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Characterisation of non-compendial reference standards for impurities: How good is good enough? Dr. Christian Zeine, Live webinar, Feb 1, 2017
Science
for a safer world
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Before we start
• In contrast to API RS (see for example Ph.Eur. Chapter
5.12.), for impurity RS not much guidance from
authorities
– ICH Q3A(R2) and Q3B(R2):
„Reference standards used in the analytical procedures for
control of impurities (Q3B: degradation products) should be
evaluated and characterised according to their intended uses.”
– Outdated document of German authority BfArM
(1996, “Randnummerndokument”*), translated:
“Impurity standards are used for purity tests and during method
development and validation of those tests. Identity must be
ensured and purity and assay must be defined.” *Erläuterungen zum Antrag auf Zulassung eines Arzneimittels beim BfArM
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Impurity reference standards
• The intended use determines the analytical effort
• Two major types of uses
– Qualitative use
• System suitability
• Peak identification
• During analytical method validation (e.g. specificity)
– Quantitative use
• Limit test
• Quantification of impurity
– With the reference standard directly at each test
– With the help of relative response factors (RRFs) [POLL]
• During analytical method validation (e.g. accuracy)
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Impurity reference standards, uses
• Impurity RS for qualitative use
– Identity must be secured
• Recommended combination of techniques:
– H-NMR
– IR
– CHN (free base resp. salt form)
– MS (from coupling with LC or GC)
– UV/VIS (from coupling with LC or GC)
plus
– Purity estimation (from LC/GC, sometimes H-NMR possible,
>85-90% should be the target, otherwise difficulties possible to interpret
H-NMR and IR appropiately)
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Impurity reference standards, uses
• Impurity RS quantitative use
– Accepted approach (in practice):
• Identity and assay to be determined
• Identity as aforementioned:
– H-NMR, IR
CHN (free base resp. salt form, relevant for quantitative use)
MS and UV/VIS (from coupling with LC or GC)
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Impurity reference standards, uses
• Impurity RS quantitative use
– Accepted approach (in practice):
• Identity and assay to be determined
• Assay per 100%-method (aka mass balance;
see also formula below):
– Water by Karl-Fischer/coulometry
– Residual solvent by H-NMR estimation, or GC/Headspace if necessary
– Subtract all absolute percentages (aka mass fractions or weight
percentages) from 100%
– Multiply then with analyte’s relative percent chromatographic purity
(LC/GC)
• Or use another, sufficiently specific assay technique (e.g. qNMR)
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Impurity reference standards, uses
Next slides: CofA, quant. impurity RS,
regularly accepted by authorites
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CofA: Impurity RS
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CofA: Impurity RS
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CofA: Impurity RS
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CofA: Impurity RS
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CofA: Impurity RS
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CofA: Impurity RS
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• CHN analysis, an underestimated tool (1)
– Extremely helpful on issues concerning free base resp. salt form
– Relevant to know in case standard is used for quantification
– „Common“ issue when user switches from one RS to another
(see also next slide)
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Points to consider during characterisation
OH2N
ClNH
O
N
O
Metoclopramide Imp. G (EP):
Metoclopramide N-Oxide
11,93 6.58 47,74 Hydrochloride [%]
13,31 7,02 53,25 specified value [%]
13,07 6,85 53,25 result [%]
N H C
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Salt form issues during
RS production
• Wanted: 1-(3-Chlorophenyl)piperazine Hydrochloride
CAS
Supplier 2
Supplier 3
Supplier 1
Supply of… Melting point Molecular mass
ClN
HN x HCl
210-214°C (lit.) 65369-76-8 M=196.68 (free base)
210°C 65369-76-8 M=233.14
189-191°C 51639-49-7 M=233.14
Dihydrochloride
Dihydrochloride
Hydrochloride
Hydrochloride
M=233.14
CAS 65369-76-8
mp=210-214°C
Dihydrochloride
M=269.60
CAS 51639-49-7
mp=189-191°C
Free base
M=196.68
CAS 6640-24-0
liquid
• Literature data:
• Order from chemical trade:
• CHN analysis, an underestimated tool (2)
– Use of corrected values helpful, here water,
residual solvent also possible
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Points to consider during characterisation
Risperidone cis-N-Oxide
C [%] H [%] N [%]
value mean (n=3) 58,80 6,99 11,55
theoretical value 62,87 6,81 12,22
difference -4,08 0,18 -0,67
correction with 6,48% water; (RES <0,05%)
C [%] H [%] N [%]
corrected value 62,87 6,76 12,29
difference 0,00 -0,05 0,07
• Look for plausibility between other available results
– Example H-NMR and HPLC, case 1
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Points to consider during characterisation
Cl
O
OH
4-Chlorobenzoic acid,
bezafibrate impurity A (EP), purity HPLC 99.3%
1H-NMR HPLC
• Look for plausibility between other available results
– Example H-NMR and HPLC, case 2
Nabumetone Imp D (EP): Imp of imp at 5.9 minutes
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Points to consider during characterisation
O
O
• Look for plausibility between other available results
– Example H-NMR and HPLC, case 2
Nabumetone Imp D (EP): No corresponding result in H-NMR
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Points to consider during characterisation
0,17% RES
Dichloromethane
organic impurities < 0,5%
TMSH
marker
Solvent
DMSO-d6
O
O
• Look for plausibility between other available results
– Example H-NMR and HPLC, case 2
– Nabumetone Imp D light sensitive
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Points to consider during characterisation
HPLC
0 h
1 h
24 h
trans cis
O
O
O O
h
• Can I use a qualitative impurity standard (research
material) for quantitative applications?
