Food Additives & Contaminants: Part A

ISSN: 1944-0049 (Print) 1944-0057 (Online) Journal homepage: http://www.tandfonline.com/loi/tfac20

Screening of veterinary drug residues in food by

LC-MS/MS. Background and challenges

Thierry Delatour, Lucie Racault, Thomas Bessaire & Aurélien Desmarchelier

To cite this article: Thierry Delatour, Lucie Racault, Thomas Bessaire & Aurélien Desmarchelier
(2018): Screening of veterinary drug residues in food by LC-MS/MS. Background and challenges,
Food Additives & Contaminants: Part A, DOI: 10.1080/19440049.2018.1426890

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FOOD ADDITIVES & CONTAMINANTS: PART A, 2018
https://doi.org/10.1080/19440049.2018.1426890

Screening of veterinary drug residues in food by LC-MS/MS. Background and

challenges
Thierry Delatour, Lucie Racault, Thomas Bessaire and Aurélien Desmarchelier
Nestlé Research Center, Institute of Food Safety and Analytical Science, Lausanne, Switzerland

ABSTRACT ARTICLE HISTORY

Regulatory agencies and government authorities have established maximum residue limits (MRL) Received 22 November 2017
Accepted 4 January 2018
in various food matrices of animal origin for supporting governments and food operators in the
monitoring of veterinary drug residues in the food chain, and ultimately in the consumer’s plate. KEYWORDS
Today, about 200 veterinary drug residues from several families, mainly with antibiotic, antipar- Veterinary drugs; food;
asitic or antiinflammatory activities, are regulated in a variety of food matrices such as milk, meat regulation; trade; global
or egg. This article provides a review of the regulatory framework in milk and muscle including market; LC-MS/MS
data from Codex Alimentarius, Europe, the U.S.A., Canada and China for about 220 veterinary
drugs. The article also provides a comprehensive overview of the challenge for food control, and
emphasizes the pivotal role of liquid chromatography-mass spectrometry (LC-MS), either in
tandem with quadrupoles (LC-MS/MS) or high resolution MS (LC-HRMS), for ensuring an adequate
consumer protection combined with an affordable cost. The capability of a streamlined LC-MS/
MS platform for screening 152 veterinary drug residues in a broad range of raw materials and
finished products is highlighted in a production line perspective. The rationale for a suite of four
methods intended to achieve appropriate performance in terms of scope and sensitivity is
presented. Overall, the platform encompasses one stream for the determination of 105 com-
pounds in a run (based on acidic QuEChERS-like), plus two streams for 23 β-lactams (alkaline
QuEChERS-like) and 10 tetracyclines (low-temperature partitioning), respectively, and a dedicated
stream for 14 aminoglycosides (molecularly-imprinted polymer).

Introduction
Today, in a global marketplace, food quality and
safety have gained increasing attention from consu-
mers, governments and food producers. A broad
range of chemical contaminants are monitored or
controlled in food commodities and products due to
their possible adverse effects on human health.
Contaminants are either natural compounds, such
as mycotoxins (Alshannaq and Yu 2017), plant tox-
ins (Koleva et al. 2012; de Nijs et al. 2017) or marine
toxins (Ralston et al. 2011; Lopes et al. 2013), or
chemical structures developed and manufactured at
industrial scale for various applications. For
instance, some are used as pesticides (González-
Rodríguez et al. 2011; Jeong et al. 2014), flame retar-
dants (Li et al. 2015; Fernandes et al. 2016) or
veterinary drugs.
The presence of veterinary drug residues in
food products constitutes a potential health risk for
consumers as they might induce various effects
such as allergic reactions, carcinogenic or teratogenic
mechanisms, or induce antimicrobial resistance
(Baynes et al. 2016). In particular, antimicrobial
resistance is considered as a quickly increasing threat
to global public that now requires appropriate
actions across governments and society. Briefly, anti-
microbial resistance happens when microorganisms
exposed to antimicrobial drugs change and ulti-
mately impair treatment with antibiotics in human
medicine (Hao et al. 2014; Lekshmi et al. 2017).
Then, infections persist in the body, with increasing
risks of spread to others. Both the World Health
Organisation (WHO) and the World Organisation
for Animal Health (OIE) have addressed the threat
specifically. In 2009, the WHO has created the
Advisory Group on Integrated Surveillance of
Antimicrobial Resistance (AGISAR) as a response
to a worldwide solicitation of experts from human

CONTACT Thierry Delatour thierry.delatour@rdls.nestle.com Nestlé Research Center, Lausanne, Switzerland

Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/tfac
© 2018 Nestlé Research Center
2 T. DELATOUR ET AL.
health and veterinary medicine areas. The AGISAR
has revised the list of critically important antimicro-
bials initially published in 2005 with the addition of
new substances (WHO 2011). The OIE has also
issued a list of veterinary drugs of particular concern
(OIE 2015). Incidentally, veterinary drugs may be
used in an incorrect manner with production ani-
mals including sometimes disrespect of withdrawal
time after treatment; this leads to residues in milk,
eggs and edible tissues that can be detected either as
the parent compound or metabolites/conjugates.
This applies beyond antibiotics as antiparasitics,
antiinflammatories, growth promoters or tranquili-
zers can also be found in food by misuse or incorrect
practice at the farm.
For food industry and authority bodies, the chal-
lenge related to the control of veterinary drug resi-
dues lies in the management of three factors
together. They are: the number of chemical com-
pounds, the range of food matrices and the regula-
tion. Today, there are about 200 veterinary drug
residues that need to be taken into account for con-
trol in foodstuffs such as meat, fat, milk, egg, fish,
seafood and honey (Robert et al. 2013; Staub Spörri
et al. 2014; Turnipseed et al. 2014; Munaretto et al.
2016). On a chemical analysis standpoint, the scope
further extents when matrix derivatives (fresh vs.
powder), species (chicken, beef . . .) and related fin-
ished products require attention. The regulation,
often different from one region to the other, drives
the requirements in terms of limit of detection,
usually in the µg/kg levels or even lower in the case
of banned compounds. Obviously, the complexity
associated with the control of veterinary drugs sig-
nificantly increases when the impact of the business
is global and the portfolio of products broad. The
analytical setup required for such monitoring from
the farm (raw materials) to the fork (finished pro-
ducts) has to be optimized carefully for ensuring an
effective control with regard to the coverage (num-
ber of analytes), the throughput (analysis turn-
around time) and the analytical cost (cost-effective
quality control). In that respect, multiresidue screen-
ing tests/methods are attractive tools for a reliable
consumer protection with regard to the possible
presence of veterinary drug residues in food.
In the food operations, screening is commonly
executed with rapid tests for a quick decision-mak-
ing process with regard to the acceptance of the
batch at the factory. Tests are usually based on
immunochemical techniques such as enzyme-linked
immuno-sorbent assay (ELISA), lateral-flow assay or
based on other devices (Abouzied et al. 2012; Sheu
et al. 2013; Bion et al. 2015). Such tests are easy to
use; however, their scope is usually limited in terms
of analytes and matrices, and the specificity of the
detection is sometimes questionable. Liquid chroma-
tography-mass spectrometry (LC-MS) is an alterna-
tive technical approach that is now popular for the
screening of more than a 100 veterinary drugs in a
single run. By the end of the 20th century, LC-MS
had evolved dramatically as a major analytical tool,
providing both sufficient sensitivity to reach the
regulatory limits and adequate certainty in the iden-
tification of the compounds detected (EC 2002;
Delatour et al. 2007; Hird et al. 2014).
Furthermore, LC-MS is versatile enough to be used
either as a screening tool or a quantitative method
(or both), depending on the application.
The present series of six articles is intended to
present the approach chosen by a worldwide food
company for the control of 152 veterinary drug
residues in a broad range of raw materials and fin-
ished products based on liquid chromatography-tan-
dem mass spectrometry (LC-MS/MS). With the
constant increase in the demand for high-through-
put analysis together with better consumer protec-
tion, particular attention was paid to the scope of the
method in terms of analytes, matrices as well as
detection levels. Compounds of interest were
grouped according to their physico-chemical proper-
ties and adequate analytical setups were developed
and validated in order to reach the appropriate
screening performance (Bessaire et al. 2018;
Delatour et al. 2018; Desmarchelier et al. 2018a,
2018b, 2018c; Savoy et al. 2018). We also studied
the stability of the analytes for providing useful data
aimed at facilitating the management of samples in
routine testing laboratories (Desmarchelier et al.
2018c).
Regulatory framework
Codex Alimentarius (Codex 2017) established max-
imum residue levels (MRL) for veterinary drugs
through the Codex Committee on Residues of
Veterinary Drugs in Foods (CCRVDF) based upon
a risk assessment of the joint FAO/WHO Expert

