DOI 10.

1007/s11094-016-1367-4
Pharmaceutical Chemistry Journal, Vol. 49, No. 11, February, 2016 (Russian Original Vol. 49, No. 11, November, 2015)

STRUCTURE OF CHEMICAL COMPOUNDS,

METHODS OF ANALYSIS AND PROCESS CONTROL

MODERN APPROACHES TO ESTIMATING THE CONTENT

OF GENOTOXIC IMPURITIES IN DRUGS (A REVIEW)

O. A. Matveeva1,* and E. L. Kovaleva1

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 49, No. 11, pp. 41 48, November, 2015.

Original article submitted May 19, 2015.

This review considered international approaches to assessment of the content of genotoxic impurities (residual
solvents and various inorganic and organic impurities) in drugs. Foreign and domestic regulations defining re-
quirements for the classification, control, and toxicological risk assessment of potential genotoxic impurities
in drug substances and drugs were compared. The use of highly sensitive and specific analytical methods for
detecting genotoxic impurities in drugs was justified. The need to improve the domestic regulatory framework
on the control of elemental genotoxic impurities (heavy metals) and to prepare guidelines on the assessment of
potentially genotoxic organic impurities in drugs was demonstrated.
Keywords: genotoxic impurities, drugs, threshold of toxicological concern (TTC).

Genotoxic (mutagenic) impurities in drugs have recently
attracted much attention abroad because they have extremely
negative effects on human health. Insignificant amounts
(concentrations of 1 ppm) of them can initiate genetic muta-
tions and chromosome breaks and rearrangements and cause
oncological diseases [1]. Genotoxicity comprises any dam-
age to DNA (including mutagenicity) and damage to cellular
components (e.g., spindle division) or enzymes (e.g.,
topoisomerases) [2] that alter genetic material of somatic
(mutations are transferred from one generation of cells to an-
other) and germinal (mutations are transferred from affected
people to offspring) cells [3]. DNA damage leads to effects
such as carcinogenesis, mutagenesis, teratogenesis, and
cytotoxicity. The medical outcomes of mutations in germinal
cells are inherited diseases and mutations in germinal and so-
matic cells such as malignant neoplasms, cell aging, and loss
of immunity. Genotoxic damage of embryonic and germinal
cells cause congenital developmental diseases, infertility, and
spontaneous abortions [4]. Control and monitoring of
1
Scientific Center for Expertise of Medical Products, Ministry of Public
Health of the Russian Federation, 8 Petrovskii Blvd., Moscow, 127051
Russia.
*
e-mail: matveeva@expmed.ru
genotoxic impurities in drugs is an important issue for devel-
opment and production of drugs and drug substances.
Chemical impurities, including genotoxic ones, in drugs
and drug substances can be divided into residual organic sol-
vents and inorganic and organic impurities.
Organic solvents can be used in the synthesis of drug
substances, for their purification, and during drug produc-
tion. In several instances, organic solvents can be formed
during the synthesis of drug substances.
The RF SP XIIth Ed. includes OFS 42-0057-07 Resid-
ual organic solvents in which classification and control of
residual amounts of organic solvents are given according to
requirements of the European Pharmacopoeia (EP) and USA
Pharmacopeia (USP) and are determined by their possible
risk to human health [5-7]. Genotoxic (carcinogenic) sol-
vents are assigned to class I highly toxic solvents that may be
used in drug production in exceptional instances when their
use cannot be avoided (benzene, 1,1-dichloroethylene,
1,2-dichloroethane, 1,1,1-trichloroethane, carbon tetrachlo-
ride) [5]. RF requirements for control and regulation of class
I highly toxic solvents correspond to the international ones.
Inorganic impurities are associated with strong acids and
bases, catalysts, starting materials, reagents, and traces of fil-
ter and construction materials containing metals [8]. Metal

