price of
commodity starch and sugar feedstocks used for fermentation [37].
The global lactic acid market required 1,220.0 kt in 2016. With
annual growth of 16.2%, it is expected that this demand will reach
1,960.1 kt in 2025. This should represent USD 9.8 billion in the
global market. Market studies point out that the largest and fastest
growth in this period will be for medicines and perfumes in the
Latin America and the Asia Pacific region. Latin America’s lactic
acid market is experiencing significant growth – 19.2% annually
– mainly because of the growth of the cosmetics industry in Brazil
and Argentina. As with lactic acid, PLA demand should grow, reach-
ing USD 6.5 billion worldwide by 2025. The reason for this would be
the Asia Pacific PLA market growth rate of 22.4% annually, because
of the establishment of various food and beverage as well as cos-
metics manufacturing units, particularly in India and China (http://
www.grandviewresearch.com).
According to another source, the lactic acid market represented
USD 1,275.00 million in 2014, and is expected to reach USD 4,129.19
million by 2022. This would represent an annual growth of 16.9%
from 2015 to 2022. In terms of volume, 2014 required around 36 kt
more lactic acid than 2013 and is expected to reach 1,844.56 kt by
2022, with annual growth of 12.9% (http://www.wtva.com).
By 2019, the lactic acid market is expected to exceed USD 3,577.5
million. The figure expected for PLA is USD 4,840.1 million. Europe
should represent the main market for PLA, while the Asia Pacific
region should represent the fastest growing market (http://www.
bioplasticsmagazine.com).
In fact, all the analysts in the sector have made positive predic-
tions for both the lactic acid and PLA markets for the next years.
There is a sense of optimism from producers, especially due to
the fact that new applications have been appearing constantly in
the market. Only in 2017, Galactic, one of the largest producers
in the world, announced five new products on its website (https://
www.lactic.com). One of the major drivers influencing the growing
market is expected to be the increasing preference of consumers
towards eco-friendly packaging, leading more brands to adopt
biodegradable materials for packaging [37]. Nevertheless, high pro-
duction costs will prove to be a major challenge, as crude oil-based
polymers are less expensive when compared to PLA (http://www.
prnewswire.com).
Techno-economic evaluations of new processes have been
developed for the market, and have shown generally positive
results for the implementation of such new processes regarding
lactic acid production. A study regarding different applications for
food waste concluded that a biorefinery producing plasticizer and
lactic acid would be economically feasible, with annual net prof-
its of around US$ 422,699, a present net value of US $ 3,028,000,
with a payback period of 7.56 years and an internal rate of return
of 18.98% [38]. In another case, the most suitable scenario was
the co-production of lactic acid and ethanol, also in a biorefinery
sense [39]. Many techno-economic evaluations are developed for
different processes and with different substrates [40–45], and for
most of them, the most expensive income is related to substrates or
nutrients [40,44,45], which are also related to the geographic loca-
tion of the production facility. Details from some techno-economic
evaluations from literature are shown in Table 1.
A recent study found the minimum selling price for lactic acid
should be 0.56 US$/kg [41]. In this case, the authors used a final
222 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239

Table 1
Techno-economic analysis of lactic acid production from renewable resources according to literature.

Substrate Downstream process Overall scenario Minimum sell price Reference

Lignocellulosic residues,
sugarcane bagasse and
leaves.
Pretreatment: Steam explosion Cellu-lignin solid fraction
Sugarcane juice
Uncontrolled pH
Sweet cheese whey ultrafiltration permeate NaOH
Whole-wheat flour NaOH
Biodetoxified corn stover.
Pretreatment: Diluted acid and enzymes Ca(OH)2
Hemicellulose liquid fraction
Ca(OH)2
Ca(OH)2
Hemicellulose liquid fraction
Acid tolerant bacteria
Cellu-lignin solid fraction
Acid tolerant bacteria
Hemicellulose liquid fraction
Mg(OH)2
Cellu-lignin solid fraction
Mg(OH)2
Reactive distillation 2nd best scenario: LA 1.30–5.00 US$/kg [42]
production rates from
cellu-lignin and Ca(OH)2
3rd best scenario: LA
production rates from
cellu-lignin and acid tolerant
bacteria
1st best scenario: LA
production rates from
cellu-lignin and Mg(OH)2
Nanofiltration The two largest cost 3.15 US $/kg, 80% (w/w), and [40]
components: raw material and 95% purity
yeast extract (6% and 87%
respectively)
Ultrafiltration, ion exchange, Fermentation step requires the 1.25 US$/kg, 50% (w/w), 99% [44]
reverse osmosis, and vacuum highest operating cost (47%), purity, and racemic mixture
evaporation yeast extract is the major
contributor to the operating
costs (25%)
Ultrafiltration, electrodialysis, The costs of raw material, the 0.83 US$/kg, 70% (w/w) [45]
and evaporation NaOH in the fermentation step,
and the conversion of lactate to
LA using electrodialysis were
the major production cost.
Batchwise step was
economically better than
continuous fermentation.
– Not considering C5 [41]
0.56 US$/kg, 88% (w/w)
consumption. Highest
operating cost was celullase

