Transcript Need, Uses and Establishment of Reference Standards, both

Pharmaceutical Reference Standards
Part 2
Dr John H McB Miller
Head of DLab
EDQM
Council of Europe
Strasbourg
France
Filling of Reference Substances
Pharmaceutical reference standards are distributed using
appropriate filling conditions, into containers (including closure
system) to ensure the integrity of the standard.
- Ampoules
- Antibiotic vials
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Packaging
Preferably pharmaceutical reference standards
should be sub-divided and be presented as single
use units. However, if the reference standard is
kept in a multi-use container then re-testing will be
more frequent since there is a greater risk of the
uptake of moisture and/or decomposition of the
standard.
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Re-test Programme
A system must be in place to ensure the continued fitness for use of
the standards.
Normally, a re-test programme is applied.
Pharmaceutical reference standards are regularly tested for stability
during their storage.
A testing programme is applied which is designed to detect at an early
stage any sign of decomposition using appropriate analytical
techniques. The methods employed, appropriate to small quantities,
are both rapid and sensitive and will have been performed during the
establishment phase.
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Re-test Programme
 The periodicity and extent of re-testing reference standards
depends on a number of factors including:
 stability,
 container and closure system,
 storage conditions,
 hygroscopicity,
 physical form,
 Intended use.
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Re-test Programme
Most pharmaceutical reference standards are prepared in a
solid powder form but some are prepared as solutions. The
manufacturer knows the consequence of these factors so
that re-test dates can be fixed.
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Re-test Programme
The testing methods are to include the determination of
water and decomposition products. The maximum permitted
variation from the assigned value should be pre-defined and
if exceeded the batch should be re-established or replaced
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MONITORING PROGRAMME
Regular screening programme to verify the continued « fitness
for use » of the reference substances
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Frequency of testing :
Microbiological assay standards - yearly
Chemical and Biological assay
standards - bi annually
Other - every 3-4 years
More frequent testing of known or
suspected unstable substances
Methodology :
Rapid
Sensitive
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Certified Reference Substances
The role of CRM’s in chemical analysis is to provide “measurement
benchmarks” that chemists can use to calculate or assess the
accuracy of their analysis. When several laboratories can achieve the
same analytical results for a given CRM, they demonstrate
comparability of their measurements.
REMCO - ISO COMMITTEE ON REFERENCE MATERIALS
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ISO GUIDE 34
GENERAL REQUIREMENTS FOR THE COMPETENCE OF
REFERENCE MATERIAL PRODUCERS
Pharmacopoeial standards and substances are established and
distributed by pharmacopoeial authorities following the general
principles of this Guide. It should be noted, however, that a different
approach is used by the pharmacopoeial authorities to give the user
the information provided by certificates of analysis and expiration
dates. Also, the uncertainty of their assigned values is not stated since
it is negligible in relation to the defined limits of the method-specific
assays of the pharmacopoeias for which they are used.
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COMPARISON OF REFERENCE MATERIALS (ISO) AND
REFERENCE SUBSTANCES (PH. EUR.)
RM’s CRM’s (Ref Materials)
Reference substances/Standards

Materials

Substances

Benchmark standard

Designated primary standard

Minor constituent of matrix

Major constituent of matrix

Quantification of analyte to compare to a
limiting conc

Quantification of analyte to predefined lower
& upper limits

Established by a no of different analytical techs

Established for a specific method

Large uncertainty

Negligible uncertainty (not indicated)

