(PDF) a General LC-MS - MS Method for Monitoring Potential Β-Lactam Contamination in Drugs and Drug-Manufacturing Surfaces

5/1/2019 (PDF) A General LC-MS/MS Method for Monitoring Potential β-Lactam Contamination in Drugs and Drug-Manufacturing Surfaces
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hod for Monitoring Potential β-Lactam Contamination in Drugs and Drug-Manufacturing Surfaces
n The AAPS Journal 20(4) · July 2018 with 184 Reads

-0224-7
Hongbin Zhu
.S. Food and Drug Administration 23.01 · Thermo Fisher Scientific
+1
zicka
ire
S Food and Drug Administration, St Louis, MO, United States
Show more authors
non-penicillin β-lactams may cause potentially life-threatening allergic reactions. Thus, possible cross
ctams in food or drugs can put people at risk. Therefore, when there is a reasonable possibility that a
t could be contaminated by penicillin, the drug products are tested for penicillin contamination. Here, a
ethod for simultaneous determination of multiple β-lactam antibiotics using high performance liquid
dem mass spectrometry (LC-MS/MS) was developed and validated. Mass spectral acquisition was
active HF mass spectrometer in positive ion mode with parallel reaction monitoring (PRM). The method
en β-lactam antibiotics including one or two from each class and a synthetic intermediate. The
on and accuracy at 200 ppb were in the range of ± 1.84 to ± 4.56 and − 5.20 to 3.44%, respectively.
(LOD) was 0.2 ppb, and the limit of quantitation (LOQ) was 2 ppb with a linear dynamic range (LDR) of
ght β-lactams. From various drug products, the recoveries of eight β-lactams at 200 and 2 ppb ranged
2.1 ± 4.2% and 89.7 ± 4.6 to 110.6 ± 1.9%, respectively. The application of the method for detecting
of trace β-lactams (0.2 ppb) and for monitoring facility surface cleaning was also investigated. This
thod was fit-for-purpose for detecting and quantifying trace amount of β-lactam contamination,
tamination in manufacturing processes, and determining potency for regulatory purposes and for
research
bers
ications
rojects
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Chen Qiu Author content Download full-text PDF
Journal (2018) 20:70

8/s12248-018-0224-7
Research Article
eral LC-MS/MS Method for Monitoring Potential β-Lactam

mination in Drugs and Drug-Manufacturing Surfaces
,1 Hongbin Zhu,1,2 Connie Ruzicka,1 David Keire, 1 and Hongping Ye 1,3
Received 5 March 2018; accepted 3 April 2018
Abstract. Penicillins and some non-penicillin β-lactams may cause potentially life
threatening allergic reactions. Thus, possible cross contamination of β-lactams in food o
drugs can put people at risk. Therefore, when there is a reasonable possibility that a non
penicillin product could be contaminated by penicillin, the drug products are tested fo
penicillin contamination. Here, a sensitive and rapid method for simultaneous determinatio
of multiple β-lactam antibiotics using high performance liquid chromatography-tandem ma
spectrometry (LC-MS/MS) was developed and validated. Mass spectral acquisition wa
performed on a Q-Exactive HF mass spectrometer in positive ion mode with parallel reactio
monitoring (PRM). The method was validated for seven β-lactam antibiotics including one o
two from each class and a synthetic intermediate. The quantification precision and accurac
at 200 ppb were in the range of ± 1.84 to ± 4.56 and − 5.20 to 3.44%, respectively. The limit o
detection (LOD) was 0.2 ppb, and the limit of quantitation (LOQ) was 2 ppb with a linea
dynamic range (LDR) of 2–2000 ppb for all eight β-lactams. From various drug products, th
recoveries of eight β-lactams at 200 and 2 ppb ranged from 93.8 ± 3.2 to 112.1 ± 4.2% and
89.7 ± 4.6 to 110.6 ± 1.9%, respectively. The application of the method for detecting cros
contamination of trace β-lactams (0.2 ppb) and for monitoring facility surface cleaning wa
also investigated. This sensitive and fast method was fit-for-purpose for detecting an
quantifying trace amount of β-lactam contamination, monitoring cross contamination
manufacturing processes, and determining potency for regulatory purposes and for qualit
control.
KEY WORDS: cross contamination; LC-MS/MS; parallel reaction monitoring; penicillin; β-lactams.
UCTION or run-off from agricultural use and landfills