lactic acid concentrated at 88% (w/w), produced from corn stover
hydrolysate. The pretreatment used was diluted acid, followed
by an enzymatic hydrolysis. They did not consider C5 sugar con-
sumption, and the acid neutralization was made using Ca(OH)2 .
Evaluating this process, the authors described cellulase as the most
expensive step in the entire process [41].
Regarding the downstream process, the traditional process for
lactic acid recovery and purification is still used: fermentation broth
is neutralized with calcium hydroxide, which forms calcium lactate
salt; the solution is filtered to remove microbial cells and evapo-
rated to concentrate; sulphuric acid is added to hydrolyse calcium
lactate, resulting in insoluble gypsum; methanol is added to ester-
ify the lactic acid and the final product is purified by distillation
and hydrolysis [37]. Many different possibilities are reported in the
literature [37,46], but the majority still face problems with costs. A
possible substitute for the traditional process is the reactive distil-
lation [47]. This process has been described in the literature as one
of the most promising on an industrial scale, also presenting some
cost advantages [42,48]. The process consists of esterification of
lactic acid with methanol or another alcohol, followed by hydrol-
ysis of the separated methyl lactate, resulting in pure lactic acid
obtained from the bottom of the reactive distillation column [47].
In the techno-economic evaluation performed by Daful et al. [42],
the authors considered the approach using ethanol in an integrated
biorefinery context with very successful results.
To boost the competitiveness of the lactic acid industry with
products from oil, the cost must be kept down, in consistency
with products from fossil sources [4,29]. Exceptions would occur in
cases with more specific applications, requiring properties of lactic
acid obtained by fermentation, such as products with higher added
value [49,50].
To sum up, since the 90s lactic acid has been gaining ground
in the market through its diverse applicability. Large companies
have dedicated themselves to its production and use in several
industrial areas. Industry-leading companies are located in devel-
oped countries, focusing their resources on R & D to serve the main
consumer markets. Among them, the following stand out (sorted
alphabetically):
3.1. Corbion–Purac (Netherlands)
This company is a well-known lactic acid producer on the mar-
ket. It supplies different sectors, from food, chemicals, plastics
(made from PLA), biomedicine, and beyond (http://www.corbion.
com, A). The manufacturer produces L-lactic acid and D-lactic acid
with high purities to be used in pharmaceutical and PLA sectors
(http://www.corbion.com, B). The company claimed the patent for
gypsum-free lactic acid production in 2014, and has also been
working on the production of lactic acid for PLA from second-
generation feedstocks (http://www.corbion.com, C). The market
of Corbion is divided into: 74.2% (net sales) for bakery supplies,
23.4% for biochemical products, and 2.4% to others. The net sales
are distributed across the Netherlands (11.2%), Europe (7.2%), North
America (63.3%) and others (18.3%) (https://www.euronext.com).
3.2. Galactic (Belgium)
Operating for more than 20 years, this company is one of the
leaders in biotechnology, mainly in the food, feed, personal and
healthcare, and industrial markets. One of the aims of lactic acid
fermentation and the development of many other derivatives is to
create sustainable, innovative and health-friendly solutions in the
field of food safety, nutrition and green chemistry (https://www.
lactic.com, A). In constant expansion, the release of new products
in 2017 is related to fish and seafood manufacture, facial lotions
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
and hand creams, bakery products, biossolvents, beverages, and
detergents (https://www.lactic.com, B).
3.3. NatureWorks LLC – Cargill (USA)
Considered one of the world leaders on lactic acid supply, using
the brad IngeoTM , the facility in Nebraska, USA, has a nameplate
capacity of 140,000 metric tons of IngeoTM biopolymer for rigid
and flexible packaging solutions, food service ware, health and per-
sonal care, durable products in home, appliance, and electronic
categories, and 3D printing filament (http://www.natureworksllc.
com). The company recently announced Thailand as a preferred
location for a second manufacturing plant, although the main R &
D facility will remain in the USA (https://www.industryintel.com).
3.4. Others
ADM; B&G; BASF; Cellulac; Danimer Scientific; Direvo Indus-
trial Biotechnology; Dow; ESUN; Futerro; Henan Jindan Lactic
Acid Technology; Hisun Biomaterials; Jiuding Biological Engi-
neering; Myriant; Musashino Chemical; Piaoan; Nantong Jiuding
Biological Engineering; Pyramid Bioplastics; Shenzhen BrightChina
Industrial; Synbra Technology; Teijin; ThyssenKrupp Industrial
Solutions; Tongjieliang; Uhde Inventa-Fischer; Yangtzelabre; Zhe-
jiang Hisun Chemical are some of the companies with activities in
lactic acid production (https://firstnewshawk.com) [37].
Musashino Chemical Laboratory, Ltd. in Japan is a producer of
synthetic lactic acid, with a total production of 7000 metric tons
per year, or about 2% of global lactic acid production [37].
4. Lactic acid biorefineries
In the last years, biochemicals have rapidly gained market share,
competing with traditional oil resources, since petrochemicals are
finite [51] and sometimes suffer price fluctuation that is not con-
ducive to successful economic planning.
Nowadays, the biorefinery concept embraces wide definitions
[52,53]. In general, it can be defined as a facility with a range of tech-
nologies able to “break” the biomass into building-block molecules,
which can be converted into value-added products, biofuels, chem-
icals, heat, and power [54,55]. The aim of this bioindustry is to be
competitive in the market and lead to the progressive replacement
of oil refinery products. This concept has been frequently associ-
ated with environmental concerns. There are three main drivers
for the development of biorefinery technologies: climate change,
energy security, and rural development [55].
Almost all types of biomass feedstocks can be converted into
different classes of biofuels and biochemicals through conversion
technologies. Biorefineries will most probably encompass a whole
range of different-sized installations due to the location of biomass
resources [55]. Biorefineries can be referred as first (1G), second
(2G), or third (3G) generation, according to the substrate used as
raw material [52]. 1G-biorefineries are those that use food crop
resources such as sugar and oil; 2G-biorefineries process non-food
raw material such as agricultural residues, wood and energy crops;
3G-biorefineries have been referred to those using algae biomass
as a feedstock [52].
Biorefineries for biochemical production have been looking for
alternative substrates, such as biomass for 2G products. Lignocel-
lulosic biomass is the most abundant source of carbohydrate in the
world, and for this reason it has received a great amount of attention
from biorefineries in the past few years.
The lactic acid-based biorefineries may exploit various types
of feedstock, such as sugar cane [56,57], sweet sorghum [58,59],
agricultural food waste [60,61], wastes from bioethanol and beer
productions [62], municipal organic solid waste [63], corn stover
223
[26], food waste [64,65], algal biomass [66], wheat bran [67], cof-
fee pulp [68], and others. Details of some processes are shown in
Table 2.
A fundamental aspect regarding these biorefineries is connected
to the fact that the processes developed and the goals of the prod-
uct are extremely dependent on the location of the site [55]. This is
one of the drivers of the way a biorefinery will operate to achieve
the economic, social and environmental goals. In addition, one of
the main challenges facing the growing bioeconomy is to develop
efficient and cost-effective green technologies for sustainable pro-
duction of commodity items from biomass, such as lactic acid.
Some examples proposing the integration of lactic acid biore-
finery with other products are shown below:
• Brewer spent grains on a biorefinery concept to produce lactic
acid, xylitol, activated carbon, and phenolic acids. The authors
performed full mass integration on water and full energy inte-
gration to achieve a configuration with the best economic and
environmental performance [43];
• Food waste enhancement using fungal hydrolysis, and microalgae
cultivation. The authors proposed producing plasticizer and lactic
acid which were found to be economically feasible [38];
• Sugarcane lignocellulose biorefineries annexed to a typical sugar
mill to co-produce ethanol, lactic acid, and/or electricity. Lactic
acid co-production with sugar was the most economically attrac-
tive scenario. However, ethanol production from xylose and lactic
acid from glucose was found to be the most desirable biorefinery
scenario, by balancing financial and environmental considera-
tions [69];
• Integrated biorefinery system combining the production of
bioethanol from winter wheat-straw and lactic acid from alfalfa.
In this case, the authors performed the exchange of useful energy
necessary for biomass processing in the production chain, con-
cluding that this approach had a better performance in the LCA
impact categories than both standalone systems [70].
5. Life-cycle assessment
According to the definition of ISO 14044:2006 (www.iso.org),
life-cycle Assessment (LCA) is a tool to assess the potential
environmental impacts (natural environment and human health)
and resources used throughout a product’s/service’s life-cycle. It
includes the process from the raw material acquisition, produc-
tion and use phases, and waste management such as disposal
and recycling [71–74]. The phases of an LCA study involve goal
and scope definition, a life-cycle inventory analysis (LCI), life-cycle
impact assessments (LCIA), and interpretation of generated data.
The results from an LCA study can be used in many different areas,
including product creation and development, strategic planning,
public policy creation, marketing, and others [71,72].
There are two main different methods for LCA: attributional
(ALCA) and consequential (CLCA). ALCA focuses on describing the
environmentally relevant physical flows to and from a life-cycle
and its subsystems. Separately, CLCA aims to describe how envi-
ronmentally relevant flows will change in response to possible
decisions [71].
LCA studies are more common for poly(lactic acid) (PLA) than
for the lactic acid production chain. The most recent studies about
the production of lactic acid from lignocellulosic material, lac-
tic acid/ethanol biorefinery and PLA production chain are shown
below.
Considering the lactic acid production from sugar cane bagasse
and leaves, Gezae Daful and Görgens [42] evaluated a cradle-to-
grave LCA analysis of six different scenarios, as shown in Table 1:
1-Hemicellulose liquid fraction and Ca(OH)2 ; 2-Cellu-lignin solid
 224
Table 2
Literature reports of lactic acid production sorted by higher titer.
◦
Microorganism Product Method Substrate Nitrogen source pH control C Titer Productivity Yield Reference
−1 −1
g/L gL h g/g

Sporolactobacillus sp. CASD D-LA Fed-batch Glucose Peanut meal 5.0–6.0 CaCO3 42 226.00 4.40 0.840 [185]
Bacillus sp. WL-S20 L-LA Fed-batch Glucose Peanut meal 9.0 NaOH 45 225.00 1.04 0.993 [186]
Bacilus coagulans C106 L-LA Fed batch Xylose YE 6.0 Ca(OH)2 50 215.70 4.00 0.950 [100]
Lactobacillus paracasei L-LA Fed-batch Glucose – 6.0 CaCO3 37 215.33 1.79 0.990 [187]
7BL (GMO) Wood chips 99.22 2.25 0.960
Rice straw 66.67 5.27 0.970
Lactobacillus rhamnosus L-LA Fed-batch Defatted rice bran – 6.25 Ca(OH)2 42 210.00 2.56 0.937 [188]
Lactococcus lactis ATCC19435 L-LA Fed-batch Jerusalem artichoke YE 6.0 NaOH 30 142.00 – – [189]

