Pharmaceutical APIs, impurities, excipients and primary reference standards October 2017

465 Pages·2017·8.48 MB·English

Pharmaceutical APIs, impurities
and excipients reference
standards
February 2018
LGC Quality - ISO 9001 • ISO/IEC 17025 • ISO Guide 34 • GMP/GLP • ISO 13485 • ISO/IEC 17043
e
Introduction
About LGC Standards needs. LGC is currently the exclusive distributor of
ATCC cultures and biological products throughout
LGC Standards has successfully established a Europe and specified countries on the continent of
global reputation for the production of impurities, Africa.
excipients, API reference standards and working
standards, and as a single source for the supply of LGC Standards’ extensive network of sales offices
pharmacopoeia reference materials. and distribution centres means we offer the widest
range of reference materials from one single source
Our production site in Germany is accredited to ISO/ for rapid delivery.
IEC 17025 and ISO Guide 34.
Our staff can provide scientific and technical
Our menu of custom services, including guidance, including shipping and customs advice,
custom synthesis of impurities and metabolites, in the local language. Our range of products also
characterisation, certification, packaging and includes reference materials for clinical and forensic
distribution, adds value to the scientific support we applications, phytochemicals, environmental
provide to our pharmaceutical customers. analysis, physical properties determination, and food
and beverage analysis.
Our relationships with the world’s leading
pharmacopoeias and their range of Chemical For more information about our range of services, or
Reference Substances (CRS) and Reference to receive any of our catalogues, please refer to our
Standards (RS), combined with in-house production website lgcstandards.com or contact your local
of certified reference materials and pharmaceutical office.
impurities, enable us to meet our customers’ specific
About LGC Examples of our comprehensive certificates are
shown at the beginning of the impurities and API
LGC Standards is part of LGC. LGC, whose Science standards sections.
and Innovation division acts as the designated UK
National Measurement Institute (NMI) for Chemical Impurity standards
and Biochemical measurement, has a long history in
the development and validation of analytical methods Impurities in a pharmaceutical substance can
and the production of reference materials. change the effects and side effects of a drug
significantly. Therefore, it is important to have an
Many of the analytical methods, which cover accurate detection of impurities.
the food, environment, industrial, clinical and The pharmacopoeial monographs regulate the
pharmaceutical sectors, are accredited to ISO/IEC legal definition but also the analysis and the
17025 (Requirements for the competence of testing limits of impurities in a given substance. A wide
and calibration laboratories). Full details of the range of known impurities is listed in individual
accreditation schedule can be found on the UKAS pharmacopoeial monographs. A great number,
website (www.ukas.com). however, of these standards are not actually
available from the pharmacopoeias. The impurity
LGC’s Science and Innovation division is accredited standards produced by LGC serve to fill this gap to a
to ISO Guide 34 (General requirements for the large extent.
competence of reference materials producers) for
the production of (certified) reference materials The increasing importance of impurity reference
as is also our production site in Germany. The materials is also becoming apparent in the
measurement capabilities used to produce certified registration of drugs, where an exact identification
reference materials in its capacity as the UK NMI and quantification of susceptible impurities is
are verified through participation on key comparison required for an assured documentation.
studies organised by the Consultative Committee
for the Amount of Substance (CCQM) of the Limits for impurities have been laid out in compendial
International Weights and Measures Organisation monographs, in specifications from the manufacturer
(BIPM). The certificates are recognised by other internally or in the International Conference on
National Measurement Institutes, under the Mutual Harmonisation (ICH) Guidelines which have been
Recognition Arrangement. agreed by Europe, Japan and the United States.
The ICH has published four guidelines on impurity
In its role as the NMI, LGC serves on the issues:
International Organisation for Standardisation (ISO)
Committee for Reference Materials (REMCO), which ICH Q3A (R1): Impurities in New Drug
aims to carry out and encourage a broad international Substances
effort for the harmonization, production and
application of certified reference materials (CRM). ICH Q3B (R2): Impurities in New Drug Products
About the catalogue ICH Q3C (R5): Impurities: Guideline for Residual
Solvents
The first chapter of this catalogue comprises over
4,800 impurity and drug substance reference ICH Q3D: Impurities: Guideline for Metal
standards produced by LGC, followed by a second Impurities
chapter of pharmaceutical excipients. The third
chapter includes a selected range of API reference The full wording of the ICH guidelines is available at
standards which are produced under the official website of the ICH: www.ich.org.
ISO Guide 34 and feature an even more detailed The ICH guidelines on impurities were originally
certificate of analysis. They fulfill the official developed for new, original drug substances and
requirements for API standards of organizations such products. However, it is now commonly agreed in
as the FDA, WHO and ICH. the three ICH regions – by FDA, EMA and Japanese
Each product is accompanied by a detailed certificate regulation documents – that these guidelines need
of analysis (CofA), which gives information on the to be applied to generic compounds as well, in
identity and purity, together with the various analytical addition to the pharmacopoeial monographs.