reactions after consumption of foods con
llin or other non-penicillin drugs containing a β- residues have been widely reported in the
ety are antibiotics with a long history in the treatment Thus, antibiotic monitoring is an essentia
range of infectious diseases in both human and measure in safe food or drug production.
applications. While these antibiotics play an impor- The massive production of antibio
n disease treatments, they pose a potential risk for another risk—cross contamination. Cross
who are hypersensitive to them (1–4). In fact, β-lactams, especially exposure of non-peni
allergy is the most common cause of drug-induced penicillins, has been shown to be a safety co
s, and the allergy accounts for up to 1000 deaths per (6,12–14). Recent cases involving potential
Hundreds of thousands of tons of antibiotics are tion in repackaging operations, loss of
each year, and 30–60% pass through animals and segregated facilities, potential undeclared
mpletely
See allunchanged.
› The different compounds then meopathic products, and contaminated comp
cean via hospital waste,municipal sewage, fish farms, have required the use
Download of testShare
citation methods stip Download full-text PDF
24 References tions. However, the current FDA’s guidance
BNon-Penicillin Beta-Lactam Drugs: A CG
f Pharmaceutical Analysis, Center for Drug Evaluation
for Preventing Cross-Contamination^) (15)
arch, U.S. Food and Drug Administration, 645 S.
Ave, St. Louis, Missouri 63110, USA. method which was published in 1965 and th
dress: ThermoFisher Scientific Inc., 3747 N Meridian Rd, sensitivit y to low levels of β-lactams (1
Illinois 61101, USA. threshold dose at which allergenic respon
m correspondence should be addressed. (e–mail: extremely low and difficult to define (11,17)
ye@fda.hhs.gov) and robust analytical method is a critical nee
1550-7416/18/0000-0001/0 # 2018 American Association of
age 2 of 9 The AAPS Journal (2018
utical ind ustries for regul atory purposes or fo r Optima LC-MS grade solvents were purch
quality control. Scientific (Pittsburgh, PA). Milli-Q water
d chromatography (LC) with UV detection has been was used for preparation of all solutions.
termine antibiotics (18–20), but such methods often lack
ivity and specificity required for β-lactam detection. Preparation of Samples, Calibration
se LC-UV techniques have been replaced by methods Validation Samples
mass spectrometry (MS) detection to provide more
etermination leading to unequivocal confirmation of the Stock solutions of each β-lactam stand
ds studied. However, most of the LC-MS methods have at 400 ppm in the mobile phase mixture w
eloped for the analysis of residue penicillin and related (A/B, 10:90, v/v, see chromatographic
in food products (21–25). In addition, these methods solutions were sonicated for 5–30 min to
timized or validated for trace amount detection in drug particulates fully dissolved. A 5% aceton
ons. For example, Bekoe et al. used an LC-MS/MS used as the diluent for the preparation
o investigate the quality of antibiotic drug products with mixtures from the individual standard stock
measurements on 13 antibiotic active pharmaceutical containing 20,000 ppb of each β-lactam stan
s (26). However, the Bekoe et al. method was developed dPNG as an internal standard was prepared
ay of antibiotics not for trace level determination. MS analysis, a series of di lutions were
e working with an FDA compliance for-cause 20,000 ppb standard mixture to obtain
nt in 2015, a sensitive LC-MS/MS method for the 2000, 200, 20, 2, and 0.2 ppb for each st
and quantification of penicillin G (PNG) and 6- concentration of the internal standard dPN
nicillanic acid (6-APA) in homeopathic products was all standard solutions. These standard mixt
d in our laboratory. In the current study, more obtain calibration curves and to determine
method development and validation were con- of detection (LOD) and limit of quantitat
extend the LC-MS/MS method for the determina- lactams. Two separate mixtures at 200 a
ll five types of β-lactam antibiotics (27) found in prepared for all standards and used for ins
formulations, including tablets, capsules, suspen- and accuracy tests.
d injections. Using thi s validated method, cross The recovery test samples were pre
ation and facility surface cleaning were also investi- eight β-lactam standards and the internal st
selected drugs. This LC-MS/MS approach is a single solutions made from the drug products
that can be used for simu ltaneous detection of capsules, composites were generated using t
β-lactams at levels as low as 0.2 ppb. Moreover, capsules or the powder from ten ground
ide LC gradient was used and the drugs tested here having an equivalent amount of the activ
persed throughout the chromatogram, the method 10 mg according to the label claim) were
e easily adapted to other β-lactams and antibiotics. 10-mL volumetric flask and dissolved
acetonitrile. Samples were sonicated for 1
IALS AND METHODS to volume with 5% acetonitrile. An aliquot
was filtered using a 0.20-μm filter. For inje
, Reagents, and Standards sion formulations, the drug containers w
ously for a minute, an amount equivalen
β-lactam standards of amoxicillin (AMX), ampicillin active compound by volume was transfe
penicillin G (PNG), cefuroxime (CFX), imipenem volumetric flask and mixed with 5 mL
oracarbef (LRC), and aztreonam (AZT) were Samples were sonicated for 10 min and
e d f r o m U S P ( R o c k v i l l e , M D ) . T h e 6 - with 5% acetonitrile. An aliquot of the
nicillanic acid (APA) was obtained from Santa Cruz filtered using a 0.20-μm filter. Filtrates w
SeeInc.
ology, all ›(Dallas, TX). The d7-penicillin G (dPNG) times while adding desired amounts of the
moxicillin (dAMX) were purchased from Toronto
24 References samples Download citation for
were prepared Share
each drug Download full-text PDF
Chemicals, Inc. (Toronto, Canada). All standards containing the internal standard only and
ies greater than 99%. Drug products were purchased 2 and 200 ppb β-lactam standards, respectiv
a pharmacy (Table I). Optima formic acid and the internal standard.
Table I. Drug Products Used in this Study
Formulations Dosages
G potassium Injection 5,000,000 units