Committee on Food Additives (JECFA). National
legislations are, however, varying significantly
from Codex Alimentarius recommendations, thus,
implying the generation of a complex regulatory
environment for international food trade. This
might be related to the differences found in risk
assessment. In Europe, the European Medicines
Agency (EMA) is the regulatory organization in
charge of proposing MRLs set by the Committee
for Medicinal Products for Veterinary Use
(CVMP). The European regulation No 470/2009
lays down rules and procedures to establish the
MRL for a pharmacologically active substance
which may be permitted in food of animal origin
(EC 2009). Substances with MRLs (or not applicable)
and a list of prohibited substances are available in a
European document (EC 2010). Europe has further
introduced the principle of minimum required per-
formance limit (MRPL) for certain residues in food
of animal origin such as chloramphenicol, nitrofur-
ans and medroxyprogesterone acetate (EC 2003),
thus ensuring public protection against drugs
which are not authorized in the European Union.
In the U.S.A., the Food and Drug Administration
(FDA) establishes tolerances for veterinary drugs
under the Federal Food, Drug, and Cosmetic Act
(FFDCA), and limits are published in the Code of
Federal Regulation (CFR 2016). The FDA also pro-
hibits the usage of some drugs under the 21 Code of
Federal Regulation for extra label animal and human
uses in food-producing animals (e.g. chlorampheni-
col, unless used for topical use). Specifically, as a
response to the threat on antimicrobial resistance,
the prohibition is also applicable to the extra-label
use of some classes of antibiotics (e.g. sulfonamide
antibiotics and potentiated sulfonamides are prohib-
ited in adult lactating dairy cattle or dairy cattle aged
above 20 months). In Canada, the Health Canada’s
Veterinary Drugs Directorate (VDD) sets standards
(MRLs) for veterinary drugs in foods; it also pro-
duced a list of banned drugs, and both the docu-
ments are available at the Health Canada’s website
(HC 2017a, 2017b). In China, the Ministry of
Agriculture (MOA) issued the National Standard
No. 235 for maximum residue level of veterinary
drugs in food of animal origin and the National
Standard No. 193 for prohibited veterinary drugs
and other chemicals in food animals (MOA 2002;
USDA 2011).
FOOD ADDITIVES & CONTAMINANTS: PART A 3
In this article, a non-exhaustive review of the
regulatory framework that encompasses data from
Codex Alimentarius, Europe, the U.S.A., Canada and
China is presented for a total of 220 veterinary drugs
(MRLs and banned) in milk and muscle (Table 1).
Methods available
In the early stage of LC-MS devoted to the analysis
of veterinary drug residues in food, the applications
were restricted to a few compounds, usually less than
20 (Oka et al. 1997; Bogialli et al. 2003), as evidenced
by the graph depicted in Figure 1. At that time, the
sensitivity of mass spectrometry platforms was not
as it is now and the electrospray sources were more
prone to matrix effects, consequently to ion suppres-
sion or enhancement. Therefore, sample prepara-
tions often required cartridge-based solid-phase
extraction (SPE) to both concentrate the analytes of
interest prior to analysis and concomitantly discard
undesirable compounds from the matrix. Obviously,
such an approach is not appropriate for handling
several tens of compounds in a single run because
it is too labor-intensive and expensive in a high-
throughput and economically demanding environ-
ment. Nonetheless, some groups succeeded to deter-
mine about a 100 or more veterinary drug residues
in a single run by LC-MS using acetonitrile extrac-
tion followed by either ultracentrifugation (Ortelli
et al. 2009), polymeric SPE (Kaufmann et al. 2008;
Stolker et al. 2008; Peters et al. 2009), or in combi-
nation with methanol (Yamada et al. 2006).
The introduction of extraction procedures like
QuEChERS (Anastassiades et al. 2003; Rejczak and
Tuzimski 2015) or salting-out-supported liquid
extraction (Kaufmann et al. 2014; Wang et al.
2015) together with the significant advances in the
performance of mass spectrometry platforms over
the years (in terms of sensitivity and ionization
stability) were pivotal in the development of multi-
residue LC-MS methods for a broad range of com-
pounds. During the period 1997–2010, eight LC-MS
methods covering from 51 to 100 analytes were
described in the literature, while 20 have been devel-
oped during the years 2011–2016. The increase is
even more obvious with methods that include more
than a 100 compounds; two methods were published
during the period 1997–2010, while 18 are from the
years 2011–2016 (Figure 1). Interestingly, most of
4 T. DELATOUR ET AL.