765
0091-150X/15/4911-0765 2015 Springer Science+Business Media New York
766
cations are the most frequently encountered impurities in
drug substances. The Heavy metals index was introduced
to limit the contents of Pb, Hg, Bi, Sb, and other toxic metals.
According to the International Conference for Harmonisa-
tion of Technical Requirements for Pharmaceuticals for Hu-
man Use (ICH) Guideline for Elemental Impurities, Q3D,
genotoxic metals include As, Cd, Ni, Rh, Ru, and V [9].
Non-specific methods based on the formation of colored sul-
fides (precipitation) with a standard set at < 0.001% are used
in the RF SP XIIth Ed. to determine heavy metals (Pb, Hg,
Bi, Sb, Sn, Cd, Ag, Cu, Mo, V, Ru, Pt, and Pd) [5]. A differ-
ent approach is given in the EP, USP, and ICH Q3D Guide-
line. The permissible daily exposure (PDE) for individual
metals and the drug administration route are considered in
setting the standards [6, 7, 9]. Specific methods using induc-
tively coupled plasma (ICP) atomic emission spectroscopy
and ICP mass spectrometry (USP Monograph Elemental
ImpuritiesProcedures) are suggested for determining ele-
mental impurities [7]. Article Heavy metals (precipita-
tion) that used non-specific analytical methods was omitted
from the USP, 38th Ed. [7].
A non-specific procedure for heavy-metal determination
is currently used in the RF. It does not guarantee a drug
safety level that corresponds to the current international ap-
proaches.
Organic genotoxic impurities in drugs come from
sources such as starting materials, side products, intermedi-
ates, degradation products, and reagents.
Special documents regarding control of organic
genotoxic impurities in drugs were non-existent abroad be-
fore 2000. ICH guidelines mention only compounds with un-
usual toxicity [10]. ICH guidelines Impurities in New Drug
Substances, Q3A, and Impurities in New Drug Products,
Q3B, gave threshold values for the identification, reporting,
and qualification of organic impurities [11, 12]. Tests used
for qualification of impurities included tests for the determi-
nation of genotoxic impurities, as a minimum tests for the in-
duction of gene mutations and chromosome aberrations
(both tests should be performed in vitro). Although the ICH
TABLE 1. Allowed Threshold Values Established by PhRMA,
FDA, and EMA for Genotoxic and Carcinogenic Impurities
Duration of activity during Threshold value of genotoxic impurities, mg/d
clinical trials PhRMA FDA EMA
Single dose 120 120 120
<14 d 120 60 120
From 14 d to 1 mo 120 60 60
From 1 to 3 mo 40 20 20
From 3 to 6 mo 20 10 10
From 6 to 12 mo 10 5 5
>12 mo 1.5 1.5 1.5
O. A. Matveeva and E. L. Kovaleva
guidelines did give recommendations for the type of tests
that should be performed, they lacked specific directions
about what must be done if both genotoxicity tests turned out
positive. The recommendations covered only a confirmation
of the need to perform additional tests, to remove the impuri-
ties, or to reduce their content to a safe level, the value of
which was not given.
In view of the current situation, regulations defining the
approaches to control of genotoxic impurities in drugs need
to be developed. The European Medicines Agency (EMA)
was one of the first regulators to develop the basic principles
for evaluating genotoxic impurities in drugs. The EMA
Guideline on the Limits of Genotoxic Impurities recom-
mends that impurities be divided into two classes, i.e.,
genotoxic compounds with sufficient evidence for a thresh-
old-related mechanism and those without such evidence [13].
Class I genotoxic impurities are evaluated according to
the principles described in the ICH guideline Impurities:
Guideline for Residual Solvents, Q3C [14] for toxicity class
2 solvents, i.e., considering the PDE calculated using the
no-observed-effect level (NOEL, maximum drug dose hav-
ing no effect) or the lowest-observed-effect level (LOEL,
minimum drug dose having an effect). The As Low As Rea-
sonably Practicable (ALARP) principle was proposed for
evaluating class 2 genotoxic impurities. According to the
ALARP principle, all possible measures should be taken in
order to avoid forming genotoxic impurities during the syn-
thesis of a drug substance. If this is impossible, these impuri-
ties must be removed by technical means during the produc-
tion process (e.g., during purification). The EMA guideline
for control of genotoxic impurities uses an approach based
on the threshold of toxicological concern (TTC) because
these impurities cannot always be completely removed from
a drug substance. The TTC value for a genotoxic impurity in
most drugs is 1.5 mg/d. This is considered an acceptable risk
(additional risk of developing cancer is case per 100,000 pa-
tients). The exceptions are genotoxic impurities containing
extraordinarily highly active structural groups that increase
the carcinogenic risk even at doses below the TTC [13]. This
group includes aflatoxin-like strongly mutagenic carcinogens
TABLE 2. Allowed Doses for Genotoxic (Mutagenic) Impurities
(ICH M7 Guideline)
Daily dose, mg/d
Drug, content
Treatment duration
several genotoxic
one genotoxic
(mutagenic) impuri-
(mutagenic) impurity
ties
1 mo 120 120
>1 12 mo 20 60
>1 10 yr 10 30
>10 yr or for life 1.5 5
Modern Approaches to Estimating the Content of Genotoxic Impurities 767