n Capsules 500 mg
Suspension for oral 125 mg/5 mL
e Injection 750 mg
V potassium Tablets 500 mg
Tablets 40 mg
Ad
Journal (2018) 20:70 70
II. Name, Structure, Molecular Weight (Mw), Water Solubility (Sw), PRM Transition, and Collision Energy fo
HCD
Mw Sw* Precursor ion
Name Chemical structure Energ
(g/mol) (g/L) quantifier
(eV
(+)-6-
Aminopenicillanic acid 216.26 4.0 217.0640 189.0692 35
(APA)
Imipenem (IMP)
317.36 10.0 300.1009 126.0374 30
Amoxicillin (AMX) 419.45 3.93 366.1115 114.0012 30
Aztreonam (AZT)
435.43 0.043 436.0589 313.0599 30
Loracarbef (LRC)
367.78 0.325 350.0898 174.0550 30
Ampicillin (AMP)
349.40 0.605 350.0898 106.0656 30
Penicillin G potassium
(PNG) 372 48 100 335 1060 176 0706 35
See all › (PNG) 372.48 100 335.1060 176.0706 35
24 References
Cefuroxime sodium
Freely
(CEF) 446.37 442.1024 211.0173 30
soluble
Penicillin G-d7
379.52 342.1496 183.1146 35
(internal standard)
Amoxicillin-d4
369.43 370.0373 212.0682 25
(internal standard)
eferences: 1. ChemIDplus (US National Library of Medicine). 2. DrugBank database
ig. 1. Chromatogram of standard solution containing eight β-lactams at 200 ppb with MS detection
he cross contamination test, samples were prepared in samples were prepared by depositing 10
ncentrated drug solutions. A 5% acetonitrile solution solutions containing 2 and 20 ng of PN
d to the powder from tablets/capsules to form a slurry two thoroughly cleaned bench areas. Aft
g 100 mg/mL of the active compounds. The slurries bench surfaces were wiped five to eight
cated for 5 min followed by centrifugation at 3000 g for pieces of filter papers (~ 2 × 2 cm) w
The supernatants and injections (100 mg/mL active acetonitrile. The filter papers were
ds) were filtered using 0.20-μm filters. Two samples 10 mL of 5% acetonitrile solution to
pared for each drug filtrate: a blank containing the PNG. A control sample was prepared o
tandard only and a sample with 0.2 ppb β-lactam area where no PNG was deposited. Al
mixture and an internal standard of 200 ppb. were filtered with 0.20-μm filters, a
mimic possible contamination in a manufacturing standard dPNG of 200 ppb was added
a surface contamination test was designed. These sample prior to LC-MS/MS analysis.
See all ›
24 References
Fig. 2. Chromatograms of all standards at 0.2 ppb extracted from PRM acquisition of a standard mixtur
with the count number labeled by each peak. AA refers to autointegrated area
Journal (2018) 20:70 70
alidation Parameters Summarized for Eight Investigated β-Lactams Determined Using Calibration Curves Within
Range (LDR) of 2–2000 ppb
APA IMP AMX AZT LRC AMP
pb LDR) 0.9878 0.9997 1 0.9999 0.9999 0.9998 0