R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239

Lactobacillus casei G-02 L-LA Fed-batch (SSF) Jerusalem artichoke Soybean flour 6.5 CaCO3 40 141.50 4.70 0.963 [190]
Bacillus coagulans XZL4 L-LA Batch Hemp hurds YE 5.5 CaCO3 50 141.00 109.00 – 0.900 0.840 [191]
(Glucose–xylose)
Bacillus coagulans LA204 LA Fed- batch (SSF) Pretreated corncob YE 6.0 NaOH 50 122.99 1.37 0.77 [192]
Lactobacillus agilis LPB 56 L-LA Batch Soybean vinasse – 6.0 Ca(OH)2 30 138.00 0.86 0.849 [193]
Bacillus coagulans LA1507 L-LA Open-fed-batch (SSF) Sweet sorghum Corn steep liquor powder 5.2–6.2 Ca(OH)2 50 111.00 1.59 0.437 [194]
bagasse
Pediococcus acidilactici (GMO) LA Batch (SSF) Detoxified corn stover – 5.5 NaOH 45 104.50 1.45 0.715 [41]
(Cellulose)
Lactobacillus plantarum (GMO) D-LA Batch (SSF) Delignified hardwood – 6.0 NaOH 37 102.30 2.29 0.879 [195]
pulp
Lactobacillus paracasei D-LA Batch (SSF) Curcuma longa waste Soybean meal 6.0 NH4 OH 34 91.61 2.08 0.690 [97]
Lactobacillus coryniformis L-LA 37 97.13 2.70 0.650
Lactobacillus pentosus LA Fed-batch (SSF) Corn stover YE 6.0 37 92.30 1.92 0.660 [196]
Bacillus coagulans JI12 L-LA Batch (SSF) oil palm empty fruit YE 6.0 Ca(OH)2 50 80.60 3.40 – [197]
bunch hydrolysate
Lactobacillus rhamnosus LA Batch (SSF) Recycled paper sludge – 5.5 CaCO3 37 73.00 2.90 0.970 [30]
ATCC7469
Streptococcus sp. LA and biogas Batch Food waste – 6.0 35 66.50 3.38 0.330 [198]
Streptococcus sp. LA Batch (SSF) Food waste YE 6.0 NaOH 35 60.50 2.16 0.810 [199]
Rhizopus oryzae L-LA Batch (SSF) Xylo-oligosaccharides – 5.5 CaCO3 40 60.29 1.00 0.600 [200]
manufacturing waste
Bacillus coagulans L-LA Batch Coffee mucilage YE 6.0 NaOH 52 45.30 4.40 0.770 [103]
Bacillus coagulans L-LA Batch Coffee pulp YE 6.0 NaOH 52 45.30 4.02 0.780 [68]
Lactobacillus paracasei KM2 L-LA Batch Whole slurry of oil YE and peptone 6.0 NH4 OH 37 40.00 – 0.895 [201]
(GMO) palm trunk
Geobacillus stearothermophilus L-LA Batch Raw potato starch YE 7.0 NaOH 60 36.62 1.80 0.660 [202]
DSM494
Lactobacillus delbrueckii LA, xylitol, activated Batch Brewer’s spent grains YE 6.0 NaOH 37 35.54 0.59 0.990 [10,43]
carbon and phenolic (Cellulose)
acids
Lactobacillus pentosus LA Heterofermentation Batch Wheat bran – 6.3 NaOH 30 18.60 0.30 0.730 [67]
DSM20314
Lactobacillus delbrueckii D-LA Batch Cassava fibrous waste YE 6.5 NaOH 37 16.15 0.90 0.500 [203]
delbrueckii NBRC 3202
Lactobacillus casei 12A LA Batch De-oiled algal Amino acids 6.5 37 11.17 – – [66]
biomass + glucose
Bacillus coagulans LA Continuous Non-sterile clarified Corn steep liquor 6.0 NaOH 50 – 3.69 0.950 [26]
corn stover