Table 1. Maximum residue limits (MRLs) established in milk and muscle by Europe (EU) ([EC] European Commission 2010), Canada
(Ca) ([HC] List of maximum residue limits (MRLs) for veterinary drugs in foods 2017a), China (Ch) ([MOA] National Standard No. 235,
2002), the U.S.A. ([HC] List of maximum residue limits (MRLs) for veterinary drugs in foods 2017a) and the Codex Alimentarius (Co)
([Codex] Codex Alimentarius Maximum residue limits (MRLs) and risk management recommendations (RMRs) for residues of
veterinary drugs in food CAC/MRL 2-2017, 2017).
Milk (µg/kg) Muscle (µg/kg)
Compounds Regulated marker EU Co Ca Ch USA EU Co Ca Ch USA
Abamectin (B1a) # # 20 10 25
Albendazole Albendazole sulfone 100A 100A 100A 100A
Albendazole Albendazole sulfoxide 100A 100A 100A 100A
Albendazole Albendazole 2-aminosulfone 100A 100A 100A 100 50 100A 50
Albendazole Oxide Albendazole oxide 100A 100A
Albendazole Oxide Albendazole sulfone 100A 100A
Albendazole Oxide Albendazole 2-aminosulfone 100A 100A
Altrenogest 1 1
Amitraz sum of metabolites containing 2,4-DMA moiety 10 10 10
Amoxicillin 4 4 10 10 50 50 10 50 10
Ampicillin 4 10 10 10 50 10 50 10
Amprolium 500 500 500
Apramycin # 1000
Avilamycin Dichloroisoeverninic acid 50 200 200
Azaperone Azaperone 100B 60B 60B
Azaperone Azaperol 100B 60B 60B
Bacitracin (A, B, C) 100 500 500 150 500 500 500
Baquiloprim 30
Betamethasone 0.3 0 0.75 1
Bromhexine #
Buquinolate 100
Cabergoline 0.10 0.15
Carazolol 1 5 5
Carbasalate #
Carbomycin 0
Carprofen Carprofen 500C
Carprofen Carprofen glucuronide 500C
Cefacetril 125
Cefalexin 100 100 200 200
Cefalonium 20
Cefapirin Cefapirin 60D 20 20 50D 100 100
Cefapirin Deacetylcefapirin 60D 50D
Cefazolin 50
Cefoperazone 50
Cefquinome 20 20 50 50
Ceftiofur Ceftiofur 100E 1000E
Ceftiofur Desfuroylceftiofur 100E 100 100 100 100 1000E 1000 1000 1000 1000
Chlorhexidine 0
Chlormadinone 2.5
Chlortetracycline Chlortetracycline 100F 100G 100 100 300G 100F 200 G
200 2000G
Chlortetracycline 4-epi-chlrotetracycline 100F 100F
Clavulanic acid 200 200 100 100
Clenbuterol 0.05 0.05 0.10 0.20
Clodronic acid #
Clopidol 20 20 5000 200 200
Clorsulon 16 35 100
Closantel 45 1000 1000 1500 1000
Cloxacillin 30 30 10 300 10 300 10
Colistin 50 50 50 150 150 150
Cyfluthrin 20 40 10 20
Cyhalothrin 50 30 20
Cypermethrin Cypermethrin 20H 100H 20H 50H
Cypermethrin Alpha-Cypermethrin 20H 100H 20H 50H
Cyromazine # 300 50
Danofloxacin 30 30 100 100 70 100 200
Decoquinate # 1000 1000 1000
Deltamethrin 20 30 30 10 30 30
Derquantel 0.3
Destomycin A 2000
Dexamethasone 0.3 0.3 0 0.75 1 1
Diazinon 20 20 20 20
Dichlorvos 50 20 100
Diclazuril 150 500 500 500 500
Diclofenac 0.1 5
Dicloxacillin 30 300
(Continued )
 FOOD ADDITIVES & CONTAMINANTS: PART A 5