Aromatic groups
OH
A A

N N N
A A
A +
N
O O

Alkyl groups
O
OH A
O NO 2
N O NH2
N
A
A H A A A NO
A
H
O Halogen A R
O N
O C (S) N N
A A A A (S)N A A

Heteroatomic groups
O O
Halogen
P A
S
EWG OR Halogen
OR

Radicals: A = alkyl, aryl, or H

Halogen = F, Cl, Br, I
EWG (electron-withdrawing group) = acceptor groups
(CN, C=O, ester, etc.)

Fig. 1. Mutagenic functional groups.

and N-nitroso- and azoxy-compounds to which the TTC
rules do not apply [15].
Potentially genotoxic (carcinogenic) compounds refer to
compounds containing known functional groups (aromatic,
alkyl, heteroatomic) that can interact with DNA and damage
it. Figure 1 shows examples of functional groups that cause
mutations in DNA (the list is not exhaustive) [16].
The Pharmaceutical Research and Manufacturers of
America (PhRMA) in 2004 formed a working group to dis-
cuss questions on the determination, classification, control,
and toxicological risk assessment of potentially genotoxic
impurities in drugs [16].
PhRMA presented two innovative concepts [16]. Classi-
fication of impurities into five classes was proposed:
Class 1 comprised impurities that are known genotoxic
compounds with established carcinogenic potential. The
group included known animal carcinogens with a proven
genotoxic mechanism and human carcinogens.
Class 2 impurities were known genotoxic compounds
with unestablished carcinogenic potential. This group in-
cluded impurities with demonstrated mutagenicity in
genotoxicity tests, e.g., a positive test for mutagenicity in test
on bacteria or other positive data on mutagenicity indicative
of chemical activity characteristic of DNA gene mutations
(e.g., signs of gene mutations under in vivo conditions).
Class 3 impurities had structures containing the func-
tional groups shown in Fig. 1 that were unrelated to the drug
substance structure and lacked mutagenicity data.
Class 4 impurities contained functional groups shown in
Fig. 1 that were analogous to the drug substance structure,
passed a genotoxicity test, and were not recognized as
mutagenic.
Class 5 impurities had an ordinary structure or a structure
given in classes 3 and 4 with a proven lack of mutagenic
properties. Impurities in this group should be considered or-
dinary organic impurities according to guidelines ICH Q3A
and ICH Q3B.
A strategy for evaluating genotoxic impurities in drugs
was proposed based on the given system for classifying im-
purities.
It was found that the TTC value could change depending
on the dose route and duration of drug clinical trials
(so-called staged TTC concept). A lower TTC value for im-
purities should be established for high doses of drugs and,
conversely, a higher TTC value for impurities if the drug is
used briefly [16]. Such an approach for evaluating genotoxic
768
impurities is justified because clinical trials are conducted
with an established dose regime and a brief total duration.
The staged TTC concept should be used at all drug develop-
ment steps and for each compound separately in those in-
stances where the drug contains several genotoxic impurities.
The staged TTC concept was included further in the EMA,
Food and Drug Administration (FDA), and ICH guidelines.
Organic genotoxic impurities came under heightened
scrutiny in 2007 after the startling detection in several
batches of the drug Viracept (nelfinavir) produced by F.
Hoffman-La Roche (Switzerland) of an ethyl methanesulfo-
nate (ethylmesylate) impurity with mutagenic and terato-
genic effects [17]. Ethylmesylate appeared in the drug sam-
ples because good manufacturing practice rules for nelfinavir
mesylate drug substance production were violated [18].
Roche Registration Ltd. decided to recall all batches of
Viracept from all countries. State registration in the RF of
Viracept powder for internal use 50 mg/g and Viracept
coated tablets 250 mg was halted (due to the detection in
them of genotoxic impurities) until the completion of the
necessary trials and incorporation of changes into the regis-
tration documents (Roszdravnadzor Order of June 28, 2007,
No 1330-Pr/07). The corresponding decree was given to the