GMO: Genetically modified organism; LA: Lactic acid; SSF: Simultaneous saccharification and fermentation; YE: Yeast extract.
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
fraction and Ca(OH)2 ; 3-Hemicellulose liquid fraction and acid
tolerant bacteria; 4-Cellu-lignin solid fraction and acid tolerant bac-
teria; 5-Hemicellulose liquid fraction and Mg(OH)2 ; 6-Cellu-lignin
solid fraction and Mg(OH)2 . The process included all raw materi-
als and emissions of sugar cane cultivations, sugar mill, industrial
activities related to auxiliary chemicals, distribution of raw mate-
rials, processing of sugar cane bagasse and harvest residues for
lactic acid. Scenarios 1 and 2 demonstrated higher environmental
burdens compared to other scenarios in almost all environmental
impact categories, mainly due to the use of Ca(OH)2 and H2 SO4 that
ends up in the production of gypsum (CaSO4 ) as solid waste. For sce-
narios 3 and 4, the main contributors to environmental impacts are
the nutrients used for the strains, while for 5 and 6 they were tri-
ethylamine and Mg(OH)2 . In conclusion, the conventional process
with gypsum as solid waste proved to be the most environmentally
unfriendly [42].
In an evaluation of the impacts of a biorefinery producing
ethanol from winter wheat-straw and lactic acid production from
alfalfa using CLCA and ALCA approaches, the authors found that
the best scenario was the integration of the production chains
when compared to standalone systems. In the current study, lactic
acid was assumed to be produced from juice fraction and glu-
cose fractions from the hydrolysed mass of the press cake. The
environmental impacts considered were global warming potential,
eutrophication potential, non-renewable energy use, and the agri-
cultural land occupation. In regards to the LCA, the main benefits
were in terms of higher net savings of greenhouse gas emissions,
non-renewable resources use, and eutrophication potential [70].
In another case, polymer-grade lactic acid and the ethyl lactate
production chain from corn stover were evaluated and compared
to petrochemical platforms. In reference to LCA results, the author
analyzed life-cycle greenhouse gas emissions and fossil energy con-
sumption. Regarding the end-of-life assumption, the bioproducts
demonstrated lower greenhouse gas emissions (23–90%) and lower
life-cycle fossil energy consumption (10–72%) than fossil-derived
compounds [75].
Considering PLA production chain, Gruber [76] analyzed the
impacts compared with other plastics using an LCI methodol-
ogy. PLA production was considered, from corn to 1 and 5 years
after the start of operations at the plant, and in the long-term. As
expected, the amount of fossil fuels needed and the amount of CO2
emissions from PLA production is significantly lower than other
plastics, tending to further reduce the plant operating time. In addi-
tion, they compared the disposal of products made from PLA and
polystyrene in terms of required fossil fuels and CO2 emissions. The
fermentation of lactic acid and PLA production is an extremely effi-
cient process, which is essential for a process to become desirable
and economically viable, especially for products from renewable
resources. In all cases reported by the author, the PLA possessed
advantages compared to other plastics, since it reduced energy con-
sumption and CO2 emissions in the process, as well as allowing for
a wider range of disposal processes since it is biodegradable. PLA is
highly stable under normal conditions, but degrades rapidly when
exposed to environments with high temperatures, humidity, and
high microbial activity. This allows alternative disposal processes,
such as compositing and anaerobic digestion [76].
In the specific case of using PLA for fruit packing, the
authors used an LCA methodology in order to compare PLA-
nanocomposite (nano-clay and surfactant) packaging, pristine PLA
and polyethylene terephthalate (PET). The analysis focused in eval-
uating physiochemical and antimicrobial properties, as well as
the environmental impacts regarding the raw material acquisi-
tion, production of materials, packaging manufacture, filling of
packaging and end-of-life solutions. The results showed that PLA-
nanocomposite displayed a better performance, thus contributing
to bringing the characteristics and behaviour of PLA packages close
225
to those of PET. Regarding the LCA, even PLA-based packaging with
additives require more energy for their production, so this material
had the highest environmental performance, being both more envi-
ronmentally friendly and having a lower impact on human health.
The results still indicated that PLA-based packaging with additives
may reduce food loss through extending the shelf-life of the product
[77].
In general, the studies for PLA compounds show better envi-
ronmental results when compared to plastic from petrochemical
sources [75–78]. Furthermore, studies of LCA made specifically for
lactic acid products from large companies [79–81] showed a bet-
ter performance when compared to petrochemical ones, especially
by facilitating climate change mitigation and reducing dependence
on fossil and scarce resources while promoting the use of local and
renewable resources [78].
Finally, LCA analysis was also used for comparing different
ways to dispose the final residues from PLA: chemical recycling,
mechanical recycling and composting. In this case, the method-
ology was used to measure the environmental impact in regards
to climate change, human toxicity, and fossil depletion. The LCA
results showed that electricity consumption represents the highest
input among mechanical and chemical recycling methods. Mechan-
ical recycling presented the lowest environmental impact, followed
by chemical recycling and composting. One of the reasons for
this result is that composting does not produce PLA while the
other two recycling alternatives produced recycled polymer as an
output. Therefore, composting the material will be replaced by tra-
ditional production that will cause the impact associated with the
whole production process again. [73]. Similar conclusions were also
achieved by Hottle et al. [82].
6. Fermentation feedstock for lactic acid production
Fermentation feedstock represents a considerable part of the
production costs in the lactic acid production process, together
with nutritional requirements for the chosen fermentation micro-
organism [40,44,45,83]. Industrially, the most used genus of
micro-organisms in the production of lactic acid is Lactobacillus sp.
It possesses specific nutritional needs, such as nitrogen, vitamins,
and minerals. These nutrients are used in cellular growth mainte-
nance and lactic acid production, which are in fact associated.
There are two main bottlenecks to produce lactic acid by micro-
bial fermentation [84]. The first one is related to the high costs of
sugars used as a substrate. The second one is due to the cost of
sterilization (thermal treatment) and downstream processes (sep-
aration and purification steps) [85]. Knowing these challenges, it
is necessary to improve the production process on issues, such
as: expensive micro-organism nutritional requirements, carbon
source cost, controlling the acidity of the medium that affects
fermentation, and controlling the process to minimize product
inhibition impact. Overcoming all these barriers means achieving a
higher lactic acid production with lower costs [86], once the costs
of the substrates cannot be overcome just by scaling-up [87].
However, there are some options of feedstock that have been
tested for cost reduction in lactic acid fermentation, such as cas-
sava starch [19], cornstarch [88], fresh sweet potato [89], sugar
cane molasses [2], Zizyphus oenophlia biomass [90], white rice bran
[91,92], corn stover [84,93,94], sugarcane bagasse [2,95], coarse rice
[96], Curcuma longa biomass [97], paper sludge [98], green algae
[99], xylose [100], inulin from Jerusalem artichoke [101], mango
peel [102], coffee residues [68,103], and whey [104]. Despite the
wide variety of feedstock tested for lactic acid production, and
even presenting some promising results, most of them have prob-
lems with price, seasonality, fermentation rate, yields of lactic acid
production, and the presence of by-products [5,105].
226 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
Carbon sources currently used industrially for the production of
lactic acid consist of carbohydrates such as glucose, lactose, starch,
maltose, and sucrose obtained from sugar beet, molasses, whey, and
barley malt [5]. These substrates are already processed, which ends
up endearing the process [19], as well as competing with the food
supply. Comparative results of different fermentation processes
for lactic acid production presented in the literature are shown in
Table 2.
6.1. Starchy materials
There are a lot of starchy materials that can be used for lactic acid
production, such as: corn, maize, rice, rye, wheat, potato, barley
and cassava [106]. In general, these substrates work very well in
lactic production, especially when associated with amylolytic lactic
acid bacteria [22,107]. Their use also allows micro-organisms to
grow without presenting substrate inhibition, generally caused by
glucose [106]. However, their use presents a well-known problem,
since these materials are used for human and animal feeding. The
competition of the lactic acid industry with the food sector is the
same already demonstrated for the biofuels sector [108].
6.2. Lignocellulosic biomass
Currently, lignocellulosic biomass is the most promising sub-
strate for lactic acid production. This kind of biomass is the most
abundant material that can be used for lactic acid production
around the world. It comprehends all green biomass and a great
amount of agro-industrial residues. These materials present the
main advantage of not competing with the food supply. Besides
that, lignocellulosic materials from agricultural, agro-industrial,
and forestry sources are a potentially inexpensive and renewable
carbohydrate feedstock for large-scale lactic acid fermentation.
These materials are abundant, low price, contain a high polysac-
charide content, and are renewable [33].
Lignocellulosic materials from agroindustry include a variety
of materials such as sawdust, poplar trees, sugar cane bagasse,
waste paper, brewer spent grains, switch-grass, and straws, stems,
stalks, leaves, husks, shells and peels from cereals like rice, wheat,
corn, sorghum and barley, among many others [109]. However, the
cellulose and hemicellulose in the lignocellulose material are not
directly available for bioconversion to lactic acid, because of their
intimate association with lignin and lack of hydrolytic enzymes in
the most common micro-organisms [33].
The process of breaking down polysaccharides into consum-
able sugars can start with a pretreatment process to break the
lignocellulose structure, followed by an enzymatic hydrolysis to
de-polymerize lignocellulose to fermentative sugars [106]. The
amounts of carbohydrate polymers and lignin obtained vary
between plants and species. Also, the ratios between the sugars
in a single plant may also vary with age, stage of growth, and other
conditions. The separation of the main fractions present in lignocel-
lulose biomass is of great interest, since the fermentation process
will subsequently be performed. Also, by-products obtained during
pretreatment hydrolysis of these materials have to be considered,
since they may affect the fermentation yield [109–112], and some-
times even change the metabolic pathways of the cells [113].
The pretreatment step for breaking the lignocellulosic struc-
ture generates a range of side-products that act as inhibitors for
the ensuing process of enzymatic hydrolysis and also for fermen-
tation [113,114]. The inhibitors can be grouped into three major
categories: weak acids such as formic (from furfural degradation),
levulinic (from HMF degradation), and acetic (formed by the de-
acetylation of hemicellulose); furans as 5-hydroxymethylfurfural
(HMF) and furfural (from pentose and hexose dehydration); and
phenolic compounds (mainly from lignin breakdown) [114].
Given all this, it is clear that, although lignocellulosic biomass
is suitable for the production of lactic acid, this process is still
expensive and not fully understood. For this reason, there is still
much to develop in the area in order to make 2G-lactic acid eco-
nomically viable on a commercial scale. Some examples of recent
studies using lignocellulosic materials for lactic acid production are
presented in Table 2.
6.3. Microalgae
Algae biomass is also a suitable substrate for lactic acid pro-
duction. It has a high content of carbohydrates and proteins, and
compared with lignocellulosic biomass, presents the advantage
of not having lignin [16,115,116]. As an example, Hydrodictyon
reticulum contains 47.5% of polysaccharides. This material can be
converted to glucose and mannose as fermentable sugars with-
out producing as many inhibitory compounds as in lignocellulosic
biomass processing [115,116]. The use of microalgae and cyanobac-
teria as lactic acid producers could also reduce the feedstock cost,
due to their ability to use light energy to fix CO2 [16,117]. An exam-
ple is presented in Table 3, using Synechocystis sp.
In summary, the main advantages of using microalgae as
biomass for producing 3G-lactic acid are the facts that it is
possible to grow everywhere with short harvesting times, they
do not present lignin content, which simplifies saccharification,
and they have high fermentable sugar contents and proteins
[16,87,115,117]. Table 2 presents an example of algae biomass as a
feedstock for lactic acid production.
6.4. Food waste
Food waste can be any material from the food supply chain, from
the production process to the wastes generated by the final con-
sumer. Food waste presents a high carbohydrate content [16], also
making it suitable as a substrate for lactic acid production. Sev-
eral studies revealed these kitchen residues/refuse are suitable for
many processes for lactic acid production such as mixes of cooked
rice, vegetables, meat, and bean curd [118]; rice, noodles, meat,
and vegetables [38,119]; vegetables such as carrot peel, cabbage,
and potato peel, fruit such as banana peel, apple peel, and orange
peel, baked fish, rice, and used tea leaves [120,121]; rice, noodles,
meat and vegetables, and unsold bakery products including cakes,
breads and pastries [64]; rice, vegetables, and meat [122,123]; cof-
fee mucilage [103]; and coffee pulp [68]. Some results of processes
using food waste materials for lactic acid production are depicted
in Table 2.
6.5. Glycerol
Glycerol, as a by-product of biodiesel production, can be used as
a substrate for lactic acid production. Biodiesel production has been
increasing every year and the glycerol yield is about 10% of biodiesel
production [115]. Since biodiesel is considered an environmentally
friendly fuel [87], the possibility of using glycerol residue for pro-
ducing lactic acid increases its visibility in the global market even
more. Furthermore, it is important to consider that a great diver-
sity of vegetable and algae is used to produce biodiesel around the
world, which makes the overproduction of glycerol as a by-product
a challenge still to be overcome [87]. Reports indicate that some
micro-organisms are able to directly consume glycerol to produce
lactic acid [124–126]. However, it is still a challenge to make this
conversion without using a genetically modified micro-organism,
or even without additional components to balance cell redox poten-
tial. For this reason, it is considered an alternative to use glycerol
with a coupled metabolism of another substrate with higher oxi-
dizing power to restore the redox balance [124]. Nevertheless, as
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239 227

Table 3
Literature reports using genetically modified micro-organisms to produce lactic acid.

