Impurities: Positions of the regulatory
authorities (like FDA and EMA) worldwide
Dr. Christian Zeine, Warsaw, Nov 18, 2014
Science
for a safer world
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Topics of today‘s talk
• Fundamental guidelines from ICH
• Influence of ICH impurity guidelines on testing of
generic drug substances/products
• Practical validation examples
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ICH guidelines – the basic fundaments
• ICH: International Conference on Harmonisation
– Members from regulation authorities and industrial
pharmaceutical associations
– From Japan, USA and Europe
– ICH guidelines also considered by authorities in other
regions (e.g. PIC/S 48 members and 4 partners)
– Also for generics, see next topic (Europe and USA)
– Plus considered by further countries
– For example Brazil adopted impurity thresholds
from ICH Q3A, in December 2013 for generics as well
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ICH guidelines – the basic fundaments
• Three ICH Guidelines important (www.ich.org)
– Q3A(R2): Impurities in new drug substances
– Q3B(R2): Impurities in new drug products
– Q3C(R5): Impurities – Guideline for residual solvents
– A fourth one (Q3D) on heavy metal impurities to come
– Draft published July 2013, plan to have step 4 status in September
2014
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ICH guidelines – the basic fundaments
• Threshold table ICH Q3A:
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Topics of today‘s talk
• Fundamental guidelines from ICH
• Influence of ICH impurity guidelines on testing of
generic drug substances/products
• Practical validation examples
6
Influence ICH impurity guidelines
on generics
• Europe
– European Pharmacopoeia (Ph.Eur.)
• Two documents of importance:
General monograph Substances for pharmaceutical use (2034)
General chapter Control of impurities in substances for
pharmaceutical use (5.10.)
• Above documents link applicable
Ph.Eur. monographs (new monographs) to ICH Q3A and its
thresholds
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Influence ICH impurity guidelines
on generics
• Europe
– European Medical Agency (EMA):
Guideline on Control of Impurities in Pharmacopoeial
Substances (CPMP/QWP/1529/04) from 2004
• Guideline requests that marketing approval be granted only
when referred-to monographs for pharmacopoeial ingredients
are compliant with 2034 and 5.10.
• Also guideline requests EDQM not to grant CEPs (certificates
of suitability) based on old monographs
not compliant with 2034 and 5.10.
– Consequences: Broad changes of Ph. Eur. monographs
since 2003/2004
• From TLC to HPLC related substances methods,
but also to different limits, see examples
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Ph. Eur. monograph changes,
acetylsaliclylic acid
Monograph 1/2008
Monograph 1/2011
• Any impurity:
NMT 0.1%
• Total imps.:
NMT 0.25%
• Disregard limit:
NMT 0.025%
• Imps. A-F:
NMT 0.15%
• Unspecified imps:
NMT 0.05%
• Total imps.:
NMT 0.25%
• Disregard limit:
0.03%
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Ph. Eur. monograph changes,
amlodipine besilate
Monograph 1/2008
TLC + HPLC methods
Monograph 4/2009
only HPLC, noTLC anymore
• TLC, any impurity:
NMT 0.3%, only 2 imps
MT 0.1%
• HPLC, imp. D:
NMT 0.3%
• HPLC, total imps.:
NMT 0.3%
• HPLC, disregard limit:
NMT 0.03%
• Imps. A-F:
NMT 0.15%
• Unspecified imps.:
NMT 0.10%
• Total imps.:
NMT 0.6%
• Disregard limit:
0.05%
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Ph. Eur. monograph changes,
ibuprofen
Monograph 1/2008
HPLC,
imp. F by GC (NMT 0.1%)
Monograph 4/2008
HPLC,
imp. F by GC (NMT 0.1%)
• Imp. B:
NMT 0.3%
• Imps. A, C-E:
NMT 0.3%
• Total imps. (w/o imp. B):
NMT 0.7%
• Disregard limit:
NMT 0.05%
• Imps. A, J, N:
NMT 0.15%
• Unspecified imps.:
NMT 0.05%
• Total imps.:
NMT 0.2%
• Disregard limit:
NMT 0.03%
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Influence ICH impurity guidelines
on generics
• USA
– USP issued in PF May/June 2014 two draft chapters on
impurities to update USP‘s opinion on impurities
• New chapter <476>:
Organic impurities in drug substances and drug products
• Amendment to <1086>:
Impurities in drug substances and drug products
– Chapter also features the ICH thresholds
– New chapter resp amendment was necessary to be in
consistence with FDA approach
• Monograph changes already ongoing
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Influence ICH impurity guidelines
on generics
• USA
– FDA issued two guidances for industry ANDAs: Impurities in
drug substances / products
• June 2009 (drug substances), November 2010 (drug products)
– Statement there
• ICH Q3A and Q3B were developed for new drug applications
(NDAs)
• However, FDA takes position that ICH principles are applicable
to ANDAs (abbreviated NDAs, i.e. generic products) as well:
“FDA believes that much of the content of the Q3A(R) guidance
applies to ANDAs. See especially sections I through V
and the Attachment, Thresholds.”