Administration of State Control of Medical Product Circula-
tion with a proposal to organize as customary the recall and
destruction of this drug. According to the company, 1,500
TABLE 3. Modern Analytical Methods for Assessing Genotoxic
Impurities
Equipment Application
HPLC Analysis of non-volatile genotoxic
impurities
UHPLC (ultrahigh efficiency liq- More rapid impurity analysis
uid chromatography)
LC-MS (liquid chromatography Structure confirmation of a known
with a mass spectral detector) impurity and preliminary struc-
tural characterization of an un-
known impurity
High sensitivity quadrupole High resolution and exact mass
time-of-flight mass spectrometry determination of microimpurities
Liquid chromatograph-mass spec- Quantitative analysis of organic
trometry with a triple quadrupole impurities
GC-MS (gas chromatography with Analysis of halides, epoxides, sul-
a mass spectral detector) fonates, etc.
Headspace GC-MS (gas chroma- Analysis of residual solvents/vola-
tography with a vapor-phase ana- tile impurities
lyzer and mass spectral detector)
ICP-AES (inductively coupled Analysis of elemental impurities
plasma-atomic emission spectros- capable of causing DNA mutations
copy)
NMR Information about the actual mo-
lecular stereochemistry and struc-
tural characterization of genotoxic
impurities and decomposition
products
O. A. Matveeva and E. L. Kovaleva
HIV-infected patients took the drug before it was recalled
from the Russian market. This included 300 pregnant women
and 210 children [19]. This instance prompted a lively dis-
cussion about the determination of the permissible level of
genotoxic impurities in drugs because Roche is among the
five largest pharmaceutical companies in the world.
The FDA published at the end of 2008 for manufacturers
the Draft Guidance for Industry, Genotoxic and Carcinogenic
Impurities in Drug Substances and Products: Recommended
Approaches [20]. Methods for qualifying genotoxic and car-
cinogenic impurities and for reducing the potential lifetime
risk to patients were described in the draft guideline. The rec-
ommended approaches to the control and risk assessment of
genotoxic and carcinogenic impurities in drugs included:
a change of synthesis pathways and/or drug purification
in order to reduce the formation of genotoxic impurities or
remove them as much as possible;
establishment for genotoxic impurities of the maximum
daily dose of 1.5 mg;
additional characteristics of the genotoxic and carcino-
genic risks.
The requirements for permissible threshold values set by
PhRMA, FDA, and EMA for genotoxic and carcinogenic im-
purities in drugs during clinical trials can differ (Table 1)
[21].
The ICH guideline Assessment and Control of DNA Re-
active (Mutagenic) Impurities in Pharmaceuticals to Limit
Potential Carcinogenic Risk, M7, the final version of which
was published in June 2014, was developed in order to har-
monize requirements for the control and risk assessment of
organic genotoxic impurities in drugs [22]. The guideline in-
cluded the classification of genotoxic (mutagenic) impurities
and directions for their assessment presented by PhRMA.
According to these, the mutagenic potential of actually iden-
tified impurities and potential impurities that could be pres-
ent in a drug substance should be assessed. The ICH M7
guideline, in contrast with those of FDA and EMA, was ap-
plicable not only for the assessment of drug impurities that
were reported for registration and clinical trials but also for
re-examination of requirements for already registered drugs
(e.g., for a drug substance or drug production process
change, inclusion of new highly sensitive analytical meth-
ods). The permissible dose of a genotoxic (mutagenic) impu-
rity that is based on the TTC and is considered safe for life-
time use is 1.5 mg/d in the ICH M7, FDA, and EMA guide-
lines. The single permissible doses for drugs intended for
clinical trials, reported for registration, previously registered,
not intended for lifetime use, and for which higher doses of
genotoxic impurities can be set are given (Table 2). In addi-
tion, permissible doses for drugs containing several