Table 1. (Continued).
Milk (µg/kg) Muscle (µg/kg)
Compounds Regulated marker EU Co Ca Ch USA EU Co Ca Ch USA
Dicyclanil Dicyclanil # 200S 150
Dicyclanil 2,4,6-triamino-pyrimidine-5-carbonitrile # 200S
Difloxacin # 300 300
Dihydrostreptomycin 200 200I 125 200I 125 500 600I 500 600I 500
Diminazene 150 150 500 500
Doramectin (B1a) # 15 # 40 5 10 10 30
Doxycycline Doxycycline # # 100 100
Enrofloxacin Ciprofloxacin 100J 100J 100J 20 100J
Enrofloxacin Enrofloxacin 100J 100J 100J 100 100J
Eprinomectin Eprinomectin (B1a) 20 20 20 12 50 100 100 100
Erythromycin 40 50 40 0 200 100 100 200 100
Ethopabate 500 500
Famphur 100
Febantel Oxfendazole sulphone 10K 100K 100K 50K 100K 100K
Fenbendazole Fenbendazole 100K 100K 100K 100 100K 400
Fenbendazole Oxfendazole sulphone 10K 100K 100K 50K 100K 100K
Fenbendazole Fenbendazole Sulfoxide 600 600
Fenthion Fenthion and metabolites 100
Fenvalerate 40 100 25 20
Florfenicol Florfenicol # 100L 200
Florfenicol Florfenicol-amine # # 100L 100 100 300
Fluazuron # 200 200
Flubendazole Flubendazole 50M 10 10M
Flubendazole 2-amino 1H-benzimidazol-5-yl-(4-fluorophenyl) 50M 10M
methanone
Flugestone acetate 1 1 0.5
Flumequine 50 50 200 500 500
Flumethrin 30 30 10 10
Flunixin Flunixin 20 20 25
Flunixin 5-hydroxyflunixin 40 6 2
Fluralaner 65
Fluvalinate 10
Gamithromycin # 50 20 150
Gentamicin(s) Sum of C1, C1a, C2, C2a 100 200 100 200 50 100 100 100 100
Halofuginone # 10 10 10
Haloxon 100
Hydrocortisone 10
Hygromycin B 0
Imidocarb 50 50 300 300
Isometamidium 100 100 100 100
Ivermectin Ivermectin B1a # 10 10 30 30 10 10 20
Kanamycin A 150 100
Ketoprofen 50 100
Kitasamycin 200
Lasalocid A # 10 400 50
Levamisole # 10 10 100 10 100
Lincomycin 150 150 150 100 200 100 100 100
Maduramicin 100 240
Malathion 4000
Marbofloxacin 75 150
Mebendazole # 60 60
Meloxicam 15 35 20 20
Metamizol 4-Methylaminoantipyrin 50 100 200
Methylprednisolone 2 10
Metoserpate 20
Monensin 2 2 10 2 10 50 50 50
Monepantel Monepantel sulfone # 300 500
Morentel N-methyl-1,3-propanediamine 50 100 100 150
Moxidectin 40 40 50 20 50 50
Nafcillin 30 300
Narasin 15 50 600
Neomycin Neomycin B 1500 1500 1500 500 150 500 500 500 500 1200
Nequinate 100
A A
Netobimin Albendazole oxide 100 100
Netobimin Albendazole sulfone 100A 100A
Netobimin Albendazole 2-aminosulfone 100A 100A
Nicarbazin 200 4000 200 4000
Nitroxinil # 400 400
Norgestonet 0.12 0.2
Novobiocin 50 100 100 1000 1000
(Continued )
6 T. DELATOUR ET AL.

Table 1. (Continued).
Milk (µg/kg) Muscle (µg/kg)
Compounds Regulated marker EU Co Ca Ch USA EU Co Ca Ch USA
Nystatin 0
Olaquindox Methylphenylquinolin-carboxylic acid 4
Ormetoprim 100
Oxacillin 30 30 300 300
Oxfendazole Oxfendazole Sulphone 10K 100K 100K 50K 100K
Oxfendazole Fenbendazol 840
Oxibendazole 100 100
Oxolinic acid # 100 100
Oxyclozanide 10 20
Oxytetracycline Oxytetracycline 100N 100 100 100 300G 100N 200 200 100 2000G
Oxytetracycline 4-epi-oxytetracycline 100N 100N
Paromomycin # 500
Penethamate Penicillin G 4O 50O
Penicillin G (Benzylpenicillin) Penicillin G 4O 4 10 4 0 50O 50 10 50 0
Penicillin V 25
(Phenoxymethylpenicillin)
Permethrin 50 50
Phoxim # 10 25 50 50
Piperazine 400 400 100
Pirlimicyn 100 200 400 400 100 100 300 300
Polymyxin B 4 u/
mL
Prednisolone 6 4
Progesterone 5
Pyrantel Pyrantel 1
Pyrantel N-methyl-1,3-propanediamine 150
Ractopamine 10 10 30
Rafoxanide 10 30 30
Rifaximin 60
Robenidine 100 100 100
Roxarsone (Arsanilic acid) Arsenic 500
Salicylate Aluminium Salicylic Acid 8 200
Salicylate Sodium Salicylic Acid # 400
Salicylic Acid Salicylic Acid #
Salinomycin 200 600
Sarafloxacin 10 10
Semduramicin 130 130 130
Sisapronil # 100
Sodium acetylsalicylate #
Spectinomycin 200 200 200 300 500 100 500 100
Spiramycin Spiramycin 200P 200P 200P 200P
Spiramycin Neo-Spiramycin 200P 200P 200P 200P
Streptomycin 200 200I 125 200I 500 600I 500 600I 500
SULFONAMIDE Sum of all substances belonging to the 100Q 100Q 100Q 100Q
sulfonamide
Sulfabenzamide 10Q 100Q
Sulfabromethazine 10 100
Sulfacetamide 10Q 100Q
Sulfachloropyrazine 0
Sulfachlorpyridazine 100Q 100
Sulfadiazine 100Q
Sulfadimethoxine 10Q 10 100Q 100
Sulfadoxine 10Q 100Q
Sulfaethoxypyridazine 10Q 0 100Q 0
Sulfaguanidine 10Q 100Q
Sulfamerazine 100Q
Sulfamethazine 25 10Q 25 100 100Q 100
(Sulfadimidine)
Sulfanilamide 10Q 100Q
Sulfanitran 100Q
Sulfapyridine 10Q 100Q
Sulfaquinoxaline 10Q 100Q 100
Sulfathiazole 10Q 100Q
Sulfomyxin 0
Tetracycline Tetracycline 100R 100 100 100 300G 100R 200 200 100 2000G
Tetracycline 4-epi-tetracycline 100R 100R
Thiabendazole Thiabendazole 100S 100S 50S 100S 50 100S 100S 100S 100S 100
Thiabendazole 5-hydroxy-thiabendazole 100S 100S 50S 100S 100S 100S 100S 100S
Thiamphenicol 50 50 50 50
Tiamulin Tiamulin 100T
(Continued )
 FOOD ADDITIVES & CONTAMINANTS: PART A 7