– Depending on the angle from which you look on it:
You can, but think twice!
– If purity indicated as for example „>80%“, or similar: With what
value should I calculate? [QUESTION TO PARTICIPANTS!]
• Do not calculate with that value (i.e. 80%)!
– Material probably purer than that value, risk of underestimation of
impurity
– If at all: Calculate with 100%! Risk of overestimation „only“!
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Points to consider during use
• Can I use a qualitative impurity standard (research
material) for quantitative applications?
– Risk of overestimation of imps
• Normally no regulatory issue, as patients not at risk to receive
medicines with impurities really out of specs
• Economic risk however for pharmaceutical manufacturer
– Lot of outcomes possible that would generate hidden costs!
– False positive OOS results for imps: unnecessary investigations!
– Issues during validation studies possible
– During development of FDF (consideration of ICH Q3A/B):
Risk of pushing yourself into unneccessary
and expensive qualification studies (last resort animal tox studies)
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Points to consider during use
• Can I use a qualitative impurity standard (research
material) for quantitative applications?
– The less analytical details – the higher the economic risk
• Depending on sources, qualitative standards often lacks
correct identity with regard to salt forms
• Also water and residual solvents not checked
– Especially water in hydrates can make a considerable part
of the substance on hand
• Salt form and water issues can lead to overestimation of
40% and more, i.e. assuming 100% assay when in fact 70% „as is“
– Even when chromatographic purity is quite high
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Points to consider during use
• For quantitative impurity standards:
Do we need a second assay method,
like for primary API RSs?
– We see these requests sometimes from clients
– Mainly due to requests from authorities
• My personal opinion:
– Not really …
• With the 100%-method (or qNMR), risk of underestimation of
assay of impurity RS is extremely low
– And then also underestimation of imps present in medicines
=> low risk for patients if at all
• Overestimation is minimised
• In backhand with our imp RS: carbon titration from CHN analysis
• Happy to discuss further … please send me an email!
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Quantitative use:
How good is good enough?
Closing remarks
• LGC Standards is part of LGC group
• Science & Innovation section of LGC acts as NMI for
chemical and biochemical measurement in the UK
(comparable to NIST in the US)
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Closing remarks
• Manufacturing of pharmaceutical reference materials
– For impurities, APIs and excipients approx. 4,300 standards
– Constantly new developments (e.g. primary standards)
• Brochure of almost 500 impurity standards available with
reference to the USP description, in most cases less
expensive price-per-mg compared to USP, plus the CofA!
– ISO 34 and ISO 17025 accredited
– Customised services
• Production of solvents
– For HPLC applications
in pharma industry
– Extremely pure for residue analysis
• Distribution
– Pharmacopoeial reference standards, phytochemicals
– CRMs/RMs from LGC, IRMM, NMIA, NIST etc. for all purposes 27
Service modules
Supplementary processes for stability monitoring and re-testing
Process steps based on internal quality standards; ISO 17025 or ISO Guide 34
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Sourcing
2
Quality Control
3
RAW-material
4
Packaging
5
Characte-risation
6
Certifi-cation
7
Storage
8
Distribution
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Services for two pharmaceutical
World Top 10 companies
1
Sourcing
2
Quality Control
3
RAW-material
4
Packaging
5
Characte-risation
6
Certifi-cation
7
Storage
8
Distribution
1
Sourcing
2
Quality Control
3
RAW-material
4
Packaging
5
Characte-risation
6
Certifi-cation
7
Storage
8
Distribution
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Services over the whole chain
1
Sourcing
2
Quality Control
3
RAW-material
4
Packaging
5
Characte-risation
6
Certifi-cation
7
Storage
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Distribution
• For several top generic / ethical companies
• Depending on the extent of the service, price per unit can
go down to less than 30 EURO
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Stability Monitoring +
QC Batch
Monitoring +
• Main topics of seminar at Day One:
– Different kinds of reference standards
and their intended application areas
– How to handle the details presented in a
certificate of analysis that help you choose
the right reference standard for
your specific purpose
– Presented by experts from EDQM, Teva, LPU and LGC
• Day Two:
– Visit our production site in Luckenwalde
– Manufacture of impurity and
primary reference standards
– Warehouse and dispensing facilities
• You will receive further information with tomorrow‘s
follow up email! 31
Join us April 6-7, 2017 in Potsdam!
http://bit.ly/2kmnDoH
„Bridge of Spies“
Source: Wikipedia
• Most of these slides were originally shown at the
International Reference Standard Symposium at USP‘s
headquarter on Nov 3, 2016:
– Thanks to the IRSS organisation team for the opportunity to
speak there last year as a representative from LGC
• Thanks to my colleagues Dr. Andreas Sieg and
Dr. Peter Weber for the analytical slides
– Join us for the seminar in April to see how we produce our
reference standards!
• And thanks of course to you as the audience today!
– Please take the short survey after leaving the webinar!
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Thank you!
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QUESTIONS?
• Of course also per email to
© Dr Christian Zeine, 2017, LGC. All rights reserved.
LGC Ltd., Queens Road, Teddington, Middlesex, TW11 0LY, UK