genotoxic (mutagenic) impurities are given (Table 2).
The ICH M7 guideline, in contrast with the EMA and
FDA guidelines, describes in detail a program of actions for
assessing and regulating genotoxic (mutagenic) impurities in
Modern Approaches to Estimating the Content of Genotoxic Impurities
drugs and proposes measures for the control of these drug
impurities [22].
The following four approaches were proposed for control
of genotoxic (mutagenic) technical impurities in drug sub-
stances.
Version 1, stipulate that tests for determining the content
of genotoxic (mutagenic) impurities be included in the drug
substance specification, that regulations on the level or con-
tent below the permissible limit be set, and that an appropri-
ate analytical procedure be used. A periodic check on the de-
termination of genotoxic impurities in a substance can be
used if it is demonstrated that the content of genotoxic
(mutagenic) impurities in a drug substance is <30% of the
permissible limit of impurity content in at least six sequential
tests or three sequential industrial batches of drug substance.
Version 2, stipulate that tests for determining the content
of genotoxic (mutagenic) impurities be included in the speci-
fication for starting material or intermediate or stipulate that
the production process be controlled, establishing regulations
on the content at or below the permissible limit using an ap-
propriate analytical procedure.
Version 3, stipulate that tests for determining the content
of genotoxic (mutagenic) impurities be included in the speci-
fication for starting material or intermediate or stipulate that
the production process be controlled. Regulations can be es-
tablished above the permissible limit of impurity content us-
ing an appropriate analytical procedure if it is proven that the
industrial production process, purification step, and control
of production processes guarantee an impurity content at or
below the permissible limit a drug substance. Additional
tests are not required. This version is applicable if the content
of genotoxic (mutagenic) impurities in a drug substance is
<30% of the permissible limit of impurity content, which
should be established from analytical data of laboratory
batches and confirmed as necessary by test data and indus-
trial batches.
Version 4, evaluate the industrial production process and
its effect on the content of residual impurities to guarantee
that the content of genotoxic impurities in a drug substance is
below the permissible limit. Additional analytical tests are
not required [22].
The ICH M7 guideline is currently the principal docu-
ment defining international approaches to classification,
qualification, control, and toxicological risk assessment of
potential genotoxic impurities in drugs.
The determination of genotoxic impurities in drugs is a
complicated problem because the impurities are present in
trace amounts and their content can be less than
0.01 0.03%. An analytical procedure should have a detec-
tion limit from 1 5 ppm (0.0001 0.0005%). Impurity
analysis at such low levels requires not only highly sensitive
analytical equipment but also highly selective instruments
because drugs can contain a large amount of other organic
impurities at lower concentrations, e.g., from excipients. The
relatively large amount of drug substance can also interfere
with low-level impurity determination. Furthermore, it is
769
very difficult to analyze all genotoxic impurities using a sin-
gle analytical procedure because the impurities may contain
different functional groups and have different sources. A sig-
nificant part of highly reactive genotoxic impurities reacts
readily with reagents during extraction, sample preparation,
or analysis. This can lead to erroneous results. Several
low-molecular-weight genotoxic impurities are rather unsta-
ble compounds. Therefore, they can be destroyed during
preparation of a test sample. Depending on the nature and
number of genotoxic drug impurities, the choice of appropri-
ate analytical methods (or combination of analytical meth-
ods) must be carefully examined [21].