Microorganism Modification Improved phenotypic Result Reference

Kluyveromyces L-lactate dehydrogenase (LDH) expression of L-lactic acid production from 24.0 g/L, yield of 0.48 g/g [204]
marxianus Staphylococcus epidermidis, Lactobacillus glucose
acidophilus, and Bos taurus
Saccharomyces Expression of cellodextrin transporter (CDT-1, Lactic acid production from yield of 0.358 g/g [205]
cerevisiae which also transports lactose) and a lactose
␤-glucosidase (GH1-1, which also acts as a
␤-galactosidase) from Neurospora crass.
Expression of lactate dehydrogenase (LDHA)
from Rhizopus oryza
Saccharomyces Expression of D-lactate dehydrogenase gene D-lactic acid production at low 82.6 g/L, yield of 0.83 g/g, [206]
cerevisiae (LDHA) from Leuconostoc mesenteroides. pH productivity of 1.50 g/L/h at pH
Deletion of genes: ADH1, ADH2, ADH3, ADH4, 3.5
ADH5, GPD1, GPD2 and DLD
Saccharomyces Expression of D-lactate dehydrogenase (LDHA) D-lactic acid production 112.0 g/L, yield of 0.80 g/g, [207]
cerevisiae gene from Leuconostoc mesenteroides subsp. productivity of 2.2 g/L/h
mesenteroides ATCC 8293. Deletion of genes:
DLD1, JEN1, PDC1, ADH1, GPD1 and GPD2.
Overexpression of HAA1
Saccharomyces Expression of 12 glycolysis-related genes and D-lactic acid production 60.3 g/L, yield of 0.646 g/g, and [208]
cerevisiae D-lactate dehydrogenase (DLDH) from productivity of 2.80 g/L/h
Leuconostoc mesenteroides
Monascus ruber Introduction of lactate dehydrogenase (LDH); Lactic acid production at low 190 g/l at pH 3.8 and 129 g/l at [209]
two genes encoding pyruvate decarboxylase pH pH 2.8
(PDC) were knocked out; 4
cytochrome-dependent LDH (CLDH) genes
were knocked out
Escherichia coli Replacement of D-lactate dehydrogenase gene L-lactic acid production from 75 g/L, yield of 85%, [210]
(LDHA) by L-lactate dehydrogenase gene molasses and corn steep liquor productivity of 1.18 g/L/h, >99%
(LDHL) from Pedicoccus acidilactici; Enhanced without additional nutrients optical purity
expression of the sucrose operon (cscA and
cscKB)
Synechocystis sp. Increasing the expression level of lactate L-lactic acid production from 12.99 ± 3.3 g/L, and carbon [211]
dehydrogenase (LDH), co-expression of a CO2 partitioning into lactic acid of
heterologous pyruvate kinase, knockdown of 50.0 ± 5.9%
phosphoenolpyruvate carboxylase, and
optimization through site-directed
mutagenesis to improve the enzyme’s affinity
for the co-factor nicotinamide adenine
dinucleotide phosphate (NADPH)
Lactobacillus plantarum Deletion of L-lactate dehydrogenase (LDH), D-lactic acid production from 38.6 g/L [212]
phosphoketolase (xpk1) gene substituted by a arabinose
heterologous transketolase (tkt) gene from
Lactococcus lactis
Lactobacillus plantarum Deletion of L-lactate dehydrogenase gene D-lactic acid production from 73.2 g/L, yield of 0.85 g/g, [213]
(LDHL1), expression of alpha-amylase (AmyA) raw corn starch optical purity of 99.6%
from Streptococcus bovis
Lactobacillus plantarum Deletion of L-lactate dehydrogenase (LDH), D-lactic acid production 27.3 g/L and productivity of [214]
expression of xylose isomerase and through simultaneous 0.75 g/L/h from corn stover;
xylulokinase genes from Lactobacillus pentosus saccharification and 22.0 g/L and productivity of
fermentation from xylose 0.55 g/L/h from sorghum stalks

innovative technology approaches, it needs to be well developed in
order to be made suitable for industrial scale .
6.6. Feedstocks concluding remarks
Research efforts have been increasingly focused on finding new
and effective nutritional sources, always associated with new fer-
mentation techniques. It reflects the attempt to implement these
processes in industrial terms with a high substrate conversion
and high lactic acid production [127]. In fact, the application of
agro-industrial residues in bioprocesses provides an alternative to
minimize, or even replace, refined and expensive raw materials
such as glucose and also helps to reduce environmental risks from
these waste [102].
Currently, the use of low-cost waste materials in the industrial
production of lactic acid is still rare [102]. Lignocellulosic biomass
is expected to be a cheap and renewable carbon source [3,128,129].
Moreover, it does not have a direct value as food [5] allowing
the use of inexpensive, abundant and renewable carbon sources
[130]. It can be a good substitute for conventional raw materials,
although not all micro-organisms are able to consume it directly.
Additionally, reuse of waste is of great interest due to legislation
and environmental issues, since the industry is increasingly being
induced to find an alternative to the use of waste material from its
production [131].
Moreover, multiple carbohydrates have been used in the pro-
duction of lactic acid, but the substrate used depends directly on
the location of the lactic acid production plant, due to both avail-
ability and logistics of transportation and use [33]. Furthermore,
there is a difficulty related to the fact that many substrates gen-
erate complex biological process which culminates in high cost of
recovery and purification of lactic acid [5].
7. Lactic acid bacteria
Lactic acid bacteria are a very heterogeneous group in terms
of classification, often suffering phylogenetic relocation. Gen-
eral descriptions of the group include characteristics, such as:
gram-positive, non-sporing, catalase negative, non-aerobic but
228 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
aero-tolerant, fastidious, acid-tolerant, which produce lactic acid
as the major end product during the fermentation of carbohydrates
[132]. They are highly adaptable, and it is already well known that
they have a great metabolic diversity. They can survive in a wide
range of environmental conditions and the only feature that cov-
ers the whole group is being gram-positive [132]. 90% of studies
on lactic acid production are related to lactic acid bacteria, which
are related to high yields, productivity [11], and its environmental
versatility, covering a pH range from 3.2 to 9.6, and temperatures
from 5 to 45 ◦ C [133].
For the industrial production of lactic acid, it is desirable that
the micro-organisms used are able to ferment cheap raw mate-
rials, have low nitrogen requirements, produce large amounts of
lactic acid, tolerate low pH conditions and high temperatures, and
produce the least amount of by-products [20]. The main fermenta-
tion micro-organisms used nowadays are homofermentative from
the genus Lactobacillus, Streptococcus, and Pediococcus [37]. Some
examples from literature are shown in Table 2. Considering the
importance that the genus Lactobacillus has for lactic acid produc-
tion, the following sections will focus on the metabolism of these
micro-organisms.
7.1. Nutritional requirements for lactic acid bacteria
Another important issue to be considered, when it comes to the
association with substrates for fermentation and lactic acid bacte-
ria, is the high nutrient requirements of these micro-organisms. In
general, besides being a source of carbon used in energy generation,
lactic acid bacteria requires nitrogen and a wide range of vitamins
and minerals to maintain cellular growth and lactic acid production.
It occurs because they have a limited ability to synthesize molecules
for their own growth [11].
The ratio between nitrogen and carbon sources is one of the
main factors affecting the sugar conversion yield into lactic acid
[11]. This situation may be overcome by the addition of complex
nitrogen sources in the fermentation medium. Yeast extract is com-
monly used, as well as peptone and meat extract. In particular, lactic
acid production gets better results when yeast extract is added to
the medium [11]. However, this addition greatly increases operat-
ing costs. For this reason, much effort has been focused on trying to
find alternative sources of nitrogen, minimizing costs without loss
in product yield.
Until the mid-90s, the vast majority of studies concluded that
yeast extract was an irreplaceable source of nitrogen when com-
pared to alternative sources such as corn steep liquor, casein
hydrolysate, hydrolyzed whey protein, among others [134,135]. It
was associated with the fact that yeast extract is an excellent source
of B vitamins and is often used to provide these factors in bacterio-
logical culture media [136]. Since then, it is considered essential to
achieve rapid rates of cellular growth and lactic acid production by
lactic acid bacteria [136,137]. However, studies have shown better
results in replacement of yeast extract for alternative and cheaper
nitrogen sources, such as malt extract, white rice bran hydrolysate,
corn steep liquor, and malt sprouts [91,138–142]. Some examples
are shown in Table 2. It has to be highlighted that the costs of
these inputs are region dependent. For example, in Brazil, yeast
extract could still be an important alternative if lactic acid pro-
duction could be carried out as an annex to a sugar, ethanol and
yeast production plant. It is important because it is believed that
the good results in lactic acid production may be a consequence
of the choice of complex sources which contain soluble proteins,
amino acids, B vitamins, and other nutrients available to the micro-
organism. At this point, it is worth mentioning that building up
2G-lactic acid facilities in a 1G-sugarcane ethanol facility may also
be quite interesting since sugar cane bagasse is readily available on
the production site, reducing the logistical costs as well as the total
capital and operation investment, since it is possible to share some
facilities and personnel.
7.2. Choosing micro-organisms – desirable characteristics of
Lactobacillus sp.
Although many micro-organisms produce lactic acid, the most
commonly used by the industry is Lactobacillus sp. [93]. They have
a high tolerance to acidic environments and are easily genetically
modified for selective production of lactic acid isomers [149]. More-
over, these micro-organisms are considered safe for the industrial
production of lactic acid, due to their long history in industrial pro-
duction in many sectors with no reports of adverse effects, both for
workers and for consumers of products [87].
When used for industrial purposes, it is desirable that micro-
organisms present some general characteristics that facilitate their
handling and increase the profitability of the process. As shown
in Table 2, Lactobacillus sp. represents the majority of micro-
organisms studied for lactic acid production, due to its beneficial
characteristics for the process.
Micro-organisms should have a high conversion efficiency of
substrate to product. At the same time, they should allow product
accumulation in the broth (that means they do not suffer by-
product inhibition), since these factors impact on the final cost of
the product [83]. It is also necessary to consider the time spent dur-
ing the process by the micro-organism to convert substrate into
product (productivity), since it will have a direct impact on the
infrastructure of the project. So, making an efficient conversion and
a high concentration of the product is essential, in order to reduce
recovery costs, among others, since they can represent up to 50%
of the total process cost [46]. It is important to consider that the
micro-organism should not produce metabolites that are incom-
patible with the product of interest, as this would jeopardize the
viability of the process. To assure the safety and stability of the
production pathway, micro-organisms should not be pathogenic,
ensuring the safety of workers, consumers and environment. They
have to be physiologically stable so the process behaviour can be
predicted, operated and easy to handle. Growing conditions should
be simple and the cultivation broth should be inexpensive, ensuring
the economic viability of the process [83].
7.3. Metabolic pathways for lactic acid production by
Lactobacillus sp.
An important subject to be considered in the production perfor-
mance of lactic acid is the metabolic pathway used by the chosen
micro-organism. There are essentially two pathways in which lactic
acid bacteria can produce lactic acid. According to these pathways,
the micro-organisms can be classified as either homofermentative
or heterofermentative bacteria.
The homofermentative uses the glycolytic pathway
(Embden-Meyerhof-Parnas pathway). Therefore, the final
product is almost exclusively lactic acid (Fig. 2A) [143]. On
the other hand, heterofermentative micro-organisms use 6-
phosphogluconate/phosphoketolase pathway (6-PG/PK), which
results in other by-products in addition to lactic acid, such as
ethanol, acetate and CO2 (Fig. 2B) [132]. The crucial difference
between these metabolic pathways is given by the presence of key
enzymes for each route [132]:
• Fructose 1,6-diphosphate (FDP) aldolase to glycolysis pathway;
• Phosphoketolase to 6-PG/PK pathway.
Strictly homofermentative micro-organisms produce lactic acid
from glucose using the glycolytic pathway, thus they are not able to
metabolize pentose sugars and related compounds. The heterofer-
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239 229

