From Ph. Eur. to EDQM - Indian Pharmaceutical Association

Report
The Ph. Eur. policy on
Reference standards
Dr Andrea Lodi
Deputy Head, Laboratory Department,
EDQM, Council of Europe
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Content of the presentation
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Definition
Role in the monograph
How established
CRS Database
Conclusion
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European Pharmacopoeia
nearly 2,000 monographs ; >1,900 reference standards
Herbals
dosage
forms Fats
Radiopharm.
Human
vaccines
Vet. Vaccines
Plastics
Blood deriv.
Chemicals
Antibiotics
Gases
homeopathy
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biologicals
Classification of reference standards
TYPE :
 Chemical Reference Substances
 Biological Reference Preparations
ESTABLISHMENT :
 Primary standards
 Secondary standards
PURPOSE :
 QUALITATIVE (Id, system suitability)
 QUANTITATIVE (Assay, external standard)
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European Pharmacopoeia reference standards
Chemical reference substance (CRS)
A chemical compound or mixture of
compounds which has been established for use
as a standard in an identity test, a purity test
and/or an assay as prescribed in a monograph.
The standard is valid only for the specific test(s)
for which it has been established
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European Pharmacopoeia reference standards
A European Pharmacopoeia reference
standard is an integral and essential
part of the monograph and as such
is an official standard that is alone
authoritative in case of doubt or
dispute.
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European Pharmacopoeia Reference Substances
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Extent of analytical testing:
according to the CRS use
Identification => structure elucidation + compliance
Peak ID, system suitability => structure elucidation
+ fitness for purpose
External standard => structure elucidation + purity
Assay: assignment based on interlaboratory study
involving five laboratories: EDQM Laboratory +
Official Laboratories and Experts; the
manufacturer is normally invited to participate.
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Requirements for a candidate CRS
Pharmaceutical Substance subject of a monograph:
The CRS must comply with the requirements of the
monograph, no special purity required.
Impurity CRS (i.e. not subject of a monograph)
Minimum content :
qualitative use: 90%;
quantitative use: 95% , otherwise value assigned
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CRS for identification
Compliance / structure elucidation :
The EDQM laboratory carries out all tests of
the monograph. The structure of the
substance is elucidated by means of NMR,
MS and FT-IR data as well as by
comparison to literature data.
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CRS used in the test for related
substances
Qualitative use
Quantitative use
- System suitability
- Peak identification
- Limit test
- Quantitative test
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CRS used in the test for related
substances
In general an impurity is to be identified, i.e.
located in the chromatogram or
electropherogram:
- when it has an individual limit and/or
- when a correction factor must be applied
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Impurity CRS : qualitative use
Individual impurity : preferred option but
sometimes difficult to obtain
Mixtures of impurities
Batches containing one or more impurities
Spiked samples
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Impurity CRS : qualitative use
A representative chromatogram is
supplied together with the CRS when
indicated in the monograph
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Example : Torasemide for
system suitability CRS
CF CF
Elution order
Rs
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Example Monograph Anise oil, GC-test for foeniculin
foeniculin
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Info provided with a CRS
Non-official information, intended to facilitate
the use of the CRS can be found in the
knowledge database (web site).
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Impurity CRS : quantitative use
 Individual impurities, with an assigned
value if necessary
 Batch containing the impurity, with an
assigned value
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Assay CRS
Assay methods :
 LC
 GC
 UV spectrophotometry
 Microbiological assay
 Bio- or immunoassay
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Establishment of assay CRS:
internal preliminary work
• Elucidation of the structure of the candidate CRS
• Verification of compliance with the monograph
requirements
• Additional tests, such as residual solvents, DSC
purity, non-aqueous titration.
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Establishment of assay CRS:
interlaboratory study
1. Protocol (method-specific approach)
developed and checked in the EDQM
laboratory
2. Samples out to the participants
3. Analysis of results
4. Report with proposed assigned value
5. Approval from the Group of Experts
6. Adoption by the Commission
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Example protocol: CRS for LC-assay
Collaborative study:
Loss on drying or det. of water (by KF /
coulometry)
Quantitative determination of the impurities by
LC
Residual solvents by head-space GC
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Establishment of assay CRS:
Results acceptance criteria
 Repeatability (water determination/ LOD)
 Selectivity test (LC-GC)
 Symmetry factor (LC-GC)
 Repeatability (LC-GC)
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Estimation of the uncertainty
of the assigned content
Ph. Eur. Commission policy :
the uncertainty of the value assigned as
a result of an interlaboratory trial should
be within a predetermined limit which is
calculated in relation with the intended
use .
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Dealing with uncertainty
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Content
If the CRS is supplied as a powder to be
weighed, the value assigned is the % (m/m)
content on an «as is» basis.
NO NEED TO DRY.
Example: Benzathine benzylpenicillin CRS 2
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CRS with assigned content
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Non-assay CRS
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Content
If the CRS is supplied in a pre-dispensed
form such as a freeze-dried substance to be
reconstituted, the value assigned is the
quantity per vial.
Example:
Calcitonin (salmon) CRS 5
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Use of Ph. Eur. CRS
• Ph. Eur. CRS are to be used in conjunction with
the corresponding monograph(s).
• Ph. Eur. CRS are to be used for the purpose for
which they are intended.
• Any different use is in the responsibility of the
user.
• Storage of opened containers is discouraged
and is in any case the responsibility of the user.
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Monitoring programme
Once established and adopted, the CRS undergoes
periodic testing in order to ensure its continuous
fitness for use.
The periodicity of testing depends on the use of the
CRS and the stability information available.
The extent of testing depends on the use of the
CRS. In general the focus is on the properties that
may change during the life cycle of a CRS, i.e.:
appearance, purity by HPLC or GC, DSC, water
content.
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REFERENCE STANDARDS CATALOG
ON LINE
Paper or PDF
3 issues a year
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Reference standards
database
Availability
Origin
Assigned Value
Batch Validity Statement
Safety Data Sheets
Info on reagents and columns
Chromatograms
Knowledge database
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Symposium 2007, All rights reserved
© AL IPA/EDQM/IDMA
Symposium 2007, All rights reserved
© AL IPA/EDQM/IDMA
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Example of a BVS
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New Chapter of the European Pharmacopoeia
5.12 Pharmaceutical Reference Standards
Effective Jan 1st, 2007
ESTABLISHMENT
USE
PRESENTATION
of pharmaceutical reference standards in
general & European Pharmacopoeia
reference standards in particular.
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Impurity Reference Standards
New opportunities / Development Areas
The Challenge:
The new Ph. Eur. policy on Impurities requires that
most if not all the specified impurities be identified.
Our Strategy:
- Develop new compounding/dispensing techniques
- Hyphenated techniques for establishment
- New rapid techniques for monitoring
- Keep no. of CRS/monograph as low as possible
- Keep price reasonable
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Symposium 2007, All rights reserved
Ph. Eur. CRS take home messages
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They are official, primary standards
They constitute an essential part of the monograph
They are guaranteed only for the intended purpose
The assay value is assigned “as is”
Their continuous fitness for purpose is assured by
a regular monitoring programme
• User interface => website
• The Ph. Eur. policy on reference standard is
reflected in general chapter 5.12
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