Table 1. (Continued).
Milk (µg/kg) Muscle (µg/kg)
Compounds Regulated marker EU Co Ca Ch USA EU Co Ca Ch USA
Tiamulin 8-alpha-hydroxymutilin 100 100 100T
Tildipirosine # 400 400
Tilmicosin 50 50 50 100 100 75 100
Tolfenamic acid 50 50
Toltrazuril Toltrazuril sulfone 100 100 100
Trenbolone Beta-trenbolone 2 2
Trichlorfon 50 50 50
Triclabendazole Ketotriclabendazole 10 225 200 100
Trimethoprim 50 50 50 50
Tripelennamine 20 200
Tulathromycin A # 300 1000
Tylosin 50 100 50 50 100 100 200 200 200
Tylvalosin Tylvalosin 50U 50 50U
Tylvalosin 3-O-acetyltylosin 50U 50U
Valnemulin 50
Virginiamycin (M1) 10 100 100 100
Zeranol 2 2 20
Zilpaterol 2 10
Zoalene (Dinitolmide) Zoalene 3000V 3000V 3000V
Zoalene (Dinitolmide) 3-amino-5-nitro-o-toluamide 3000V 3000V 3000V
Superscripted capitals flag residues regulated as a sum; # stands for analytes which are ‘not for use in animals for which milk are produced for human
consumption’.

Figure 1. Methods from the literature (years 1997–2016) devoted to the analysis of veterinary drug residues by LC-MS techniques,
including both triple-quadrupole and high-resolution platforms.

these methods (years 2011–2016) have been devel-
oped for a single food matrix (11 methods), showing
the challenge related to the development of an analy-
tical approach applicable to a broad range of food
matrices, from raw materials and processed ingredi-
ents to finished products. Five LC-MS-based methods
have been single-laboratory validated for the determi-
nation of veterinary drug residues in more than two
raw materials. The LC-MS/MS technology has been
used to screen about 130 compounds in egg, honey,
milk and tissue (Robert et al. 2013), 120 residues in
tissue, milk and egg (Chen et al. 2016) or quantify 115
compounds in milk powder, fish and egg (Dasenaki
and Thomaidis 2015). High-resolution mass spectro-
metry has been applied for the quantification of veter-
inary drugs in tissue, fish, honey, kidney and liver
(Kaufmann et al. 2011) and the screening 105 com-
pounds in meat, milk and egg (Deng et al. 2001).
Despite significant recent progress in sample pre-
paration and instrument performance, the analysis
of a ‘comprehensive’ list of veterinary drug residues
(>120) in a broad range of food materials
(raw materials, processed ingredients and finished
products) remains a challenge for a single multiresi-
due LC-MS method. Such a method is expected to
be designed for high-throughput, cost-effective and
business-oriented with the ultimate goal to protect
consumers and facilitate trade in a global market.
Today, this method does not exist and only a com-
bination of methods can fit best with the needs, in
terms of throughput, cost and consumer protection.
Screening versus quantification
LC-MS is a versatile technology, now broadly
accepted and recognized as the ‘gold standard’ for
8 T. DELATOUR ET AL.
both quantification and screening of chemical con-
taminants in food, and specifically veterinary drug
residues (Hird et al. 2014). Several multiresidue
methods based on LC-MS/MS or LC-HRMS have
been described in the literature for the quantitative
determination of veterinary drugs in food.
Interestingly, over 18 methods designed for more
than a 100 compounds were published in the years
2011–2016; 10 of them have been established for
quantification purposes. The other eight methods
are intended to offer a screening capability.
Although isotope dilution-based quantification
remains the most reliable approach for LC-MS
(Delatour 2004), it is unfortunately not applicable
to multiresidue analysis because most of the isoto-
pomers are commercially not available and, if they
would, the impact on the cost would render the
analysis not sustainable in a challenging economic
environment.
Technically, matrix-matched calibration is often
applied for quantification because it appears as a
convenient manner to mimic the response of the
analytes in the matrix of interest. However, food
composition is complex and subjected to natural
variation triggering significant variability in the
response factors, at least in the some sections of
the chromatographic profile (Figure 2). Therefore,
it is a challenge to select a mixture of blank matrix
samples used for the calibration that accounts for the
possible variations within the matrix of interest. In a
routine testing laboratory, such an approach requires
the usage of several calibrations (one per matrix
category) which may impair both the cost-effective-
ness and the throughput of the laboratory when a
Figure 2. Comparison of penicillin G responses in various food matrices.
broad range of food samples needs to be processed
daily. It should be emphasized that validation pro-
vides performance data only in a certain range based
on performance assessment at some levels defined in
the validation plan (recovery, precision and accu-
racy). Some groups have assessed performance at
four (Schneider et al. 2012; Wang et al. 2015) or
three levels (Gómez-Pérez et al. 2012, 2014, 2015)
and sometimes at a single one (Dasenaki and
Thomaidis 2015). Piatowska and coworkers (2016)
have single-laboratory validated at the MRL accord-
ing to the criteria defined by the European
Commission (EU 2002). It has also been proposed
to build two calibration curves with concentrations
that differ by one order of magnitude and assign
appropriate compounds to the curve with a range
that fits the best to the MRL (Kaufmann et al. 2011,
2014). In practice, the validation of a quantitative
LC-MS method for the simultaneous determination
of more than a 100 compounds is a labor-demand-
ing task which does not guarantee adequate preci-
sion due to unpredictable matrix effects from the
sample. Furthermore, such a work does not spare
additional tests for samples that contain analyte(s) at
levels outside the validated range.
Interestingly, recent surveys conducted in the U.S.
A. and Europe have identified only low rates of non-
compliant samples with regard to veterinary drug
residues in live animals and animal products. In
the U.S.A., the rate of non-compliance was found
at 1.15% (11 positive samples out of 953 targeted
samples) in milk (FDA 2015). In Europe, rates of
non-compliance were found at 0.04% for the β-ago-
nists, at 0.72% for antibacterials, at 0.03% for