Fig. 2. Metabolic pathways for lactic acid production: (A) Embden-Meyerhof-Parnas pathway (EMP); (B) 6-phosphogluconate/phosphoketolase pathway (6-PG/PK).

mentative bacteria group produce lactic acid and other compounds

using 6-PG/PK pathway from hexose and also from pentose sugars
[144].
However, facultative heterofermentative bacteria metabolize
glucose by the glycolytic pathway, but pentose metabolism occurs
by the 6-PG/PK pathway. In this case, the production of lactic acid
can or cannot be associated with the production of other com-
pounds of 2 carbons, depending on the micro-organism [144].
These micro-organisms have the enzymes needed to work in
both the above-mentioned metabolic pathways. Thus, such micro-
organisms use FDP aldolase to ferment hexose, but in the presence
of pentose, they are induced to produce phosphoketolase. This
means that the presence of hexose results in an homo-lactic
fermentation, whereas pentose can result in hetero-lactic fermen-
tation [132].
In the case of the facultative heterofermentative micro-
organisms, what determines the behaviour to lead to homo or
heterofermentation can either be the source of carbon or the expo- Fig. 3. Metabolic pathways using xylose for the production of lactic acid.
sure to certain environmental parameters, such as nutritional,
osmotic and/or thermal stresses, depending on the micro-organism If one continues to consider the sugar supplement, it is impor-
species. tant to consider that some Lactobacillus sp. suffer suppressed
In fact, many lactic acid bacteria are able to consume pen- growth due to the excess of monosaccharides, since this can gen-
tose molecules as arabinose, ribose, xylose and carbohydrates as erate excess glucose in the cell [145]. To avoid this condition, the
gluconate. Note that xylulose-5-P are present in both heterofer- micro-organism releases glucose to the medium, spending energy
mentative (Fig. 2B) and xylose assimilation pathways (Fig. 3), that could be used in the production of lactic acid. Thus, the excess
allowing pentose sugars to be consumed by any of these routes of fermentable sugar is a major drawback in the industrial produc-
depending on the chosen micro-organism. tion of lactic acid.
The theoretical value of the lactic acid production by pentose Another important issue to be considered when it comes to
molecule is 1.67 in homolactic fermentations (3 xylose molecules to lactic acid bacteria is the high nutrient requirements for these
generate 5 molecules of lactic acid, totalling 15 carbons) (Fig. 3). In micro-organisms. All lactic acid bacteria have high nutritional
this case, the pentose-phosphate metabolic pathway is used, with requirements due to their extremely specific environments and low
the action of transketolase and transaldolase enzymes [144]. ability to synthesise amino acids [146]. In general, besides a source
230 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
of carbon used in energy generation, these bacteria require nitro-
gen, plus a wide range of vitamins and minerals for the maintenance
of cellular growth and to support the lactic-acid-releasing mecha-
nism. This occurs because they have a limited ability to synthesize
molecules for their own growth [11]. It also probably happens
because these micro-organisms have gone through an evolution
process associated with rich media, such as meat and milk. It pre-
sumably prevented them from developing/keeping cell machinery
that synthesizes some molecules for growth, once it was present in
the substrate. For this reason, these bacteria have difficulty to cap-
ture inorganic nitrogen from the medium. However, they are quite
efficient at breaking down complex proteins [144]. For this reason,
they are dependent on the presence of peptides and amino acids in
the culture medium [145].
Acetate is another nutritional factor present in almost the whole
culture medium. Some researchers suggest that the presence of
sodium acetate is critical in the production of a particular isomer of
lactic acid [147]. For example: in absence of acetate, Lactobacillus
sakei produces a racemic mixture of lactic acid [147]. Also, sodium
acetate has an inhibitory effect on the growth of fungi [148] and
other contaminant lactic acid bacteria, allowing the growth of Lac-
tobacillus in general.
7.4. Main metabolic characteristics of Lactobacillus sp. under
stress conditions
There are several factors that must be considered when
discussing the industrial production of lactic acid by these micro-
organisms, since they are always subjected to stress conditions
during the fermentation process.
Product inhibition can be caused by several factors, such as: the
collapse of cell membrane due to the change of membrane poten-
tial, anions accumulation inside the cells, high concentration of
solutes, or even acidification of cytosol [130,150,151]. An important
example is the acid stress condition caused by lactic acid. Although
lactic acid bacteria have cellular mechanisms of protection against
a pH drop, they suffer inhibition caused by the product, since this
phenomenon is caused by the cell’s own lactic acid production.
In gram-positive bacteria, acid stress directly affects the ATP
available in the cell for proton pump maintenance [152]. It results in
a reduction of energy available for the synthesis of biomass, and also
for the catabolic flux of the micro-organism. Although the mecha-
nism is not fully explained, it is known that such disturbances alter
gene transcription of the central metabolism of the cell, which is
sensed due to the increased presence of proteins. These changes
are not noticed during a fast drop in pH, possibly due to an increase
in the stability of mRNA. But, since the environment is acidic, there
is a substantial increase in glycolytic enzymes. This process allows
the cell to be prepared for fast growth recovery and normalization
of metabolism when pH stress is removed.
Zhai et al. [153] used L. delbrueckii bulgaricus to demonstrate the
consequences of acid stress to cells. The pH used in the tests was 3.7
which is quite close to the pH reached in lactic acid fermentations
without neutralization (around 3.8) [154]. In the case of acid stress,
they showed that the pyruvate from a sugar breakdown is shifted
to the production of acetyl-CoA and not to further lactate produc-
tion. This deviation allows the acetyl-CoA to be diverted to fatty
acid biosynthesis, which modifies the fluidity of the cell membrane
[153,155]. It makes the membrane more resistant to trades with
the external environment, achieving energy savings for the cell in
the transfer of protons [153], while all ATP are converted to proton
motive force maintenance. Similar processes were observed for L.
casei [156] and for L. rhamnosus [157]. It was also suggested that
acid stress leads to the production of one more ATP synthase [155].
Other studies corroborate this fact, revealing that exposure to acid
stress leads bacteria to counteract the influx of protons through
changes in the cytoplasmic membrane, making them more com-
pact and rigid [152,153,158]. They all corroborate that this theory
is widely accepted for different species of Lactobacillus sp.
Besides acid stress, there are many other factors that influ-
ence the survival of lactic acid bacteria. Among the main ones, the
most emphatic are nutritional stresses, temperature, oxidative and
osmotic stress, and the presence of chemicals.
Environmental changes are sensed by the bacterial cell through
the translational signal system, which is responsible for adap-
tive cell changes in metabolism, physiology, and behaviour [159].
This system sends signals to the various cellular mechanisms each
time that an environmental change is detected. This system has
two main components: the sensor membrane and the cytoplas-
mic response regulator. Based on this model, Zhai et al. [153] were
able to detect changes in both protein and transcription levels for L.
delbrueckii bulgaricus since the cells respond quickly to the delete-
rious effects of acid stress using molecular rapid responses to repair
damage and allow for survival.
Peptidases over-expression was observed in L. casei [160] and in
L. rhamnosus [157]. The authors believe that this happens because
the intracellular amino acids become limited, since the efficiency
of amino acid transporters is at a reduced low pH. In this case, the
cell is forced to find alternatives to their own amino acid supply
through the over-expression of proteins that assist in the transport
of peptides and peptidases that help in the degradation of misfolded
proteins to recycle amino acids [153].
It is already known that nutritional changes can cause big
impacts on lactic acid bacteria [147]. In the previous section, the
role of different carbon sources in the metabolic pathways of lac-
tic acid production by lactic acid bacteria was mentioned. But, not
only different types of sugars affect lactic acid production. Other
components such as inorganic salts, acids and peptides as well as
their concentrations also have major impacts on both lactic acid
production and productivity.
In low glucose concentrations, L. plantarum metabolism is
shifted to acetate production, and not to lactic acid (Fig. 4). This
happens due to the need to produce at least one ATP to maintain
cellular homeostasis [161]. This process begins with the conver-
sion of lactate to pyruvate by lactate oxidases (LOX). Pyruvate is
then converted to acetate in order to generate ATP. This mecha-
nism can occur via three different routes: pyruvate formate lyase
(PFL), pyruvate dehydrogenase complex (PDH), or pyruvate oxidase
(POX) (Fig. 4).
The first one may occur under anaerobic conditions by pyru-
vate formate lyase (PFL), phosphotransacetylase (PTA) and acetate
kinase (ACK), resulting in the production of formate and acetate.
However, Lorquet et al. [161] highlighted that it was not possible
to detect formate during acetate production.
The second possible route occurs via pyruvate dehydrogenase
complex (PDH), PTA and ACK. In this way, NAD+ is converted in
NADH + H+ . This does not occur in the presence of O2 because in this
case there are already high levels of NADH in the cell. Furthermore,
since there is no transformation of pyruvate to lactate, NAD+ levels
fall, since NADH recycling does not occur. This further complicates
the use of this route.
Finally, the highest yields of acetate are given in aerobic condi-
tions [161–165] and glucose limitation, by reaching a homoacetic