%) 200 ppb − 5.12 − 5.20 1.04 0.05 2.03 3.44 3
400 ppb 0.87 −1.50 5.84 5.54 0.92 − 0.80 3
d%) 200 ppb 1.84 3.34 4.56 2.69 3.86 2.19 2
400 ppb 5.34 4.48 3.01 4.21 2.86 2.63 3
system. A Waters Acquity UPLC BEH C18

graphic and Mass Spectrometric Analyses
mm) column at 35°C was used for sample se
phase A was water-acetonitrile-methanol at 9
S/MS analysis was performed on a Thermo Q-
HF mass spectrometer coupled with a Vanquish LC mobile phase B was water-acetonitrile-metha
See all ›
24 References
overies of eight β-lactams at 2 ppb from five different drug matrixes. The recoveries and standard errors were ca
ons
mobile phases contained 0.1% formic acid (98%). The and samples were normally Bdirty,^ to prot
ent consisted of several steps starting with 1% (B) MS data was only acquired within short ti
or 5 min (0–5 min) and increasing to 75% (B) during the targeted compounds (e.g., PNG) eluted
–20 min). Isocratic elution at 75% (B) for 1 min (20– For each standard, collision-induced
as followed by mobile phase A increasing back to 99% ucts of precursors were detected in the po
min (21–22 min) and equilibrating for another 8 min reaction mo nitoring (PRM) mode. To
in). Flow rate was 250 μL min−1, and the injection experiment, selected precursor ion for e
as 10 μL with the autosampler set at 4°C. added to Binclusion list^ with correspond
mass spectrometer was operated in the positive ion window. PRM transitions and collision
d calibrated using an LTQ Positive Ion Calibration compound are listed in Table II. Peak are
ce). Xcalibur™ instrument control software (version performed using the Thermo QualBrowser
used for data acquisition. The key parameters were
ows: ionization voltage at 3.5 kV, sheath gas at 4 and RESULTS AND DISCUSSION
gas at 1 arbitrary unit, and capillary temperature at
ass scan range was 100 to 500 m/z with resolution of Method Development and Optimization
1 2
MS d 30 000 f MS D t i iti ti
MSSeeand
all
30,0001 for MS . Data acquisition time was
for› MS and MS , respectively.
2
8 min Since all For Download
this work,citation
the challenge
Share in sampl Download full-text PDF
ds eluted before 16 min, the MS2 acquisition was
24 References the solubility differences of the eight β-lact
at 18 min. LC elute was diverted to waste when not make stock solutions at the highest concent
acquisition. For cross contamination test samples, the sample solvent closest to mobile phase A
he concentrations of the drug APIs were very high mixtures of water, methanol, and acetonitrile
Fig. 4. Detection of trace amounts of β-lactams in drug products. a 0.2 ppb penicillin G
spiked into amoxicillin capsules: blue trace represents amoxicillin drug only, red trace
represents 0.2 ppb penicillin G spiked into amoxicillin drug. b 0.2 ppb amoxicillin spiked
into penicillin G injection: blue trace represents penicillin G only, red trace represents
0.2 ppb amoxicillin spiked into penicillin G
Journal (2018) 20:70 70
See all ›
24 References
Fig. 5. Detection of penicillin G from a contaminated facility surface. Blue line represents the control area
red line represents contamination of 0.2 ppb, and green line represents contamination of 2 ppb penicillin G
re of mobile phases A and B at 10 to 90 was found to IMP. However, because APA and IM
solutions for all compounds at 400 ppm. Sonication precursor/quantifier ions (Table II), accur
d for compounds with low solubility. can be achieved despite non-baseline sepa
ugh chemical structures, acid-base properties, and split into two peaks that have the same ma
of these targeted β-lactams are different, they are These peaks represent the presence of
and reverse phase liquid chromatography was secondary amine in equilibrium. Thus, two
r separation on column. The best possible resolu- summarized for quantification of IMP.
desired, because the LC-MS/MS method was to
usly detect and quantify all five classes of β- Method Validation
echnically, these β-lactams can be analyzed with
ive and negative ionization modes, or by switching Through properly designing the PRM
wo modes for different lactams. Here, to simplify assigning each precursor in a specific time w
phase composition and to make method transfer inclusion list, the high specificity of detec
ent LC-MS system more feasible, only the positive lactam was achieved. Comparing with selecte
chosen in the method development. (SIM), the low noise of the selective PRM m
β-lactam standards were injected separately for the sensitivity of the method. Figure 2 show
optimize the chromatographic and mass spectro- of all eight β-lactams at a concentration of 0
ditions and to obtain individual MS spectra. Then, had similar full width at half height and
of eight standards was injected together for further sufficient ion counts for identification and
on and for appropriate selection of the precursor/ lowest concentration investigated in this st
for each β-lactam standard (Table II). A typical which was defined as limit of detection (LO
ram of the mixture is shown in Fig. 1. Figure 1 The peak area ratios of analytes to the
t most of the standards were well separated and were used for quantification to minimize the
throughout the chromatogram except APA and by instrument conditions, possible degradat
Table IV. Potency of β-lactams in Drug Products
cts Concentrations determined b
(capsules) 1111.3 ± 33.4

