USP, EDQM Reference standard

Presented By-
Lalit Kumar
Jubilant Generic Ltd.

 Introduction
 Source
 Utilization
 Preparation
 COA
 Storage

 A reference standard is a substance prepared for
use as the standard in an assay, identification, or
purity test and should have a quality appropriate
for its use.
 A reference standard is a prerequisite to measuring
potency.
 To measure potency, a sample of unknown
potency must be compared to a standard of known
potency, so that the potency ratio can be
calculated.

 RSs are generally obtained and prepared from United
States of Pharmacopeia-National Formulary (USP-NF)
 USP RSs collection consists of more than 3,000 items
ranging from drug substances, related impurities, residual
solvents, biologics, excipients, botanicals, polymers and
melting point standards.
 In India, Central Drug Laboratory is responsible for
making available IP RSs.
 NIST (National Institute of Standard & Technology)
provide a wide variety of standard reference materials
(SRMs) for validating and calibrating analytical methods.

 As Per USP :- USP Reference Standards are highly-
characterized physical specimens used to ensure the
identity, strength, quality, and purity of medicines
(drugs, biologics, and excipients), dietary supplements,
and food ingredients.
 FDA :- Specifically prepared drug substance batch and
an authentic material of the highest purity used for
structural elucidation and benchmark for working
standards .
 ICH (Q6A):- A reference standard from new drug
substances intended for assays, its impurities should be
adequately identified and/or controlled and purity
should be measured by a quantitative procedure.

 Reference standards are utilized to support
measurements concerned with chemical
composition, biological, clinical, physical and
miscellaneous areas.
 Substances characterized for chemical purity
and/or trace impurities.
 Reference objects characterized for functional
properties such as taste, odour, octane number, and
hardness.
 Physico-chemical reference materials
characterized for properties such as melting point,
viscosity

 Qualitative analysis of materials by comparison of RS &
chemical substance in aspects.
1- IR- Functional Group Conformation
2- Melting point & HPLC- Purity identification
3- U.V.- identification.
 Quantitative analysis
1- HPLC
2- Limit tests
 Specific Uses
1- Method validation
2- Calibration of Instruments

 Includes following aspects,
1- Identification
2- Purity analysis
3- Assay of sample.
Data of Analysis must be meet with the standards of
Reference Standards.

 Generally in a method validation estimation of
Bias is most critical aspect .
 RSs will have limited values of Uncertainty.
 Uncertainty associated with RS should be NMT
1/3rd of sample measurement.

 Analytical Reference Standards
1- Reference Material (RM): A material or substance one or
more properties of which are sufficiently well established
to be used for the calibration of apparatus the assessment
of a measurement method or for assigning values to
materials.
2- Certified Reference Material (CRM): A reference material
one or more of whose property values are certified by a
technically valid procedure accompanied by or traceable
to a certificate or other documentation which is issued by
a certifying body.

 Standard that is used routinely to calibrate or
check material measures, measuring instruments or
reference materials. A working standard is
usually calibrated against a reference standard.

The EDQM supplies chemical reference
substances (CRS), herbal reference
standards (HRS) and biological
reference preparations (BRP) as well
as reference spectra for the tests and
assays to be carried out in accordance
with the official methods prescribed in
the European Pharmacopoeia.

 On 4 May 2006, as decided during the 56th meeting of the WHO Expert
Committee on Biological Standardisation (ECBS), the EDQM took
over responsibility for the establishment, storage and distribution
of WHO International Standards for Antibiotics (ISA) from the
National Institute for Biological Standards and Control (NIBSC).
 ISA are generally intended for the establishment of regional or national
secondary standards subsequently used in routine laboratory tests and
assays.
ISA Establishment Studies
 The decision whether or not to start a new ISA establishment study is
taken by the WHO ECBS.
 This committee is composed of scientists from different backgrounds
who meet annually and who report directly to the WHO Executive Board.
 The EDQM is responsible for providing scientific and technical support
and for co-ordinating the studies. This entails procurement of suitable
bulk material, organisation of the study, production of candidate batches,
storage and distribution of the established standards.

 On 16 April 2010, the EDQM took over responsibility for the
establishment, storage and distribution of WHO ICRS from Apoteket AB,
the previous WHO Collaborating Centre for these substances.
 ICRS are adopted by the WHO Expert Committee on Specifications for
Pharmaceutical Preparations. They are intended primarily for use in
physical and chemical tests and assays described in the specifications
published in ‘The International Pharmacopoeia' for the quality control
of pharmaceutical substances and preparations.
Secretariat of The International Pharmacopoeia – Intended use of ICRS
 The International Pharmacopoeia constantly develops new monographs
and revises existing ones to stay abreast of advances in analytical science
and regulatory affairs. Along with these changes the intended use of
already established ICRS often needs to be adjusted, for example,
because an ICRS previously used for identification only shall newly also
be employed in quantitative tests.

 The user of The International Pharmacopoeia
finds information on the actually established
intended uses of an ICRS in the leaflet
enclosed with the substance when distributed
or accessible via the ICRS online database. The
information found in current leaflets is
applicable to all standards of the respective
batch number.
The ICRS Establishment Studies
 DQM organises international collaborative
studies to establish new standards when
required, with the WHO's assistance.

 Should understand Physico chemical Profile of RS
 ARS should have good chemical stability on wide range of storage
 Requirements for characterization should be cross-checked to
avoid Analytical errors.
 The validity (i.e., accuracy, precision, sensitivity, specificity) of
the analytical methods used for purity determination should be
demonstrated .
 Highly pure (i.e., ≥99.5%).
 In total the degradation and by-products should not be more then
0.5% .
 The levels of all impurities found (including those not chemically
identified, isolated, and characterized) should be provided as a
summary tabulation.
 Content of enantiomer in case of chiral compound is not taken
into account as by- products and degradation products by
normalized area percent

 Purity
1- Loss On Drying (LOD)
2- Karl Fisher Titration
3-Thermo Gravimetric Analysis (TGA)
4-Differential Scanning Calorimetry (DSC)
5-Residue On Ignition (ROI)
6-Thin Layer Chromatography (TLC)
7-High Performance Liquid Chromatography (HPLC)
8-Gas Chromatography (GC)
 Assay
1- Titration
2- Phase - Solubility Analysis

 Expiration and Retest Date:-
1-For any new chemical entity an initial expiry or
retest date decided as 6 months if stock material
stored at -20⁰C.
2-Availability of stability data for 3 months at
40⁰C/75%RH demonstrates the retest period of 24
months if stored at -20⁰C.
3-Expiry date is periodically extended on the basis of
retest performed and stability proved.
4-Reference standard may have a maximum 5 years
expiry period.

 The United States Pharmacopeia–National
Formulary (USP–NF) is continuously Revisions
include Revision Bulletins, Interim Revision
Announcements (IRAs), and Errata-
1-A Revision Bulletin posted on the USP website
indicates its official date and the date that it will be
incorporated into an official publication.
2- IRAs are proposed in PF for a 90-day public
comment period. Once comments (if any) are
reviewed and the IRA is approved by the
appropriate Expert Committee, final IRAs are
posted on the USP website.

3- Errata are posted on the Web site and
are official the first day of the following
month. Errata are incorporated into the
next available official publication.
Once published in the print and online
publications, Revision Bulletins and
IRAs are official as of the date indicated
on the website and are not subject to the
general six-month delayed official date
for the particular publication.

USP, EDQM Reference standard

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USP, EDQM Reference standard