fermentation. The proposed route for this process uses POX and
ACK. In this pathway, there is a final production of acetate, CO2 ,
and an ATP molecule, with no use or recycling of NAD+ . The activa-
tion of this pathway is made by a group of genes called pox, which
are responsible for producing the enzyme POX. The gene poxB is
mainly responsible for producing the enzyme and is therefore the
target of several studies. It is known that this group of genes can be
activated by three factors: low glucose concentration, and the pres-
ence of O2 and/or H2 O2 . When glucose is available, but the gene is
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
Fig. 4. Lactate and acetate production pathways in L. plantarum [161].
activated by O2 or H2 O2 , the productions of acetate and lactate are
concomitant. Oxygen is required as a substrate for the POX enzyme
and it strongly induces transcription from the poxB promoter by an
unknown mechanism [161].
An interesting fact is that since the pathway LOX-POX-ACK
stops working, the biomass is degraded by cell lysis. This happens
because, in the absence of ATP, protons cannot be removed and cell
homeostasis is disrupted by dissipation of the proton motive force.
Apparently, this is an autolysis mechanism that occurs in gram-
positive bacteria [152]. A product of the LOX-POX-ACK pathway
acts as a messenger to regulate cell death and lysis in L. plan-
tarum, since a strong correlation between the acetate production
rate and cell viability is established [162]. It was found that the
slower lactate was converted to acetate, the longer cells retained
their viability. Besides this, more acetate was produced than lac-
tate was consumed, resulting in a carbon balance greater than one
[162]. The authors suggested that the additional acetate could be
produced at the expense of other compounds present in the growth
medium, such as serine catabolism, which seems to be associated
with acetate formation [146,166]. In this case, serine is converted
into ammonia and pyruvate, which is degraded to form acetate and
other compounds, depending on the strain under study. According
to Liu et al. [166], L. plantarum cells in the stationary phase convert
serine to ammonia, acetate and CO2 , which could be an explanation
for the carbon balance greater than one.
Using proteomic techniques, it was demonstrated that pro-
tein expression from L. plantarum depends on both the medium
composition and the strain used [155]. The authors reported that
the main proteins regulated by the composition of the medium
231
are from the functional categories related to transportation and
carbohydrate metabolism, energy metabolism, stress responses,
nucleotide and nitrogen metabolism, and biosynthesis of proteins.
Thus, depending on the selected strain, L. plantarum is able to
metabolize 15–25 different carbon sources. In relation to the car-
bohydrate metabolism, osmotic stress caused by high levels of
carbohydrates inhibits glucose metabolism and induces alterna-
tive mechanisms. Thus, they showed that the highest number of
carbon sources metabolised by L. plantarum occurs when cells are
pre-cultured in medium with little or no glucose.
These findings corroborate with carbon catabolite repression
(CCR), which is a hierarchical system of carbon consumption. Thus,
by a complex regulatory system, the consumption of glucose leads
to a suppression of the synthesis of enzymes that are related to
the use of other carbohydrates [155]. Thus, it is concluded that the
expression of proteins responsible for input and metabolism of car-
bohydrate is highly dependent on the carbon source present in the
culture medium. It is further considered that hostile environments
such as low pH, high level of carbohydrates, and buffering capacity
negatively affect the kinetics and growth of this micro-organism
[155].
Iino et al. [147] tested about 50 different lactic acid bacteria.
Although the authors showed that L. plantarum is a resistant bac-
teria to applied environmental variations, there are some factors
that shown to be more effective for obtaining higher concentration
and productivities during lactic fermentation. The effects of pres-
ence/absence and concentration of salts and other components in
the culture medium for L. plantarum are highlighted since many of
them directly affect the lactic acid production [147]:
232 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
• Carbon Source: Carbon sources such as arabinose and ribose
resulted in a production of around 50% of acetic acid and 50%
of lactic acid. The highest lactic acid production occurred using
sucrose;
• Organic salts: Presence of salts from organic sources resulted in
an increase of lactic acid production;
• Sodium acetate: Presence of sodium acetate in the broth resulted
in an increase of 45% in production of lactic acid;
• Temperature: The best temperatures to produce lactic acid were
around 30 ◦ C–37 ◦ C. Although Ghaffar et al. [5] had mentioned
43 ◦ C for L. plantarum, many studies used temperatures of around
30 ◦ C–37 ◦ C;
• Oxygen presence: A decrease in lactic acid production and an
increased production of concomitant acetic acid in aerobic cul-
tures was observed compared to stationary cultures (35% of acetic
acid production in aerobic cultures);
Bron et al. [164] used the fractional factorial design to study
variables on the metabolism of L. plantarum in producing lac-
tic acid, such as temperature, pH, O2 , amino acid concentration,
and the presence of NaCl. The results were focused on studies of
ODmax (maximum optical density for biomass yield), ␮max (maxi-
mum growth rate), and the whole transcriptome of expressed genes
influenced by the parameters analysed. Its results corroborate with
all results previously presented for this micro-organism:
• The ␮max was observed at the temperature of 37 ◦ C and pH of 5.2;
• The concentration of amino acids had no influence in the process.
The authors suggest that when glucose is a limiting factor the
addition of amino acids will not have a great impact;
• The production of acetate was substantially higher in the pres-
ence of O2 ; this is explained by the conversion of lactate to acetate
aerobically [162,163];
• The ODmax was considerably lower in the presence of NaCl;
• The conversion of citrate to succinate depends on NaCl presence.
This conversion is associated with a decrease in OD. It is likely
that lactate degradation cascade generating an additional ATP is
non-functional in the presence of NaCl. In addition, salt presence
works altering the osmotic pressure of the cell, decreasing citrate
transport efficiency through the membrane.
The transcriptome analysis showed that genes associated with
the responses tested are conserved genes within the L. plantarum
sub-species [164]. This allows us to assume that this type of
response presents similarities independent of the strain used. The
authors also assert that the tested parameters associated with
physiological parameters increase the probability that these results
can be extrapolated with other culture media, conditions and
scales.
7.5. Genetically engineering lactic acid bacteria
Genetically engineered lactic acid bacteria have been widely
studied in the last few years. The major challenges associated with
lactic acid production that can be addressed by employing genetic
engineering strategies are isomer purity, micro-organism acid tol-
erance, carbon source, and industrial parameters, such as: lactic
acid yield (% of theoretical maximum from carbon source), volu-
metric productivity (g/L/h), and titer (g/L) [16,167].
The genomes of many strains of industrial importance have been
sequenced, which allows new developments in engineering lac-
tic acid bacteria for many industrial and commercial applications.
These studies allow us to better understand the metabolic path-
ways used for each substrate, the production of by-products, and
even stress conditions. This field of work has developed quickly,
leading to improvements of important strains, such as the ones
used in the food industry.
The Lactobacillus genus represents the largest and most diverse
genus of all the lactic acid bacteria. These micro-organisms are easy
to genetically modify and present a great capacity for adaptation to
new environmental conditions. The increasing number of available
Lactobacillus sp. genome sequences has allowed for understand-
ing of the genetic and metabolic potential of this group. They are
recognized as potential cell factories, confirmed by the successful
production of many compounds [168].
Some examples of genetic modification of strains to produce lac-
tic acid are shown in Table 3. In the most recent studies, yeasts have
a central role in the development of new potential micro-organisms
for lactic acid production, especially dealing with low pH in organic
acid fermentation. The reason behind this is that acid stress and
end-product inhibition are still among the greatest bottlenecks in
commercial lactic acid production, and the heterologous expres-
sion of enzymes in yeasts and fungi renders them more tolerant to
acid than lactic acid bacteria [167].
Additionally, genetic engineering is also focusing on the pro-
duction of one specific lactic acid isomer. The most recent studies
are concentrated on the expression of lactate dehydrogenase (LDH)
enzymes in micro-organisms that naturally do not contain the gene
for lactic acid production, in order to achieve high D- or L-lactic acid
concentration and productivity.
As raw material is a major cost factor in lactic acid production,
many efforts have been directed towards the utilization of lignocel-
lulosic biomass and biomass-derived waste streams [167]. Genetic
engineering efforts in this direction were very well depicted in the
work of Mazzoli et al. [169], presenting recombinant lactic acid
bacteria with improved amylolytic, cellulolytic or hemicellulolytic
properties. In Table 3, Lactobacillus plantarum is the main example
of a micro-organism with genetic modification directed towards
substrate consumption.
New technologies such as the CRISPR/Cas system represent a
new advance for all areas related to micro-organisms. CRISPR (clus-
tered regularly interspaced short palindromic repeats), together
with CRISPR-associated genes (cas) form a bacterial immune sys-
Fig. 5. The traditional process of lactic acid purification: extraction by precipitation.
 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239 233