suspension) 899.0 ± 23.2
(injection) 1145.4 ± 31.5
(injection) 1093.1 ± 25.8
es. Calibration curves for all eight β-lactams were undoubtedly detected and identified. Fig
f d d i b 2 2000 b d i f 02 b PNG i i il
from standard
See all › concentrations
2 between 2 to 2000 ppb detection of 0.2 ppb PNG in amoxicil
ficients of determination (r ) were greater than 0.99 Fig. 4b Download
shows the detection
citation Share of 0.2 Download full-text PDF
24 References
actams in linear fits of the data across this range. All penicillin G injection. Because the meth
ere the average of three injections. The lowest with a LOQ of 2 ppb, quantification to
ation of calibration curves, 2 ppb, was defined as the was not attempted. If desired and the
quantitation (LOQ). Instrument precision was have sufficient signal to noise, the am
ted using data from six injections of β-lactam present can be estimated using calibrati
mixtures at 200 and 400 ppb. Precision was results demonstrate that the method
as a percentage of standard deviation at two detecting and quantifying trace levels
ations and was between 1.84 and 5.34 (Table III). various therapeutic formulations. Thus, th
accuracy at 200 and 400 ppb for each β-lactam was used for both limit and quantification
rmined with six injections using calibration curves. trace levels of contaminates, the sample
sults indicate the method was suitable for simulta- the API must be very high, to the poin
antification of all β-lactams from different classes. does not need to be completely dissolved
effect of drug excipients (matrix effect) was exam- of the highly concentrated sample, the
spiking β-lactam standards into different drug contaminates present should all be in sol
ons including tablets, capsules, suspension s, and the saturated sample removed any rema
(both intravenous and muscular). The standard ulates from the sample before analysis.
t concentrations of 2 and 200 ppb each along with drugs can be analyzed Bas is^ after s
nal standard dPNG was added to five drug matrix internal standard and filtering. For quan
ons, and the recovered amount was determined the deuterated internal standard solution
bration curves. For each drug preparation, a blank freshly to reduce possible H/D excha
piked with dPNG only (no other β-lactam) was deuterated compound may appear if th
with LC-MS/MS and the background concentration standard solution is not fresh.
acted from the spiked pool concentration to obtain
very. For example, to determine spiked AMX
n an amoxicillin injection, the amount of amoxicillin Detection of Facility Surface Contamination
gredient) was determined from the blank sample.
unt was subtracted from the spiked pool concentra- Therapeutics are generally manufactured
AMX, and the resulting concentration was compared plants and production lines for a range
ominal concentration to obtain AMX recovery. At pharmaceutical ingredients are often run in p
entration of 200 ppb, the recoveries were between same equipment. The facility should be tested f
and 112.1 ± 4.2% for all eight β-lactams in all five switching to a different production line to pr
rixes (data not shown). Figure 3 shows the recover- ination and to ensure the safety of the finis
h β-lactam standard from five drug matrixes at 2 ppb cleaning test samples along with a blank sam
anging from 89.7 ± 4.6 to 110.6 ± 1.9%. These results and analyzed with the β-lactam validated me
ated that the existence of drug excipients did not Fig. 5, 0.2 ppb of penicillin G was clearly
quantification of β-lactams using this method. contaminated surface. For the 2 ppb contam
experimental concentration of penicillin G w
from three LC-MS/MS injections. The small
on of the Method
sample is the minor un-deuterated impu
penicillin G which was added as an internal st