Expiry date

Status in catalogue

Certificate

No certificate (all information required on
label & in pharmacopoeial mono

Integral part of the monograph - a legally
binding standard

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SECONDARY
CHEMICAL REFERENCE SUBSTANCE
A substance whose characteristics are assigned and/or calculated by
comparison with a primary chemical reference substance. The extent
of characterisation and testing may be less extensive than for a
primary chemical reference substance. This definition may apply inter
alia to some substances termed “working standards”.
WHO/PHARM/96.590
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DEFINITIONS
FDA Guideline for Submitting Documentation in Drug Applications
for the Manufacturing of Drug Substances
Working Standard
Drug substance of established quality and purity as shown by
comparison to the Reference Standard material, used as a
standard substance for routine laboratory work, as in analysis of
production batches of new drug substance or drug product(s).
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ISO/CD Guide 80
ISO/REMCO, Reference Materials Committee of ISO, WG8
Non-certified reference materials (NRM) are intended
to be be used for quality control (assurance)
purposes, such as, demonstrating a measurement
system is under statistical control, performs as
expected and provides reliable results
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NRM
 Preparation of QA charts
 Result comparison
 Release of products
 Instrument performance
verification
 Verification of samples
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NRM
NRM’s are often produced by a laboratory for internal use
and are often referred to as in-house reference
substances, working standards etc
A NRM must be sufficiently homogeneous and stable an
NRM must be stable for a period of time that is at least as
long as that during which it is intended to be used.
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Secondary Standards
 Only homogeneity & Stability required
 Assigned value, Associated Uncertainty & Traceability required
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Secondary Standards
“General Guidelines for the Establishment, Maintenance &
Distribution of Chemical Reference Substances”
WHO Expert Committee on Specifications for Pharmaceutical
Preparations
41st Report Annex 3
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WHO Guide Part B
….is intended to apply to secondary reference
substances supplied as “official” eg regional or
national standards and not to the working standards
of manufacturers or other laboratories
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WHO Guide Part B
Adoption of secondary reference standards
The report of the collaborative trial to establish the
secondary reference standard is submitted to the
appropriate national or regional body to approve the
secondary standard for the uses described.
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Part B
• Assessment of need
• Obtaining source material
• Packaging
• Interlaboratory testing to establish the assigned content
• Adoption of the secondary reference substance
• Period of use
• Distribution & supply
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Secondary standard
The purpose of establishing secondary reference
substances for use in routine analysis to determine the
identity, purity and, in particular, the content of
pharmaceutical substances in pharmaceutical
preparations…..is traceable to a primary reference
substance….
In the cases of doubtful results or dispute when using
secondary reference substances, the test should be
repeating using the primary standard.
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Identification
 infrared spectroscopy: the absorbance bands should correspond to
the wave-numbers of the absorbance bands of the primary
reference standard within predefined tolerances ;
 separation techniques: the migration distance, migration time and
retention time for the secondary reference standard corresponds to
those of the primary reference standard within pre-defined
tolerances for thin-layer chromatography or electrophoresis,
capillary electrophoresis and gas or liquid chromatography
respectively.
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Purity test
Separation techniques as for identification but when used
for quantification the measured signal is to be similar to
that of primary reference standard within pre-defined
tolerances. Otherwise, a content is to be assigned.
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Assay
The secondary reference standards are assayed against the
primary reference standard with an assigned content or
potency. Both the number of independent replicate
determinations to be performed and acceptance criteria to
be applied must be pre-defined.
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Secondary pharmaceutical reference standard
A secondary pharmaceutical reference standard should exhibit the
same property(ies), as the primary reference standard, for the test(s)
for which it is established. The extent of testing is not so great as is
required for the establishment of a primary reference standard.
The secondary pharmaceutical reference standard is established by
comparison to the primary reference standard to which it is traceable.
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Secondary Standard
A secondary standard is established and employed, usually
for a specific purpose, to reduce the use of the primary
standard which requires much more work for
characterisation and evaluation any may only be available in
limited quantity
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Secondary Standard
Secondary standards (working standards, in-house
standards) are mostly employed for determination of the
content of the active pharmaceutical ingredient in a
medicinal product. It is, therefore, important to assign a
content to this substance which is directly related to the
official compendial standard.
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Traceability
The property of a result of measurement which can be
related to the appropriate standards, generally international
or national standards through an unbroken chain of
comparison
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Secondary Standard
The assigned value of a secondary chemical reference
standard is traceable to the relevant primary reference
substance.
In the context of WHO quality specifications the relevant
primary chemical reference substance is usually the ICRS
established for use with the International Pharmacopoeia.
Other internationally recognised standards may be used eg
Ph. Eur CRS, BP CRS, USP CRS etc.
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Potential Secondary Reference Standard
1) Confirm the identity of the proposed standard
2) Determine the water content or loss on drying
3) Establish the organic impurity profile
4) Determine the content of the active substance using an
official compendial standard with an assigned content
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Establishment of secondary regional standard
Collaborative Trial
6 x Laboratories, 6 individual determinations in each
Lab Individual Determination of Content (versus primary
A
96.6
96.7
96.1
96.4
95.7
B
96.5
96.1
95.2
95.9
95.7
C
96.6
96.6
95.9
97.8
96.4
D
95.7
95.7
96.2
94.3
94.8
E
96.3
96.7
96.7
95.1
95.9
F
95.4
95.8
95.9
95.1
95.7
SR = 0.71
Sr = 0.61
One way analysis of variance
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standard)
94.7
95.8
94.9
95.2
96.4
96.3
Example : LC assay standard by one laboratory
Minimum
Standard
2 individual reference substances
2 replicate injections of each
Test
6 individual test solutions
2 replicate injections of each
Performed by different analysts on different days estimation of the intermediate precision
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If it is assumed that the reproducibility of a liquid
chromatographic assay is 2.0 per cent, then the precision of
the determination of content of the proposed standard
should be better than 0.67 per cent RSD.
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Acceptance Criteria
Verify also the repeatability of the areas test substances
when normalised to a content concentration or mass.
Verify also the repeatability of the areas of the test solutions
when normalised to a constant concentration or mass
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International Chemical Reference Substances
General information
International Chemical Reference Substances are
established upon the advice of the WHO Expert Committee
on Specifications for Pharmaceutical Preparations. They
are supplied primarily for use in physical and chemical tests
and assays described in the specifications for quality
control of drugs published in The International
Pharmacopoeia or proposed in draft monographs. The
International Chemical Reference Substances are mainly
intended to be used as primary standards to calibrate
secondary standards.
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General Information
Directions for use and required analytical data for the intended
use in the relevant specifications of The International
Pharmacopoeia are given in the certificates enclosed with the
substances when distributed.
International Chemical Reference Substances may also be used
in tests and assays not described in The International
Pharmacopoeia. However, the responsibility for assessing the
suitability of the substances then rests with the user or with the
pharmacopoeia commission or other authority that has
prescribed this use
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General Information
It is generally recommended that the substances should be stored
protected from light and moisture and preferably at a temperature
of about +5 °C. When special storage conditions are required, this
is stated on the label or in the certificate. It is recommended to the
user to purchase only sufficient amount for immediate use.
The stability of the International Chemical Reference Substances
kept at the Collaborating Centre is monitored by regular reexamination and any material that has deteriorated is replaced by
new batches when necessary. Lists giving control numbers for the
current batches are issued in the annual reports from the Centre
and new lists may also be obtained on request.
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