Table 4 olutionized the idea of genetic engineering [168]. CRISPR-based

Main techniques available for product separation processes [46,179].
technologies have opened new opportunities for the develop-
Separation Process Principle ment of next-generation food micro-organisms and probiotics with
Equilibrium-based processes enhanced functionalities and safety. A review of the possibilities
Absorption Uses of ion-exchange resins to absorb the using CRISPR-based technologies for lactic acid bacteria is pre-
interest product sented by Hidalgo-Cantabrana et al. [170].
Distillation Based on heat and volatility of the compounds Genetic engineering is already a fundamental tool in the devel-
involved in the process
opment of an efficient bioprocess to produce lactic acid, bringing
Liquid-liquid extraction Separates chemicals from one solution to
(solvent extraction) another based on the different solubility of the many benefits of fast accomplishment for the industrial sector.
solute in two solvents
Affinity-based separation
8. Lactic acid separation and purification – downstream
Adsorption Uses of ion-exchange resins to adsorb the
interest product processes
Ion exchange Uses of ion-exchange resins to adsorb the
interest product The lactic acid purification process currently used has several
Simulated moving-bed Mobile phase moves countercurrent to a
economic and ecological implications for the final product. In gen-
chromatography stationary phase
Membrane separation
eral, costs of recovery and purification of biorefinery products,
Electrodialysis Extract ions from a solution through including lactic acid, represent 20–50% of the operating costs of
ion-exchange membrane to another solution the process [46]. In the conventional lactic acid recovery process
based on electric potential difference (extraction method by precipitation), lactic acid is precipitated with
Filtration Particles or molecules are retained in a
calcium hydroxide to form calcium lactate. This compound is recov-
membrane depending on the pore size, flow
and pressure used ered by a filtration process. Finally, sulfuric acid is used for the
Solid-liquid separation release of lactic acid, which generates a large amount of CaSO4 [46].
Conventional filtration Particles are retained in a membrane The diluted lactic acid product is then purified sequentially using
depending on the pore size, flow and pressure
activated carbon, evaporation, and crystallization processes (Fig. 5).
used
Precipitation and The product of interest is concentrated by
The precipitation extraction method has some disadvantages, such
crystallization evaporation and then crystallized as high cost due to the many reagents employed, the need for many
Reaction-separation systems for process intensification filtration steps, and the generation of large quantities of calcium
Reaction-membrane Bioreactors-membrane sulphate sludge as solid waste, leading to environmental problems
separation systems
[171–173]. It is known that approximately one ton of calcium sul-
Extractive fermentation Product extraction in situ
Reactive distillation Distillation preceded by a chemical reaction. phate of reduced economic value is produced for each ton of pure
Used when the product is of low volatility lactic acid produced [1], and this process can reach up to 50% of the
Reactive absorption Product extraction in situ using of total lactic acid production costs [172–174].
ion-exchange resins To obtain purified lactic acid it is necessary to eliminate: resid-
ual ions, residual sugar, cells, and other broth components at the
end of the process. As lactic acid is non-volatile and has a high affin-
tem against foreign DNA, such as phage or plasmids. According to ity for water molecules, the distillation, as well as the evaporation
Stefanovic et al. [168], analysis using this methodology provides processes, are energetically inefficient.
evidence of previous phage/strain interaction. It opens possibilities In this sense, research in regards to alternative separation and
for enhancing phage resistance of industrial strains such as Lacto- purification processes for lactic acid produced by fermentation
bacillus sp. Inspired by the mechanism of action of Type II CRISPR with lower costs and less environmental impact are necessary to
systems, genome editing represents a novel approach that has rev- increase process competitiveness.

Table 5
Most recent downstream studies for lactic acid recovery.

Separation method LA feedstock LA final concentration Yield (%) LA final purity Reference
(g/L) (wt %)

Short path evaporation Synthetic - - 7.13 ± 0.80 [215]

Reactive distillation Synthetic 347.68 99.94 ± 2.17 - [177]
Hybrid Short Path Evaporation Fermentation - - 89.7 [216]
Micro and nanofiltrations, Fermentation 937 - 99.7 [68]
softening, mono and bipolar
electrodialysis, anion and cation
exchange chromatography, and
distillation
Amberlite resins FPA 53 and CR Fermentation - 90 - [217]
5550
Fermentation and separation Fermentation 183.4 97 - [218]
integration system
(microfiltration and resin
adsorption)
Three-stage membrane- integrated Fermentation 250 96 95 [219]
hybrid reactor system
Membrane-Integrated Separation Fermentation - 76 99.5 [220]
Processes
Vapor permeation-assisted Fermentation - 95 - [221]
esterification
Cross-flow nanofiltration Fermentation - - 85.6 [180]
Molecular Distillation Fermentation - 74.09 95.6 [222]

LA: lactic acid

234 R. Alves de Oliveira et al. / Biochemical Engineering Journal 133 (2018) 219–239
There are many techniques available for product separation pro-
cesses, as can be seen in Table 4. Advantages and disadvantages of
some separation processes for lactic acid recovery are presented by
Komesu et al. [175].
Many studies have been carried out using different extrac-
tion and purification techniques for lactic acid. A glance at
such processes leads to the use of solvent/solvent extraction,
ion-exchange/adsorption, vacuum distillation, direct distilla-
tion, esterification and hydrolysis methods, membrane sepa-
ration/membrane bioreactor, electro-dialysis, reverse osmosis,
nanofiltration and ultrafiltration, liquid surfactant membrane
extraction, chromatographic methods, drying, hybrid short path
evaporation, among others [176–184]. The most recent down-
stream studies are summarized in Table 5.
9. Conclusions
The attainment of pure lactic acid to be used in several applica-
tions in different industrial sectors is a very complex process. In the
near future, the outlook for the lactic acid market is of continued
growth, achieving new applications and better prices. Nowadays,
investments in the sector are focused on using new technolo-
gies and new substrates to improve the production process and
achieve better micro-organism performance. Genetic engineering
tools are developing quickly, focusing on creating more resistant
and productive micro-organisms. It promises to be one of the sec-
tors with more innovation in the near future. This review presents
the basic settings that should be considered throughout the lac-
tic acid production process, the nutritional needs of the producing
micro-organisms, the metabolic implications of the most common
factors of the fermentation, and the downstream process, as well
as the most recent achievements of the sector.
Funding
This work was supported by Foundation for Research of the State
of São Paulo—FAPESP, Process 2013/26290-5.
Acknowledgments
The authors thank Espaço da Escrita – Pró Reitoria de Pesquisa
– Unicamp – for the language services provided.
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