of Trace Amounts of β-Lactams in Drug Products
validated method was applied to detect trace Assay of β-Lactam APIs in Drug Products
of β-lactams in drug products and cross contam-
between different β-lactam drugs. Two β-lactam Although this method was developed fo
moxicillin capsules and a cefuroxime injection, at of trace levels of β-lactams, the method ca
mL API (as label stated) were spiked with 0.2 ppb measure the potency of β-lactam drug pro
d 200 ppb dPNG as an internal standard. A validated for quantification in the range of 2–
c sample, penicillin G injection at 100 mg/mL in the recovery study section, for each
ed with 0.2 ppb AMX and 200 ppb dAMX as an preparations, a blank sample spiked with an
standard, was also analyzed to examine the only (no other β-lactam) was analyzed using L
flexibility. In addition, a non β-lactam drug, background concentration was subtracted fro
n tablets at 100 mg/mL API, was tested by concentration to obtain the recovery. The b
with 0.2 ppb PNG and 200 ppb dPNG to trations were API concentrations in the dru
ate the capability of the method to detect trace drug preparations were made at 1000 ppb
contamination in a non β-lactam drug product. claims. The concentration of penicillin G was
these four samples, a blank drug preparation the label claim was 5,000,000 units per vial an
with dPNG or dAMX only was analyzed for weight claim. Table IV shows the experim
on. In all cases, spiked β-lactams at 0.2 ppb were concentrations of the β-lactam API using
https://www.researchgate.net/publication/325164066_A_General_LC-MSMS_Method_for_Monitoring_Potential_b-Lactam_Contamination_in_Drugs_and… 10/16
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24 References
Journal (2018) 20:70 70
curves. The poten cy for penicillin V was not 8. Marazuela MD, Bogialli S. A review of n
d, because its standard curve was not pursued. sample preparation for the determination
residues in foodstuffs using liquid chromato
lytical methods. Anal Chim Acta. 2009;645(1
SIONS 9. Dewdney JM, Maes L, Raynaud JP, Blanc F,
T, et al. Risk assessment of antibiotic residu
method developed and validated in this study and macrolides in food products with regard
allergic potential. Food Chem Toxicol. 1991;2
the advantages of using liquid chromatography in 10. Olatoye IO, Daniel OF, Ishola SA. Screening
on with mass spectrometry for drug contaminant chemical analysis of penicillin residue in
The approach was designed for simultaneous traditional dairy products in Oyo state, N
f multiple β-lactams and liquid chromatography 2016;9(9):948–54.
11. Dayan AD. Allergy to antimicrobial residu
he primary separation. Then mass spectrometric
ment of the risk to man. Vet Microbiol. 1993
especially using PRM and deuterated internal 12. Romano A, Gaeta F, Arribas Poves MF, V
provided high sensitivity, selectivity, accuracy, and reactivity among beta-lactams. Curr Aller
or identification and quantitation. 2016;16(3):1–12.
se the method was developed with eight standards 13. Buonomo A, Nucera E, Pecora V, Rizzi
Pascolini L, et al. Cross-reactivity and toler
ng all five classes o f β-lactam antibiotics, the sporins in patients with cell-mediated allerg
as presented can analyze drugs containing these β- Investig Allergol Clin Immunol. 2014;24(5):3
While different formulations may require minor 14. Zagursky RJ, Pichichero ME. Cross-reactiv
ons to the method, overall, the method is robust allergy. J Allergy Clin Immunol Pract. 2018;6
15. FDA guidance for industry. Availabl
erences in excipients across the antibiotics tested
www.fda.gov/downloads/Drugs/Guidances/UC
recovery. An advantage of the mass detector in this 16. Carter GG. A review of procedures for the de
that both known and unknown impurities can be penicillins in drugs. FDA By-Lines. 1977;8:11