Modern analytical methods, e.g., NMR, are used simul-
taneously to establish the structure and quantitative content
of drug impurities, including genotoxic ones, without using
standards. A compound is identified directly by determining
the composition, structure, and stereochemistry. The pres-
ence of certain structural fragments and their arrangement in
the molecule are determined [23].
Various analytical methods such as NMR, HPLC-UV
(high efficiency liquid chromatography with a UV detector),
and GC-FID (gas chromatography with a flame-ionization
detector) are used to detect impurities and have different sen-
sitivities and capabilities for determining impurities at the
10 ppm level [24]. Therefore, the sensitivity of analytical
equipment must be increased in order to determine impuri-
ties at 1-5 ppm or even lower. This can be achieved by com-
bining mass spectroscopy with other analytical methods,
e.g., LC-MS (liquid chromatography with a mass-spectral
detector), GC-MS (gas chromatography with a mass-spectral
detector), ICP-MS (mass spectrometry with inductively cou-
pled plasma), etc. Appropriate analytical equipment is se-
lected depending on the type of genotoxic impurity to be an-
alyzed (Table 3) [25].
The use of modern highly sensitive and specific analyti-
cal methods established that drug substances of methanesul-
fonate, toluenesulfonate, and benzenesulfonate salts form
genotoxic impurities of methyl-, ethyl-, and isopropylmetha-
nesulfonates; -toluenesulfonates; and -benzenesulfonates if
alcohols (MeOH, EtOH, i-PrOH) are used to purify the drug
substances. The monograph in EP 8.2 on drug substances
that are methanesulfonate salts (betahistine mesylate, bromo-
criptine mesylate, co-dergocrine mesylate, deferoxamine me-
sylate, dihydroergocristine mesylate, dihydroergotamine
mesylate, doxazosin mesylate, pefloxacin mesylate dihyd-
rate, pergolide mesylate, phentolamine mesylate, saquinavir
mesylate, ziprasidone mesylate trihydrate) includes a deter-
mination of genotoxic impurities methyl-, ethyl-, and
isopropylmethanesulfonates. In addition, the EP includes
monographs with the corresponding determination proce-
dures [6]. The journal Pharmeuropa published changes to EP
monographs for amlodipine besylate, atracurium besylate,
and sultamicillin tosylate dihydrate that define the determi-
nation and regulation of methyl-, ethyl-, and isopropylbenz-
enesulfonates and -toluenesulfonates, respectively, in these
substances [26, 27].
770
Regulations and procedural materials defining the ap-
proaches to control of genotoxic organic drug impurities are
currently lacking in the RF.
Information and data on genotoxic impurities were re-
ported by several applicants in drug registration dossiers.
Thus, epichlorohydrin can be used as starting material to
synthesize bisoprolol fumarate drug substance. Epichloro-
hydrin is a genotoxic compound. Seven bisoprolol fumarate
drug substances from different manufacturers are included in
the State Drug Registry [28]. Epichlorohydrin is used in the
processes for synthesizing six drug substances. Four
bisoprolol fumarate manufacturers do not report any infor-
mation of the control of epichlorohydrin in the drug sub-
stances. One manufacturer controls residual amounts of the
genotoxic compound in an intermediate. Another manufac-
turer reports data on control of epichlorohydrin in the sub-
stance itself (<2 ppm). The permissible amount of
epichlorohydrin in the bisoprolol fumarate drug substance is
0.04 mg based on the given impurity standard considering the
maximum daily dose. This corresponds to the permissible
doses of genotoxic drug impurities (ICH M7 guideline).
Thus, the present analysis found that RF requirements
for the control and regulation of genotoxic organic solvents
correspond to international ones.
A non-specific method is used in the RF to evaluate
genotoxic elemental impurities (heavy metals). Regulatory
requirements were established without considering the per-
missible daily exposure for individual metals and the drug
administration route, which could not guarantee the drug
safety level according to current international requirements.