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New FDA impurity guidance:
Relevant points
• Setting acceptance criteria
– First point of reference:
Pharmacopoeias (namely USP)
• If impurity specified in USP, then specification there should be kept
• If pharmacopoeia specification cannot be kept
then impurity enters into qualification process
– If impurity is not specified in compendia
• Use decision tree provided (based on ICH design)
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New FDA
impurity guidance:
Decision tree
(!)
(!)
(!)
Check impurity level
with a dedicated
reference standards before
taking further actions!
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Topics of today‘s talk
• Fundamental guidelines from ICH
• Influence of ICH impurity guidelines on testing of
generic drug substances/products
• Practical validation examples
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Validation guideline ICH
Q2(R1), parameters
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Examples
• Specifity of HPLC assay method (1)
– Show absence of interference of
•
•
•
•
solvent,
matrix (in case of drug preparation),
mobile phase,
and of the individual (specified) impurities.
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Examples
• Specifity of HPLC assay method (2)
– Chromatograms (Drug Product, 3 specified imps.)
Blank
Imp. A
Placebo
Imp. B
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Examples
• Specifity of HPLC assay method (3)
– Chromatograms (Drug Product, 3 specified imps.)
Imp. C
Imp. A
Imp. B
API
Imp. C
API XYZ
Imp. B
Chromatogram of the API and
all three impurities (imps. at
limit conc.)
Need to define resolution criteria
(SST) at this point at the latest
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Examples
• Specifity of HPLC assay method (4)
– Alternatively, set up two analytical series of drug product
– One with original drug product
• Another one with imps. spiked in,
preferably to maximum concentration
– Do statistical analysis (t-Test, additionally F-Test)
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Examples
• Specifity of HPLC assay method (5)
– Statistical approach
Series 1
(mg API/dosage form)
Mean value
Standard deviation
Series 2 (imps. spiked)
(mg API/dosage form)
19,62
19,74
20,12
19,52
19,76
19,64
19,98
19,34
19,86
19,72
19,66
19,8
19,83
19,63
0,19
0,17
t-Test and F-Test show a coincidental difference.
The test value for the t-Test (significance in mean value!) is 1.92, being lower
than the tabulated value (t(5%;10)=2.228) => statistically no difference.
The test value for the F-Test (significance in standard deviation!) is 1.25, being
lower than the tabulated value (F(5%;5,5)=5.05) => no systematic deviation.
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Examples
• Accuracy (trueness) of impurity determination
by HPLC (1), example acetylsalicylic acid
– Recovery of impurity A (spiked into drug substance)
– Range from reporting level - 120% of specification
(spec. 0,15%)
(0.05-0.18%, resp. 0.15-0.54 mg for 300 mg samples)
– See ICH
Examples
• Accuracy (trueness) of impurity determination
by HPLC (2), example acetylsalicylic acid
– See ICH
Examples
• Accuracy (trueness) of impurity determination
by HPLC (1)
– Range from reporting level - 120% of specification
(spec. 0,15%)
(0.05-0.18%, resp. 0.15-0.54 mg for 300 mg samples)
Level (%)
0,05
0,1
0,15
0,18
Amount added (µg)
Amount found (µg)
Recovery rate (%)
155
158
101,7
161
162
100,9
164
162
99,1
303
301
99,3
306
304
99,3
295
292
98,8
454
457
100,6
459
456
99,3
444
437
98,5
545
542
99,5
551
549
99,6
531
530
99,7
Recovery at level (%)
100,6
99,1
99,5
99,6
Topics of today‘s talk
• Fundamental guidelines from ICH
• More and more accpeted worldwide,
not just in core ICH regions
• Influence of ICH impurity guidelines on testing of
generic drug substances/products
• Will increase further, already the case in Europe/USA/Brazil
• Reference standards important for correct measurements
• Practical validation examples
• Neat impurity materials (reference standards) most effective
tool for validation tests
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QUESTIONS?
Now, or to christian.zeine@lgcstandards.com
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