Figure 3. Distribution of the RASFF notifications (%) for the major safety-related food hazards (years 2013–2016, n: total number of
notifications). Source: RASFF Annual Reports 2013–2016.
sedatives in pig, and at 0.03–0.54% for anthelmintics
and 0.19–0.51% for the non-steroidal antiinflamma-
tory drugs depending on the species (EFSA 2016).
These data show that screening methods would
operationally be more appropriate for clearing com-
pliant raw materials to be accepted in the production
line. Any positive sample that requires quantitative
determination can anyway be tested by an adequate
quantitative approach such as isotope dilution or
standard addition. With regard to risk management
and business efficiency, it appears more effective to
obtain a quick response of the compliant samples/
parameters while keeping enough attention to the
four major risks of public health concern that are
pathogenic microorganisms, mycotoxins, pesticides
and heavy metals (Figure 3).
A streamlined LC-MS/MS platform
Due to the large portfolio of products to be con-
trolled for the possible presence of veterinary drug
residues, our primary intention was to establish a
LC-MS/MS analytical platform applicable to regu-
lated raw materials, namely milk, meat/muscle,
fish/seafood, egg and fat. In a global food business,
most of these stuffs are traded after being pro-
cessed as powdered materials for being incorpo-
rated in recipes. We therefore included these
powdered materials (e.g. beef meat powder, white
and yolk egg powders) in the scope of the
FOOD ADDITIVES & CONTAMINANTS: PART A 9
analytical platform in order to obtain a tool that
fits with the current business practices. Specifically,
the following dairy powdered ingredients were
included in the scope: full-cream, fat-filled and
skimmed milk, whey proteins, lactose and case-
inate. Some baby/infant-related finished products
(infant formulae and cereals, baby food) were also
part of the scope for an effective control of these
product categories. Particular emphasis was put on
hydrolyzed infant formulae as free amino acids and
low molecular mass peptides can interfere with
some sample preparation conditions, leading to
impaired method performance for this category of
product.
The list of veterinary drugs (152 in total) was estab-
lished based on inputs from different sources such as
regulations from various countries and Codex
Alimentarius, field information from corporate agri-
culture services, specific market needs and constraints,
positive findings or assessment of likelihood of occur-
rence. In essence, aminoglycosides, amphenicols, aver-
mectins, benzimidazoles, β-lactams, coccidiostats,
lincosamides, macrolides, non-steroidal antiinflamma-
tories, quinolones, sulfonamides, tetracyclines and
others were selected in the scope (Figure 4). From an
analytical standpoint, the goal was to first develop a
method based on a generic sample preparation
intended to include as many compounds as possible.
Then, specific methods were developed additionally
for drug classes that required dedicated conditions, in
10 T. DELATOUR ET AL.