Drugs can be tested as is, or may require minimal 17. Blanca M, Garcia J, Vega JM, Miranda
eparation. With simplified mobile phases and LC- Mayorga C, et al. Anaphylaxis to peni
therapeutic exposure: an immuno logical i
s, up to 16 samples can be run within 24 h. Exp Allergy. 1996;26(3):335–40.
tial applications of the method include detection 18. Samanidou VF, Nisyriou SA, Papadoyannis
i fication of trace level contaminates, monitoring and validation of an HPLC method for the
ontamination in manufacturing processes or final penicillin antibiotics residues in bovine musc
and potency determination for quality control. European Union Decision 2002/657/
2007;30(18):3193–201.
n, consumed antibiotics passing through animals 19. Camara M, Gallego-Pico A, Garcinuno
ns and entering the food supply chain have also Hernando P, Durand-Alegria JS, Sanchez PJ
ncern. Although the sample preparation proce- method for the simultaneous determination o
uld vary, this method may also be used for the antibiotics in ewe milk. Food Chem. 2013;141
20. Hsieh SH, Huang HY, Lee S. Determination
of antibiotic residues in food products. The key antibiotics in pharmaceuticals, milk and porcin
ful use of this approach is the use of an internal liquid chromatography. J Chromatogr A. 2009
o obtain reliable quantitative results with mass 21. Fedorava G, Nebesky V, Randak T, Grabi
try analysis. determination of 32 antibiotics in aquacultu
LC-MS/MS. Chem Pap. 2014;68(1):29–36.
22. Rezende CP, Almeida MP, Brito RB, Nonak
This publication reflects the views of the authors and Optimisation and validation of a quantitative
be construed to represent the FDA’s views or policies. LC-MS method for multi-residue analyses
tetracycline antibiotics in bovine muscle. Fo
2012;29(4):541–9.
NCES 23. Macarov CA, Tong L, Martinez-Hu elamo
Chirila E, Wang YX, et al. Multi residue de
penicillins regulated by the European Union,
an d c h ic k en mu sc le, b y L C- MS /MS
S. In: Rossi S, editor. Australian medicines handbook. 2012;135(4):2612–21.
Pty Ltd: Adelaide; 2006. 24. Jank L, Hoff RB, Tarouco PC, Barreto F, P
lez-Estrada A, Radojicic C. Penicillin allergy: a practical lactam antibiotics residues analysis in bovine
or clinicians. Cleve Clin J Med. 2015;82(5):295–300. MS/MS: a simple and fast liquid-liquid extrac
I, Blanca-Lopez N, Torres MJ, Garcia-Campos J, Garcia- Addit Contam Part A Chem Anal Control
I, Gomez F, et al. Drug hypersensitivity reactions: 2012;29(4):497–507.
se patterns, drug involved, and temporal variations in a 25. Canzani D, Hsieh K, Standland M, Hamm
series of patients. J Investig Allergol Clin Immunol. UHPLC-MS/MS method for the quantitation
2(5):363–71. metabolites in citrus fruit using inter
AT, Gallagher JC. Beta-lactam hypersensitivity and Chromatogr B Analyt Technol Biomed Lif
eactivity. J Pharm Pract. 2014;27(6):530–44. 1045:87–94.
alla RS, Pirmohamed M. Clinical practice. Antibiotic 26. Bekoe SO, Bak SA, Bjorklund E, Krogh
N Engl J Med. 2006;354(6):601–9. Adosraku RK, et al. Determination of thir
hero ME, Zagursky R. Penicillin and cephalosporin drug products—a new LC-MS/MS tool fo
Ann Allergy Asthma Immunol. 2014;112(5):404–12. product quality. Anal Methods. 2014;6:5847–
E, Contreras R. Health care use and serious infection 27. Yao J, Moellering R. Antibacterial agents.
ence associated with penicillin Ballergy^ in hospitalized Carroll K, Funke G, Jorgensen J, Landry
s: a cohort study. J Allergy Clin Immunol. 2014;133(3):790–6. editors. Manual of clinical microbiology. 10t
DC: American Society for Microbiology; 201
See all ›
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eferences (24)
ctam Allergy
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Francesco Gaeta · Maria Francisca Arribas Poves · Rocco Luigi Valluzzi
ctical guide for clinicians