methods and their conditions. LGC impurity standards are thoroughly tested
chemical reference substances and are used for and can be released into the production process.
reliable identification and quantification of impurities
in pharmaceutical ingredients and products. What is special about LGC’s excipients standards?
They are also valuable tools for spiking experiments
during validation studies of specificity and accuracy •Detailed certificate of analysis with identity, purity
of analytical methods. and assay data
The abbreviations EP, Pharmeuropa, BP and USP •Suitable for use with non-compendial analytical
in the article description indicate that the particular methods
substance is mentioned as an impurity in that
particular compendial publication. They do not •Appropriate pack sizes for ease of use
indicate that certain specification of reagents or drug
substances mentioned in the publications are fulfilled. •Custom preparation and certification services to
meet your specific needs
The standards – where they are actually listed
as reagents or drug substances – may fulfill this •Storage and logistical management of customised
specification, but this is not the intention and is not material possible
certified on the CofA.
Pharmaceutical excipients
Controlled substances
Excipients are substances used during the
production of finished dosage forms (FDFs), to add A number of the pharmaceutical substances
certain galenic or general characteristics to the FDFs, described in this catalogue, such as narcotics and
or to facilitate the production process. FDFs – also tranquillisers, are substances controlled by German
called drug products or drug preparations – consist legislation. You will find such substances marked in
of a mixture of one or more active pharmaceutical the catalogue with a ‘CS’ in the corresponding
ingredients (APIs) and then normally several column (after the column featuring the CAS number).
excipients. The purchase, possession and use of controlled
substances are subject to national and international
At the end of the production process, excipients regulations designed to limit their abuse. It is
may or may not be present anymore in the FDF. the responsibility of the customer to obtain any
For example, solvents used during production might authorization necessary to both purchase and
not be present anymore, whereas filler materials or possess controlled substances, complying with
conservation agents (e.g. antioxidants) will of course the laws of the importing country, before ordering.
still be present. Customers wishing to obtain controlled substances
must contact their LGC Standards sales office before
Excipients are to be distinguished from the APIs. On ordering, and clarify with the sales specialists
rare occasions, excipients can also be considered
APIs, for example macrogol can be a laxans as well.
Ascorbic acid (Vitamin C) as another example can be
an antioxidant to protect the real API from oxidation,
it can also be of therapeutic use of course to cure
scurvy.
Why reference materials for excipients?
Excipients used in the production of pharmaceutical
finished dosage forms must fulfill GMP quality
aspects. Quality specifications can be found in
compendial monographs, or are set by the excipient
manufacturers themselves. Reference materials for
excipients are essential tools to determine identity,
purity and assay figures according in order to check
if the incoming excipients are fulfilling specifications
the relevant national requirements, the associated Contents
charges and consequential delivery times. All orders
for controlled substances must be provided in writing Pharmaceutical impurities......................... A-1 (p. 13)
and signed by an authorised person. The orders
must be accompanied with the original import permit Pharmaceutical excipients....................... B-1 (p. 442)
and/or possession permit.
Pharmaceutical API standards................ C-1 (p. 448)
Use, safety and handling
Some pharmaceutical substances are toxic and
require special handling. Virtually all pharmaceutical
reference substances have a pharmacological and/
or biological activity. We therefore recommend that
all the products described in this catalogue should be
handled as if they were bio-active, toxic or infective,
and that opened packs should only be handled
by trained laboratory personnel. We also strongly
recommend to read the information provided by
material safety data sheets coming with our products.
All pharmaceutical reference substances and
standards are for laboratory analytical use only and
not for use in humans.
How to buy from LGC Standards?
LGC is the most comprehensive source of reference
materials, offering more than 100,000 for online
ordering at lgcstandards.com. Once registered, you
will also be able to view pricing and place orders.
Alternatively, please feel free to contact our local
offices worldwide for product information and prices.
All contact details are given on the back cover of this
catalogue.
Email: [email protected]
Website: lgcstandards.com
General ordering information
The majority of products mentioned in this catalogue
are available from stock; others may have a delivery
time of approximately four weeks. For substances
marked with ‘request’ in the column featuring the unit
size, longer delivery times may apply. For custom
synthesis, the time is estimated from previous
experience. Customers will be notified if unforeseen
complications arise during the synthesis. In the
unlikely event that a synthesis does not reach the
expected result, LGC Standards reserves the right
to cancel the order. Please note that once delivered
to the customer, reference substances are not
returnable. Customers requiring assistance with the
purchase, use or application of a particular reference
substance should contact LGC Standards where
technical staff are available to advise on the use and
suitability of the products.
Impurities
@LGCStdsPharma
lgcstandards.com
Certificate of analysis - Impurity reference materials