Figure 4. Categories of veterinary drug compounds included in the scope of the current study.

terms of both sample preparation and LC-MS/MS
conditions (β-lactams, aminoglycosides, tetracyclines).
In the end, a suite of four methods was necessary to
screen the entire set of 152 veterinary drug residues in
a broad range of raw materials, processed powdered
ingredients and some finished products at levels that fit
with the regulatory requirements. Some groups have
concluded earlier the need for a suite of methods
(instead of a single one) for an appropriate screening
that matches the established scope (Martos et al. 2010;
Staub Spörri et al. 2014).
Our analytical platform, as a suite of four methods,
was defined as follows. Streams are depicted in Figure 5,
and full technical details are available elsewhere
(Bessaire et al. 2018; Desmarchelier et al., 2018a,
2018b; Savoy et al. 2018).
a. Multiclass (105 compounds): The QuEChERS
procedure was adapted in order to cover the
broadest drug/matrix combination as possible.
Specific reconstitution conditions with a higher
amount of methanol and dedicated LC-MS/MS
conditions with a lower source temperature
were required for a suitable analysis of aver-
mectins (6 compounds).
b. β-Lactams (23 compounds): Another variation
of the QuEChERS method was optimized due
to the insufficient sensitivity of amoxicillin and

Figure 5. Flowchart for the analysis of 152 veterinary drug residues in food raw materials, processed ingredients and some finished
products by LC-MS/MS.

ampicillin with the ‘Multiclass’ procedure
(stringent regulatory limits at 4 µg/kg in
milk). Despite the significant relevance for
monitoring these two compounds, they are
often not included in large-scope multiresidue
methods or, if so, validated at levels higher
than regulatory limits. Briefly, the modifica-
tions from the ‘Multiclass’ protocol are the
use of an alkaline aqueous extraction buffer,
the absence of primary secondary amines for
dispersive SPE, and extract volume reduction
without evaporation to dryness.
c. Tetracyclines (10 compounds): Poor absolute
recovery and sensitivity were observed for these
analytes using the extraction protocol and LC-
MS/MS conditions of the ‘Multiclass’ procedure.
This was rationalized in terms of chelation of
these compounds with metal ions available in
the matrix, the LC column or the stainless steel
parts of the LC system. To circumvent this
phenomenon, ethylenediaminetetraacetic acid
(EDTA) was supplemented in the sample pre-
paration media, and oxalic acid was added in
both the dilution solvent and the mobile phase.
Furthermore, a 10-min extended gradient was
developed for the separation of the epimers
regulated in Europe.
d. Aminoglycosides (14 compounds): This
important class of antibiotics cannot be
extracted with organic solvents due to a strong
hydrophilic behavior. For the same reason,
they also require LC conditions that do not
make use of conventional reversed phase chro-
matographic conditions. Therefore, a dedicated
procedure was optimized with an extraction
under acidic aqueous conditions followed by
a selective clean-up with molecularly imprinted
polymer-solid phase extraction (MIP-SPE).
Analytes were subsequently detected by ion-
pair reversed phase LC-MS/MS.
The monitoring of chemical contaminants, particu-
larly with veterinary drugs, is a dynamic field that
requires constant assessments and adaptations, lead-
ing to scope extensions and possibly method mod-
ifications in order to fit with an evolving context. In
that regard, the complementarity of the two
QuEChERS-based extraction conditions developed
in the current work, either acidic for the
FOOD ADDITIVES & CONTAMINANTS: PART A 11
‘Multifamily’ stream or alkaline for the β-lactams,
offers interesting perspectives in terms of analyte
scope extension.
The four methods developed in the current work
have been validated as screening tools and, in that
regard, the concept of screening target concentration
(STC) has been used. Due to the occurrence of
matrix effects that sometimes induce unpredictable
variations in the response factor we have chosen to
apply a double extraction for each sample; the first
test portion is extracted as such, while the second
one is spiked at the STC. Both extracts are processed,
analyzed, and corresponding signals compared
against a cutoff value determined during the valida-
tion. This approach is very reliable as it takes into
account the intrinsic matrix effect of each sample to
be analyzed. We did not retain the common
approach that compares absolute signal abundances
because it does not guarantee sufficient reliability,
and ultimately does not prevent false negative
responses, which is not acceptable in a food safety
perspective.
Acknowledgment
We would like to thank Weijia Gan and Longfei Wang,
Nestlé Food Safety Institute (China), for their invaluable
help in accessing an English version of the National
Standard No. 235 (Ministry of Agriculture of the People’s
Republic of China).
Disclosure statement
No potential conflict of interest was reported by the authors.
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