The OFS Heavy Metals in which the use of selective analyt-
ical methods (AAS, ICP-AES, MS-ICP) was stipulated was
prepared for inclusion in the RF SP XIIIth Ed. This was the
first step toward harmonization with the EP and USP [29].
The corresponding documents and procedural materials
must be prepared in order to assure the safety of drug sub-
stances and drugs circulating in the RF because the RF lacks
regulations on the evaluation of genotoxic organic impurities
in drugs.
REFERENCES
1. T. McGovern and D. Jacobson-Kram, Trends Anal. Chem.,
25(8), 790 795 (2006).
2. K. L. Dearfield, M. C. Cimino, N. E. McCarroll, et al., Mutat.
Res., Genet. Toxicol. Environ. Mutagen., 521, 121 135 (2002).
3. R. Wear and C. Sharma, Int. J. Toxicol. Pharmacol. Res., 5(1),
33 41 (2013).
4. A. D. Durnev and A. S. Lapitskaya, Ekol. Genet., X(3), 41 52
(2012).
5. Russian Federation State Pharmacopoeia, XIIth Ed., Moscow
(2007).
6. European Pharmacopoeia, 7th Ed., Suppl. 8.2;
URL: http://online6.edqm.eu/ep802/.
7. United States Pharmacopeia, 38th Ed.;
URL: http://www.uspnf.com/uspnf/.
O. A. Matveeva and E. L. Kovaleva
8. E. L. Kovaleva, Standardization of Drug Substances and Drugs
in Tablet Dosage Form [in Russian], Grif i K, Moscow (2012),
p. 66.
9. Guideline for Elemental Impurities Q3D ICH Harmonised
Guideline; URL: http://www.ich.org/fileadmin/Public_Web_
Site/ICH_Products/Guidelines/Quality/Q3D/ Q3D_Step_4.pdf
10. R. W. Kashyap, B. Mitali, S. S. Rao, et al., Pharm. Technol.,
36(3), 58 72 (2012).
11. Impurities in New Drug Substances Q3A(R2) ICH Harmonized
Tripartite Guideline; URL: http://www.ich.org/fileadmin/Pub-
lic_Web Site/ICH_Products/Guidelines/Qual-
ity/Q3A_R2/Step4/Q3A_R2_Guideline.pdf
12. Impurities in New Drug Products Q3B(R2) ICH Harmonised
Tripartite Guideline; URL: http://www.ich.org/fileadmin/Pub-
lic_Web Site/ICH_Products/Guidelines/Quality/Q3B_R2/ Step4/
Q3B_R2_Guideline.pdf
13. Guideline on the Limits of Genotoxic Impurities
(EMEA/CHMP/QWP/251344/2006); URL: http://www.ema.
europa.eu/docs/en_GB/document library/Scientific_guideline/
2009/09/WC500002903.pdf
14. Impurities: Guideline for Residual Solvents, Q3C(R5) ICH
Harmonised Tripartite Guideline; URL: http://www.ich.org/
fileadmin/Public_Web_Site/ICH Products/Guidelines/Quality/
Q3C/Step4/Q3C_R5_Step4.pdf
15. R. Kroes, A. G. Renwick, M. Cheeseman, et al., Food Chem.
Toxicol., 42(1), 65 83 (2004).
16. L. Muller, R. J. Mauthe, C. M. Riley, et al., Regul. Toxicol.
Pharmacol., 44(3), 198 211 (2006).
17. Press Release. European Medicines Agency, EMEA/ 275367/
200; URL: http://www.ema.europa.eu/docs/en GB/document_
library/Press_release/2009/11/WC500014204.pdf
18. D. Polyakova, Apteka.ua online, 699(28) (2009);
URL: http://www.apteka.ua/article/9065
19. http://www.pharmvestnik.ru/publs/lenta/novosti-kompanij/307
2.html#.VUyfm2zk_7U
20. Draft Guidance for Industry, Genotoxic and Carcinogenic Impu-
rities in Drug Substances and Products: Recommended Approaches
(CPMP/QWP/159/96 Cor.); URL: http://www.fda.gov/down-
loads/drugs/guidancecompliance regulatoryinformation/gui-
dances/ucm079235.pdf [http://www.fda.gov/ohrms/dockets/
98fr/fda-2008-d-0629-gdl.pdf]
21. A. V. B. Reddy, J. Jaafar, K. Umar, et al., J. Sep. Sci., 38(5),
764 779 (2015).
22. Assessment and Control of DNA Reactive (Mutagenic) Impu-
rities in Pharmaceuticals to Limit Potential Carcinogenic Risk,
M7 ICH Harmonised Tripartite Guideline;
URL: http://www.ich.org/fileadmin/Public_Web_Site/ICH
Products/Guidelines/Multidisciplinary/M7/M7_Step 4.pdf (ac-
cession date: Aug. 25, 2014).
23. S. V. Moiseev, V. I. Krylov, T. V. Masterkova, et al., Vedomosti
NTsESMP, No. 1, 15 19 (2014).
24. A. A. Illarionov, L. N. Grushevskaya, L. M. Gaevaya, et al.
Khim.-farm. Zh., 48(6), 48 53 (2014); Pharm. Chem. J., 48(6),
408 413 (2014).
25. D. Paul and K. Paul, World J. Pharm. Pharm. Sci., 4(2),
1124 1153 (2015).
26. Pharmeuropa, 26.2, 7 9 (2014).
27. Pharmeuropa, 26.3, 206 207 (2014).
28. http://grls.rosminzdrav.ru/grls.aspx
29. http://www.rosminzdrav.ru/ministry/61/11/materialy-po-deya-
telnosti-deparatamenta/stranitsa-856/spisok-obschih-farmako-
peynyh-statey