CERTIFICATE

Reference Substance
4-Methoxy-2-[[(5-methoxy-1H-benzimidazol-
2-yl)sulphonyl]methyl]-3,5-dimethylpyridine
1-Oxide (Omeprazole Sulphone N-Oxide)
O
NH
O
N S
O O N
O
Catalogue Number: MM0095.16
Lot Number: 15573
Molecular Formula: C17H19N3O5S Long-term Storage: 2 to 8 °C, dark
Molecular Weight: 377.42
CAS Number: [ 158812-85-2 ] Appearance: white solid
Melting Point: 185 °C (dec.)
Assay ‘as is’: 99.2 %
Date of shipment:
This certificate is valid for two years from the date of shipment provided
the substance is stored under the recommended conditions.
6 pages
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Certificate of analysis - Impurity reference materials
I. Identity
The identity of the reference substance was established by following analyses.
Ia. 1H-NMR Spectrum
Conditions: 400 MHz, DMSO-d6
The structure is confirmed with the signals of the spectrum and their interpretation.
MM0095.16 lot number 15573 page 2/6

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Certificate of analysis - Impurity reference materials
Ib. Mass Spectrum
Method: 4.5 kV ESI; vaporization temperature: 200 °C, direct inlet
m/z fragments
376 [ M – H ]
211 [ C8H7N2O3S ]
147 [ C8H7N2O ]
The signals of the mass spectrum and their interpretation are consistent with the structural formula.
MM0095.16 lot number 15573 page 3/6

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Certificate of analysis - Impurity reference materials
Ic. IR Spectrum
Method: Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) Spectroscopy
The signals of the IR spectrum and their interpretation are consistent with the structural formula.
II. Purity
The purity of the reference substance was analysed by high performance liquid chromatography (HPLC).
HPLC Conditions:
Column: Conditions: Detector: Injector:
Hypersil Gold (C18) 1.0 ml/min, 40 °C DAD Auto
5 µm, 150 x 4.6 mm 0 – 15 min Water/Acetonitrile 80/20 220 nm 5 µl; 0.0654 mg/ml in
15 – 20 min Water/Acetonitrile to 60/40 Water/Acetonitrile 50/50 (v/v)
20 – 25 min Water/Acetonitrile 60/40
25 – 30 min Water/Acetonitrile to 80/20
30 – 35 min Water/Acetonitrile 80/20 (v/v);
0.1 % H3PO4
MM0095.16 lot number 15573 page 4/6

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