ble
a · C. Radojicic
andbook. Adelaide
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erability of Cephalosporins in Patients With Cell-Mediated Allergy to Penicillins

ble
ERG CLIN
Eleonora Nucera · Valentina Pecora · Domenico Schiavino Schiavino
itivity and Cross-Reactivity

ble
See all ›
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son Gallagher
en antibiotics in drug products – A new LC-MS/MS tool for screening drug product quality
ble
Søren Alex Bak · Erland Björklund · Martin Hansen
porin allergy
ASTHMA IM
bert Zagursky
rious infection prevalence associated with penicillin "allergy" in hospitalized patients: A cohort
mmunol
ntreras
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(PDF) a General LC-MS - MS Method for Monitoring Potential Β-Lactam Contamination in Drugs and Drug-Manufacturing Surfaces

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5/1/2019 (PDF) A General LC-MS/MS Method for Monitoring Potential β-Lactam Contamination in Drugs and Drug-Manufacturing Surfaces

n The AAPS Journal 20(4) · July 2018 with 184 Reads

Show more authors

Chen Qiu Author content Download full-text PDF

Journal (2018) 20:70

eral LC-MS/MS Method for Monitoring Potential β-Lactam

,1 Hongbin Zhu,1,2 Connie Ruzicka,1 David Keire, 1 and Hongping Ye 1,3

Received 5 March 2018; accepted 3 April 2018

UCTION or run-off from agricultural use and landﬁlls

1550-7416/18/0000-0001/0 # 2018 American Association of

age 2 of 9 The AAPS Journal (2018

Table I. Drug Products Used in this Study

G potassium Injection 5,000,000 units

Journal (2018) 20:70 70

Amoxicillin (AMX) 419.45 3.93 366.1115 114.0012 30

eferences: 1. ChemIDplus (US National Library of Medicine). 2. DrugBank database

age 4 of 9 The AAPS Journal (2018

Journal (2018) 20:70 70

APA IMP AMX AZT LRC AMP

pb LDR) 0.9878 0.9997 1 0.9999 0.9999 0.9998 0

system. A Waters Acquity UPLC BEH C18

age 6 of 9 The AAPS Journal (2018

Journal (2018) 20:70 70

Table IV. Potency of β-lactams in Drug Products

cts Concentrations determined b

(capsules) 1111.3 ± 33.4

age 8 of 9 The AAPS Journal (2018

Journal (2018) 20:70 70

wayemisi Folashade Daniel · Sunday Ayobami Ishola

ctical guide for clinicians

I Vitry · Genevieve Gabb · Eve Hurley

erability of Cephalosporins in Patients With Cell-Mediated Allergy to Penicillins

itivity and Cross-Reactivity

Søren Alex Bak · Erland Björklund · Martin Hansen

Glycosylation mapping . Host cell proteins monitoring.

Article Full-text available

N. Kannappan · Mahendra Kumar · Madhukar Akkala

Article Full-text available

Aman Sentosa Panggabean · Tika Widyastuti · Noor Hindryawati

© ResearchGate 2019. All rights reserved. Imprint · Terms · Privacy

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